WO2003057161A2 - BENZOTHIENO [3,2-c]PYRAZOLYL AND BENZOFURANO [3,2-c] PYRAZOLYL COMPOUNDS, THEIR USE IN DISEASES ASSOCIATED WITH THE 5-HT2C RECEPTOR AND INTERMEDIATE COMPOUNDS THEREOF - Google Patents

Abstract

Disclosed are benzothieno[3,2-c]pyrazolyl and benzofurano[3,2-c]pyrazolyl compounds of the formula (I) and (II), and intermediates of the formula (Ia) and (IIa) which are tautomers, wherein the variables A, X, y, R1, R2, R3 and R4 are as defined in the specification. The compounds are useful for the treatment or prevention of diseases and/or behaviors involving the 5-HT2C receptor site.

Description

BENZOTHIENO[3,2-c]PYRAZOLYL AND BE NZOFURANO[3,2-c] PYRAZOLYL

COMPOUNDS, THEIR USE IN DISEASES ASSOCIATED WITH THE 5-HT_2c

RECEPTOR AND INTERMEDIATE COMPOUNDS THEREOF

Description of the Invention

The present invention relates to:

(1) Benzothieno[3,2-c] pyrazolyl and benzofurano[3,2-c]pyrazolyl compounds or purified stereoisomers or stereoisomer mixtures of said compounds and salts or prodrug forms thereof;

(2) Pharmaceutical compositions comprising one or more of the compounds or purified stereoisomers or stereoisomer mixtures of the invention, or their salt or prodrug forms thereof, with a pharmaceutically acceptable ingredient;

(3) Methods of preparing the compounds of (1); and

(4) Methods of treating diseases associated with the 5-HT₂c receptor in mammals by administering an effective amount of (1) or (2) to a patient in need thereof.

Description of the Compounds and Intermediates Thereof

The benzothieno[3,2-c] pyrazolyl and benzofurano[3,2-c]pyrazolyl compounds or purified stereoisomers or stereoisomer mixtures of said compounds have structural formulae:

or

(I) (ii) wherein

X is O or S(=O)_n ; n is 0, 1 or 2; each R¹ is independently selected from the group consisting of:

(a) halogen,

(b) nitro,

(c) cyano, (d) OR⁵,

(e) C(=O)R⁵,

(f) C(=O)OR⁵,

(g) C(=O)NR⁶R⁷, (h) SR⁸,

(i) S(=O)R⁸,

G) S(=O)₂R⁸,

(k) S(=O)₂NR⁶R⁷,

(I) NR⁶R⁷, (m) NR⁶C(=O)R⁵,

(n) NR⁶S(=O)₂R⁸,

(o) (C C₆)-alkyl optionally substituted with halogen, phenyl, and/or (C C₄)- alkoxy, and

(p) (C₆-C₁₀)-aryl, wherein (p) is optionally substituted with one or more substituents selected from the group consisting of halogen, (C C )-alkyl and (C-ι-C₄)-alkoxy;

y is 0 - 4;

R² is hydrogen, halogen, (C C₄)-alkoxy, or -(C C₄)-alkyl optionally substituted with halogen and/or (C-ι-C₄)-alkoxy;

R³ and R⁴ are each independently selected from the group consisting of hydrogen, C(=O)R⁵, C(=O)OR⁵, C(=O)NR⁶R⁷, S(=O)₂R⁸ and (C C₄)-alkyl optionally substituted by halogen and/or (C C₄)-alkoxy;

R⁵ is hydrogen, or (CrC₆)-alkyl optionally substituted with halogen and/or (C C₄)- alkoxy, R⁶ and R⁷ are each independently selected from the group consisting of: hydrogen, and (CrC₆)-alkyl optionally substituted with halogen and/or (Cι-C₄)- alkoxy;

R⁸ is (CjrC₆)-alkyl optionally substituted with halogen;

A is a two to four carbon alkylene chain optionally interrupted by one or two atoms independently selected from the group consisting of N, O and S atoms, and the alkylene chain is optionally substituted with one or two (CrC^-alkyl groups, (C-|-C₄)- alkoxy groups or a combination thereof.

Stereoisomers or stereoisomer mixtures of said compounds, salts of said compounds, stereoisomers or stereoisomer mixtures, as well as prodrug forms of these compounds are also within the scope of the invention.

Detailed Description

The preferred compounds of the invention are further defined below. In the following description of these preferred compounds, the definitions for the various groups and variables represent the preferred definitions when they differ from those as broadly defined above, and are to be understood as independent of each other.

In the preferred embodiment, the benzothieno[3,2-c] pyrazolyl and benzofurano[3,2- cjpyrazolyl compounds have structural formulae:

(I) (N) wherein

X is O or S(=O)_n n is 0, 1 or 2; each R¹ is independently selected from the group consisting of:

(a) halogen,

(b) nitro, (c) cyano,

(d) OR⁵,

(e) SR⁸,

(f) S(=O)R⁸,

(g) S(=O)₂R⁸, (h) (Cι-C₆)-alkyl optionally substituted with halogen, phenyl, and/or (C C₄)- al oxy, and

(i) (C₆-C₁₀)-aryl, wherein (i) is optionally substituted with one or more substituents selected from the group consisting of halogen, (C₁-C₄)-alkyl and (C C₄)-alkoxy;

y is 0 - 2;

R² is hydrogen, halogen, (C C₄)-alkoxy, or -(C C₄)-alkyl optionally substituted with halogen and/or (C-,-C )-alkoxy;

R³ and R⁴ are each independently selected from the group consisting of hydrogen and (C C )-alkyl optionally substituted with halogen and/or (d-C )-alkoxy;

R⁵ is hydrogen, or (d-CβJ-alkyl optionally substituted with halogen and/or (C C₄)- alkoxy;

R⁸ is (CrC₆)-alkyl optionally substituted with halogen; and A is a two to four carbon alkylene chain optionally substituted with one or two (CrC₆)-alkyl groups, (CrC₄)-alkoxy groups or a combination thereof.

The more preferred compounds of the invention are further defined below. In the following description of these more preferred compounds, the definitions for the various groups and variables represent the more preferred definitions when they differ from those as broadly defined above, and are to be understood as independent of each other.

In the more preferred embodiment, the benzothieno[3,2-c] pyrazolyl and benzofurano[3,2- cjpyrazolyl compounds have structural formulae:

n is 0, 1 or 2; each R¹ is independently selected from the group consisting of:

(a) halogen,

(b) nitro,

(c) cyano,

(d) OR⁵, and (e) (Cι-C₆)-alkyl optionally substituted with halogen, phenyl, and/or (C C₄)- alkoxy;

y is 0 - 2;

R² is hydrogen, halogen, or -(C-|-C₄)-alkyl; R and R are each hydrogen;

R⁵ is hydrogen, or (Cι-C₆}-alkyl optionally substituted with halogen and/or (C C₄)-alkoxy, and

A is a two carbon alkylene chain optionally substituted with one or two (CrC₆)-alkyl groups.

Intermediate compounds to prepare the compounds of formula (I) and (II) are also a subject of the present invention and have the formula (la) and (lla) below which are tautomers:

(^la) (lla) wherein

X is O or S(=O)_n ; n is 0, 1 or 2; each R¹ is independently selected from the group consisting of: (a) halogen,

(b) nitro,

(c) cyano,

( ) OR⁵,

(e) C(=O)R⁵,

(f) C(=O)OR⁵,

(g) C(=O)NR⁶R⁷

(h) SR⁸,

(i) S(=O)R⁸,

G) S(=O)₂R⁸, (k) S(=O)₂NR⁶R⁷,

(I) NR⁶R⁷,

(m) NR⁶C(=O)R⁵,

(n) NR⁶S(=O)₂R⁸,

(o) (C]:-C₆)-alkyl optionally substituted with halogen, phenyl, and/or (CrC₄)- alkoxy, and

(p) (C₆-C₁₀) aryl, wherein (p) is optionally substituted with one or more substituents selected from the group consisting of halogen, (C₁-C₄)-alkyl and (C C₄)-alkoxy;

y is 0 - 4;

R² is hydrogen, halogen, (C-ι-C )-alkyl optionally substituted with halogen and/or (C C₄)-alkoxy; R⁵ is hydrogen and (CrC₆)-alkyl optionally substituted with halogen and/or (C C₄)- alkoxy;

R⁶ and R⁷ are each independently hydrogen or (CrC₆)-alkyl optionally substituted with halogen and/or (C C₄)-alkoxy;

R⁸ is (CrC₆)-alkyl optionally substituted with halogen;

or a purified stereoisomer or stereoisomer mixture of said compound, or salt of said compound, stereoisomer or stereoisomer mixture.

The above compounds of formula (la) and (lla) include compounds wherein:

X is O or S(=O)„; n is 0, 1 or 2; each R¹ is independently selected from the group consisting of halogen and (C₁-C₆)-alkyl optionally substituted with halogen and/or (C C₄)-alkoxy; y is O - 1;

R² _. is hydrogen, halogen, (C_rC₄)-alkyl optionally substituted with halogen and/or (C C₄)-alkoxy; or a purified stereoisomer or stereoisomer mixture of said compound, or salt of said compound, stereoisomer or stereoisomer mixture.

The compounds of the present invention may contain asymmetric centers on the molecule, depending upon the nature of the various substituents. Each such asymmetric center will produce two optical isomers. In certain instances, asymmetry may also be present due to restricted rotation about a central bond joining the two aromatic rings of the specified compounds. It is intended that all isomers, either by nature of asymmetric centers or by restricted rotation as described above, as separated, pure or partially purified isomers or racemic mixtures thereof, be included within the scope of the invention.

In cases where the compounds may exist in tautomeric forms, each tautomeric form is contemplated as being encompassed by the scope of the invention whether existing in equilibrium with its corresponding tautomeric form or whether set in that form due through chemical derivatization.

Pharmaceutically acceptable salts of these compounds as well as commonly used prodrugs of these compounds are also within the scope of the invention.

Salts are especially the pharmaceutically acceptable salts of compounds of formulae (I) or (II) such as, for example, organic or inorganic acid addition salts of compounds of formulae (I) or (II). Suitable inorganic acids include but are not limited to halogen acids (such as hydrochloric acid), sulfuric acid, or phosphoric acid. Suitable organic acids include but are not limited to carboxylic, phosphonic, sulfonic, or sulfamic acids, with examples including acetic acid, trifluoroacetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, 2- or 3-hydroxybutyric acid, γ-aminobutyric acid (GABA), gluconic acid, glucosemonocarboxylic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, methanesulfonic acid, trifluoromethanesulfonic acid, fumaric acid, oxalic acid, succinic acid, adipic acid, pimelic acid, suberic acid, azeiaic acid, malic acid, tartaric acid, citric acid, glucaric acid, galactaric acid, amino acids (such as glutamic acid, aspartic acid, N-methylglycine, acetytaminoacetic acid, N-acetylasparagine or N-acetylcysteine), pyruvic acid, acetoacetic acid, phosphoserine, and 2- or 3-glycerophosphoric acid.

In addition, pharmaceutically acceptable salts include acid salts of inorganic bases, such as salts containing alkaline cations (e.g., Li⁺ Na⁺ or K⁺), alkaline earth cations (e.g., Mg⁺², Ca⁺² or Ba⁺²), the ammonium cation, as well as acid salts of organic bases, including aliphatic and aromatic substituted ammonium, and quaternary ammonium cations such as those arising from protonation or peralkylation of triethylamine, Λ/,/V-diethylamine, N,N- dicyclohexylamine, pyridine, V,Λ/-dimethylaminopyridine (DMAP), 1 ,4- diazabicyclo[2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1 ,8- diazabicyclo[5.4.0]undec-7-ene (DBU).

Prodrugs are considered to be any covalently bonded carriers which release the active parent compound of formula (I) or (II) in vivo. Formation of prodrugs is well known in the art in order to enhance the properties of the parent compound; such properties include solubility, absorption, biostability and release time (see "Pharmaceutical Dosage Form and Drug Delivery Systems" (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, pgs. 27-29, (1995) which is hereby incorporated by reference).

Commonly used prodrugs of the disclosed compounds of formula (I) and (II) are designed to take advantage of the major drug biotransformation reactions and are also to be considered within the scope of the invention. Major drug biotransformation reactions include N- dealkylation, O-dealkylation, aliphatic hydroxylation, aromatic hydroxylation, N-oxidation, S- oxidation, deamination, hydrolysis reactions, glucuronidation, sulfation and acetylation (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al., publ. by McGraw-Hill, pages 12-18, (2001), which is hereby incorporated by reference).

Definitions

The term "halogen" or "halo" as it appears in the specification and claims refers to fluorine, chlorine, bromine, and iodine substituents for the purposes of this invention. When halogen is a possible substituent on an alkyl group, the alkyl may be fully substituted, up to perhalo. The term "fused bicyclo ring" as it appears in the specification and claims refers to a substituent which is a two ring structure which share two carbon atoms. The bonding between the fused bicyclo ring and the compound and/or atom to which it is attached can be through either of the two rings.

Description of the Compositions

The invention also includes pharmaceutical compositions comprising one or more of the compounds of Formula (I) or (II), or a purified stereoisomer or stereoisomer mixture or their salt or prodrugs form thereof, with a pharmaceutically acceptable ingredient.

The invention also relates to pharmaceutical compositions containing a therapeutically effective amount of the compounds of Formula (I) and (II), or a purified stereoisomer or stereoisomer mixture or their salt or prodrug form thereof, and their use in combination with other drugs or therapies for the treatment of diseases and/or behaviors associated with the 5-HT₂c receptor.

The pharmaceutical compositions are prepared so that they may be administered orally, dermally, parenterally, nasally, ophthalmically, otically, sublingually, rectally or vaginally. Dermal administration includes topical application or transdermal administration. Parenteral administration includes intravenous, intraarticular, intramuscular, and subcutaneous injections, as well as use of infusion techniques. One or more compounds of the invention may be present in association with one or more non-toxic pharmaceutically acceptable ingredients and optionally, other active anti-prol iterative agents, to form the pharmaceutical composition. These compositions can be prepared by applying known techniques in the art such as those taught in Remington's Pharmaceutical Sciences (Fourteenth Edition), Managing Editor, John E. Hoover, Mack Publishing Co., (1970) or Pharmaceutical Dosage Form and Drug Delivery Systems (Sixth Edition), edited by Ansel et al., publ. by Williams & Wilkins, (1995), each of which is hereby incorporated by reference.

Commonly used pharmaceutical ingredients which can be used as appropriate to formulate the composition for its intended route of administration include: acidifying agents (examples include but are not limited to acetic acid, citric acid, fumaric acid, hydrochloric acid, nitric acid); alkalinizing agents (examples include but are not limited to ammonia solution, ammonium carbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide, triethanolamine, trolamine); adsorbents (examples include but are not limited to powdered cellulose and activated charcoal); aerosol propellants (examples include but are not limited to carbon dioxide, CCI₂F₂,

F₂CIC-CC1F₂ and CCIF₃) air displacement agents (examples include but are not limited to nitrogen and argon); antifungal preservatives (examples include but are not limited to benzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben, sodium benzoate); antimicrobial preservatives (examples include but are not limited to benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosal); antioxidants (examples include but are not limited to ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodium metabisulfite); binding materials (examples include but are not limited to block polymers, natural and synthetic rubber, polyacrylates, polyurethanes, silicones and styrene-butadiene copolymers); buffering agents (examples include but are not limited to potassium metaphosphate, potassium phosphate monobasic, sodium acetate, sodium citrate anhydrous and sodium citrate dihydrate) carrying agents (examples include but are not limited to acacia syrup, aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, syrup, corn oil, mineral oil, peanut oil, sesame oil, bacteriostatic sodium chloride injection and bacteriostatic water for injection) chelating agents (examples include but are not limited to edetate disodium and edetic acid) colorants (examples include but are not limited to FD&C Red No. 3, FD&C Red No. 20,

FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, D&C Red

No. 8, caramel and ferric oxide red); clarifying agents (examples include but are not limited to bentonite); emulsifying agents (examples include but are not limited to acacia, cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitan monooleate, polyethylene 50 stearate); encapsulating agents (examples include but are not limited to gelatin and cellulose acetate phthalate) flavorants (examples include but are not limited to anise oil, cinnamon oil, cocoa, menthol, orange oil, peppermint oil and vanillin); humectants (examples include but are not limited to glycerin, propylene glycol and sorbitol); levigating agents (examples include but are not limited to mineral oil and glycerin); oils (examples include but are not limited to arachis oil, mineral oil, olive oil, peanut oil, sesame oil and vegetable oil); ointment bases (examples include but are not limited to lanolin, hydrophilic ointment, polyethylene glycol ointment, petrolatum, hydrophilic petrolatum, white ointment, yellow ointment, and rose water ointment); penetration enhancers (transdermal delivery) (examples include but are not limited to monohydroxy or polyhydroxy alcohols, saturated or unsaturated fatty alcohols, saturated or unsaturated fatty esters, saturated or unsaturated dicarboxylic acids, essential oils, phosphatidyl derivatives, cephalin, terpenes, amides, ethers, ketones and ureas) plasticizers (examples include but are not limited to diethyl phthalate and glycerin); solvents (examples include but are not limited to alcohol, corn oil, cottonseed oil, glycerin, isopropyl alcohol, mineral oil, oleic acid, peanut oil, purified water, water for injection, sterile water for injection and sterile water for irrigation); stiffening agents (examples include but are not limited to cetyl alcohol, cetyl esters wax, microcrystalline wax, paraffin, stearyl alcohol, white wax and yellow wax); suppository bases (examples include but are not limited to cocoa butter and polyethylene glycols (mixtures)); surfactants (examples include but are not limited to benzalkonium chloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium lauryl sulfate and sorbitan monopalmitate); suspending agents (examples include but are not limited to agar, bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, kaolin, methylcellulose, tragacanth and veegum); sweetening agents (examples include but are not limited to aspartame, dextrose, -glycerin, mannitol, propylene glycol, saccharin sodium, sorbitol and sucrose); tablet anti-adherents (examples include but are not limited to magnesium stearate and talc); tablet binders (examples include but are not limited to acacia, alginic acid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, povidone and pregelatinized starch); tablet and capsule diluents (examples include but are not limited to dibasic calcium phosphate, kaolin, lactose, mannitol, microcrystalline cellulose, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate, sorbitol and starch); tablet coating agents (examples include but are not limited to liquid glucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, cellulose acetate phthalate and shellac); tablet direct compression excipients (examples include but are not limited to dibasic calcium phosphate); tablet disintegrants (examples include but are not limited to alginic acid, carboxymethylcellulose calcium, microcrystalline cellulose, polacrillin potassium, sodium alginate, sodium starch glycollate and starch); tablet glidants (examples include but are not limited to colloidal silica, corn starch and talc); tablet lubricants (examples include but are not limited to calcium stearate, magnesium stearate, mineral oil, stearic acid and zinc stearate); tablet/capsule opaquants (examples include but are not limited to titanium dioxide); tablet polishing agents (examples include but are not limited to carnuba wax and white wax); thickening agents (examples include but are not limited to beeswax, cetyl alcohol and paraffin); tonicity agents (examples include but are not limited to dextrose and sodium chloride); viscosity increasing agents (examples include but are not limited to alginic acid, bentonite, carbomers, carboxymethylcellulose sodium, methylcellulose, povidone, sodium alginate and tragacanth); and wetting agents (examples include but are not limited to heptadecaethylene oxycetanol, lecithins, polyethylene sorbitol monooleate, polyoxyethylene sorbitol monooleate, polyoxyethylene stearate,).

Depending on the route of administration, the compositions can take the form of aerosols, capsules, creams, elixirs, emulsions, foams, gels, granules, inhalants, lotions, magmas, ointments, peroral solids, powders, sprays, syrups, suppositories, suspensions, tablets and tinctures.

Optional additional agents which can be added to the composition include but are not limited to compounds which are known to treat obesity and obesity related disorder such as diabetes, abnormal feeding behavior, eating disorders (such as bulimia nervosa and anorexia nervosa) and premenstrual tension. Examples of agents for treating obesity include appetite suppressants such as benzphetamine, diethylpropion, Mazindol, phendimetrazine and phentermine.

Examples of agents for treating diabetes include insulin for insulin-dependent diabetes (IDDM) and sulfonylurea compounds for non-insulin dependent diabetes (NIDDM). Examples of sulfonylureas include tolbutamide, chlorpropamide, tolazamide, acetohexamide, glycburide, glipizide and gliclazide.

It had previously been disclosed that psychosomatic disorders such as bulimia nervosa may respond at least partly to treatment with antidepressants such as tricyclic monoamine oxidase (MAO) inhibitors and serotonin reuptake inhibitors (see Goodman and Gilman's The Pharmacological Basis of Therapeutics (Tenth Edition), editor Hardman et al., publ. by McGraw-Hill, page 469, (2001), the contents of which is hereby incorporated by reference. Likewise it would be expected that these agents (e.g. fluoxetine) in combination with the applicants described compounds would have similar effects.

For all regimens of use disclosed herein for compounds of formulae (I) or (II), the daily oral dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily dosage for administration by injection, including intravenous, intramuscular, subcutaneous and parenteral injections, and use of infusion techniques will preferably be from 0.01 to 200 mg/kg of total body weight. The daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight. The daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily. The transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg. The daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.

It will be appreciated by those skilled in the art that the particular method of administration will depend on a variety of factors, all of which are considered routinely when administering therapeutics. It will also be understood, however, that the specific dose level for any given patient will depend upon a variety of factors, including, but not limited to the activity of the specific compound employed, the age of the patient, the body weight of the patient, the general health of the patient, the gender of the patient, the diet of the patient, time of administration, route of administration, rate of excretion, drug combinations, and the severity of the condition undergoing therapy. It will be further appreciated by one skilled in the art that the optimal course of treatment, i.e., the mode of treatment and the daily number of doses of a compound of formulae (I) or (II) or a pharmaceutically acceptable salt thereof given for a defined number of days, can be ascertained by those skilled in the art using conventional treatment tests.

Description or preparative Methods

Formula I and II compounds may be prepared in the manner shown in Scheme 1 below (see next page).

Scheme 1

(III) (IV) (V)

(l) (ll)

Boc = t-BuOC(=0)-₂CH₂- R⁴=Boc, R³=H)

(la) (lla)

A commercially available and optionally substituted phenol or thiophenol (III) is alkylated with a 2-halo acetic acid ester in the presence of a base such as potassium carbonate in an inert solvent such as methylene chloride by stirring at a temperature from 0 to 40°C to provide the intermediate (IV) which is hydrolyzed in an aqueous base such as sodium hydroxide at 20 to 120 °C. Upon acidic workup, the intermediate acid (V) is obtained. Intramolecular cyclization of (V) to (VI) is accomplished by treatment of the acid with a halogenating agent such as oxalyl chloride and N,N-dimethylformamide (DMF) in an inert solvent and stirring for up to 8 hours, removal of volatile solvent and reagent, and treatment of the residue with a Lewis Acid such as aluminum chloride in an inert solvent at 20 to 100°C. The intermediate ketone (VI) is then acylated by treatment with a base such as lithium bis(trimethylsilyl)amide in an aprotic solvent such as tetrahydrofuran (THF) at -78°C, followed by addition of an acylating agent such as pyruvonitile at -78°C and warming up to room temperature. The resulting diketone intermediate (VII) is then allowed to react with hydrazine in acetic acid at room temperature to reflux, providing the tricyclic intermediate (VIII) upon workup. Treatment of (VIII) with a protected haloalkylamine such as t-butoxy-N- (2-bromoethyl)carboxamide and a base such as cesium carbonate in an inert solvent such as methylene chloride at room temperature to reflux gives the N-protected mixture of products (I) and (II) (R³ = H, R⁴ = protecting group). These two regioisomers are separated by chromatography, such as HPLC (reverse phase) and individually deprotected to provide the formula (I) and (II) compounds respectively where R³, R⁴ = H. For example, deprotection may be accomplished in the case where R⁴ = N-t-butoxycarbonyl by treatment with trifluoroacetic acid (TFA) in methylene chloride at ambient temperature. The resulting formula (I) and (II) compounds may be isolated as their TFA salts. Conversion of the formula (I) and (II) compounds where R³ and R⁴ = H to those where R³ and R⁴ = alkyl may be accomplished by straightforward N-alkylation methods such as reductive amination with a carbonyl containing compound and a reducing agent, such as formaldehyde and formic acid, or reaction with a base and a haloalkane such as triethylamine and ethyl iodide.

Alternatively, Formula (VII) compounds may be prepared from commercially available substituted salicylic or thiosalicylic acid esters (IX) as shown in Scheme 2.

Scheme 2

acidic work-up

(IX) (X)

In this scheme, an alkyl salicylate or thiosalicylate is alkylated with the corresponding acetal or ketal of an α-halo aldehyde, or α-halo ketone, in the presence of a base such as triethylamine in an inert solvent such as acetonitrile at room temperature to reflux. The intermediate product (X) is typically not isolated, but subjected to aqueous acid work up to give the carbonyl compound (XI). Cyclization to the heteroketone VII is accomplished by treatment of (X) with a base such as lithium bis(trimethylsilyl)amide in an aprotic solvent such as THF at -78°C to room temperature.

Formula (I) and (II) compounds where X is SO or SO₂ may be prepared by oxidation of the corresponding Formula (VIII) compounds where X is S, as shown in Scheme 3. Treatment of (Villa) with an oxidizing agent such as hydrogen peroxide in acetic acid gives a mixture of (VIHb) and (Vlllc) which may be separated and individually carried on to Formula (I) and (II) final products where X is SO and SO₂.

Scheme 3

(Villa) (VIHb): n = 1 (Vlllc): n = 2 Alternatively, treatment of Formula (I) and (II) compounds where X is S with an oxidizing agent such as m-chloroperbenzoic acid (MCPBA) gives Formula (I) and (II) compounds where X = SO and SO₂ as shown in Scheme 4.

Scheme 4

(lb) (lc): n = 1 (Id): n = 2

(lib) (lie): n = 1 (lid): n = 2

In order to facilitate a further understanding of the invention, the following examples are presented to illustrate more specific details thereof. The examples are not to be construed as limiting the scope of the invention in any way.

It is also understood that the R₅R₆NCH(R₄)CH(R₃)-NHNH₂ compound may be protected and deprotected (e.g., BocNH-CH₂CH₂NHNH₂) as needed in order to carry out the above Schemes.

ABBREVIATIONS AND ACRONYMS

When the following abbreviations are used herein, they have the following meaning:

Ac₂O acetic anhydride

AcOH acetic acid anhy anhydrous Boc .etf-butyloxycarbonyl

DMF Λ,Λ/-dimethylformamide

DMSO dimethylsulfoxide

EDTA ethylenediamine tetraacetic acid

ES-MS electrospray - mass spectroscopy

HPLC high performance liquid chromatography

¹²⁵l-DOI 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane

LiHMDS lithium bis(trimethylsilyl)amide m-CPBA 3-chloroperoxybenzoic acid mCPP 1 -tr?-chlorophenyl)piperazine

MS mass spectroscopy

RT retention time

SB-242084 6-chloro-2,3-dihydro-5-methyl-/V-[6-[(2-methyl-3-pyridinyl)oxy]-3- pyridinyl]-

1 -indole-1 -carboxamide rt room temperature

TFMPP 1-[3-(trifluoromethyl)phenyl]-piperazine

THF tetrahydrofuran

TFA trifluoroacetic acid

TLC thin layer chromatography

Tris Base Tris(hydroxymethyl)aminomethane

Tris-HCl Tris(hydroxymethyl)aminomethane hydrochloride

GENERAL EXPERIMENTAL PROCEDURES Unless otherwise stated, the term "concentration in vacuo" refers to use of a Buchi rotary evaporator at approximately 15 mmHg. All temperatures are reported uncorrected in degrees Celsius (°C). Unless otherwise indicated, all parts and percentages are by volume.

Proton (¹H) nuclear magnetic resonance (NMR) spectra were measured with a General Electric GN-Omega 300 (300 MHz) spectrometer with either Me₄Si (δ 0.00) or residual protonated solvent (CHCI₃ δ 7.26; MeOH δ 3.30; DMSO δ 2.49) as standard. Carbon (¹³C) NMR spectra were measured with a General Electric GN- Omega 300 (75 MHz) spectrometer with solvent (CDCI3 δ 77.0; MeOD-d₃; δ 49.0; DMSO-d₆ O 39.5) as standard.

HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard 100 HPLC equipped with a quaternary pump, a variable wavelength detector, a YMC Pro C18 2.0 mm x 23 mm column, and a Finnigan LCQ ion trap mass spectrometer with electrospray ionization. Gradient elution from 90% A to 95% B over 4 minutes was used on the HPLC. Buffer A was 98% water, 2% Acetonitrile and 0.02% TFA. Buffer B was 98% Acetonitrile, 2% water and 0.018% TFA. Spectra were scanned from 140-1200 amu using a variable ion time according to the number of ions in the source.

The compounds useful in the therapeutic method of this invention are prepared by conventional methods of organic chemistry. Unless otherwise noted, reagents and solvents were obtained from commercial suppliers and were used without further purification. The IUPAC names of compounds exemplified were obtained using the ACD/Lab Web Service.

Example 1

Preparation of f(2-methylphenyl)sulfanvπacetic acid

To a solution of o-thiocresol (10.0 g, 80.5 mmol) in dichloromethane (80.5 mL) at rt was added ethyl bromoacetate (13.4 mL, 120.8 mmol) and potassium carbonate (22.3 g, 161 mmol). The reaction mixture was stirred at rt for 18 hours then quenched with water. The aqueous phase was then extracted twice with ethyl acetate. The combined organic phases were then washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified with silica gel flash column chromatography using 12:1 hexanes:ethyl acetate as the eluant. Some ethyl bromoacetate co-eluted with ethyl 2-(2-methylphenylthio)acetate. The mixture was used for the next step without further purification. To the solution of ethyl 2-(2-methylphenylthio)acetate in tetrahydrofuran (150 mL) at rt was added aqueous sodium hydroxide (3 N, 150 mL). Methanol was added to bring mixture to one phase. The resulting reaction mixture was stirred for 20 hours at rt then concentrated in vacuo. The resulting white residue was taken up in water and washed with diethyl ether. The aqueous phase was acidified to a pH of 5 with aqueous hydrochloric acid (1 N) and then extracted twice with ethyl acetate. The organic extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo, giving the product as a white solid (12.1 g, 82%):¹H NMR (d₆ DMSO) δ 2.27 (s, 3H), 3.76 (s, 2H), 7.10-7.23 (m, 4 H), 12.74 (s, 1 H).

Example 2 . Preparation of 7-methyl-1-benzothiophen-3(2H)-one

To a solution of [(2-methylphenyl)sulfanyl]acetic acid (12.1 g, 66.0 mmol) in dichloromethane (94 mL) was added oxalyl chloride (11.5 mL, 132 mmol) and a catalytic amount of N, Λ/-dimethylformamide (3 drops). The reaction mixture was stirred for 2 hours then concentrated in vacuo. The resulting residue was dissolved in dichloromethane (165 mL) and aluminum chloride (17.6 g, 132 mmol) was slowly added. The reaction mixture turned dark immediately. The resulting mixture was stirred for 15 hours before it was poured into ice. The aqueous solution was extracted twice with dichloromethane. The combined organic layer was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered through a short pad of silica gel and concentrated in vacuo to afford the product as an orange solid (2.28 g, 21%): R_f = 0.66 (hexane/ethyl acetate = 2/1));¹H NMR (d₆-DMSO) δ 2.27 (s, 3H), 3.98 (s, 2H), 7.10-7.24, (m, 1H), 7.46- 7.54 (m, 2H).

Example 3

Preparation of 2-acetyl-7-methyl-1-benzothiophen-3(2H)-one

A solution of 7-methyl-1-benzothiophen-3(2H)-one (2.28 g, 13.9 mmol) in tetrahydrofuran (70 mL) was cooled to -78°C and lithium bis(trimethylsilyl)amide (1 M in THF, 16.7 mL, 16.7 mmol) was added. The resulting reaction solution was stirred at -78°C for 1 hour and pyruvonitrile (1.2 mL, 16.7 mmol) was added dropwise. The reaction mixture was warmed to room temperature over a four hour period. The reaction solution became an opaque green and was quenched with saturated ammonium chloride solution. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified with silica gel flash chromatography by using 1 :1 hexanes:ethyl acetate as the eluant to provide the desired product (3 g, 100%):¹H NMR (d₆-DMSO) δ 2.43 (s, 3H), 2.58 (s, 3H), 7.35-7.40 (m, 2H), 7.91-9.97 (m, 1H).

Example 4 Preparation of 3,5-dimethyl-2A7-rπbenzothienor3,2-clpyrazole

To a solution of 2-acetyl-7-methyl-1-benzothiophen-3(2H)-one (3 g, 14.0 mmol) in acetic acid (47 mL) at rt was added hydrazine monohydrochloride (2.9 g, 42 mmol). The reaction solution was heated to reflux for 2 hours and then cooled to room temperature and stirred for 48 hours. An additional equivalent of hydrazine monohydrochloride was then added and the reaction mixture was heated to reflux for 4 hours then concentrated in vacuo. The resulting residue was taken up in water, neutralized with aqueous sodium hydroxide (1 N), and extracted twice with ethyl acetate. The combined organic extracts were washed with brine and water, dried over magnesium sulfate, filtered and concentrated to provide the product as a dark purple solid (2.85 g, 100%): R_f = 0.16 (hexanes/ethyl acetate = 2/1 ); ES- MS m/z 203 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 2.41 (s, 3H), 2.44 (s, 3H), 7.24 (d, J = 7.8 Hz, 1 H), 7.34 (dd, J = 7.8, 7.8 Hz, 1 H), 7.77 (d, J = 7.8 Hz, 1 H), 13.0 (br s, 1 H).

Example 5

Preparation of tert-butyl 2-(3,5-dimethyM/-/-ri 1benzothienor3,2-c.pyrazol-1- vDethylcarbamate and fert-butyl 2-(3,5-dimethyl-2H-rπbenzothienof3,2-c1pyrazol-2- vDethylcarbamate

To a solution of 3,5-dimethyl-3a - -[1]benzothieno[3,2-c]pyrazole (2.85 g, 14 mmol) in dichloromethane(140 mL) at rt was added cesium carbonate (9.1 g, 28 mmol) and (tert- butoxy)-N-(2-bromoethyl)carboxamide (4.7 g, 21 mmol). The reaction mixture was heated to 85°C for 42 hours before it was cooled to rt and diluted with water. It was extracted twice with ethyl acetate and the combined organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide a crude mixture of two N-alkyl regioisomers. The regioisomers were separated with reversed HPLC to provide tert-b ty\ 2- (3,5-dimethyl-1H-[1]benzothieno[3,2-c]pyrazol-1-yl)ethylcarbamate (960 mg, 20%): R_f = 0.43 (hexane/ethyl aόetate = 2/1); ES-MS m/z 346 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 1.26 (s, 9H), 2.34 (s, 3H), 2.45 (s, 3H), 3.30-3.38 (m, 2H), 4.47 (t, J = 6.2 Hz, 2H), 6.96 (t, J = 5.7 Hz, 1 H), 7.27 (d, J =7.4 Hz, 1 H), 7.37 (dd, J = 7.4 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1 H). tert- butyl 2-(3,5-dimethyl-2 -/-[1]benzothieno[3,2-c]pyrazol-2-yl)ethylcarbamate (510 mg, 11%) was also isolated: R_f = 0.34 (hexane/ethyl acetate = 2/1); ES-MS m/z 346 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 1.32 (s, 9H), 2.42 (s, 3H), 2.45 (s, 3H), 3.28-3.36 (m, 2H), 4.26 (t, J = 6.2 Hz, 2H), 6.97 (t, J = 5.8 Hz, 1 H), 7.23 (d, J = 6.9 Hz, 1 H), 7.32 (dd, J = 6.9, 7.9 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1 H).

Example 6 Preparation of 2-(3,5-dimethyl-1W-rnbenzothienof3.2-c1pyrazol-

1-yl)ethylamine trifluoroacetate

To a solution of tert-butyl 2-(3,5-dimethyl-1W-[1]benzothieno[3,2-c]pyrazol-1- yl)ethylcarbamate (100 mg, 0.29 mmol) in dichloromethane(3.5 mL) was added trifluoroacetic acid (0.7 mL). The resulting reaction solution was stirred for 16 hours then concentrated in vacuo. The resulting residue was triturated with ether to obtain the product as a white solid (88 mg, 84%): ES-MS m/z 246 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 2.38 (s, 3H), 2.47 (s, 3H), 3.25-3.38 (m, 2H), 4.71 (t, J = 6.4 Hz, 2H), 6.97 (t, J = 5.8 Hz, 1 H), 7.31 (d, J = 7.3 Hz, 1 H), 7.43 (dd, J = 7.3, 7.7 Hz, 1 H), 7.98 (d, J = 7.7 Hz, 1 H).

Example 7 Preparation of 2-(3,5-dimethyl-2H-ri ιbenzothienor3,2-c1pyrazol-2-yl)ethylamine trifluoroacetic acid salt

To a solution of terf-butyl 2-(3,5-dimethyl-2 - -[1]benzothieno[3,2-c]pyrazol-2- yl)ethylcarbamate (95 mg, 0.27 mmol) in dichloromethane(3.5 mL) was added trifluoroacetic acid (0.7 mL). The resulting reaction solution was stirred for 4 hours before it was concentrated in vacuo to provide the product as a white solid (100 mg, 100%): ES-MS m/z 246 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 2.44 (s, 3H), 2.51 (s, 3H), 3.28-3.40 (m, 2H), 4.46 (t, J = 6.2 Hz, 2H), 7.27 (t, J = 7.2 Hz, 1 H), 7.31 (d, J = 7.3 Hz, 1H), 7.34 (dd, J = 7.4, 7.4 Hz, 1 H), 7.79 (d, J = 7.4 Hz, 1 H), 7.94 (br s, 2H).

Example 8 Preparation of methyl 2-r(2-oxoethyl)sulfanyl.benzoate

To a round-bottomed flask at rt was charged with methyl thiosalicylate (3.36 g, 20.0 mmol), acetonitrile (50 mL), bromoacetaldehyde diethyl acetal (4.34 g, 22.0 mmol), and triethylamine (6.06 g, 60.0 mmol). The mixture was refluxed for 2 hours until no methyl thiosalicyclate left in the mixture as shown by TLC. It was cooled to rt and hydrochloric acid (1 M, 20 mL) was added. The mixture was stirred at rt for another 0.5 hour before water (40 mL) was added and the mixture was extracted with ethyl acetate twice and the combined organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified with silica gel flash chromatography (hexane: ethyl acetate = 6:1 to 4:1) to provide methyl 2-(2-oxoethylthio)benzoate as a yellow solid (2.1 g, 50%).¹H NMR (de-DMSO) δ 3.84 (s, 3H), 4.01 (d, J = 2.4 Hz, 2H), 7.23-7.29 (m, 1 H), 7.32 (d, J = 8.0 Hz, 1 H), 7.49-7.56 (m, 1 H), 7.89 (dd, J = 1.6, 8.0 Hz, 1 H), 9.48 (t, J = 2.4 Hz).

Example 9 Preparation of 1tf-M .benzothieno.3,2-c1pyrazole

To a round-bottomed flask at rt was charged with methyl 2-[(2-oxoethyl)sulfanyl]benzoate

(2.10 g, 10.0 mmol) and THF (150 mL). The mixture was cooled to -78 °C before lithium bis(trimethylsilyl)amide (1 M in THF, 15.0 mL, 15.0 mmol) was added dropwise. The reaction was left warming up to rt overnight. In the next morning, the reaction was quenched with water and extracted with diethyl ether once. The two layers were separated and the aqueous layer was acidified carefully with concentrated hydrochloric acid to adjust the pH to 1. It was then extracted with ethyl acetate twice. The combined organic layer was washed with water and brine and dried over sodium sulfate before it was filtered and concentrated to give 3-oxo-2-hydrobenzo[b]thiophene-2-carbaldehyde as an yellow solid

(700 mg). The product was dissolved in acetic acid (120 mL) and hydrazine hydrochloride

(822 mg, 12.0 mmol) was added. The resulting mixture was refluxed for 1 hour. The mixture was cooled to rt and concentrated. Aqueous sodium hydroxide solution (1 M) was added to the mixture to adjust the pH to > 10 and the resulting mixture was extracted with ethyl acetate twice. The combined organic layer was washed with water, brine and dried over sodium sulfate before it was filtered through a pad of silica gel. Concentration of the filtrate left the product as a red solid (570 mg, 34% for 2 steps). ES-MS m/z 175 ((M+H)⁺);

¹H NMR (de-DMSO) δ 7.37-7.47 (m, 2H), 7.86-8.02 (m, 2H), 8.08 (s, 1 H), 13.44 and 13.69 (br s, 1H).

Example 10

Preparation of ferf-butyl 2-(1r/-f1lbenzothienor3,2-clpyrazol-1-yl)ethylcarbamate and ferf-butyl 2-(2H-rnbenzothienof3,2-c1pyrazol-2-yl)ethylcarbamate

To a round-bottomed flask at rt was charged with 1 - -[1]benzothieno[3,2-c]pyrazole (570 mg, 3.35 mmol), acetonitrile (15 mL), cesium carbonate (3.28 g, 10.1 mmol), and (tert- butoxy)-N-(2-bromoethyl)carboxamide (1.50 g, 6.67 mmol). The resulting mixture was refluxed for 2 hours before it was cooled to rt. Water was added and the mixture was extracted with ethyl acetate twice. The combined organic layer was washed with water, brine and dried with sodium sulfated before it was concentrated to give a mixture of regioisomers (1 :1 ). The mixture was purified with silica gel flash chromatography (THF: hexane = 1 :1) to give 330 mg of ferf-butyl 2-(1 -/-[1]benzothieno[3,2-c]pyrazol-1- yl)ethylcarbamate (31 %) and 130 mg of ferf-butyl 2-(2H-[1]benzothieno[3,2-c]pyrazol-2- yl)ethylcarbamate (12%) along with some overlapped material. Data for terf-butyl 2-(1H- [1]benzothieno[3,2-c]pyrazol-1-yl)ethylcarbamate e:¹H NMR (d₆-DMSO) δ 1.25 (s, 9H), 3.38 (dd, J = 5.6, 6.1 Hz, 2H), 4.58 (t, J = 6.1 Hz, 2H), 6.98 (t, J = 5.6 Hz), 7.39-7.48 (m, 2H), 7.82 (s, 1 H), 7.93-7.97 (m, 1 H), 8.09-8.12 (m, 1 H). Data for terf-butyl 2-(2H- [1]benzothieno[3,2-c]pyrazol-2-yl)ethylcarbamate:¹H NMR (d₆-DMSO) δ 1.45 (s, 9H), 3.40 (dd, J = 5.6, 6.3 Hz, 2H), 4.34 (t, J = 6.3 Hz, 2H), 6.98 (t, J = 5.6 Hz), 7.39-7.44 (m, 2H), 7.86-7.89 (m, 1 H), 9.95-8.01 (m, 1 H), 8.02 (s, 1 H).

Example 11 Preparation of 2-(1H-ri1benzothieno.3,2-clpyrazol-1-yl)ethylamine trifluoroacetate and 2-(2H-rπbenzothieno.3,2-clpyrazol-2-v0ethylamine trifluoroacetate

To a round-bottomed flask at rt was charged with of terf-butyl 2-(1H-[1]benzothieno[3,2- c]pyrazol-1-yl)ethylcarbamate (330 mg, 1.05 mmol) and dichloromethane (5 mL). To the resulting solution was added trifluoroacetic acid (1 mL) and the mixture was left stirring at rt overnight. In the morning, the mixture was concentrated to give an oil, to which was added diethyl ether. The mixture was sonicated and the solid formed was collected (240 mg, 69%): ES-MS m/z 218 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 3.40 -3.50 (m, 2H), 4.82 (t, J = 6.4 Hz, 2H), 7.44-7.54 (m, 2H), 7.94 (s, 1H), 7.97 (br s, 2H), 7.98-8.08 (m, 1H), 8.14-8.18 (m, 1 H).

In a similar fashion, 110 mg of 2-(2H-[1]benzothieno[3,2-c]pyrazol-2-yl)ethylamine trifluoroacetate (81 %) was produced by the treatment of tetf-butyl 2-(2H-[1]benzothieno[3,2- c]pyrazol-2-yl)ethylcarbamate (130 mg, 0.41 mmol) with trifluoroacetic acid (0.6 mL) in dichloromethane (3 mL). ES-MS m/z 218 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 3.35-3.45 (m, 2H), 4.57 (t, J = 6.0 Hz, 2H), 7.39-7.45 (m, 2H), 7.85-8.10 (m, 4H), 8.12 (s, 1H).

Example 12 Preparation of ferf-butyl 2-(5-chloro-3-methyl-4,4-dioxido-1H-.11benzothienor3,2- clpyrazol-1 -vQethylcarbamate and fert-butyl 2-(5-chloro-3-methyl-4,4-dioxido-2H-rπbenzothienof3,2-c1pyrazol-2- vDethylcarbamate

To a 1:1 mixture of terf-butyl 2-(5-chloro-3-methyl-1 --[1]benzothieno[3,2-c]pyrazol-1- yl)ethylcarbamate and terf-butyl 2-(5-chloro-3-methyl-2 - -[1]benzothieno[3,2-c]pyrazol-2- yl)ethylcarbamate (492 mg, 1.34 mmol) in dichloromethane (10 mL) at rt was added m- chloroperbenzoic acid (997 mg, 4.03 mmol). Saturated sodium bicarbonate and sodium thiosulfate were added to the reaction mixture and the mixture was extracted with dichloromethane twice. The combined organic layer was washed with brine and dried over sodium sulfate. The residue after concentration was purified with reversed phase HPLC to give 180 mg of tert-butyl 2-(5-chloro-3-methyl-4,4-dioxido-1H-[1]benzothieno[3,2-c]pyrazol- 1-yl)ethylcarbamate (34%) and 250 mg of te/if-butyl 2-(5-chloro-3-methyl-4,4-dioxido-2/-/- [1]benzothieno[3,2-c]pyrazol-2-yl)ethylcarbamate (47%). Data for terf-butyl 2-(5-chloro-3- methyl-4,4-dioxido-1 - -[1]benzothieno[3,2-c]pyrazol-1-yl)ethylcarbamate:¹H NMR (d₆- DMSO) δ 1.21 (s, 9H), 2.30 (s, 3H), 3.30 -3.45 (m, 2H), 4.36 (t, J = 5.6 Hz, 2H), 7.02 (t, J = 5.4 Hz, 1 H), 7.64 (dd, J = 1.2, 8.2 Hz, 1H), 7.70 (dd, J = 7.3 Hz, 8.2 Hz, 1H), 7.79 (dd, J = 1.2, 7.3 Hz, 1 H). Data for terf-butyl 2-(5-chloro-3-methyl-4,4-dioxido-2H-[1]benzothieno[3,2- c]pyrazol-2-yl)ethylcarbamate:¹H NMR (d₆-DMSO) δ 1.32 (s, 9H), 2.45 (s, 3H), 3.29 -3.35 (m, 2H), 4.17 (t, J = 5.6 Hz, 2H), 7.06 (t, J = 5.0 Hz, 1 H), 7.59-7.74 (m, 3H).

Example 13 Preparation of 2-(5-chloro-3-methyl-4,4-dioxido-1W-rnbenzothienor3,2-c1pyrazol-1-yl)ethvIamine trifluoroacetate and 2-(5-chloro-3-methyl-4,4-dioxido-2H-rnbenzothienof3,2-clpyrazol-2-yl)ethylamine trifluoroacetate

To a round-bottomed flask at rt was charged with terf-butyl 2-(5-chloro-3-methyl-4,4-dioxido- 1H-[1]benzothieno[3,2-c]pyrazol-1-yl)ethylcarbamate (110 mg, 0.28 mmol), dichloromethane (5 mL) and trifluoroacetic acid (1 mL). The resulting mixture was left stirring at rt overnight. In the next morning, the mixture was concentrated to give 2-(5- chloro-3-methyl-4,4-dioxido-1 -/-[1]benzothieno[3,2-c]pyrazol-1-yl)ethylamine trifluoroacetate as a yellow solid (110 mg, 96%): ES-MS m/z 298 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 2.32 (s, 3H), 3.30 -3.40 (m, 2H), 4.57 (t, J = 6.0 Hz, 2H), 7.68 (dd, J = 1.0, 8.1 Hz, 1 H), 7.75 (dd, J = 7.5, 8.1 Hz, 1 H), 7.86 (dd, J = 1.0, 7.5 Hz, 1H), 7.97 (br s, 2H).

In a similar manner, 2-(5-chloro-3-methyl-4,4-dioxido-2H-[1]benzothieno[3,2-c]pyrazol-2- yl)ethylamine trifluoroacetate (180 mg, 96%) was prepared from ferf-butyl 2-(5-chloro-3- methyl-4,4-dioxido-2 -/-[1]benzothieno[3,2-c]pyrazol-2-yl)ethylcarbamate (180 mg, 0.45 mmol): ES-MS m/z 298 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 2.49 (s, 3H), 3.27 -3.37 (m, 2H), 4.35 (t, J = 6.0 Hz, 2H), 7.61-7.72 (m, 3H), 7.92 (br s, 2H).

Example 14 Preparation of 7-chloro-3-methyl-2tf-fnbenzothienor3,2-c1pyrazole 4.4-dioxide

To a solution of 7-chloro-3-methyl-2H-[1]benzothieno[3,2-c]pyrazole (150 mg, 0.67 mmol) in acetic acid (1.7 mL) at rt was added aqueous hydrogen peroxide (30 wt. %, 0.3 mL). The reaction mixture was stirred at rt for 48 hours then cooled to 0°C and quenched with water and made basic with aqueous sodium hydroxide (1 N). The aqueous phase was then extracted three times with ethyl acetate. The combined organic phases were then washed with saturated aqueous sodium thiosulfate, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was combined with a second batch of crude material that was synthesized through the same method on a scale of 2.7 7-chloro-3- methyl-2H-[1]benzothieno[3',2-c]pyrazole. The combined batch was triturated with ethyl ether to obtain the product as a yellow solid (479 mg, 56%): R_f = 0.31 (hexanes/ethyl acetate = 1/1); ES-MS m/z 255 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 2.44 (s, 3H), 7.61-7.66 (m, 1H), 7.81-7.85 (m, 1 H), 7.87-7.93 (s, 1 H), 13.72 (br s, 1 H).

Example 15

Preparation of terf-butyl 2-(7-chloro-3-methyl-4,4-dioxido-1 /-.1.benzothienor3,2- clpyrazol-1 -vDethylcarbamate and terf-butyl 2-(7-chloro-3-methyl-4,4-dioxido-2H-ri1benzothieno .3,2-clpyrazol-2- vDethylcarbamate

To a solution of 7-chloro-3-methyl-2H-[1]benzothieno[3,2-c]pyrazole 4,4-dioxide (479 mg, 1.9 mmol) in acetonitrile (9.5 mL) at rt was added cesium carbonate (1.24 g, 3.8 mmol) and (ferf-butoxy)-N-(2-bromoethyl)carboxamide (639 mg, 2.85 mmol). The reaction mixture was heated to reflux for 20 hours and no reaction was observed by TLC. Additional (terf- butoxy)-N-(2-bromoethyl)carboxamide (852 mg, 3.8 mmol) was then added and heating was continued at 82°C for 1 hour. The reaction was then cooled to rt and quenched with water. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting yellow solid was purified with silica gel flash chromatography (hexane: THF = 2:1), yielding two major, slightly impure products and 178 mg of co-eluted mixture. The major eluted products were then triturated with diethyl ether to provide as white solids. Data for terf-butyl 2-(7-chloro-3-methyl-4,4-dioxido-1H- [1]benzothieno[3,2-c]pyrazol-1-yl)ethylcarbamate (44 mg, 6%): R = 0.33 (hexanes: THF = 2:1); ES-MS m/z 398 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 1.21 (s, 9H), 2.29 (s, 3H), 3.32-3.39 (m, 2H), 4.36 (t, J = 5.5 Hz, 2H), 7.06 (t, J = 6.01 Hz, 1 H), 7.65-7.69 (m, 1H), 7.89 (m, 1 H), 7.92-7.95 (m, 1H); data for terf-butyl 2-(7-chloro-3-methyl-4,4-dioxido-2H-[1]benzothieno [3,2-c]pyrazol-2-yl)ethylcarbamate (6 mg, 0.8%): R_f = 0.27 (hexanes: THF = 2:1); ES-MS m/z 398 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 1.32 (s, 9H), 2.45 (s, 3H), 3.31 (m, 2H), 4.17 (t, J = 5.4 Hz, 2H), 7.06 (t, J = 6.4 Hz, 1H), 7.62-7.66 (m, 1 H), 7.83-7.84 (m, 1H), 7.89-7.92 (m, 1H).

Example 16 Preparation of 2-(7-chloro-3-methyl-4,4-dioxido-1 H-. πbenzothienor3.2-clpyrazol-1 - vDethylamine trifluoroacetate and 2-(7-chloro-3-methyl-4,4-dioxido-2tf-rnbenzothienor3,2-c1pyrazol-2-yl)ethylamine trifluoroacetate

To a solution of terf-butyl 2-(7-chloro-3-methyl-4,4-dioxido-1H-[1]benzothieno[3,2-c]pyrazol- 1-yl)ethylcarbamate (44 mg, 0.11 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.4 mL). The reaction solution was stirred at rt for15 hours then concentrated in vacuo to provide 2-(7-chloro-3-methyl-4,4-dioxido-1H-[1]benzothieno[3,2- c]pyrazol-1-yl)ethylamine trifluoroacetate as a white solid (35 mg, 77%): ES-MS m/z 298 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 2.33 (s, 3H), 3.33 (m, 2H), 4.58 (t, J = 6.0 Hz, 2H), 7.69- 7.73 (m, 1H), 7.90 (br s, 2H), 7.94-7.97 (m, 1H), 8.01-8.02 (m, 1 H).

In a similar fashion, 2-(7-chloro-3-methyl-4,4-dioxido-2H-[1]benzothieno[3,2-c]pyrazol-2- yl)ethylamine trifluoroacetate was produced by the treatment of terf-butyl 2-(7-chloro-3- methyl-4,4-dioxido-2H-[1]benzothieno [3,2-c]pyrazol-2-yl)ethylcarbamate (6 mg, 0.015 mmol) with trifluoroacetic acid (0.2 mL) in dichloromethane (1 mL): ES-MS m/z 298 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 2.49 (s, 3H), 3.35 (m, 2H), 4.35 (t, J = 5.9 Hz, 2H), 7.66- 7.70 (m, 1H), 7.81-7.82 (m, 1 H), 7.89 (br s, 2H), 7.94-7.97 (m, 1 H).

Example 17 Preparation of .-f2-(1H-rnbenzothienor3,2-clpyrazol-1-yl)ethvn-Λ.,Λ.-dimethylamine trifluoroacetate and Λ.-r2-(2W-rilbenzothienor3,2-c1pyrazol-2-yl)ethyll-Λ.,Λ.-dimethylamine, trifluoroacetate

To a solution of 1 -/-[1]benzothieno[3,2-c]pyrazole (80 mg, 0.5 mmol) in N,N- dimethylformamide (5 mL) at rt was added sodium hydroxide powder (80 mg, 2 mmol). The resulting mixture was stirred for 30 minutes then tetrabutylammonium hydrogen sulfate (7 mg, 0.02 mmol) and 2-dimethylaminoethyl chloride hydrochloride (108 mg, 0.75 mmol) were added. The reaction mixture was heated to reflux for 4 hours the cooled to rt and quenched with water. The aqueous phase was extracted three times with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting residue was purified with reversed phase HPLC to yield Λ/-[2-(1/-/-[1]benzothieno[3,2-c]pyrazol-1-yl)ethyl]-Λ/,Λ/-dimethylamine trifluoroacetate (8 mg, 4.5%): ES-MS m/z 246 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 2.86 (s, 6H), 3.67(t, J = 6.3, 2H), 4.98 (t, J = 6.3, 2H), 7.44-7.54 (m, 2H), 7.95 (s, 1 H), 7.99-8.02 (m, 1 H), 8.18-8.20 (m, 1H) and Λ/-[2-(2H-[1]benzothieno[3,2-c]pyrazol-2-yl)ethyl]-Λ/,Λ/-dimethylamine, trifluoroacetate (16 mg, 8.9%): ES-MS m/z 246 ((M+H)⁺);¹H NMR (d₆-DMSO) δ 2.83 (s, 6H), 3.67 (t, J = 6.13 Hz, 2H), 4.74 (t, J = 6.2 Hz, 2H), 7.40-7.46 (m, 2H), 7.91-8.00 (m, 2H), 8.17 (s, 1 H).

The compounds listed in Table 1 below can be synthesized by the preparative methods described in Examples 1-18 above or by using other known synthetic techniques in the art examples of which include those described by Schofield et al., Heteroaromatic Nitrogen Compounds: The Azoles, published by Cambridge University Press, (1976); and "Five Membered Heterocycles with Two Heteroatoms" from section 3 (1,2-Azoles), Chapter 4 of Heterocyclic Chemistry II - Five Membered Heterocycles, ed. by Gupta et al., publ. by Springer- Verlag, pages 435-454, (1999), each of which is incorporated in its entirety by reference. Table 1 Additional Preparative Examples of the Invention

Description of Method of Use

The compounds of Formula (I) and (II) interact with the 5-HT_2C receptor and are used in the treatment or prevention of diseases and/or behaviors that involve the 5-HT₂c receptor. These diseases and/or behaviors include obesity, obesity related disorders such as diabetes, feeding behavior, eating disorders such as bulimia, anorexia nervosa and premenstrual tension. Further diseases and/or behaviors which can be treated or prevented include central nervous disorders, depressions, anxiety disorders, obsessive-compulsive disorders, sleep disorders, sexual dysfunction, psychoses, migraine, schizophrenia, drug or alcohol addiction and chronic fatigue syndrome.

Obesity is considered a major medical problem largely because it is a factor for a number of other diseases, and obese individuals have a higher chance of dying at a younger age than their leaner counterparts. Obesity is correlated with a much higher incidence of Type II diabetes (NIDDM), hypertension, hyperlipidemia, myocardial infarction, cancers, gallbladder disease, respiratory disease, gout, arthritis, and dermatological disease.

Targeting the 5-HT₂c receptor as method of treating obesity has previously been described (J. Pharmacology, 141, 429-435, (1987) and Psychopharmacology, 96, 93-100, (1988) each of which is hereby incorporated by reference). Agonists that are selective for this receptor would be expected to have superior properties with respect to other known appetite suppressants, such as serotonin/noradrenaline re-uptake inhibitors, which can lead to hypertension and/or cardiac valve defects.

Serotonin has been implicated in the regulation of feeding behavior and the infusion of 5-HT into the brain, resulting in lower food intake by promoting satiety. Furthermore, drugs which increase the concentration of 5-HT in the synaptic cleft by increasing 5-HT release and/or inhibiting re-uptake of the transmitter (such as Redux® (dexfenfluramine) and sibutramine) are effective long term treatments for obesity. However, while activation of several (5-HT-ι_A, 5-HT-I_B, 5-HT_2A, and 5-HT_2C) subtypes of 5-HT receptors has been demonstrated to elicit effects on food intake, the best data available to date suggests that 5-HT_2G receptor agonists produce a decrease in food intake which is associated with the least likely potential for side effects. 5-HT₂c receptors are localized to the hypothalamus and the brainstem, two brain regions known to play a critical role in the modulation of food intake.

Serotonin produces physiological effects by acting on a heterogeneous family of receptors. The lack of selective agonists and antagonists for all of the individual subtypes of serotonin receptors has prevented a complete characterization of the physiological role of each receptor subtype. Activation of both 5-HT_2A and 5-HT₂c receptors decrease food intake. However, while the 5- HT_2C receptor has been implicated in the regulation of satiety, 5-HT_2A receptor agonists are thought to decrease food intake by disrupting the ability of the animal to feed. Non-selective agonists/partial agonists (mCPP, TFMPP) at the 5-HT₂c receptor have been shown to reduce food intake in rats and to accelerate the appearance of the behavioral satiety sequence. Importantly, the hypophagic effects of mCPP are antagonized by the highly selective (at least 100-fold selective) 5-HT_2G receptor antagonist SB-242084. Recent findings from studies in normal human volunteers and obese subjects administered mCPP have also shown decreases in food intake. Thus, a single injection of mCPP decreased food intake in female volunteers and subchronic treatment for a 14 day period decreased the appetite and body weight of obese male and female subjects.

Although mCPP is a non-selective 5-HT agonist, the observations that the anorectic action of the drug is: (a) absent in 5-HT_2C knockout mice; and

(b) antagonized by the 5-HT_2C receptor antagonist SB-242084 in rats, suggests that it decreases food intake via an agonist action at the 5-HT_2G receptor. Therefore, both animal and human data strongly implicate the involvement of the 5-HT_2C receptor in satiety.

Antagonist studies have shown that the selective 5-HT_2C receptor antagonist SB-242084 is highly effective in reversing the hypophagic actions of dexfenfluramine in the rat. Furthermore, the 5-HT₂ receptor antagonist, ritanserin, reversed the anorectic effect of dexfenfluramine in human volunteers. As ritanserin has a 10, 000-fold selectivity for the 5- HT₂ receptors (pKi 8.9) over 5-HTi receptors, a crucial role for the 5-HT₂ receptors in the anorectic action of dexfenfluramine in humans is suggested.

The importance of the 5-HT_2C receptor in mediating feeding behavior is further supported by studies on mutant 5-HT_2G-knockout mice lacking this receptor (Nature, 374, 542-546 9(1995) and British Journal of Pharmacology, 128, 113-209 (1999), which is hereby incorporated by reference). Interestingly, the knockout mice show significantly greater weight gain and adipose tissue deposits over time compared to wild-type mice. Additional studies have confirmed that 5-HT_2C knockout mice overeat and become obese which appears due to a defect in their satiety mechanism. In the behavioral satiety sequence model, knockout animals continued to eat for a significantly longer period of time than the wild-type controls. The prolonged eating in the 5-HT_2C receptor knockout mice was enhanced by access to a sweet diet, suggesting that the 5-HT_2C receptor may play a role in palatability.

It is significant that the decrease in food intake induced by dexfenfluramine is markedly attenuated in 5-HT₂c receptor knockout mice. These results suggest that dexfenfluramine enhances satiety and decreases food intake via an agonist action on 5-HT_2C receptors. In addition, in wild-type animals these anorectic effects of dexfenfluramine are blocked by the 5-HT₂c-selective antagonist SB-242084. These data are consistent with the clinical evidence that the anorectic effect of dexfenfluramine was blocked by the 5HT₂ receptor antagonist ritanserin.

Thus, anorectic activity of the compounds of Formula (I) and (II) can be determined by measurement of their binding affinity to the 5-HT_2C receptor. Other research groups have explored this approach and have disclosed a number of ligands for the 5-HT₂c receptor. (Cerebrus Pharmaceuticals: WO 00/12502, WO 00/12481, WO 00/12475, WO 00/12510, WO 00/12482; Hoffman-La Roche: US005292732, US005646173;

Yamanouchi Pharmaceutical: WO98/56768; and

Akzo Nobel: EP 0 863 136 A1, each of which is hereby incorporated by reference).

The following assay was performed to determine the effect of the compounds of formula (I) and (II) on the 5-HT_2C receptor site:

AV-12 cell pellets expressing 5-HT_2C, 5-HT₂A or 5-HT_2B receptors are homogenized in binding buffer (50 mM Tris-HCl, 10 mM MgCI₂, 10 uM pargyline, 0.1% Sodium Ascorbate, 0.5 mM EDTA, pH 7.4 using saturated Tris Base). Radioligand binding assays were performed as follows: 50 μL of various concentrations of test compound or reference compound (5-HT) are added to 50 μL of¹²⁵l-DOI (1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane). Non-specific binding is defined by 10 uM 5-HT. The reaction is initiated by the addition of 100 μL membrane homogenate and incubated for 45 minutes at room temperature (23°C). Bound radioactivity is determined after rapid filtration using a Brandel Cell Harvester. Filter plates (GF/B pretreated with 0.5% polyethyleneimine) are washed twice with ice-cold wash buffer (50 mM Tris-HCl, pH 7.4 using saturated Tris Base) and radioactivity determined using a Microbeta counter. Data (IC₅₀ values) are analyzed using a four parameter logistic equation (Graph Pad).

All example compounds of formula I and II were tested in the above assays and were found to have an effect on 5-HT_2C at or below a concentration of 10 μM.

Other embodiments of the invention will be apparent to the skilled in the art from a consideration of this specification or practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with the scope and spirit of the invention being indicated by the following claims.

Claims

What is claimed is:

A compound of formula:

(I) (ii) wherein

X is O or S(=O)_n ; n is 0, 1 or 2; each R¹ is independently selected from the group consisting of:

(a) halogen,

(b) nitro,

(c) cyano,

(d) OR⁵,

(e) C(=O)R⁵,

(f) C(=O)OR⁵,

(g) C(=O)NR⁶R⁷, (h) SR⁸,

(i) S(=O)R⁸,

(j) S(=O)₂R⁸,

(k) S(=O)₂NR⁶R⁷,

(I) NR⁶R⁷,

(m) NR⁶C(=O)R⁵,

(n) NR⁶S(=O)₂R⁸,

(o) (CpCe^alkyl optionally substituted with halogen, phenyl, and/or (C C₄)-alkoxy, and (p) (C₆-C₁₀)-aryl, wherein (p) is optionally substituted with one or more substituents selected from the group consisting of halogen, (C-ι-C )-alkyl and (C C )-alkoxy;

y is 0 - 4;

R² is hydrogen, halogen, (C C )-alkoxy, or ~(d-C₄)-alkyl optionally substituted with halogen and/or (C C₄)-alkoxy;

R³ and R⁴ are each independently selected from the group consisting of hydrogen,

C(=O)R⁵, C(=O)OR⁵, C(=O)NR⁶R⁷, S(=O)₂R⁸ and (C C₄)-alkyl optionally substituted by halogen and/or (C C₄)-alkoxy;

R⁵ is hydrogen, or (CrC₆)-alkyl optionally substituted with halogen and/or (C C₄)-alkoxy;

R⁶ and R⁷ are each independently selected from the group consisting of: hydrogen and (CrC₆)-alkyl optionally substituted with halogen and/or (C C₄)-alkoxy;

R⁸ is (CjrC₆)-alkyl optionally substituted with halogen;

A is a two to four carbon alkylene chain optionally interrupted by one or two atoms independently selected from the group consisting of N, O and S atoms, and the alkylene chain is optionally substituted with one or two (CrC₆)-alkyl groups, (C C₄)-alkoxy groups or a combination thereof;

or a purified stereoisomer or stereoisomer mixture of said compound, or salt of said compound.

The compound of claim 1 having a structural formula:

or

(I) (ii) wherein

X is O or S(=O)_n ; n is 0, 1 or 2; each R¹ is independently selected from the group consisting of:

(a) halogen,

(b) nitro,

(c) cyano,

(d) OR⁵,

(e) SR⁸,

(f) S(=O)R⁸,

(g) S(=O)₂R⁸,

(h) (CrC_θJ-alkyl optionally substituted with halogen, phenyl, and/or (C C )-alkoxy, and

(i) (C₆-C₁₀)-aryl, wherein (i) is optionally substituted with one or more substituents selected from the group consisting of halogen, (C C₄)-alkyl and (C C )-alkoxy;

y is 0 - 2;

R² is hydrogen, halogen, (C C₄)-alkoxy, or -(C C₄)-alkyl optionally substituted with halogen and/or (C C₄)-alkoxy; R³ and R⁴ are each independently selected from the group consisting of hydrogen and (CrC₄)-alkyl optionally substituted with halogen and/or (C C₄)-alkoxy;

R⁵ is hydrogen, or (Cτ-C₆)-alkyl optionally substituted .with halogen and/or (C C₄)-alkoxy;

R⁸ is (CrC₆)-alkyl optionally substituted with halogen; and

A is a two to four carbon alkylene chain optionally substituted with one or two (C C₆)-alkyl groups, (C-ι-C )-alkoxy groups or a combination thereof.

3. A pharmaceutical composition for the treating or preventing a disease and/or behavior involving the 5-HT₂c receptor which comprises a therapeutically effective amount of a compound of claim 1 and one or more pharmaceutically acceptable ingredients.

4. The pharmaceutical composition of claim 3 which further comprises at least one additional pharmaceutical agent other than a compound of claim 1.

5. The pharmaceutical composition of claim 4 wherein said additional pharmaceutical agent is an appetite suppressant selected from the group consisting of benzphetamine, diethylpropion, mazindol, phendimetrazine and phentermine.

6. The pharmaceutical composition of claim 4 wherein said additional pharmaceutical agent is an agent for treating obesity related disorders selected from the group consisting of insulin-dependent diabetes, non-insulin dependent diabetes, abnormal feeding behavior, eating disorders and premenstrual tension.

7. The pharmaceutical composition of claim 6 wherein said agent for treating obesity related disorders is selected from the group consisting of insulin, tolbutamide, chlorpropamide, tolazamide, acetohexamide, glycburide, glipizide, gliclazide, tricyclic monoamine oxidase (MAO) inhibitors and serotonin reuptake inhibitors.

8. A method of treating or preventing a disease and/or behavior involving the 5-HT₂c receptor which comprises administering a therapeutically effective amount of a compound of claim 1 or the composition of claim 3.

9. The method of claim 8 wherein said disease and/or behavior involving the 5-HT₂c receptor is selected from the group consisting of obesity, obesity related disorders, abnormal feeding behavior, eating disorders, and premenstrual tension.

10. The method of claim 9 wherein said disease and/or behavior involving the 5-HT_2C receptor is obesity.

11. The method of claim 9 wherein said eating disorders are bulimia or anorexia nervosa.

12. A method of treating or preventing a disease correlated to obesity selected from the group consisting of Type II diabetes (NIDDM), hypertension, hyperlipidemia, myocardial infarction and dermatological disease which comprises administering a therapeutically effective amount of a compound of claim 1 or the composition of claim 3.

13. A compound of the formula:

(^|a) (lla) wherein

X is O or S(=O)_n; n is 0, 1 or 2; each R¹ is independently selected from the group consisting of:

(a) halogen,

(b) nitro,

(c) cyano, (d) OR⁵,

(e) C(=O)R⁵,

(f) C(=O)OR⁵,

(g) C(=O)NR⁶R⁷,

(h) SR⁸,

(i) S(=O)R⁸,

0) S(=O)₂R⁸,

(k) S(=O)₂NR⁶R⁷,

(1) NR⁶R⁷,

(m) NR⁶C(=O)R⁵,

(n) NR⁶S(=O)₂R⁸,

(0) CrCβ-alkyl optionally substituted with halogen, phenyl, and/or C C₄- alkoxy, and

(P) C₆-C₁₀ aryl, wherein (p) is optionally substituted with one or more substituents selected from the group consisting of halogen, C C₄-alkyl and C C₄-alkoxy;

y is 0 - 4;

R² is hydrogen, halogen, C C₄-alkyl optionally substituted with halogen and/or C

C₄- alkoxy;

R⁵ is hydrogen and C C₆-alkyl optionally substituted with halogen and/or C C₄- alkoxy;

R⁶ and R⁷ are each independently hydrogen or C C₆-alkyl optionally substituted with halogen and/or C-_t-C -alkoxy;

R⁸ is C-rC₆-alkyl optionally substituted with halogen; or a purified stereoisomer or stereoisomer mixture of said compound, or salt of said compound, stereoisomer or stereoisomer mixture.

14. The compound of claim 13 wherein:

X is O or S(=O)_n; n is 0, 1 or 2; each R¹ is independently selected from the group consisting of halogen and CrC₆- alkyl optionally substituted with halogen and/or C-ι-C₄-alkoxy; y is 0 - 1; and

R² is hydrogen, halogen, Cι-C₄-alkyl optionally substituted with halogen and/or C C - alkoxy.