WO2009058810A1

WO2009058810A1 - Process for the preparation of substituted 2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene derivatives

Info

Publication number: WO2009058810A1
Application number: PCT/US2008/081513
Authority: WO
Inventors: Anusuya Choudhury; Kirk Sorgi
Original assignee: Janssen Pharmaceutica N.V.
Priority date: 2007-11-02
Filing date: 2008-10-29
Publication date: 2009-05-07

Abstract

The present invention is directed to processes for the preparation of substituted 2, 4, 5, 6, 7, 8 - hexahydro -1, 2, 6 - triaza-azulene derivatives of formula (I) and (II), useful for the treatment of disease states mediated by serotonin receptor activity.

Description

PROCESS FOR THE PREPARATION OF SUBSTITUTED 2,4,5,6,7,8- HEXAHYDRO-1 ,2,6-TRIAZA-AZULENE DERIVATIVES

FIELD OF THE INVENTION The present invention is directed to processes for the preparation of substituted 2,4,5,6,7,8-hexahydro-1 ,2,6-thaza-azulene derivatives, useful for the treatment of disease states mediated by serotonin receptor activity.

BACKGROUND OF THE INVENTION US Patent Application Publication US 200501 19295, published June 2,

2005, which is hereby incorporated by reference, discloses fused heterocyclic compounds, useful as modulators of serotonin receptors, useful in methods for treating or preventing diseases and conditions mediated by serotonin receptors, particularly the 5HT₇ and/or 5HT₂ receptor subtypes. More particularly, the compounds are useful for treating or preventing CNS disorders, such as sleep disorders, depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, alcohol abuse, addictive disorders, nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities. The compounds may also be used in the treatment and prevention of hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, urinary incontinence, and other disorders related to the gastrointestinal and vascular systems. In addition, the compounds may be used in the treatment or prevention of a range of ocular disorders including glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration.

Substituted pyrazoles are important synthetic targets in the pharmaceutical industry, as the pyrazole motif makes of the core structure of numerous biologically active compounds (Elguero, J.; Goya, P.; Jagerovic, N.; Silva, A.M. S. Targets in Heterocyclic Systems 2002, 6, 52-98) including marketed drugs such as sildenafil (Terrett, N. K. et al. Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824) and celecoxib (Penning, T.D. et al. J. Med. Chem. 1997, 40, 1347-1365). Pyrazoles are often prepared by the reaction of hydrazines with 1 ,3-dicarbonyl compounds or their equivalents, such as α,β- ethynylketones or esters. These condensation reactions generally result in mixtures of regioisomers, which complicates isolation and purification processes. Cyclization reactions of 1 ,3-dipoles such as deazoalkanes or nitrilimines with olefins has also been used, but these reactions often suffer from low yields and harsh conditions (Elguero, J. Comp. Heterocycl. Chem. 1984, 5,167; Elguero, J. Comp. Heterocycl. Chem. Il 1996, 3, 1-75 and 817- 932, and references cited therein). These processes are therefore unsuitable for large scale production of substituted pyrazoles. Thus, there remains a need for a process for the preparation of fused pyrazole compounds, wherein a pyrazole regioisomer of Formula (I) and or a pyrazole regioisomer of Formula (II), as hereinafter defined, are preferentially prepared.

SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation of a mixture of a compound of formula (I) and a compound of formula (II)

wherein q is an integer from 0 to 1 ;

ALK is selected from the group consisting of C 1-4 alkyl; CYC is selected from the group consisting of hydrogen, Cs-scycloalkyl and aryl;

AR is selected from the group consisting of aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, C_1-4alkyl, Ci_-4alkoxy, CF₃ and -OCF₃; or pharmaceutically acceptable salts thereof; comprising

(XII) (XIII) reacting a compound of formula (X), wherein PG¹ is a nitrogen protecting group with a compound of formula (Xl); in an organic solvent; to yield a mixture of the corresponding compound of formula (XII) and the corresponding compound of formula (XIII);

de-protecting the mixture of the compound of formula (XII) and the compound of formula (XIII) to yield a mixture of the corresponding compound of formula (I) and the corresponding compound of formula (II).

The present invention is further directed to a process for the preparation of a compound of formula (I)

wherein q is an integer from 0 to 1 ;

ALK is selected from the group consisting of C-|.₄alkyl; CYC is selected from the group consisting of hydrogen, C₃-₈cycloalkyl and aryl;

AR is selected from the group consisting of aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, Ci_-4alkyl, Ci_-4alkoxy, CF₃ and -OCF₃; or pharmaceutically acceptable salts thereof; comprising

(XII) reacting a compound of formula (X), wherein PG¹ is a nitrogen protecting group with a compound of formula (Xl); in an organic solvent; to yield a the corresponding compound of formula (XII);

(XIl) (I) de-protecting the compound of formula (XII) to yield the corresponding compound of formula (I).

The present invention is further directed to a process for the preparation of a compound of formula (II)

(N) wherein q is an integer from 0 to 1 ; ALK is selected from the group consisting of Ci_-4alkyl;

CYC is selected from the group consisting of hydrogen, C₃-₈cycloalkyl and aryl;

reacting a compound of formula (X), wherein PG¹ is a nitrogen protecting group with a compound of formula (Xl); in an organic solvent; to yield the corresponding compound of formula (XIII);

(XIII) (II) de-protecting the compound of formula (XIII) to yield the corresponding compound of formula (II).

In an embodiment, the present invention is directed to a process for the preparation of a compound of formula (I-S)

(I-S) also known as 3-(4-fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro- 1 ,2,6-triaza-azulene; comprising

reacting a compound of formula (X-S) with a compound of formula (Xl- S), in an organic solvent; to yield the corresponding compound of formula (XII- S);

de-protecting the compound of formula (XII-S), to yield the corresponding compound of formula (I-S).

In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (N-S)

also known as 1-benzyl-3-(4-chloro-phenyl)-1 ,4,5,6,7,8-hexahydro-1 ,2,6- thaza-azulene; comprising

reacting a compound of formula (X-T) with a compound of formula (Xl- T), in an organic solvent, to yield the corresponding compound of formula (XIII- T);

de-protecting the compound of formula (XII-T), to yield the corresponding compound of formula (N-S). The present invention is further directed to a compound of formula (X)

(X) wherein

PG¹ is a nitrogen protecting group; AR is selected from the group consisting of aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, Ci_-4alkyl, Ci_-4alkoxy, CF₃ and -OCF₃; or pharmaceutically acceptable salts thereof. In an embodiment, the present invention is directed to compounds of formula (X) wherein AR is selected from the group consisting of 4-chlorophenyl and 4-fluorophenyl and pharmaceutically acceptable salts thereof.

The present invention is further directed to processes for the preparation of the compound of formula (X), as described in more detail herein (more particularly, as described in Scheme 4-9 which follow herein). In an embodiment, the present invention is directed to processes for the preparation of compounds of formula (X) wherein AR is selected from the group consisting of 4-chlorophenyl and 4-fluorophenyl, and pharmaceutically acceptable salts thereof, as described in more detail in Schemes 5, 7 and 9 which follow herein.

The present invention is further directed to a product prepared according to the process described herein.

Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product prepared according to the process described herein. An illustration of the invention is a pharmaceutical composition made by mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing the product prepared according to the process described herein and a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating or preventing a disease or condition selected from the group consisting of depression, anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress disorders, sleep disturbances, sexual dysfunction, eating disorders, migraine, addictive disorders, and peripheral vascular disorders comprising administering to a subject in need thereof a therapeutically effective amount of any of the compounds prepared according to the processes described herein.

Another example of the invention is the use of any of the compounds described herein in the preparation of a medicament for treating or preventing (a) depression, (b) anxiety, (c) generalized anxiety disorder, (d) schizophrenia, (e) bipolar disorders, (f) psychotic disorders, (g) obsessive-compulsive disorder, (h) mood disorders, (i) post-traumatic stress disorders, (j) sleep disturbances, (k) sexual dysfunction, (I) eating disorders, (m) migraine, (n) addictive disorders or (o) peripheral vascular disorders, in a subject in need thereof.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to processes for the preparation of compounds of formula (I),

to processes for the preparation of compounds of formula (II)

(H) , and to processes for the preparation of mixtures thereof, wherein q, ALK, CYC and AR are as herein defined; and pharmaceutically acceptable salts thereof. The compounds of formula (I) and compounds of formula (II) for the treatment and / or prevention of disease states mediated by the serotonin receptors, particularly, 5-HT₇ and/or 5-HT₂ receptor subtypes.

More particularly, the compounds of formula (I) and formula (II) may be used in the treatment or prevention of CNS disorders, such as sleep disorders, depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress and other stress-related disorders, migraine, pain, eating disorders, obesity, sexual dysfunction, metabolic disturbances, hormonal imbalance, alcohol abuse, addictive disorders, nausea, inflammation, centrally mediated hypertension, sleep/wake disturbances, jetlag, and circadian rhythm abnormalities. The compounds of formula (I) and formula (II) may also be used in the treatment and prevention of hypotension, peripheral vascular disorders, cardiovascular shock, renal disorders, gastric motility, diarrhea, spastic colon, irritable bowel disorders, ischemias, septic shock, urinary incontinence, and other disorders related to the gastrointestinal and vascular systems. In addition, compounds of formula (I) and formula (II) may be used in the treatment or prevention of a range of ocular disorders including glaucoma, optic neuritis, diabetic retinopathy, retinal edema, and age-related macular degeneration.

The compounds of formula (I) and formula (II) are 5-HT₇ modulators and many are 5-HT₇ antagonists. As such, the compounds of formula (I) and formula (II) are useful in the treatment of 5-HT₇-mediated disease states. Where the compounds of formula (I) and formula (II) possess substantial 5-HT₇ antagonist activity, they may be particularly useful in the treatment or prevention of depression/anxiety, sleep/wake disturbances, jetlag, migraine, urinary incontinence, gastric motility, and irritable bowel disorders. Many of the compounds of formula (I) and formula (II) are 5-HT₂ modulators and many are 5-HT₂ antagonists. As such, the compounds of formula (I) and formula (II) are useful in the treatment of 5-HT₂-mediated diseases and conditions. Where the compounds of formula (I) and formula (II) possess substantial 5-HT₂ antagonist activity, they may be particularly useful in the treatment or prevention of depression/anxiety, generalized anxiety disorder, schizophrenia, bipolar disorders, psychotic disorders, obsessive-compulsive disorder, mood disorders, post-traumatic stress disorders, sleep disturbances, sexual dysfunction, eating disorders, migraine, addictive disorders, and peripheral vascular disorders.

In an embodiment of the present invention, q is 1. In an embodiment of the present invention, ALK is selected from the group consisting of Ci-₃alkyl. In another embodiment of the present invention, ALK is selected from the group consisting of methyl and isopropyl. In an embodiment of the present invention, CYC is selected from the group consisting of hydrogen, Cs-_δCycloalkyl and phenyl. In another embodiment of the present invention, CYC is selected from the group consisting of hydrogen, cyclopentyl and phenyl. In another embodiment of the present invention, CYC is selected from the group consisting of hydrogen and phenyl.

In an embodiment of the present invention, AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of halogen, C_1-4alkyl, Ci_-4alkoxy, CF₃ and -OCF₃. In another embodiment of the present invention, AR is AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of halogen, Ci_-4alkyl and CF₃. In another embodiment of the present invention, AR is AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of chloro, fluoro, methyl, ethyl and CF₃. In another embodiment of the present invention, AR is AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of halogen and Ci_-4alkyl. In another embodiment of the present invention, AR is AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of halogen. In another embodiment of the present invention, AR is AR is phenyl, wherein the phenyl is optionally substituted with a substituent selected from the group consisting of chloro and fluoro.

As used herein, "halogen" shall mean chlorine, bromine, fluorine and iodine.

As used herein, the term "alkyl" whether used alone or as part of a substituent group, include straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t- butyl, pentyl and the like. Unless otherwise noted, "Ci_-4" when used with alkyl means a carbon chain composition of 1-4 carbon atoms.

As used herein, unless otherwise noted, "alkoxy" shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like. Unless otherwise noted, "Ci_-4" when used with alkoxy means an oxygen ether radical of the above described carbon chain composition of 1-4 carbon atoms.

As used herein, unless otherwise noted, "aryl" shall refer to unsubstituted carbocylic aromatic groups such as phenyl, naphthyl, and the like.

As used herein, unless otherwise noted, the term "C3-8cycloalkyl" shall mean any stable 3-8 membered monocyclic, saturated ring system, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When a particular group is "substituted" (e.g., alkkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, etc.), that group may have one or more substituents, preferably from one to five substituents, more preferably from one to three substituents, most preferably from one to two substituents, independently selected from the list of substituents.

With reference to substituents, the term "independently" means that when more than one of such substituents is possible, such substituents may be the same or different from each other.

As used herein, the notation "^*" shall denote the presence of a stereogenic center.

Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably, wherein the compound is present as an enantiomer, the enantiomer is present at an enantiomeric excess of greater than or equal to about 80%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein the compound is present as a diastereomer, the diastereomer is present at an diastereomeric excess of greater than or equal to about 80%, more preferably, at an diastereomeric excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.

Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. Under standard nomenclature used throughout this disclosure, the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment. Thus, for example, a "phenylCr C₆alkylaminocarbonylCrC₆alkyl" substituent refers to a group of the formula

Abbreviations used in the specification, particularly the Schemes and

Examples, are as follows:

BOC or Boc t-Butoxycarbonyl

CBz Benzyloxycarbonyl

DCM Dichloromethane

DIPEA Diisopropylethylamine

DMSO Dimethylsulfoxide

EtOAc Ethyl a acetate

IPA lsopropyl Alcohol

LDA Lithium Diisopropylamide

MeOH Methanol

MTBE t-Butyl Methyl Ether

NBS N-Bromosuccinimide

TEA Triethylamine

TFA Trifluoroacetic acid

THF Tetrahydrofuran

As used herein, unless otherwise noted, the term "isolated form" shall mean that the compound is present in a form which is separate from any solid mixture with another compound(s), solvent system or biological environment. In an embodiment, the compound of formula (I) is prepared as an isolated form. In another embodiment, the compound of formula (II) is prepared as an isolated form. In another embodiment, the compound of formula (I-S) is prepared as an isolated form. In another embodiment, the compound of formula (N-S) is prepared as an isolated form.

As used herein, unless otherwise noted, the term "substantially pure compound" shall mean that the mole percent of impurities in the isolated compound is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably, less than about 0.1 mole percent. In an embodiment, the compound of formula

(I) is prepared as a substantially pure compound. In another embodiment, the compound of formula (II) is prepared as a substantially pure compound. In another embodiment, the compound of formula (I-S) is prepared as a substantially pure compound. In another embodiment, the compound of formula (N-S) is prepared as a substantially pure compound.

As used herein, unless otherwise noted, the term "substantially free of a corresponding salt form(s)" when used to described the compound of formula (I) shall mean that mole percent of the corresponding salt form(s) in the isolated base of formula (I) is less than about 5 mole percent, preferably less than about 2 mole percent, more preferably, less than about 0.5 mole percent, most preferably less than about 0.1 mole percent. In an embodiment, the compound of formula (I) is prepared in a form which is substantially free of a corresponding salt form(s). In another embodiment, the compound of formula

(II) is prepared in a form which is substantially free of a corresponding salt form(s). In another embodiment, the compound of formula (I-S) is prepared in a form which is substantially free of a corresponding salt form(s). In another embodiment, the compound of formula (N-S) is prepared in a form which is substantially free of a corresponding salt form(s).

The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment. Preferably, the subject has experienced and / or exhibited at least one symptom of the disease or disorder to be treated and / or prevented. The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.

As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) is performed under suitable conditions, according to known methods, to provide the desired product.

One skilled in the art will recognize that, in the specification and claims as presented herein, wherein a reagent or reagent class/type (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same of different from each other. For example wherein two steps of a process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

As used herein, unless otherwise noted, the term "leaving group" shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like. As used herein, unless otherwise noted, the term "nitrogen protecting group" shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates - groups of the formula -C(O)O-R wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH₂=CH-CH₂-, and the like; amides - groups of the formula -C(O)-R' wherein R' is for example methyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivatives - groups of the formula -SO₂-R" wherein R" is for example tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found in texts such as T.W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.

One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.

Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartahc acid and/or (+)-di-p-toluoyl-L-tartahc acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 . The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands, e.g., quaternary ammonium salts. Thus, representative pharmaceutically acceptable salts include the following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, thethiodide and valerate.

Representative acids and bases which may be used in the preparation of pharmaceutically acceptable salts include the following: acids including acetic acid, 2,2-dichloroactic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(1 S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuhc acid, ethane-1 ,2- disulfonic acid, ethanesulfonic acid, 2-hydrocy-ethanesulfonic acid, formic acid, fumaric acid, galactahc acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucoronic acid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hipuric acid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1 ,5- disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotine acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmithc acid, pamoic acid, phosphoric acid, L- pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)- ethanol, ethanolamine, ethylenediamine, N-methyl-glucamine, hydrabamine, 1 H-imidazole, L-lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1 -(2-hydroxyethyl)-pyrrolidine, secondary amine, sodium hydroxide, triethanolamine, tromethamine and zinc hydroxide.

The present invention is directed to a process for the preparation of compounds of formula (I), compounds of formula (II) and mixtures thereof, as described in more detail in Scheme 1 below.

(XII) (XIII)

(D <">

Scheme 1

Accordingly, a suitably substituted compound of formula (X), wherein PG¹ is a suitably selected nitrogen protecting group such as BOC, CBz, benzyl, trityl, and the like, preferably BOC; is reacted with a suitably substituted hydrazine, a compound of formula (Xl), a known compound or compound prepared by known methods; wherein the compound of formula (Xl) is preferably present in an amount in the range of from about 0.90 to about 1.25 molar equivalents, more preferably in an amount of about 1.0 molar equivalents; in an organic solvent such as ethanol, methanol, isopropanol, MTBE, THF, ethyl acetate, and the like, preferably in THF; preferably, at about room temperature; to yield a mixture of the corresponding compound of formula (XII) and the corresponding compound of formula (XIII). Preferably, the compound of formula (Xl) is added slowly to a mixture of the compound of formula (X) in the selected organic solvent. Wherein the process as described above, the compound of formula (I) is the desired product, then the compound of formula (X) is reacted with the compound of formula (Xl), preferably in the presence of less than about 1 molar equivalent of water, more preferably in the presence of between about 0.1 and about 0.25 molar equivalents, more preferably in the presence of about 0.1 molar equivalents.

Optionally, the mixture comprising the compound of formula (XII) and the compound of formula (XIII) is separated according to known methods, for example by column chromatography, selective crystallization, and the like. The mixture of the compound of formula (XII) and the compound of formula (XIII) is de-protected according to known methods, to yield the corresponding compound of formula (I). For example, wherein PG¹ is BOC, the compound of formula (XII) is de-protected by reacting with an acid such as HCI, and the like, preferably HCI, in an organic solvent such as IPA, and the like, preferably IPA, to yield a mixture of the corresponding compound of formula (I) and the corresponding compound of formula (II).

Optionally, the mixture comprising the compound of formula (I) and the compound of formula (II) is separated according to known methods, for example by column chromatography, selective crystallization, and the like.

In an embodiment, the present invention is directed to a process for the preparation of a compound of formula (I-S) as described in more detail in Scheme 2, below.

Scheme 2

Accordingly, a suitably substituted compound of formula (X-S), wherein PG¹ is a suitably selected nitrogen protecting group such as BOC, CBz, benzyl, trityl, and the like, and the like, preferably BOC, a known compound or compound prepared by known methods, is reacted with a suitably substituted hydrazine, a compound of formula (Xl-S), a known compound or compound prepared by known methods; wherein the compound of formula (IX-S) is preferably present in an amount in the range of from about 0.90 to about 1.25 molar equivalents, more preferably about 1 molar equivalent; preferably in the presence of less than about 1 molar equivalent of water, more preferably in the presence of between about 0.1 and about 0.25 molar equivalents, more preferably in the presence of about 0.1 molar equivalents; in an organic solvent such as ethanol, methanol, THF, ethyl acetate, IPA, MTBE and the like, preferably in THF; preferably, at about room temperature; to yield the corresponding compound of formula (XII-S). Preferably, the compound of formula (Xl-S) is added slowly to a mixture of the compound of formula (X-S) in the selected organic solvent. The compound of formula (XII-S) is de-protected according to known methods, to yield the corresponding compound of formula (I-S). For example, wherein PG¹ is BOC, the compound of formula (XII-S) is de-protected by reacting with an acid such as HCI, and the like, preferably HCI, in an organic solvent such as IPA, and the like, preferably IPA, to yield the corresponding compound of formula (I-S).

Preferably, the compound of formula (I-S) (as a free base) is preferably isolated according to known methods, for example by filtration. Preferably, the compound of formula (I-S) is purified according to known methods, for example by recrystallization from a suitably selected organic solvent such as THF, IPA, methanol, ethanol, and the like, more preferably, from IPA.

Preferably, the compound of formula (I-S) is reacted with a suitably selected acid, according to known methods, to yield its corresponding pharmaceutically acceptable salt. In an embodiment, the compound of formula (I-S) is reacted with citric acid, wherein the citric acid is preferably present in an amount in the range of from about 0.9 to about 1.5 molar equivalents, more preferably about 1.4 molar equivalents; in an organic solvent or mixture of organic solvents, such as ethanol, methanol, IPA, ethyl acetate, and the like, preferably in a mixture of methanol and ethyl acetate, to yield the corresponding citrate salt of the compound of formula (I-S).

In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (N-S) as described in more detail in Scheme 3, below.

Scheme 3

Accordingly, a suitably substituted compound of formula (X-T), wherein PG¹ is a suitably selected nitrogen protecting group such as BOC, CBz, benzyl, trityl, and the like, and the like, preferably BOC, a known compound or compound prepared by known methods, is reacted with a suitably substituted hydrazine, a compound of formula (Xl-T), a known compound or compound prepared by known methods; wherein the compound of formula (Xl-T) is preferably present in an amount in the range of from about 0.90 to about 1.25 molar equivalents, more preferably about 1 molar equivalent; in an organic solvent such as ethanol, methanol, THF, ethyl acetate, IPA, MTBE, and the like, preferably in THF; preferably, at about room temperature; to yield the corresponding compound of formula (XIII-T). Preferably, the compound of formula (Xl-T) is added slowly to a mixture of the compound of formula (X-T) in the selected organic solvent.

The compound of formula (XIII-T) is de-protected according to known methods, to yield the corresponding compound of formula (N-S). For example, wherein PG¹ is BOC, the compound of formula (XIII-T) is de-protected by reacting with an acid such as HCI, and the like, preferably HCI, in an organic solvent such as IPA, and the like, preferably IPA, to yield the corresponding compound of formula (N-S).

Preferably, the compound of formula (N-S) is preferably isolated according to known methods, for example by filtration. Preferably, the compound of formula (N-S) is preferably purified according to known methods, for example by column chromatography.

Preferably, the compound of formula (N-S) is reacted with a suitably selected acid, according to known methods to yield its corresponding pharmaceutically acceptable salt. For example, the compound of formula (N-S) is reacted with citric acid, in an organic solvent such as methanol, to yield the corresponding citrate salt of the compound of formula (N-S).

The present invention is further directed to processes for the preparation of compounds of formula (X) as outlined in Scheme 4, Scheme 6 and Scheme 8, which follow herein. The present invention is directed to processes for the preparation of a compound of formula (X-A)

wherein PG¹ is a nitrogen protecting group such as BOC, Cbz, and the like, preferably BOC; and wherein Q is chloro or fluoro, as outlined in Schemes 5, 7 and 9 which follow herein. In an embodiment of the present invention, Q is chloro. In another embodiment of the present invention, Q is fluoro.

The compounds of formula (X) may be prepared as outlined in Scheme 4, adapting the procedure as described in Rathke, M.W., et al., J. Org. Chem, (1985), Vol. 50, pp. 2622-2624.

Scheme 4

More particularly, a suitably substituted compound of formula (XV), wherein A¹ is a Ci_-4alkyl and wherein PG¹ is a suitable selected nitrogen protecting group such as BOC, CBz, benzyl, trityl, and the like, preferably BOC, a known compound or compound prepared by known methods, is reacted with a suitably substituted acid chloride, a compound of formula (XVI), a known compound or compound prepared by known methods; wherein the compound of formula (XVI) is preferably present in an amount in the range of from about 0.9 to about 1.25 molar equivalents, more preferably in an amount of about 1.0 molar equivalents; in the presence of a Lewis acid such as magnesium chloride, wherein the Lewis acid is preferably present in an amount in the range of from about 0.9 to about 1.25 molar equivalents, more preferably in an amount of about 1.0 molar equivalent; and in the presence of an organic base, wherein the organic base, when in the presence of the Lewis acid is capable of removing the hydrogen atom bound at the 4-position of the azepanyl group, (i.e. the hydrogen atom denoted by the arrow in the structure of compound (XV) as drawn below

an organic base such as pyridine, wherein the organic base is preferably present in an amount in the range of from about 0.9 to about 1.25 molar equivalents, more preferably in an amount of about 1 .0 molar equivalents; preferably at a temperature in the range of from about 0⁰C to about room temperature, more preferably at a temperature in the range of from about 0⁰C to about 5°C; to yield the corresponding compound of formula (XVII).

The compound of formula (XVII) is reacted with a suitably selected decarboxylating agent such as lithium chloride, sodium chloride, sodium iodide, sodium acetate, and the like, preferably lithium chloride, wherein the decarboxylating agent is preferably present in an amount in the range of from about 1.0 to 1 .25 molar equivalents, more preferably in an amount of about 1 .1. molar equivalents; in the presence of water, preferably in the presence of from about 0.9 to about 1.25 molar equivalents of water, more preferably about 1.1 molar equivalents of water; in DMSO; at an elevated temperature in the range of from about 145°C to about 175°C, more preferably at a temperature in the range of from about 150⁰C to about 155 ⁰C; to yield the corresponding compound of formula (X).

In an embodiment, the present invention is directed to a process for the preparation of compounds of formula (X-A)

wherein PG¹ is a nitrogen protecting group, preferably BOC; and wherein Q is chloro or fluoro; as outlined in more detail in Scheme 5 below.

Scheme 5

Accordingly, a suitably substituted compound of formula (XV-A), wherein A¹ is a Ci_-4alkyl and wherein PG¹ is a suitable selected nitrogen protecting group such as BOC, CBz, benzyl, trityl, and the like, preferably BOC, a known compound or compound prepared by known methods, is reacted with a suitably substituted acid chloride, a compound of formula (XVI-A), wherein Q is chloro or fluoro, a known compound or compound prepared by known methods; wherein the compound of formula (XVI) is preferably present in an amount in the range of from about 0.9 to about 1.25 molar equivalents, more preferably in an amount of about 1 .0 molar equivalents; in the presence of a Lewis acid such as magnesium chloride, wherein the Lewis acid is preferably present in an amount in the range of from about 0.9 to about 1.25 molar equivalents, more preferably in an amount of about 1 .0 molar equivalent; and in the presence of an organic base, wherein the organic base, when in the presence of the Lewis acid is capable of removing the hydrogen atom bound at the 4-position of the azepanyl group, (i.e. the hydrogen atom denoted by the arrow in the structure of compound (XV) as drawn below

an organic base such as pyridine, wherein the organic base is preferably present in an amount in the range of from about 0.9 to about 1.25 molar equivalents, more preferably in an amount of about 1 .0 molar equivalents; preferably at a temperature in the range of from about 0⁰C to about room temperature, more preferably at a temperature in the range of from about 0⁰C to about 5°C; to yield the corresponding compound of formula (XVII-A).

The compound of formula (XVII-A) is reacted with a suitably selected decarboxylating agent such as lithium chloride, sodium chloride, sodium iodide, sodium acetate, and the like, preferably lithium chloride, wherein the decarboxylating agent is preferably present in an amount in the range of from about 1.0 to 1 .25 molar equivalents, more preferably in an amount of about 1.1. molar equivalents; in the presence of water, preferably in the presence of from about 0.9 to about 1.25 molar equivalents of water, more preferably about 1.1 molar equivalents of water; in DMSO; at an elevated temperature in the range of from about 145°C to about 175°C, more preferably at a temperature in the range of from about 150⁰C to about 155 ⁰C; to yield the corresponding compound of formula (X-A).

The compounds of formula (X) may alternatively be prepared according to the process outlined in Scheme 6, below.

(XXIII)

Scheme 6

More particularly, a suitably substituted compound of formula (XX), a known compound is protected according to known methods, to yield the corresponding compound of formula (XXI), wherein PG¹ is the corresponding nitrogen protecting group. For example, wherein PG¹ is BOC, the compound of formula (XX) is reacted with for example, BOC anhydride in methanol. Other suitable nitrogen protecting groups include, but are not limited to, CBz, benzyl, trityl, and the like. The compound of formula (XXI) is reacted with a suitably substituted compound of formula (XXII), a known compound or compound prepared by known methods, in the presence of a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA; in an organic solvent such as THF, MTBE, dioxane, and the like, preferably THF; preferably at a temperature in the range of from about 0° to about -78°C, more preferably at about -78°C; to yield a mixture of the desired regioisomer, the corresponding compound of formula (X) and the undesired regioisomer, the corresponding compound of formula (XXIII). Preferably, the compound of formula (X) is isolated according to known methods, for example by column chromatography, selective crystallization, and the like.

In an embodiment, the present invention is directed to a process for the preparation of a compound of formula (X-A)

wherein PG¹ is a nitrogen protecting group, preferably BOC; and wherein Q is chloro or fluoro, as outlined in more detail in Scheme 7 below.

(XXIII-A)

Scheme 7 More particularly, a suitably substituted compound of formula (XX-A), a known compound is protected according to known methods, to yield the corresponding compound of formula (XXI-A), wherein PG¹ is the corresponding nitrogen protecting group. For example, wherein PG¹ is BOC, the compound of formula (XX-A) is reacted with for example, BOC anhydride in methanol. Other suitable nitrogen protecting groups include, but are not limited to CBz, benzyl, trityl, and the like.

The compound of formula (XXI-A) is reacted with a suitably substituted compound of formula (XXII-A), wherein Q is chloro or fluoro, a known compound or compound prepared by known methods, in the presence of a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA; in an organic solvent such as THF, MTBE, dioxane, and the like, preferably THF; preferably at a temperature in the range of from about 0° to about -78°C, more preferably at about -78°C; to yield a mixture of the desired regioisomer, the corresponding compound of formula (X-A) and the undesired regioisomer, the corresponding compound of formula (XXIII-A).

Preferably, the compound of formula (X-A) is isolated according to known methods, for example by column chromatography, selective crystallization, and the like.

Alternatively still, the compounds of formula (X) may be prepared according to the process as outlined in Scheme 8, below.

Scheme 8

Accordingly, a suitably substituted compound of formula (XX), a known compound is protected according to known methods, to yield the corresponding compound of formula (XXI), wherein PG¹ is the corresponding nitrogen protecting group. For example, wherein PG¹ is BOC, the compound of formula (XX) is reacted with for example, BOC anhydride in methanol. Other suitable nitrogen protecting groups include, but are not limited to, CBz, benzyl, trityl, and the like.

The compound of formula (XXI) is reacted with a suitably substituted compound of formula (XXV), a known compound or compound prepared by known methods, in the presence of a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA; in an organic solvent such as THF, MTBE, dioxane, and the like, preferably THF; preferably at a temperature in the range of from about 0° to about -78°C, more preferably at about -78°C; to yield a mixture of the four corresponding isomers, a mixture of the two isomers of formula (XXVII) and the two isomers of formula (XXVIII).

The mixture of the compounds of formula (XXVI) and the compounds of formula (XXVIII) is reacted with a suitably selected oxidizing agent such as Dess-Martin reagent, Swern oxidizing reagent, and the like; in an organic solvent such as methylene chloride, THF, toluene, and the like; according to known methods, to yield a mixture of the corresponding compound of formula (XXIII) and the corresponding compound of formula (X).

Preferably, the compound of formula (X) is isolated according to known methods, for example by column chromatography, selective crystallization, and the like.

wherein Q is chloro or fluoro, as outlined in more detail in Scheme 9 below.

(XXVI-A)

(XXIII-A)

Scheme 9

Accordingly, a suitably substituted compound of formula (XX), a known compound is protected according to known methods, to yield the corresponding compound of formula (XXI), wherein PG¹ is the corresponding nitrogen protecting group. For example, wherein PG¹ is BOC, the compound of formula (XX) is reacted with for example, BOC anhydride in methanol. Other suitable nitrogen protecting groups include, but are not limited to, CBz, benzyl, trityl, and the like. The compound of formula (XXI) is reacted with a suitably substituted compound of formula (XXV-A), wherein Q is chloro or fluoro, a known compound or compound prepared by known methods, in the presence of a base such as LDA, lithium t-butoxide, potassium t-butoxide, and the like, preferably LDA; in an organic solvent such as THF, MTBE, dioxane, and the like, preferably THF; preferably at a temperature in the range of from about 0° to about -78°C, more preferably at about -78°C; to yield a mixture of the four corresponding isomers, a mixture of the two isomers of formula (XXVII-A) and the two isomers of formula (XXVIII-A).

The mixture of the compounds of formula (XXVII-A) and the compounds of formula (XXVIII-A) is reacted with a suitably selected oxidizing agent such as Dess-Martin reagent, Swern oxidizing reagent, and the like; in an organic solvent such as methylene chloride, THF, toluene, and the like; according to known methods, to yield a mixture of the corresponding compound of formula (XXIII-A) and the corresponding compound of formula (X-A). Preferably, the compound of formula (X-A) is isolated according to known methods, for example by column chromatography, selective crystallization, and the like. The present invention further comprises pharmaceutical compositions containing one or more compounds prepared according to any of the processes described herein with a pharmaceutically acceptable carrier. Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives. To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 0.1-1000 mg or any range therein, and may be given at a dosage of from about 0.01-300 mg/kg/day, or any range therein, preferably from about 0.5-50 mg/kg/day, or any range therein. The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.

Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate. The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating disorders described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.01 mg and 1000 mg of the compound, or any range therein; preferably about 10 to 500 mg of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions. Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired. To prepare a pharmaceutical composition of the present invention, a compound of formula (I) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain. Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders as described herein is required.

The daily dosage of the products may be varied over a wide range from 0.01 to 5000 mg per adult human per day, or any range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 300 mg/kg of body weight per day, or any range therein. Preferably, the range is from about 0.5 to about 50.0 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 25.0 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 10.0 mg/kg of body weight per day, or any range therein. The compounds may be administered on a regimen of 1 to 4 times per day.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.

One skilled in the art will further recognize that human clinical trails including first-in-human, dose ranging and efficacy trials, in healthy patients and / or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.

The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter. In the Examples which follow, some synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term "residue" does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1

4-(4-Fluoro-benzoyl)-5-oxo-azepane-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethvl ester

A 2L 4n reactor equipped with air stirrer, N₂-inlet, thermocouple and addition funnel was flushed with nitrogen for 0.5 h. Dry acetonithle (500 mL) was charged to the reactor. The reactor was cooled using ice bath. At 10⁰C was added MgCI₂ (68.2 g, 0.71 mol ) with stirring (exotherm T=50°C). The resulting heterogeneous mixture was allowed to reach ambient temperature. To the resulting mixture was then added 5-oxo-azepane-1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (200 g, 0.7 mol) was added followed by a rinse of acetonitrile (180 mL). The reactor was immerged in an ice bath. At 5°C, pyridine (1 10 mL) was added in one portion. The resulting mixture was stirred for 15 minutes at and between 0-5⁰C, then neat p-fluorobenzoyl chloride (1 12 g, 0.7 mol, Aldrich lot# 01217TC, 99.99% pure) was added. The resulting mixture was stirred for 15 minutes, then allowed to warm to ambient temperature, where it is stirred for 1 h. The resulting mixture was cooled to 5°C and quenched slowly adding H₂O (400 mL). The resulting mixture was stirred overnight at ambient temperature, then cooled to ice bath temperature and quenched with aqueous HCI (140 mL of cone. HCI diluted to 680 ml in H₂O). The resulting mixture was stirred for 1 h and then extracted with 1 LX2 of ethyl acetate. The resulting mixture was diluted to a total volume of 1440 mL and charged to a 2L reactor. To the mixture was then added 1 N NaOH (210 mL) in one portion and the resulting mixture was stirred for 0.5 h. To the resulting biphasic mixture was added H₂O (210 mL) and the mixture stirred for 15 minutes. The resulting mixture was transferred to a separatory funnel, the aqueous layer was removed. The organic layer was washed with of H₂O (30OmL), then with brine (2X 50 ml_). The extracted organic layer was dried over anhydrous Na₂SO₄ (223 g), filtered and concentrated via rotary evaporation to yield the title compound as a thick oily solid

¹H NMR (300 MHz, CDCI₃) δ: 8.15-8.10 (m, 1 H), 0.62-0.67 (m, 1 H), 1.15-0.78 (m, 2H), 4.31-4.21 (m, 2H), 3.76-2.3 (series of m, 8H), 1.45 (s, 9H), 1.26-1.23 (m, 3H).

MS (ESI+) for C_2IH₂₆FNO₆ [MW+Na]⁺: Calculated: 430.4, Detected: 430.4

Example 2 4-(4-Fluoro-benzoyl)-5-oxo-azepane-1-carboxylic acid tert-butyl ester

A 1 L, 4N Morton flask was charged 4-(4-fluoro-benzoyl)-5-oxo-azepane-

1 ,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (195 g, 0.478 mole), DMSO (230 ml.) and H₂O (9.5 ml_, 0.52 mol, 1.1 equiv). To the resulting mixture was then added LiCI (22.32 g, 0.53 mol, 1.1 equiv). The resulting heterogeneous mixture was heated to 153°C for 2 hrs, then cooled to ambient temperature. The resulting mixture was then transferred to a 2L, 4N reactor. The original reactor was washed with H₂O (500 mL) and ethyl acetate (1 L) and the washes combined with the reaction mixture in the 2L reactor. The resulting mixture was stirred for 15 minutes, then transferred to a 2L separatory funnel. The aqueous layer was discarded. The organic layer was washed with water (500 mL), then charged back to the 2L reactor, and stirred with ice cold dilute NaOH (230 mL : 72 mL of 1 N NaOH made up-to 580 mL using ice+H₂O) for 30 minutes. The organic layer was separated and washed with brine (100 mL), then dried over anhydrous Na₂SO₄ (1 1 1 g). The eluents were concentrated to a semisolid, which was then slurried in IPA (65 mL) filtered and dried under high vacuum at ~30°C to yield the title compound as a white crystalline solid.

The filtrate was concentrated to a reddish oil and saved in the cold room (T= ~5°C). Solids precipitated, were filtered and washed with IPA to yield a second crop of the title compound,

M. P. 1 13.4°C

¹H NMR (300 MHz, CDCI₃) δ: 7.93-7.87 (m, 2H), 7.16-7.10 (m, 2H), 4.64-4.59 (m, 1 H), 4.17-3.81 (m, 2H), 3.61-3.29 (series of m, 2H), 2.99-2.77 (m, 2H), 2.15-2.03 (m, 2H), 1.45 (s, 9H).

MS (ESI+) for Ci₈H₂₂FNO₄ [MW+Na]⁺: Calculated : 359.4; Detected: 359.4

Example 3 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahvdro-1 ,2,6-triaza-azulene, as its corresponding S-carboxy-S-hydroxy-pentanedioic acid salt

STEP A:

A 500 mL 4-N reactor equipped with thermocouple, nitrogen inlet, addition funnel and an air stirrer was charged with 4-(4-fluoro-benzoyl)-5-oxo- azepane-1-carboxylic acid ferf-butyl ester (18 g, 53.7 mmol). To the reactor was then added IPA (91 mL) and water (1 .1 mL). The resulting mixture was stirred and a solution of isopropyl hydrazine/THF (235 mL solution) was added slowly over about 1 h. The resulting mixture was stirred for 2.5 h. The resulting mixture was concentrated in a rotary evaporator (bath temp 55°C-60°C). The resulting semi-solid was dissolved in ethyl acetate (140 ml.) and then water (140 mL) was added. The resulting mixture was transferred to a separatory funnel and shaken well. The organic layer was extracted and was washed with water (100 mL), then with 0.5 N HCI (once with 25 mL and then with 15 mL). The organic layer was washed again with water (100 mL), then with brine (50 mL). The resulting mixture was dried over anhydrous Na₂SO₄ (20 g), then filtered and concentrated to yield a white solid. The white solid was determined to be a 94:7 mixture of regioisomers. STEP B:

The white solid mixture of regioisomers was charged to a 200 mL 1 N reactor with a magnetic stirring bar and dissolved in a 5.2N HCI/IPA mixture (51.5 mL), with the resulting mixture stirred overnight at ambient temperature. The resulting mixture was concentrated on a rotary evaporator (bath temperature 50⁰C), to yield an easily stirrable oily mass, which was isolated and then dissolved in ethyl acetate (240 mL). The resulting mixture was transferred to a 500 mL 4N reactor. To the resulting mixture in the reactor was then added 1 N NaOH (230 mL, pH=12) and the resulting mixture stirred for 0.5 h. The mixture was then transferred to a separatory funnel, the reactor was rinsed with ethyl acetate (15 mL) and the wash added to the separatory funnel. The organic layer was separated, washed with brine, dried over anhydrous Na₂SO₄ (1 16 g), then filtered and concentrated to yield the title compound, as its corresponding free base, as an off-white solid. STEP C:

The off white solid prepared as in STEP B above was charged to a 500 mL 4N- reactor equipped with air stirrer, thermocouple, nitrogen-inlet and addition funnel. To the reactor was then added methanol (90 mL). To the resulting stirred mixture was added a solution of citric acid in methanol (13. 65 g, 71 mmol in 70 mL of MeOH). The resulting mixture was stirred overnight (total 23 h of stirring). To the resulting mixture was then added ethyl acetate (60 mL) and the mixture stirred at room temperature for 4.5 h. The resulting mixture was then filtered, and the solids and reactor rinsed with a 10:90 mixture of methanol : ethyl acetate (25 mL). The isolated solids were dried in a vacuum oven to yield the title compound. The filtrate was allowed to stand for about 1 month, over which time a dry sticky solid was formed and isolated. The dry sticky solid was slurried in methanol (50 mL) and stirred overnight in a filter flask. The solids were then filtered, and the filter flask and solids washed with a 50:50 mixture of methanol ethyl acetate (10 mL). The filter cake solids were then washed with a 50:50 mixture of methanol : ethyl acetate (10 mL). Nitrogen was passed through the filter cake solid for 15 minutes in vacuum, then dried at 40⁰C under house vacuum to afford a constant weight, to yield a second crop of the title compound as a white crystalline solid. M. P. 182°C.

¹H NMR (300 MHz, CD₃OD) δ: 7.37-7.24 (m, 4H), 4.38-4.25 (m, 1 H), 3.4-3.29 (m, 6H), 2.83-2.78 (m, 6H), 1.37 (d, 6H, J= 6.7Hz).

MS (ESI+) for (free base) Ci₆H₂₀FN₃ [MW+H]⁺: Calculated: 274.35; Detected: 274.35

Example 4 Isopropyl Hydrazine (from its corresponding HCI salt)

H To a 1 L, 4N reactor equipped with an air stirrer, thermocouple, condenser and nitrogen-inlet was charged THF (500 mL) and the reactor set to stir. TEA (46 g, 455 mmol, 63.4 mL) was added to the reactor in one portion. Isopropyl-hydrazine HCI (50 g, 452 mmol) was added to the stirred reactor mixture, in one portion. The resulting heterogeneous mixture was stirred overnight at ambient temperature, then using a very light house vacuum the resulting mixture was filtered via a sintered funnel. The reactor was rinsed with THF (2X 50 mL) and the rinse was used to wash the filtered solids, lsopropyl hydrazine was isolated. The isopropyl hydrazine was then stored as a solution in THF, at about 0-5⁰C for up to 4 weeks. Example 5

4-(4-Chloro-benzoyl)-5-oxo-azepane-1-carboxylic acid tert-butyl ester via aldehyde and oxidation

To a solution of 4-xo-azepane-i-carboxylic acid tert-butyl ester (640 mg,

3 mmol) in THF (5 ml_), cooled to -70⁰C was added LDA (1.6 ml_ of 2M solution/THF/Heptane/ethylbenze), while maintaining the temperature at 65- 70⁰C. The resulting mixture was held for 0.75 h at ~70°C. To the resulting mixture was then added a solution of 4-chlorobenzaldehyde (436 mg, 3.1 mmol) in THF (3.1 ml_), slowly over 10 minutes, while maintaining the temperature at -60⁰C to -70⁰C. The resulting mixture was then stirred for ~1 h. The reaction was quenched by adding saturated NH₄CI (3 ml_). The resulting mixture was allowed to warm to ambient temperature and then partitioned between EtOAc (10 ml) and water. The organic layer was collected, washed with saturated brine (5 ml_). The organic layer was dried over anhydrous MgSO₄, filtered, then concentrated to yield a residue,

To a solution of the residue (760 mg, 2.14 mmol) in DCM (9 ml_) was added solid NaHCU3 (230 mg, 2.74 mmol) followed by addition of Dess-Martin reagent (948.3 mg, 2.33 mmol). The addition resuled in an exotherm which raised the internal temperature of the mixture from 22°C to 31.8⁰C. The resulting mixture was allowed to cool ambient temperature. Water (10 ml_) was added, resulting in the formation of solids. DCM (10 ml_) was added to the mixture, and the solids were filtered off. The filtrate was transferred to a separatory funnel and organic layer was separated, dried over anhydrous MgSO₄, filtered and concentrated. Additional DCM (10 ml_) was added, and the solids filtered off. Part of filtrate was concentrated and chromatographed using 60:30 mixture of hexanes:ethylacetate. The top fraction was characterized to be the title compound, which was isolated as a thick oil.

¹H NMR (300 MHz, CDCI₃) δ: 7.80-7.7 (m, 2H), 7.5-7.4 (m, 2H), 4.64- 4.56(m, 1 H), 4.17-3.81 (m, 2H), 3.61-3.29 (series of m, 2H), 2.99-2.77 (m, 2H), 2.15-2.03 (m, 2H), 1 .45 (s, 9H).

MS (ESI+). for Ci₈H₂₂CINO₄ [MW+Na]⁺: Calculated: 374.8; Detected: 374.8

Example 6 1 -Benzyl-3-(4-chloro-phenyl)-1 ,4,5,6, 7,8-hexahvdro-1 ,2,6-triaza-azulene

4-(4-Chloro-benzoyl)-5-oxo-azepane-1-carboxylic acid tert-butyl ester (8 mg, 0.02274 mmol) was taken up into THF (1 ml_). Diisopropylethylamine (8 microliter, 0.0274 mmol) was added and the resulting mixture was stirred for 2 days. Additional DIPEA (8 μl_) and 4.5 mg of benzyl hydrazine. HCI (4.5 mg) was added and the resulting mixture stirred until the starting ketone was depleted. The resulting mixture was concentrated and subjected to preparative chromatography to yield a residue.

The residue was taken up in DCM (0.2 ml_) and TFA (15μl_), then stirred overnight at ambient temperature. The resulting mixture was neutralized to a pH~7 using aqueous saturated NaHCO₃. To the resulting mixture was then added ethyl acetate (6 ml_), the resulting mixture stirred and the organic layer extracted. The organic layer was dried over anhydrous Na₂SO₄ , filtered and filtrate was concentrated to yield the title compound as a residue. ¹H NMR (300 MHz, CDCI₃): 87.48-7.44 (m, 2 H), 7.44-7.38 (m, 3 H), 7.38-7.27 (m, 3 H), 7.14-7.06 (m, 2 H), 5.36 (s, 2 H), 3.30-3.16 (m, 4 H), 3.10- 2.98 (m, 4 H).

MS {m/z): for C₂₀H₂OCIN₃ [M+H]⁺: Calculated: 337.13; Detected, 338.3.

Example 7 4-(4-Fluoro-benzoyl)-5-oxo-azepane-1-carboxylic acid tert-butyl ester

To a solution of 4-oxo-azepane-1-carboxylic acid tert-butyl ester (283 mg, 1.3 mmol) in THF (3 ml_), cooled to -70⁰C was added LDA (0.73 ml_, 2M solution/THF/Heptane/ethylbenzene, 1.46 mmol) while maintaining the temperature at 65-70⁰C. The resulting mixture was stirred for ~1.5 h at ~70°C. To the resulting mixture was then added p-fluorobenzoyl benzothazole (341.7 mg, 1 .32 mmol) slowly, portion-wise, while maintaining the temperature at - 60⁰C to-70°C. The resulting mixture was then allowed to react overnight at ambient temperature. The reaction was quenched by adding saturated NH₄CI (3 ml_). The resulting mixture was allowed to warm to ambient temperature and then partitioned between EtOAc (10 ml) and water. The organic layer was collected, washed with saturated brine (5 ml_), dried over anhydrous MgSO₄, filtered and concentrated to yield a residue. The residue was chromatographed using 70:30 mixture of hexanes:ethylacetate to yield the title compound as a thick oil. Example 8 1-(4-Methoxy-benzyl)-azepan-4-one

To azepine-4-one HCI (70 g, 0.47 mol) of azepine-4-one was added anhydrous THF (350 ml.) and the resulting mixture stirred to a uniform slurry. TEA (131 ml_, 95 g, 0.94 mol) was added and the resulting mixture heated to 40⁰C. A solution of p-methoxybenzylchlohde (62 g, 0.40 mol, 0.85 equiv) and THF (140 mL) was then added to the mixture over about 15 minutes. The resulting slurry was heated to 50⁰C and was held at this temperature until the reaction is deemed complete. The resulting mixture was cooled to ambient temperature, the solids were filtered off via sintered funnel and then washed with THF (50 mL). The filtrate was concentrated to half the volume. To the filtrate was then added ethyl acetate (600 mL) was water (200 mL). The organic layer was separated, washed with brine (100 mL) and the organic layer extracted. The organic phase was dried over anhydrous Na₂SO₄ (10Og), filtered, and the filtrate concentrated yield the title compound as a thick oil.

¹H NMR (CDCI₃, δ): 7.23 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.6 Hz, 2H), 3.8 (s, 3H), 3.58 (s, 2H), 2.74-2.5 (3m, 8H), 1 .87-1.79 (m, 2H); ¹³C NMR (CDCI₃, δ): 240, 158.74, 130.8, 129.9, 128.6, 1 13.9, 1 13.7, 62.0, 57.8, 55.2, 50.2, 44.3, 42.9, 24.1 .

MS (ESI+) for C₁₄H₁₉NO₂ [M+H]⁺: Calculated: 234.3; Detected: 234.3 Example 9 5-(4-Chloro-benzoyl)-1-(4-methoxy-benzyl)-azepan-4-one

To 1-(4-Methoxy-benzyl)-azepan-4-one (236 mg) in THF (3 ml_), cooled to -75°C was added LDA (0.6 ml_, 2M, THF, heptane/ethylbenzene) while maintaining the temperature at -76°C to -65°C. The resulting mixture was stirred for -35 minutes at this temperature range. To the resulting mixture was then added solid p-chlorophenylbenzotriazole (258 mg) in one portion. The resulting mixture was then allowed to warm overnight to ambient temperature. The reaction was then quenched by adding water (3 ml_). To the resulting mixture was then added ethyl acetate (10 mL) and the mixture stirred. The organic layer concentrated to yield a brown oil which was purified using 30% ethylacetate/hexanes to yield the title compound as a residue.

¹H NMR (CDCI₃, δ): 16.27 (s), 7.91 (d, J=8.6 Hz, 1 H), 7.43(d, d= 8.6 Hz, 1 H), 7.38 (s, 2H), 7.23 (d, J=8.6 Hz, 2H), 6.86 (dd, J= 8.5 & 3.3 Hz, 2H), 4.50 (dd, J= 1 1 .1 & 3.9 Hz, 1 H), 3.80 (s, 3H), 3.57(d, J=16.0 Hz), 3.03-2.00 (series of m, 8H)

MS (ESI+) for C2iH₂₂CNθ3 [M+H]⁺: Calculated: 372.8; Detected: 372.8

Example 10 1-Benzyl-3-(4-chloro-phenyl)-1 ,4,5,6,7,8-hexahvdro-1,2,6-triaza-azulene

STEP A: 5-(4-Fluoro-benzoyl)-1-(4-methoxy-benzyl)-azepan-4-one (10 mg, 0.027 mmol) was dissolved in THF (3 ml_). To the resulting mixture was then added benzylhydrazine-2HCI (17 mg, 0.088 mmol), followed by 4 drops of aqueous 4N NaOH. The resulting mixture was stirred for 2h, then partitioned between ethyl acetate (20 mL) and water (20 ml_). The organic layer was separated and concentrated to yield a residue (determined to be an 80:20 mixture of desired:undesired regioisomer mixture). The residue (mixture of regioisomers) was separated and purified by preparative chromatography using 70:30 (hexanes:ethylacetate) to yield 1-benzyl-3-(4-chloro-phenyl)-6-(4-methoxy- benzyl)-1 ,4,5,6,7,8-hexahydro-1 ,2,6-triaza-azulene as a residue. 1H NMR (300 MHz, CDCI₃) δ: 7.93-6.65 (series of m, 13H), 5.35 (s, 2H),

3.85 (bs, 5H), 3.02-2.62 (bm, 8H),

MS (ESI+). for C₂₈H₂₈CINSO [MW+H]⁺: Calculated: 459.0; Detected: 459.1 STEP B: 1 -Benzyl-3-(4-chloro-phenyl)-6-(4-methoxy-benzyl)-1 ,4,5,6,7,8- hexahydro-1 ,2,6-triaza-azulene was de-protected by reacting with NBS in DCM, according to known methods, to yield the title compound as a residue. Example 11

As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 3 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.

Claims

We Claim:

1. A process for the preparation of a compound of formula (I)

wherein q is an integer from 0 to 1 ;

ALK is selected from the group consisting of Ci_-4alkyl; CYC is selected from the group consisting of hydrogen, C₃-₈cycloalkyl and aryl;

(XII) reacting a compound of formula (X), wherein PG¹ is a nitrogen protecting group with a compound of formula (Xl); in an organic solvent; to yield the corresponding compound of formula (XII);

2. A process as in Claim 1 wherein the compound of formula (X) is reacted with the compound of formula (Xl) in the presence of from about 0.1 and about 0.25 molar equivalents of water.

3. A process as in Claim 1 , wherein the compound of formula (Xl) is added slowly to a mixture of the compound of formula (X) in the organic solvent.

4. A process as in Claim 1 , further comprising

reacting a compound of formula (XV), wherein A¹ is a Ci_-4alkyl with a compound of formula (XVI); in the presence of a Lewis acid; in the presence of an organic base, wherein the organic base, when in the presence of the Lewis acid is capable of removing the hydrogen atom bound at the 4-position of the azepanyl group; to yield the corresponding compound of formula (XVII);

reacting the compound of formula (XVII) with a decarboxylating agent; in DMSO; in the presence of water; at a temperature in the range of from about 145° to about 170⁰C; to yield the corresponding compound of formula (X).

5. A process as in Claim 1 , further comprising

reacting a compound of formula (XXI), with a compound of formula (XXII); in the presence of a base; to yield a mixture of the corresponding compound of formula (X).

6. A process as in Claim 1 , further comprising

reacting a compound of formula (XXI) with a compound of formula (XXV); in the presence of a base; at a temperature in the range of from about 0° to about -78°C; to yield the corresponding compound of formula (XXVIII);

reacting the compound of formula (XXVIII) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (X).

7. A process for the preparation of a compound of formula (II)

(II) wherein q is an integer from 0 to 1 ;

ALK is selected from the group consisting of Ci_-4alkyl; CYC is selected from the group consisting of hydrogen, C3-8cycloalkyl and aryl; AR is selected from the group consisting of aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, Ci_-4alkyl, Ci_-4alkoxy, CF₃ and -OCF₃; or pharmaceutically acceptable salts thereof; comprising

(^{XN I}) (II) de-protecting the compound of formula (XIII) to yield the corresponding compound of formula (II).

8. A process as in Claim 7, wherein the compound of formula (Xl) is added slowly to a mixture of the compound of formula (X) in the organic solvent.

9. A process as in Claim 7, further comprising

10. A process as in Claim 7, further comprising

1 1. A process as in Claim 7, further comprising

12. A process for the preparation of a compound of formula (I-S)

or a pharmaceutically acceptable salt thereof; comprising

13. A process as in Claim 12, wherein the compound of formula (X-S) is reacted with the compound of formula (Xl-S) in the presence of from about 0.1 to about 0.25 molar equivalents of water.

14. A process as in Claim 12, wherein the compound of formula (Xl-S) is present in an amount in the range of from about 0.9 to about 1.5 molar equivalents.

15. A process as in Claim 12, wherein the organic solvent is THF and wherein the compound of formula (X) is reacted with the compound of formula (Xl-S) at about room temperature.

16. A process as in Claim 12, wherein the compound of formula (Xl-S) is added slowly to a mixture of the compound of formula (X-S) in the organic solvent.

17. A process as in Claim 12, wherein the compound of formula (I-S) is prepared as its corresponding pharmaceutically acceptable salt and wherein the pharmaceutically acceptable salt is citrate salt.

18. A process as in Claim 12, further comprising

reacting a compound of formula (XV-A), wherein A¹ is a Ci_-4alkyl and wherein PG¹ is BOC, with a compound of formula (XVI-A), wherein Q is fluoro; in the presence of a Lewis acid; in the presence of an organic base, wherein the organic base, when in the presence of the Lewis acid is capable of removing the hydrogen atom bound at the 4-position of the azepanyl group; to yield the corresponding compound of formula (XVII-A);

reacting the compound of formula (XVII-A) with a decarboxylating agent; in DMSO; in the presence of water; at a temperature in the range of from about 145° to about 170⁰C; to yield the corresponding compound of formula (X-S).

19. A process for the preparation of a compound of formula (N-S)

or a pharmaceutically acceptable salt thereof; comprising

de-protecting the compound of formula (XII-T), to yield the corresponding compound of formula (N-S).

20. A process as in Claim 19, wherein the compound of formula (Xl-T) is added slowly to a mixture of the compound of formula (X-T) in the organic solvent.

21. A process as in Claim 19, further comprising

reacting a compound of formula (XV-A), wherein A¹ is a Ci_-4alkyl and wherein PG¹ is BOC with a compound of formula (XVI-A), wherein Q is chloro; in the presence of a Lewis acid; in the presence of an organic base, wherein the organic base, when in the presence of the Lewis acid is capable of removing the hydrogen atom bound at the 4-position of the azepanyl group; to yield the corresponding compound of formula (XVII-A);

reacting the compound of formula (XVII-A) with a decarboxylating agent; in DMSO; in the presence of water; at a temperature in the range of from about 145° to about 170⁰C; to yield the corresponding compound of formula (X-T).

22. A process as in Claim 19, wherein the compound of formula (N-S) is prepared as its corresponding pharmaceutically acceptable salt and wherein the pharmaceutically acceptable salt is citrate salt.

23. A compound of formula (X)

wherein

AR is selected from the group consisting of aryl; wherein the aryl is optionally substituted with one to three substituents independently selected from the group consisting of halogen, Ci_-4alkyl, Ci_-4alkoxy, CF₃ and -OCF₃; or a pharmaceutically acceptable salt thereof.

24. A compound as in Claim 23, wherein AR is selected from the group consisting of 4-chlorophenyl and 4-fluorophenyl.