WO2003057213A2 - Cyclohexano- and cycloheptapyrazole derivative compounds, for use in diseases associated with the 5-ht2c receptor - Google Patents

Cyclohexano- and cycloheptapyrazole derivative compounds, for use in diseases associated with the 5-ht2c receptor Download PDF

Info

Publication number
WO2003057213A2
WO2003057213A2 PCT/US2002/041637 US0241637W WO03057213A2 WO 2003057213 A2 WO2003057213 A2 WO 2003057213A2 US 0241637 W US0241637 W US 0241637W WO 03057213 A2 WO03057213 A2 WO 03057213A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
heterocyclic ring
optionally substituted
ring
Prior art date
Application number
PCT/US2002/041637
Other languages
French (fr)
Other versions
WO2003057213A3 (en
Inventor
Gaetan H. Ladouceur
Emil Velthuisen
Soongyou Choi
Yamin Wang
Jeremy L. Baryza
Philip Coish
James H. Ii Cook
Original Assignee
Bayer Pharmaceuticals Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Pharmaceuticals Corporation filed Critical Bayer Pharmaceuticals Corporation
Priority to AU2002360819A priority Critical patent/AU2002360819A1/en
Publication of WO2003057213A2 publication Critical patent/WO2003057213A2/en
Publication of WO2003057213A3 publication Critical patent/WO2003057213A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to: (1) Cyclohexano- and cycloheptapyrazole derivative 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
  • cyclohexano- and cycloheptapyrazole derivative compounds or purified stereoisomers or stereoisomer mixtures of said compounds and their salts or prodrug forms thereof have the structural formulas (I), (la), (II) or (Ila):
  • (b4) a fused bicyclo ring wherein one ring is a four to eight membered heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atoms and said heterocyclic ring is optionally substituted with one to two oxo substituents, and the other ring is a saturated or unsaturated three to eight membered carbocyclic ring which is optionally substituted with (C C 5 )-alkyl,
  • R forms a six to eight membered saturated heterocyclic ring with the -NH 2 of the ethylamino chain attached to the 1 -position of the pyrazole ring, wherein the nitrogen from said -NH 2 is the only heteroatom of the heterocyclic ring and the heterocyclic ring is optionally substituted with one oxo group;
  • Ri and R 2 are i independently selected from the group consisting of:
  • R-i and R 2 together with the carbon atoms to which they are attached form an additional (C 3 - C 8 )-saturated cycloalkyl ring, or
  • R-i and R 2 together with the carbon atoms to which they are attached form a bridged cycloalkyl ring to which a further (C 3 -C 8 ) saturated cycloalkyl ring may be fused, or
  • R-i and R 2 together form a four to eight membered heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom wherein said heterocyclic ring is optionally substituted with (C C 5 )-alkyl;
  • R 3 and R are independently selected from the group consisting of
  • R 3 is (C C 5 )-alkyl and R 4 is oxo;
  • R 3 forms a five to eight membered saturated heterocyclic ring with the -NH 2 of the ethylamino chain attached to the 1 -position of the pyrazole, wherein the nitrogen from said -NH 2 is the only heteroatom of the heterocyclic ring, and R 4 is hydrogen;
  • R 5 and Re are independently selected from the group consisting of
  • R 7 is selected from the group consisting of hydrogen and (C C 5 )-alkyl;
  • R 8 and R 9 are independently selected from the group consisting of: (a) hydrogen,
  • Rio is selected from the group consisting of (a) (C 6 -C-jo)-aryl optionally substituted with one to three substituents selected from the group consisting of halogen, (d-C 5 )-alkoxy and (C C 5 )-alkyl optionally substituted with halogen, and
  • a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom wherein said heterocyclic ring is optionally substituted with one to three substituents selected from the group consisting of halogen, (d- C 5 )-alkoxy and (C- ⁇ -C 5 )-alkyl optionally substituted with halogen.
  • cyclohexano- and cycloheptapyrazole derivative compounds have the structural formulas:
  • R is selected from the group consisting of:
  • (b1) a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and (c) (C 6 -C 10 )-aryloxy;
  • R-i and R 2 are independently selected from the group consisting of:
  • R-i and R 2 together with the carbon atoms to which they are attached form an additional (C 3 - C 8 )-saturated cycloalkyl ring, or R-[ and R 2 together with the carbon atoms to which they are attached form a bridged cycloalkyl ring to which a further (C 3 -C 8 ) saturated cycloalkyl ring may be fused;
  • R 3 and R 4 are independently selected from the group consisting of (a) hydrogen, and (b) (CrCi -alkyl.
  • cyclohexano- and cycloheptapyrazole derivative compounds have the structural formula (I):
  • R is selected from the group consisting of methyl and ethyl
  • R-i and R 2 are independently selected from the group consisting of:
  • R 3 and R are independently selected from the group consisting of hydrogen and methyl.
  • 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.
  • 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.
  • Salts are especially the pharmaceutically acceptable salts of compounds of Formulas (I), (la), (II) or (Ila) such as, for example, organic or inorganic acid addition salts of compounds of Formulas (I), (la), (II) or (Ila).
  • 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, ⁇ -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,
  • 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, ⁇ /, ⁇ /-diethylamine, N,N- dicyclohexylamine, pyridine, ⁇ /,/V-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 (DMAP
  • Prodrugs are considered to be any covalently bonded carriers which release the active parent compound of Formula (I), (la), (II) or (Ila) 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).
  • prodrugs of the disclosed compounds of Formulas(l) 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 ydroxylation, 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).
  • 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.
  • halogen is a possible substituent on an alkyl group, the alkyl may be fully substituted, up to perhalo.
  • fused bicyclo ring 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.
  • dialkyl refers to double substitution with an alkyl substituent (see example below for illustration):
  • the invention also includes pharmaceutical compositions comprising one or more of the compounds of Formulas(i), (la), (II) or (Ila), 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 Formulas (I), (la), (II) and (Ila), 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-HT 2 c receptor.
  • 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-proliferative 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, CCI 2 F 2 , F 2 CIC-CCIF 2 and CCIF 3 ) 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, methyl
  • caramel and ferric oxide red 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
  • 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.
  • obesity and obesity related disorder such as diabetes, abnormal feeding behavior, eating disorders (such as bulimia nervosa and anorexia nervosa) and premenstrual tension.
  • agents for treating obesity include appetite suppressants such as benzphetamine, diethylpropion, Mazindol, phendimetrazine and phentermine.
  • agents for treating diabetes include insulin for insulin-dependent diabetes (IDDM) and sulfonylurea compounds for non-insulin dependent diabetes (NIDDM).
  • IDDM insulin for insulin-dependent diabetes
  • NIDDM non-insulin dependent diabetes
  • sulfonylureas include tolbutamide, chlorpropamide, tolazamide, acetohexamide, glycburide, glipizide and gliclazide.
  • 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.
  • these agents e.g. fluoxetine
  • these agents e.g. fluoxetine
  • 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.
  • 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.
  • the optimal course of treatment i.e., the mode of treatment and the daily number of doses of a compound of Formula (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.
  • cyclohexanone or cycloheptanone starting materials, (1) are commercially available or can be prepared by known methods in the literature.
  • Compound (1) is reacted in the presence of a base with an acyl halide wherein X is halogen and R is as described above for Formulas (I), (la), (II) and (Ila) in step (a), to form compound (2).
  • Compound (2) can form compound (4) by two different pathways, (b1) and (b2) or (b3) and (b4).
  • compound (2) is first reacted with hydrazine, (b1), to form a cyclohexano- or cycloheptapyrazole ring, (3A), which is then reacted with a chloroethylamine, (b2), to form the substituted cyclohexano- or cycloheptapyrazole compound, (4).
  • compound (2) is reacted with te/t-butyl 2- hydrazinoethylcarbamate or a 1 -substituted derivative thereof, (b3), to form a substituted cyclohexano- or cycloheptapyrazole ring, (3B), which is subsequently treated with an acid, e.g. HCI or TFA, (b4), to afford the substituted cyclohexano- or cycloheptapyrazole compound, (4).
  • an acid e.g. HCI or TFA
  • Compound (4) may exist as a stereoisomeric or tautomeric mixture, which can be separated by conventional means (e.g. chiral chromatography) to afford the individual compounds, (5A) or (5B).
  • HPLC-electrospray mass spectra were obtained using a Hewlett-Packard
  • diisopropylamine (2.78 mL, 19.8 mmol) was combined with 7.92 mL of n- butyllithium (2.5 M in hexanes) in 13.2 L of THF. After 30 minutes, a solution of 3,3- dimethylcyclohexanone (2.5 g, 19.8 mmol) dissolved in 2.6 mL of THF was added dropwise. The reaction solution was stirred for two hours after which a solution of acetyl chloride (1.4 mL, 19.8 mmol) in 8.6 mL of THF was added dropwise. Then, the reaction solution was allowed to warm to room temperature and stirred for 16 hours.
  • Example 5 A mixture of Example 5 (40 mg, 0.20 mmol), hydrazine-hydrate (15.4 mg, 0.202 mmol) in ethanol (6.7 mL) was heated at 70°C for 3 h. The mixture was cooled, and concentrated. Purification via radial chromatography (1 mm, 6/4 hexane/ethyl acetate, applied as a hexane/ethyl acetate/methanol solution) provided 6 (32 mg, 81 %): MS (electron spray) 195.1 (M+H) + ; 1 H-NMR (CDCI 3l 300 MHz) ⁇ 1.22 (t, 3H), 1.68-1.9 (m, 4H), 2.6-2.8 (m, 4H), 4.37 (q, 2H)
  • Example 6 To a mixture of Example 6 (6.5 mg, 0.34 mmol) and terf-butyl 2-bromoethyl carbamate (161 mg, 0.674 mmol) in dry dimethylformamide (3.4 mL) was added solid cesium carbonate (330mg, 1.01 mmol). The mixture was stirred vigorously for 29h. Water (10 mL) and ethyl acetate (10 mL)"n/vere added and the mixture was acidified to pH 6-6.5 using 1N hydrochloric acid. The layers were separated and the organic layer was washed with water (2X10 mL) and brine (10 mL), dried (sodium sulfate) and concentrated. The resulting oil was purified via radial chromatography (2 mm plate, 6/4 then 4/6 hexane/ethyl acetate) to afford 7 (64 mg, 56%) and 8 (28 mg, 25%).
  • Example 9 Aqueous lithium hydroxide (1N, 0.83 mL) was added to a solution of Example 7 (22 mg, 0.066 mmol) in DME (0.83 mL) and the resulting mixture was stirred at room temperature for 16 hrs. The DME was removed by rotary evaporation and was replaced with ethyl acetate. The aqueous layer was adjusted to pH 6 using 10% of citric acid and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated to afford Example 9 which was employed without further purification.
  • Example 10 Aqueous LiOH (1N, 7.5 L) was added to a solution of Example 8 (0.60 g, 1.8 mmol) in DME (922 mL) and the resulting mixture was stirred at room temperature for 17.5 hours. Work up as per above afforded Example 10 (442 mg, 80%). MS (electron spray) 309.9 (M+H)4
  • Trifluoroacetic acid (244 mg, 2.14 mmol) was added to a solution of carbamate (26.0 mg, 0.0713 mmol) in methylene chloride (1.2 mL) and the resulting mixture was stirred at room temperature for 4 hours.
  • Example 11 (22.1 mg, %): MS (electron spray) 265.2 (M+H)4 1 H-NMR (CDCI 3 , 300 MHz) ⁇ : 1.09 (t, 3H), 1.17 (t, 3H), 4.44-4.86 (m's, 4H), 2.26-2.46 (m, 2H), 2.48-2.71 (m, 2H), 3.11- 3.66 (m's, 6H), 4.2-4.4 (m, 2H), 8.6 (br s, 3H).
  • Example 12
  • Trifluoroacetic acid (153 mg, 1.34 mmol) was added to a solution of carbamate (16 mg, 0.45 mmol) in methylene chloride (0.7 mL) and the resulting mixture was stirred at room temperature for 4 h. Concentration of the mixture under high vacuum gave an oil which was purified by reverse phase chromatography (5/5 acetonitrile/water) to afford Example 12 (3.8 mg, 22%) amide.
  • Trifluoroacetic acid (36 mg, 0.31 mmol) was added to a solution of Example 7 (21 mg, 0.062 mmol) in dry methylene chloride (420 ⁇ L) and stirred for 12.5 h. A second portion of trifluoroacetic acid (36 mg) and methylene chloride (120 ⁇ L) were added and the mixture was stirred for 5 h at room temperature.
  • Trifluoroacetic acid (338mg, 2.96 mmol) was added to a solution of Example 8 (50 mg, 0.15 mmol) in dry methylene chloride (685 ⁇ L). The mixture was stirred at room temperature for 4 hours and concentrated under high vacuum to provide 14 (51 mg, 98% yield): MS (electron spray) 238.1 (M+H) + ; 1 H-NMR (CDCI 3 , 300 MHz) ⁇ : 1.37 (t, 3H), 1.6-2.0 (m's, 4H), 2.46-2.8 (m's, 4H), 3.54 (br signal, 2H), 4.26 (q, 2H), 4.46 (br signal, 2H).
  • Example 15 A solution of trifluoroacetic acid (966 mg, 8.47 mmol) and Example 9 (131 mg, 0.423) in methylene chloride (2.1 mL) was stirred at room temperature for 18.5 h. The mixture was concentrated and purified by reverse chromatography (acetonitrile/water) to afford Example 15 (100 mg, quantitative) as a white solid.
  • Example 9 A solution of Example 9 (75 mg, 0.32 mmol) and triethylamine (27 mg, 0.35 mmol) in anhydrous toluene (1.0 mL) was stirred at room temperature for 15 minutes. A solution of diphenylphosphoryl azide (75 mg, 0.356 mmol) in toluene was added via pipette. The resulting mixture was heated at 80°C for 2 hours, then cooled. N- propylamine (75 ⁇ L, 0.912 mmol) was added and the mixture was stirred overnight. Aqueous citric acid (2 mL) was added and the aqueous phase was extracted in ethyl acetate.
  • Example 16 A solution of carbamate (23.8mg, 0.0651 mmol) and trifluoroacetic acid (223 mg, 1.95 mmol) in dry methylene chloride (1.1 mL) was stirred at room temperature for 7 hours. The mixture was concentrated under high vacuum to afford Example 16 (quantitative).
  • Step 1 Methyl iodide (69 mg, 0.48 mmol) was added to a suspension of Example 9 (50 mg, 0.162 mmol) and cesium carbonate (105 mg, 0.323 mmol) in dry dimethylformamide (1.6 mL). The mixture was stirred at room temperature for 17 h. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (sodium sulfate) and concentrated.
  • Example 18 1 ,8-diazabicyclo[4.3.0]non-5-ene (0.89 mL, 5.9 mmol) was added to a solution of Example 13 (0.59 mmol) in tetrahydrofuran (6.0 mL) and the resulting mixture was stirred for 27 hours.
  • the reaction mixture was diluted with ethyl acetate (20 mL) and saturated aqueous ammonium chloride (20 mL). The layers were separated and the organic layer was washed with saturated aqueous ammonium chloride and brine. The organic layer was dried (sodium sulfate) and concentrated to give Example 18 as a white solid which was used in the next step without further purification.
  • Example 21 tert- butyl-2-[3-(bromomethyl)-4,5,6,7-tetrahydro-2 --indazol-2-yl]-ethylcarbamate (4.19 g, 11.7 mmol, 85% yield).
  • the product was used in the next step without further purification.
  • 1 H- NMR 300 MHz, CDCI 3 ) ⁇ 5.18-5.00 (m, 1 H), 4.41 (s, 2H), 4.21-4.13 (m, 2H), 3.65-3.52 (m, 2H), 2.68-2.58 (t, 2H), 2.51-2.43. (t, 2H), 1.81-1.71 (m, 4H), 1.36 (s, 9H).
  • Example 21 (281 mg, 0.78 mmol), dimethylamine hydrochloride (319 mg, 3.9 mmol), and potassium carbonate (1.09 g, 7.83 mmol) in tetrahydrofuran (15 mL) was refluxed for 12 hours.
  • the reaction mixture was cooled and poured into diethyl ether/water (1 :1, 80 mL). The layers were separated and the organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified (Biotage, 10% methanol in ethyl acetate) to afford the carbamate (108 mg, 43%).
  • the compounds of Formulas (I), (la), (II) and (Ila) interact with the 5-HT 2 c receptor and are used in the treatment or prevention of diseases and/or behaviors that involve the 5-HT 2C receptor ⁇
  • 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.
  • NIDDM Type II diabetes
  • 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.
  • 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 are effective long term treatments for obesity.
  • Redux® diexfenfluramine
  • 5-HT 2C 5-HT 2C receptor agonists produce a decrease in food intake which is associated with the least likely potential for side effects.
  • 5-HT 2C 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 ⁇ -HT ⁇ and 5-HT 2C receptors decrease food intake.
  • 5-HT 2 c 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-HT 2C receptor have been shown to reduce food intake in rats and to accelerate the appearance of the behavioral satiety sequence.
  • the hypophagic effects of mCPP are antagonized by the highly selective (at least 100-fold selective) 5-HT 2 c receptor antagonist SB-242084.
  • Recent findings from studies in normal human volunteers and obese subjects administered mCPP have also shown decreases in food intake.
  • 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.
  • ritanserin reversed the anorectic effect of dexfenfluramine in human volunteers.
  • ritanserin has a 10, 000-fold selectivity for the 5- HT 2 receptors (pKi 8.9) over 5-HT- ⁇ receptors, a crucial role for the 5-HT 2 receptors in the anorectic action of dexfenfluramine in humans is suggested.
  • anorectic activity of the compounds of Formulas (I), (la), (II) and (Ila) can be determined by measurement of their binding affinity to the 5-HT 2 c receptor.
  • Other research groups have explored this approach and have disclosed a number of ligands for the 5-HT 2C receptor.
  • the following assay was performed to determine the effect of the compounds of Formulas (I), (la), (II) and (Ila) on the 5-HT 2C receptor: AV-12 cell pellets expressing 5-HT 2c , 5-HT ⁇ or 5-HT 2B receptors are homogenized in binding buffer (50 mM Tris-HCI, 10 mM MgCI 2 , 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 ⁇ L of various concentrations of test compound or reference compound (5-HT) are added to 50 ⁇ L: I of 125 l-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 ⁇ L 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-HCI, pH 7.4 using saturated Tris Base) and radioactivity determined using a Microbeta counter. Data (IC 50 values) are analyzed using a four parameter logistic equation (Graph Pad).

Abstract

Disclosed are cyclohexano- and cycloheptapyrazole derivative compounds or purified stereoisomers or stereoisomer mixtures of said compounds and their salts or prodrug forms thereof which have structural formulas (I), (Ia), (II) or (IIa): wherein the variables R, 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.

Description

CYCLOHEXANO- AND CYCLOHEPTAPYRAZOLE DERIVATIVE COMPOUNDS, FOR USE IN DISEASES ASSOCIATED WITH THE 5-HT2C RECEPTOR
Description of the Invention
The present invention relates to: (1) Cyclohexano- and cycloheptapyrazole derivative 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 cyclohexano- and cycloheptapyrazole derivative compounds or purified stereoisomers or stereoisomer mixtures of said compounds and their salts or prodrug forms thereof have the structural formulas (I), (la), (II) or (Ila):
Figure imgf000003_0001
(II) (Ila) wherein: dotted lines represent optional double bonds R is selected from the group consisting of:
(a) hydrogen, (b) (CrC5)-alkyl optionally substituted with: (b1) halogen,
(b2) hydroxy,
(b3)> a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom,
(b4) a fused bicyclo ring wherein one ring is a four to eight membered heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atoms and said heterocyclic ring is optionally substituted with one to two oxo substituents, and the other ring is a saturated or unsaturated three to eight membered carbocyclic ring which is optionally substituted with (C C5)-alkyl,
(b5) NR8R9, (b6) SR10,
(c) (C C5)-alkyloxy,
(d) (C1-C5)-alkyloxy-(C1-C5)-alkyl, (e) C(=O)R7,
(f) C(=O)OR7,
(g) (C3-C8)-cycloalkyl,
(h) (C6-C10)-aryl- optionally substituted with halogen,
(i) (C6-Cιo)-aryl-CrC5-alkyl wherein the (C6-Cι0)-aryl is optionally substituted with halogen,
(j) (C6-Cιo)-aryloxy,
(k) (C6-C10)-aryloxy-Cι-C5-alkyl wherein the (C6-C10)-aryloxy is optionally substituted with halogen,
(I) (Ce-C^-ary C Q -alkoxy^C-rCs^alkyl, (m) a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and
(n) -NR8R9 ; or
R forms a six to eight membered saturated heterocyclic ring with the -NH2 of the ethylamino chain attached to the 1 -position of the pyrazole ring, wherein the nitrogen from said -NH2 is the only heteroatom of the heterocyclic ring and the heterocyclic ring is optionally substituted with one oxo group;
Ri and R2are i independently selected from the group consisting of:
(a) hydrogen,
(b) hydroxy,
(c) oxo,
( ) (CrCeJ-alkyl,
(e) (C C5)-dialkyl,
(f) C(=O)R7,
(g) C(=O)OR7,
(h) C(=O)NR5R6;
(i) (C6-C1o)-aryl, and
(j) (C6-C10)-aryl-(CrC5)-alkyl; or
R-i and R2 together with the carbon atoms to which they are attached form an additional (C3- C8)-saturated cycloalkyl ring, or
R-i and R2 together with the carbon atoms to which they are attached form a bridged cycloalkyl ring to which a further (C3-C8) saturated cycloalkyl ring may be fused, or
R-i and R2 together form a four to eight membered heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom wherein said heterocyclic ring is optionally substituted with (C C5)-alkyl; R3 and R are independently selected from the group consisting of
(a) hydrogen,
(b) (C C5)-alkyl, and
(c) (CrC5)-dialkyl; or
R3 is (C C5)-alkyl and R4 is oxo; or
R3 forms a five to eight membered saturated heterocyclic ring with the -NH2 of the ethylamino chain attached to the 1 -position of the pyrazole, wherein the nitrogen from said -NH2 is the only heteroatom of the heterocyclic ring, and R4 is hydrogen;
R5 and Re are independently selected from the group consisting of
(a) hydrogen,
(b) (C.-C5)-alkyl, (c) (C3-C8)-cycloalkyl,
Figure imgf000006_0001
(e) (C6-C10)-aryl-(C1-C5)-alkyl;
R7 is selected from the group consisting of hydrogen and (C C5)-alkyl; R8 and R9 are independently selected from the group consisting of: (a) hydrogen,
(b) C(=O)R7,
(c) C(=O)OR7, and
(d) C(=O)NR5R6;
Rio is selected from the group consisting of (a) (C6-C-jo)-aryl optionally substituted with one to three substituents selected from the group consisting of halogen, (d-C5)-alkoxy and (C C5)-alkyl optionally substituted with halogen, and
(b) a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom wherein said heterocyclic ring is optionally substituted with one to three substituents selected from the group consisting of halogen, (d- C5)-alkoxy and (C-ι-C5)-alkyl optionally substituted with halogen.
Purified stereoisomers or stereoisomer mixtures of said compounds, or salts of said compounds, stereoisomer or stereoisomer mixtures are also within 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 cyclohexano- and cycloheptapyrazole derivative compounds have the structural formulas:
Figure imgf000007_0001
(I) (II) wherein: dotted lines represent optional double bonds
R is selected from the group consisting of:
(a) hydrogen,
(b) (Cι-C5)-alkyl optionally substituted with:
(b1) a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and (c) (C6-C10)-aryloxy;
R-i and R2 are independently selected from the group consisting of:
(a) hydrogen, (b) (C C5)-alkyl, and
(c) (C C5)-dialkyl, or
R-i and R2 together with the carbon atoms to which they are attached form an additional (C3- C8)-saturated cycloalkyl ring, or R-[ and R2 together with the carbon atoms to which they are attached form a bridged cycloalkyl ring to which a further (C3-C8) saturated cycloalkyl ring may be fused;
R3 and R4 are independently selected from the group consisting of (a) hydrogen, and (b) (CrCi -alkyl.
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 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 cyclohexano- and cycloheptapyrazole derivative compounds have the structural formula (I):
Figure imgf000008_0001
wherein: dotted lines represent optional double bonds;
R is selected from the group consisting of methyl and ethyl;
R-i and R2 are independently selected from the group consisting of:
(a) hydrogen,
(b) (C C5)-alkyl, and
(c) (CrCβϊ-dialkyl, and
R3 and R are independently selected from the group consisting of hydrogen and methyl.
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 in which the compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this 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 Formulas (I), (la), (II) or (Ila) such as, for example, organic or inorganic acid addition salts of compounds of Formulas (I), (la), (II) or (Ila). 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/,Λ/-diethylamine, N,N- dicyclohexylamine, pyridine, Λ/,/V-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), (la), (II) or (Ila) 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 Formulas(l) 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 ydroxylation, 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.
The term "dialkyl" as it appears in the specification and claims refers to double substitution with an alkyl substituent (see example below for illustration):
Figure imgf000011_0001
X = dimethyl
Description of the Compositions
The invention also includes pharmaceutical compositions comprising one or more of the compounds of Formulas(i), (la), (II) or (Ila), 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 Formulas (I), (la), (II) and (Ila), 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-proliferative 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-CCIF2 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 Formulas (I), (la), (II) or (Ila), 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 Formula (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 of Preparative Methods
Abbreviations and Acronyms
Boc fe-Y-butoxycarbonyl DMAP dimethylamino-pyridine
DME dimethoxyethane
DMF dimethylformamide
DMSO dimethylsulfoxide
EDCI 1 -(3-Dimethylaminopropyl)-3-ethyIcarbodiimide hydrochloride ES-MS electrospray - mass spectroscopy
LDA lithium diisopropylamide
NMM 4-methylmorpholine
NMR nuclear magnetic resonance
NOE nuclear Overhauser effect TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
Compounds of Formulas (I), (la), (II) and (Ila), where R is bonded to the pyrazole portion of the cyclohexano- or cycloheptapyrazole ring, may generally be prepared by the methods illustrated in Reaction Scheme I and II below.
The cyclohexanone or cycloheptanone starting materials, (1), are commercially available or can be prepared by known methods in the literature. Compound (1) is reacted in the presence of a base with an acyl halide wherein X is halogen and R is as described above for Formulas (I), (la), (II) and (Ila) in step (a), to form compound (2). Compound (2) can form compound (4) by two different pathways, (b1) and (b2) or (b3) and (b4).
In one pathway of Scheme I, compound (2) is first reacted with hydrazine, (b1), to form a cyclohexano- or cycloheptapyrazole ring, (3A), which is then reacted with a chloroethylamine, (b2), to form the substituted cyclohexano- or cycloheptapyrazole compound, (4).
In another pathway of Scheme II, compound (2), is reacted with te/t-butyl 2- hydrazinoethylcarbamate or a 1 -substituted derivative thereof, (b3), to form a substituted cyclohexano- or cycloheptapyrazole ring, (3B), which is subsequently treated with an acid, e.g. HCI or TFA, (b4), to afford the substituted cyclohexano- or cycloheptapyrazole compound, (4).
Compound (4) may exist as a stereoisomeric or tautomeric mixture, which can be separated by conventional means (e.g. chiral chromatography) to afford the individual compounds, (5A) or (5B).
Other cyclic ketones or derivatives thereof can be used as starting materials (the structures of (1A-D) are shown in Scheme II by way of example for bicyclic or tricyclic ketones) in order to derive additional compounds within the scope of the applicants' invention.
Figure imgf000019_0001
Figure imgf000019_0002
Scheme II other ketones
Figure imgf000019_0003
It is also understood that the -CH(R4)CH(R3)-NH2 portion of the compound of formula (I) and (II) may be protected and deprotected (e.g., BocNH-CH2CH2NHNH2) as needed in order to carry out the above Scheme.
HPLC-electrospray mass spectra (HPLC ES-MS) were obtained using a Hewlett-Packard
1100 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.
EXAMPLES
Example 1
Figure imgf000021_0001
1
At -28°C, diisopropylamine (2.78 mL, 19.8 mmol) was combined with 7.92 mL of n- butyllithium (2.5 M in hexanes) in 13.2 L of THF. After 30 minutes, a solution of 3,3- dimethylcyclohexanone (2.5 g, 19.8 mmol) dissolved in 2.6 mL of THF was added dropwise. The reaction solution was stirred for two hours after which a solution of acetyl chloride (1.4 mL, 19.8 mmol) in 8.6 mL of THF was added dropwise. Then, the reaction solution was allowed to warm to room temperature and stirred for 16 hours. At this time, it was quenched with saturated aqueous ammonium chloride. The aqueous phase was extracted with ether. The organic extract was washed with saturated aqueous sodium bicarbonate, brine, and water. It was then dried over magnesium sulfate, filtered, and concentrated in- vacuo. The resulting crude residue was purified through silica gel flash column chromatography using 8:1 hexanes:ethyl acetate as the eluant to provide 1 as a clear oil (1.83 g, 55%): ES-MS m/z 167 ((M-H)"); 1H-NMR (CDCI3) δ 0.97 (s, 6H), 1.46 (t, 2H), 2.11 (s, 2H), 2.14 (s, 3H), 2.34 (t, 2H).
Example 2
Figure imgf000021_0002
2 To a solution of 1 (1.83 g, 10.88 mmol) in 54 mL of ethanol was added hydrazine (1.3 mL, 27.2 mmol). The reaction solution was stirred at room temperature of 14 hours then concentrated in-vacuo. The resulting residue was taken up in water, acidified with 1N hydrochloric acid , and washed with ethyl acetate. The aqueous solution was then neutralized with 1N sodium hydroxide and extracted three times with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in-vacuo to provide 2 as a white crystalline solid (1.37 g, 77%): Rf = 0.13 (1 :1 hexanes:ethyl acetate); 1H-NMR (d6-DMSO) δ 0.92 (s, 6H), 1.42 (t, 2H), 2.04 (s, 3H), 2.25 (s, 2H), 2.30 (t, 2H), 11.82 (br. s, 1 H). Example 3
Figure imgf000022_0001
Sodium hydroxide powder (1.34 g, 33.4 mmol) was added to a solution of 2 (1.37 g, 8.34 mmol) in 41.7 mL of acetonitrile. The reaction mixture was stirred at room temperature for 30 minutes then 2-chloroethylamine monohydrochloride (1.45 g, 12.51 mmol) and tetrabutylammonium sulfate (0.11 g, 0.33 mmol) were added. The reaction mixture was heated to 85°C for 14 hours then cooled to room temperature and taken up in water. The aqueous solution was extracted three times with ethyl acetate. The organic extracts were combined, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in-vacuo to provide 3 as a mixture of regioisomers for N-alkyl (1.19 g, 69%): 1H- NMR (d6-DMSO) δ 0.92 (s, 2.5H), 0.95 (s, 3.5H), 1.42 (t, 2H), 2.01 (s, 1.75H), 2.11 (s, 1.25H), 2.24-2.34 (m, 4H), 2.73-2.81 (m, 2H), 3.78 (t, 1.2H), 3.85 (t, 0.8H).
Example 4
Figure imgf000022_0002
4A 4B
To a solution of 3 (1.19 g, 0.69 mmol) dissolved in ether was added maleic acid (0.66g, 5.7 mmol). The reaction solution was stirred at room temperature for 4 days at which time a white solid precipitate was observed and collected through vacuum filtration to provide 4 (1.57 g, 85%) as a mixture of regioisomers 4A (60%) and 4B (40%): ES-MS m/z 208 ((M+H)+); 1H-NMR (d6-DMSO) δ 0.95 (s, 2.4H), 0.98 (s, 3.6H), 1.46 (t, 2H), 2.06 (s, 1.8), 2.14 (s, 1.2H), 2.28-3.36 (m, 4H), 3.12-3.21 (m, 2H), 4.06 (t, 1.2H), 4.13 (t, 0.8H), 7.82 (br. s, 2H). Example 5
Figure imgf000023_0001
To a chilled (-78°C) solution of cyclohexanone (200 mg, 2.04 mmol) in dry, degassed tetrahydrofuran (10.4 mL) was added a 2.0 M solution of lithium aluminium hydride in tetrahydrofuran (1.1 mL) giving a white suspension. Neat ethyl oxalate (298 mmol, 2.04 mmol) was added, causing the mixture to become clear and slightly yellow. The mixture was allowed to warm to room temperature over 5 h. Saturated aqueous amonium chloride was added, followed by ethyl acetate (15 mL). The layers were separated and the organic layer was washed with water and brine, dried (sodium sulfate) and concentrated. Purification of the crude product via radial chromatography (1 mm plate, 85/15 hexane/ethyl acetate) provided 5 (255 mg, 63%): MS (electron spray) 199.2 (M+H)4 216.0 (M+NH4); 1H- NMR (CDCI3, 300 MHz) δ 1.36 (t, 3H), 1.6-1.8 (m, 4H), 2.4-2.5 (m, 4H), 4.32 (q, 2H) (enol form).
Example 6
Figure imgf000023_0002
A mixture of Example 5 (40 mg, 0.20 mmol), hydrazine-hydrate (15.4 mg, 0.202 mmol) in ethanol (6.7 mL) was heated at 70°C for 3 h. The mixture was cooled, and concentrated. Purification via radial chromatography (1 mm, 6/4 hexane/ethyl acetate, applied as a hexane/ethyl acetate/methanol solution) provided 6 (32 mg, 81 %): MS (electron spray) 195.1 (M+H)+; 1H-NMR (CDCI3l 300 MHz) δ 1.22 (t, 3H), 1.68-1.9 (m, 4H), 2.6-2.8 (m, 4H), 4.37 (q, 2H)
Examples 7 and 8
Figure imgf000023_0003
To a mixture of Example 6 (6.5 mg, 0.34 mmol) and terf-butyl 2-bromoethyl carbamate (161 mg, 0.674 mmol) in dry dimethylformamide (3.4 mL) was added solid cesium carbonate (330mg, 1.01 mmol). The mixture was stirred vigorously for 29h. Water (10 mL) and ethyl acetate (10 mL)"n/vere added and the mixture was acidified to pH 6-6.5 using 1N hydrochloric acid. The layers were separated and the organic layer was washed with water (2X10 mL) and brine (10 mL), dried (sodium sulfate) and concentrated. The resulting oil was purified via radial chromatography (2 mm plate, 6/4 then 4/6 hexane/ethyl acetate) to afford 7 (64 mg, 56%) and 8 (28 mg, 25%).
7: MS (electron spray) 338.1 (M+H)+; 1H-NMR (CDCI3, 500 MHz) δ 1.37 (t, 3H), 1.40 (s, 9H), 1.69-1.82 (m, 4H), 2.62 (t, 2H), 2.71 (t, 2H), 3.48-3.60 (m, 2H), 4.31 (q, 2H), 4.55-4.62 (m, 2H), 4.97 (br s, 1H). NOE observed between signals at δ 4.31 and 4.55-4.62.
8: MS (electron spray) 338.1 (M+H)+; 1H-NMR (CDCI3, 500 MHz) δ 1.37 (t, 3H), 1.42 (s, 9H), 1.69-1.85 (m's, 4H), 2.56 (t, 2H), 2.61 (t, 2H), 3.49-3.6 (m, 2H), 4.11-4.2 (m, 2H), 4.36 (q, 2H), 4.75 (br s, 1H). NOE observed between signals at δ 2.56 and 4.11-4.2.
Example 9
Figure imgf000024_0001
Aqueous lithium hydroxide (1N, 0.83 mL) was added to a solution of Example 7 (22 mg, 0.066 mmol) in DME (0.83 mL) and the resulting mixture was stirred at room temperature for 16 hrs. The DME was removed by rotary evaporation and was replaced with ethyl acetate. The aqueous layer was adjusted to pH 6 using 10% of citric acid and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried (sodium sulfate) and concentrated to afford Example 9 which was employed without further purification. MS (electron spray) 310.0 (M+H)+; 1H-NMR (C6H6, 300 MHz) δ 1.20 (s, 9H), 1.34-1.54 (m's, 4H), 2.57-2.8 (m's, 4H), 3.2-3.54 (m, 2H), 4.63 (t, 2H).
Example 10
Figure imgf000025_0001
Aqueous LiOH (1N, 7.5 L) was added to a solution of Example 8 (0.60 g, 1.8 mmol) in DME (922 mL) and the resulting mixture was stirred at room temperature for 17.5 hours. Work up as per above afforded Example 10 (442 mg, 80%). MS (electron spray) 309.9 (M+H)4
Example 11
Figure imgf000025_0002
Diethylamine (46mg, 0.775 mmol) was added to a solution of Example 9 (50 mg, 0.16 mmol), EDCI (64 mg, 0.33 mmol), dimethylaminopyridine (36mg, 0.295 mmol) and NMM (19.5 μL) in methylene chloride (3 mL) and the resulting mixture was stirred at room temperature for 3 days. Ethyl acetate and 0.35 M hydrochloric acid were added and the layers separated. The organic layer was washed 0.35 M hydrochloric acid, saturated aqueous sodium bicarbonate and brine, and was then dried (sodium sulfate) and concentrated. The crude material was purified by reverse chromatography (acetonitrile/H2O) to afford the carbamate (26.0 mg, 44%). MS (electron spray) 365.1 (M+H)4
Trifluoroacetic acid (244 mg, 2.14 mmol) was added to a solution of carbamate (26.0 mg, 0.0713 mmol) in methylene chloride (1.2 mL) and the resulting mixture was stirred at room temperature for 4 hours. The mixture was concentrated under high vacuum to afford Example 11 (22.1 mg, %): MS (electron spray) 265.2 (M+H)4 1H-NMR (CDCI3, 300 MHz) δ: 1.09 (t, 3H), 1.17 (t, 3H), 4.44-4.86 (m's, 4H), 2.26-2.46 (m, 2H), 2.48-2.71 (m, 2H), 3.11- 3.66 (m's, 6H), 4.2-4.4 (m, 2H), 8.6 (br s, 3H). Example 12
Figure imgf000026_0001
Diethylamine (28.6 mg, 0.45 mmol) was added to a solution of Example 10 (50 mg, 0.162 mmol) , EDCI ( 64 mg, 0.33 mmol) , dimethylaminopyridine ( 36 mg, 0.29 mmol) and NMM (19.5 μL) in methylene chloride (3 mL) and the resulting mixture was stirred at room temperature for 3 days. TLC analysis indicated partial conversion and so diethylamine (2 equivalents), EDCI (1.1 equivalents), DMAP (1.1 equivalents) and NMM (1.1 equivalents) were added and stirring was continued overnight. Workup as per above. The crude material was purified by reverse phase chromatography (acetonitrile/H2O) to afford 16.3 mg (28%) of carbamate: MS (electron spray) 365.0 (M+H)+
Trifluoroacetic acid (153 mg, 1.34 mmol) was added to a solution of carbamate (16 mg, 0.45 mmol) in methylene chloride (0.7 mL) and the resulting mixture was stirred at room temperature for 4 h. Concentration of the mixture under high vacuum gave an oil which was purified by reverse phase chromatography (5/5 acetonitrile/water) to afford Example 12 (3.8 mg, 22%) amide. MS (electron spray) 265.1 (M+H)+; 1H-NMR (CDCI3, 300 MHz) δ 1.17 (m, 6H), 1.54-2.89 (m, 4H), 2.25-2.6 (m, 4H), 3.2-3.6 (m, 2H), 4.2-4.31 (m, 2H), 4.5-4.89 (m, 4H), 8.3 (br s, 3H).
Example 13
Figure imgf000026_0002
Trifluoroacetic acid (36 mg, 0.31 mmol) was added to a solution of Example 7 (21 mg, 0.062 mmol) in dry methylene chloride (420 μL) and stirred for 12.5 h. A second portion of trifluoroacetic acid (36 mg) and methylene chloride (120 μL) were added and the mixture was stirred for 5 h at room temperature. The mixture was then concentrated under high vacuum to afford 13 (21 mg, 98%): MS (electron spray) 238.1 (M+H)+ ; 1H-NMR (CDCI3, 300 MHz) δ 1.40 (t, 3H), 1.65-2.89 (m, 4H), 2.46-3.8 (m's, 4H), 3.45 (br signal, 2H), 4.31 (q, 2H), 4.8 (br signal, 2H), 8.5 (br s, 3H).
Example 14
Figure imgf000027_0001
Trifluoroacetic acid (338mg, 2.96 mmol) was added to a solution of Example 8 (50 mg, 0.15 mmol) in dry methylene chloride (685 μL). The mixture was stirred at room temperature for 4 hours and concentrated under high vacuum to provide 14 (51 mg, 98% yield): MS (electron spray) 238.1 (M+H)+ ; 1H-NMR (CDCI3, 300 MHz) δ: 1.37 (t, 3H), 1.6-2.0 (m's, 4H), 2.46-2.8 (m's, 4H), 3.54 (br signal, 2H), 4.26 (q, 2H), 4.46 (br signal, 2H).
Example 15
Figure imgf000027_0002
A solution of trifluoroacetic acid (966 mg, 8.47 mmol) and Example 9 (131 mg, 0.423) in methylene chloride (2.1 mL) was stirred at room temperature for 18.5 h. The mixture was concentrated and purified by reverse chromatography (acetonitrile/water) to afford Example 15 (100 mg, quantitative) as a white solid. MS (electron spray) 210.1 (M+H)+; 1H-NMR (DSMO, 300 MHz) δ: 1.54-1.80 (m's, 4H), 2.49-2.71 (m's, 4H), 3.06-3.29 (m, 2H), 4.51-4.66 (t, 2H), 7.89 (br s, 2H), 13.54 (br s, 1 H).
Example 16
Figure imgf000027_0003
Caution: azide reagent. A solution of Example 9 (75 mg, 0.32 mmol) and triethylamine (27 mg, 0.35 mmol) in anhydrous toluene (1.0 mL) was stirred at room temperature for 15 minutes. A solution of diphenylphosphoryl azide (75 mg, 0.356 mmol) in toluene was added via pipette. The resulting mixture was heated at 80°C for 2 hours, then cooled. N- propylamine (75 μL, 0.912 mmol) was added and the mixture was stirred overnight. Aqueous citric acid (2 mL) was added and the aqueous phase was extracted in ethyl acetate. The combined organic layers were dried (sodium sulfate), concentrated and the residue was purified by radial chromatography (1 mm, 93/7, methylene chloride/methanol) to afford the carbamate urea (25.2 mg, 21%) after recrystallization from hot ethyl acetate. MS (electron spray) 366.1 (M+Hf. 1H-NMR (CDCI3, 300 MHz) δ 0.89 (t, 3H), 1.26-1.60 (overlapping signals, including a singlet centered at δ 1.37, 12H), 1.26-1.86 (m, 4H), 2.29- 2.46 (m, 2H), 2.51-2.66 (m, 2H), 3.17 (q, 2H), 3.37-3.41 (m, 2H), 4.0-4.11 (m, 2H), 5.06 (t, 1H), 5.57 (br s, 1H), 6.37 (br s, 1H).
A solution of carbamate (23.8mg, 0.0651 mmol) and trifluoroacetic acid (223 mg, 1.95 mmol) in dry methylene chloride (1.1 mL) was stirred at room temperature for 7 hours. The mixture was concentrated under high vacuum to afford Example 16 (quantitative). MS (electron spray) 266.2 (M+H)+; 1H-NMR (CDCI3, 300 MHz) δ: 0.91 (t, 3H), 1.40-1.60 (m, 2H), 1.66-1.91 (m's, 4H), 2.31-2.71 (m's, 4H), 3.14 (t, 2H), 3.51 (m, 2H), 4.54 (m, 2H), 8.49 (br s, 2H), 9.03 (brs, 1H), 11.46 (br s, 1H).
Example 17
Figure imgf000028_0001
Step 1. Methyl iodide (69 mg, 0.48 mmol) was added to a suspension of Example 9 (50 mg, 0.162 mmol) and cesium carbonate (105 mg, 0.323 mmol) in dry dimethylformamide (1.6 mL). The mixture was stirred at room temperature for 17 h. Water and ethyl acetate were added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine, dried (sodium sulfate) and concentrated. The crude material was purified by radial chromatography (1 mm, 6/4 hexane/ethyl acetate) to afford the carbamate methyl ester as a white solid. MS (electron spray) 323.9 (M+H)+ ; 1H-NMR (CDCI3, 300 MHz) δ: 1.66-1.86 (m, 4H), 2.51-2.80 (m, 4H), 3.40-3.60 (m, 2H), 3.86 (s, 3H), 4.71-4.88 (t, 3H), 8.17 (br s, 2H), 9.11 (br s, 1 H).
Step 2. A solution of trifluoroacetic acid (592 mg, 5.19 mmol) and carbamate in methylene chloride (0.81 mL) was stirred at room temperature for 4h. The mixture was concentrated under high vacuum to afford Example 17 (44 mg, 80% over two steps). MS (electron spray) 224.1 (M+H)+; 1H-NMR (CDCI3, 300 MHz) δ: 1.66-1.86 (m, 4H), 2.51-2.80 (m, 4H), 3.40- 3.60 (m, 2H), 3.86 (s, 3H), 4.71-4.88 (m, 2H), 8.17 (br s, 2H).
Example 18
Figure imgf000029_0001
1 ,8-diazabicyclo[4.3.0]non-5-ene (0.89 mL, 5.9 mmol) was added to a solution of Example 13 (0.59 mmol) in tetrahydrofuran (6.0 mL) and the resulting mixture was stirred for 27 hours. The reaction mixture was diluted with ethyl acetate (20 mL) and saturated aqueous ammonium chloride (20 mL). The layers were separated and the organic layer was washed with saturated aqueous ammonium chloride and brine. The organic layer was dried (sodium sulfate) and concentrated to give Example 18 as a white solid which was used in the next step without further purification. MS (electron spray) 192.3 (M+H)+; 1H-NMR (CDC , 300 MHz) δ: 1.6-1.9 (m's, 4H), 2.65 (m, 2H), 2.75 (m, 2H), 3.7.(m, 2H), 4.3 (m, 2H), 5.8 (br s, 1H).
Example 19
Figure imgf000029_0002
Lithium aluminum hydride (0.44 mmol, 0.44 mL) in tetrahydrofuran (1.0 M) was added to a room temperature suspension of Example 18 in dry tetrahydrofuran (2.6 mL), causing rapid degassing. The mixture was warmed to reflux and stirred for 70 min. The mixture was cooled and water was added (0.5 mL). Sodium sulfate was added, the solids were filtered and the filtrate was concentrated to give a solid which was purified by radial chromatography (1 mm plate, 85/15 MeOH) to afford product (30.9 mg, 29% over 3 steps). mp 117-119°C; MS (electron spray) 178.2 (M+H)+; 1H-NMR (CDCI3, 300 MHz): 1.6-1.8 (m,
4H), 2.29-2.40 (m, 2H), 2.41-2.65 (m, 2H), 3.2 (t, 2H), 3.9 (s, 2H), 4.1 (t, 2H). Example' 20
Figure imgf000030_0001
A solution of methyl 2-{2-[(te/τf-butoxycarbonyi)amino]ethyl}-4,5,6,7-tetrahydro-2H-indazole- 3-carboxylate (14.1 g, 41.7 mmol) (prepared in a manner similar to that described for the corresponding ethyl ester) in anhydrous tetrahydrofuran (25 mL) was added dropwise to a 1M solution of lithium aluminum hydride in tetrahydrofuran (125 mL, 125 mmol) at 0°C under argon. After the addition, the mixture was stirred at room temperature for 1 hour. Celite (200 mg) was added, followed by the careful addition of water (0.2 mL), 1N sodium hydroxide (0.4 mL), and water (0.6 mL) at 0°C. The mixture was stirred for 1 hour, then the solids were filtered and washed with ethyl acetate (30 mL). The filtrate was concentrated to give Example 20, terf-butyl 2[3-(hydroxymethyl)-4,5,6,7-tetrahydro-2 -/-indazol-2- yljethylcarbamate (12.1 g, 41.0 mmol, 98%). 1H-NMR (300 MHz, CDCI3) δ 5.18-5.09 (m, 1H), 4.52 (s, 2H), 4.19-4.11 (m, 2H), 3.60-3.49 (m, 2H), 2.60-2.52 (t, 2H), 2.48-2.40 (t, 2H), 1.78-1.62 (m, 4H), 1.36 (s, 9H).
Example 21
Figure imgf000030_0002
To a solution of phosphorous tri-bromide (0.66 mL, 6.91 mmol) in dichloromethane (5 mL) was added a solution of pyridine (0.11 mL) in dichloromethane (5 mL). The mixture was added to a solution of Example 20 (4.07 g, 13.8 mmol) and pyridine (0.28 mL) in dichloromethane (55 mL) at -5°C under argon. The reaction was then stirred at room temperature for 16 hours. The reaction mixture was washed with water (100 mL) and dried with magnesium sulfate. The organic phase was concentrated to yield Example 21 , tert- butyl-2-[3-(bromomethyl)-4,5,6,7-tetrahydro-2 --indazol-2-yl]-ethylcarbamate (4.19 g, 11.7 mmol, 85% yield). The product was used in the next step without further purification. 1H- NMR (300 MHz, CDCI3) δ 5.18-5.00 (m, 1 H), 4.41 (s, 2H), 4.21-4.13 (m, 2H), 3.65-3.52 (m, 2H), 2.68-2.58 (t, 2H), 2.51-2.43. (t, 2H), 1.81-1.71 (m, 4H), 1.36 (s, 9H).
Example 22
Figure imgf000031_0001
Example 21 (281 mg, 0.78 mmol), dimethylamine hydrochloride (319 mg, 3.9 mmol), and potassium carbonate (1.09 g, 7.83 mmol) in tetrahydrofuran (15 mL) was refluxed for 12 hours. The reaction mixture was cooled and poured into diethyl ether/water (1 :1, 80 mL). The layers were separated and the organic phase was dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified (Biotage, 10% methanol in ethyl acetate) to afford the carbamate (108 mg, 43%). The product was dissolved in dichloromethane (2 mL), followed by dropwise addition of trifluoroacetic acid (0.26 mL, 3.35 mmol). The solution stirred for 1 hour and concentrated to give 22. Trituration with diethyl ether (5 mL) gave pure 22 as a powder (189 mg, 0.34 mmol, quantitative). MS (Electronspray) 223 (M+H)4 1H-NMR (300 MHz, CDCI3) δ 4.48-4.39 (m, 4H), 3.48-3.41 (m, 2H), 2.95-2.88 (s, 6H), 2.71-2.64 (t, 2H), 2.61-2.55 (t, 2H), 1.91-1.4 (m, 4H).
Compounds 23 - 62 in Table 1 below were synthesized by the preparative methods described 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
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Description of Method of Use
The compounds of Formulas (I), (la), (II) and (Ila) interact with the 5-HT2c 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-HT1A, 5-HT-IB, 5-HT^, and 5-HT2C) subtypes of 5-HT receptors has been demonstrated to elicit effects on food intake, the best data available to date suggests that 5-HT2c 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 δ-HT^ and 5-HT2C receptors decrease food intake. However, while the 5- HT2c receptor has been implicated in the regulation of satiety, 5-HT2A 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-HT2c 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-HT2c knockout mice; and
(b) antagonized by the 5-HT2C receptor antagonist SB-242084 in rats, suggests that it decreases food intake via an agonist action at the 5-HT2c receptor. Therefore, both animal and human data strongly implicate the involvement of the 5-HT2C receptor in satiety.
Antagonist studies have shown that the selective 5-HT2c 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-HT-ι receptors, a crucial role for the 5-HT2 receptors in the anorectic action of dexfenfluramine in humans is suggested.
The importance of the 5-HT2c receptor in mediating feeding behavior is further supported by studies on mutant 5-HT2c-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-HT2c 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-HT2C receptor knockout mice was enhanced by access to a sweet diet, suggesting that the 5-HT2c 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-HT2c 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 Formulas (I), (la), (II) and (Ila) can be determined by measurement of their binding affinity to the 5-HT2c 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 Formulas (I), (la), (II) and (Ila) on the 5-HT2C receptor: AV-12 cell pellets expressing 5-HT2c, 5-HT^ or 5-HT2B receptors are homogenized in binding buffer (50 mM Tris-HCI, 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: I of 125l-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-HCI, 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 Formulas (I), (la), (II) and (Ila) were tested in the above assays and were found to have an effect on 5-HT2C 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 the formula (I), (la), (II) or (Ila): (II) (Ila) wherein: dotted lines represent optional double bonds; R is selected from the group consisting of: (a) hydrogen, (b) (C-ι-C5)-alkyl optionally substituted with:
(b1) halogen,
(b2) hydroxy,
(b3) a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom,
(b4) a fused bicyclo ring wherein one ring is a four to eight membered heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atoms and said heterocyclic ring is optionally substituted with one to two oxo substituents, and the other ring is a saturated or unsaturated three to eight membered carbocyclic ring which is optionally substituted with (C1-C5)- alkyl, (b5) NR8R9,
(b6) SR10,
(c) (C C5)-alkyloxy,
(d) (CrCgJ-alkyloxy- CrCi -alkyl,
(e) C(=O)R7, (f) C(=O)OR7,
(g) (C3-C8)-cycloalkyl,
(h) (C6-Ci0)-aryl- optionally substituted with halogen,
(i) (C6-Cιo)-aryl-Cι-C5-alkyl wherein the (C6-Cι0)-aryl is optionally substituted with halogen, (j) (C6-C10)-aryloxy,
(k) (C6-C-ιo)-aryloxy-CrC5-alkyl wherein the (C6-C10)-aryloxy is optionally substituted with halogen,
(I) (C6-C1o)-aryl-(C1-C5)-alkoxy-(C1-C5)-alkyl,
(m) a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and
(n) -NR8R9 ; or R forms a six to eight membered saturated heterocyclic ring with the -NH2 of the ethylamino chain attached to the 1 -position of the pyrazole ring, wherein the nitrogen from said -NH2 is the only heteroatom of the heterocyclic ring and the heterocyclic ring is optionally substituted with one oxo group;
Ri and R2are independently selected from the group consisting of: (a) hydrogen,
(b) hydroxy,
(c) oxo,
(d) (C C5)-alkyl,
(e) (C C5)-dialkyl,
(f) C(=O)R7,
(g) C(=O)OR7,
(h) C(=O)NR5R6; (i) (C6-C10)-aryl, and
(1) (C6-C10)-aryl-(C1-C5)-alkyl or
R-i and R2 together with the carbon atoms to which they are attached form an additional (C3-C8)-saturated cycloalkyl ring, or
R-i and R2 together with the carbon atoms to which they are attached form a bridged cycloalkyl ring to which a further (C3-C8) saturated cycloalkyl ring may be fused, or
R-i and R2 together form a four to eight membered heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom wherein said heterocyclic ring is optionally substituted with (CrC5)-alkyl;
R3 and R4 are independently selected from the group consisting of
(a) hydrogen,
(b) (C C5)-alkyl, and (c) (C-ι-C5)-dialkyl; or
R3 is (C C5)-alkyl and R4 is oxo; or R3 forms a five to eight membered saturated heterocyclic ring with the -NH2 of the ethylamino chain attached to the 1 -position of the pyrazole, wherein the nitrogen from said -NH2 is the only heteroatom of the heterocyclic ring, and R is hydrogen;
R5 and R6 are independently selected from the group consisting of
(a) hydrogen,
(b) (C C5)-alkyl,
(c) (C3-C8)-cycloalkyl, (d) (C6-Cιo)-aryl, and
(e) (C6-C10)-aryl-(C1-C5)-alkyl; R is selected from the group consisting of hydrogen and (CrC5)-alkyl; R8 and R9are independently selected from the group consisting of:
(a) hydrogen, (b) C(=O)R7,
(c) C(=O)OR7, and
(d) C(=O)NR5R6 ;
R-io is selected from the group consisting of
(a) (C6-C10)-aryl optionally substituted with one to three substituents selected from the group consisting of halogen, (C C5)-alkoxy and
(C-|-C5)-alkyl optionally substituted with halogen, and
(b) a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom wherein said heterocyclic ring is optionally substituted with one to three substituents selected from the group consisting of halogen, (C-i-C5)-alkoxy and (C C5)-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 compound of claim 1 having the formula (I) or (II)
Figure imgf000052_0001
(I) (II) wherein: dotted lines represent optional double bonds;
R is selected from the group consisting of:
(a) hydrogen,
(b) (C-|-C5)-alkyl optionally substituted with:
(b1) a four to eight membered saturated or unsaturated heterocyclic ring which contains one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, wherein said heterocyclic ring contains at least one carbon atom, and
(c) (C6-C10)-aryloxy;
Ri and R2 are independently selected from the group consisting of:
(a) hydrogen,
(b) (C C5)-alkyl, and
(c) (C C5)-dialkyl, or
Ri and R2 together with the carbon atoms to which they are attached form an additional (C3-C8)-saturated cycloalkyl ring; or R-i and R2 together with the carbon atoms to which they are attached form a bridged cycloalkyl ring to which a further (C3-C8) saturated cycloalkyl ring may be fused;
R3 and R are independently selected from the group consisting of
(a) hydrogen, and
(b) (C C5)-alkyl.
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 an additional pharmaceutical agent other than said compound of claim 1 for the treatment or prevention a disease and/or behavior involving the 5-HT2c receptor.
5. The pharmaceutical composition of claim 4 wherein said additional 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 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 4 wherein said agent(s) for treating obesity related disorders are 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-HT c 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-HT2c 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.
PCT/US2002/041637 2001-12-28 2002-12-28 Cyclohexano- and cycloheptapyrazole derivative compounds, for use in diseases associated with the 5-ht2c receptor WO2003057213A2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002360819A AU2002360819A1 (en) 2001-12-28 2002-12-28 Cyclohexano- and cycloheptapyrazole derivative compounds, for use in diseases associated with the 5-ht2c receptor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US34415001P 2001-12-28 2001-12-28
US60/344,150 2001-12-28

Publications (2)

Publication Number Publication Date
WO2003057213A2 true WO2003057213A2 (en) 2003-07-17
WO2003057213A3 WO2003057213A3 (en) 2004-02-19

Family

ID=23349268

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2002/041637 WO2003057213A2 (en) 2001-12-28 2002-12-28 Cyclohexano- and cycloheptapyrazole derivative compounds, for use in diseases associated with the 5-ht2c receptor

Country Status (2)

Country Link
AU (1) AU2002360819A1 (en)
WO (1) WO2003057213A2 (en)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007132841A1 (en) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and use thereof
US7446118B2 (en) 2005-11-30 2008-11-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and aza-substituted indoles and uses thereof
WO2009063992A1 (en) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Condensed pyridine derivative and use thereof
US7638517B2 (en) 2005-11-30 2009-12-29 Roche Palo Alto Llc 3-Amino-1-arylpropyl azaindoles and uses thereof
JP2010509201A (en) * 2006-11-03 2010-03-25 グレンマーク・ファーマシューティカルズ・エスエー Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and methods for their preparation
EP2248524A2 (en) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Preventives/remedies for stress urinary incontinence and method of screening the same
EP2277513A2 (en) 2003-04-25 2011-01-26 Pfizer Inc. Treatment of incontinence with 5htc2 agonists
US7897595B2 (en) 2006-05-26 2011-03-01 Forest Laboratories Holdings Limited Pyridoazepine derivatives
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
WO2011071136A1 (en) 2009-12-11 2011-06-16 アステラス製薬株式会社 Therapeutic agent for fibromyalgia
WO2011124430A1 (en) * 2010-04-08 2011-10-13 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Tricyclic indazole compound, method of preparation and pharmaceutical composition containing it
JP4839377B2 (en) * 2005-08-31 2011-12-21 エフ．ホフマン−ラ ロシュ アーゲー 11-β-hydroxysteroid dehydrogenase-1-inhibitor 2-1 type diabetes
WO2019131902A1 (en) 2017-12-27 2019-07-04 武田薬品工業株式会社 Therapeutic agent for stress urinary incontinence and fecal incontinence

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998030548A1 (en) * 1997-01-13 1998-07-16 Yamanouchi Pharmaceutical Co., Ltd. 5-HT2c RECEPTOR AGONISTS AND AMINOALKYLINDAZOLE DERIVATIVES
WO2000012481A2 (en) * 1998-09-01 2000-03-09 Vernalis Research Limited Indazole derivatives with 5-ht2 receptor activity________________
EP0990650A1 (en) * 1997-06-13 2000-04-05 Yamanouchi Pharmaceutical Co. Ltd. Tricyclic pyrrole or pyrazole derivatives
WO2001070702A1 (en) * 2000-03-17 2001-09-27 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
WO2001083487A1 (en) * 2000-04-28 2001-11-08 Yamanouchi Pharmaceutical Co., Ltd. Froindazole derivative
WO2002098350A2 (en) * 2001-06-01 2002-12-12 Alcon, Inc. Pyranoindazoles and their use for the treatment of glaucoma

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998030548A1 (en) * 1997-01-13 1998-07-16 Yamanouchi Pharmaceutical Co., Ltd. 5-HT2c RECEPTOR AGONISTS AND AMINOALKYLINDAZOLE DERIVATIVES
EP0990650A1 (en) * 1997-06-13 2000-04-05 Yamanouchi Pharmaceutical Co. Ltd. Tricyclic pyrrole or pyrazole derivatives
WO2000012481A2 (en) * 1998-09-01 2000-03-09 Vernalis Research Limited Indazole derivatives with 5-ht2 receptor activity________________
WO2001070702A1 (en) * 2000-03-17 2001-09-27 Alcon, Inc. 6-hydroxy-indazole derivatives for treating glaucoma
WO2001083487A1 (en) * 2000-04-28 2001-11-08 Yamanouchi Pharmaceutical Co., Ltd. Froindazole derivative
WO2002098350A2 (en) * 2001-06-01 2002-12-12 Alcon, Inc. Pyranoindazoles and their use for the treatment of glaucoma

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
AINSWORTH ET AL.: "Substituted Aminoethylindazoles" JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 80, 1958, pages 965-967, XP002237633 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2277513A2 (en) 2003-04-25 2011-01-26 Pfizer Inc. Treatment of incontinence with 5htc2 agonists
EP2305352A1 (en) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. 5-alpha-reductase inhibitors for use in the treatment of men with metabolic and anthropometric disorders
EP2248524A2 (en) 2004-08-25 2010-11-10 Takeda Pharmaceutical Company Limited Preventives/remedies for stress urinary incontinence and method of screening the same
EP2400300A1 (en) 2004-08-25 2011-12-28 Takeda Pharmaceutical Company Limited Method of screening preventives/remedies for stress urinary incontinence
JP4839377B2 (en) * 2005-08-31 2011-12-21 エフ．ホフマン−ラ ロシュ アーゲー 11-β-hydroxysteroid dehydrogenase-1-inhibitor 2-1 type diabetes
US7638517B2 (en) 2005-11-30 2009-12-29 Roche Palo Alto Llc 3-Amino-1-arylpropyl azaindoles and uses thereof
US7446118B2 (en) 2005-11-30 2008-11-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and aza-substituted indoles and uses thereof
US7803830B2 (en) 2005-11-30 2010-09-28 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and AZA-substituted indoles and uses thereof
EP2727585A1 (en) 2006-05-16 2014-05-07 Takeda Pharmaceutical Company Limited In-vivo screening method
WO2007132841A1 (en) 2006-05-16 2007-11-22 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and use thereof
EP2742936A1 (en) 2006-05-16 2014-06-18 Takeda Pharmaceutical Company Limited Fused heterocyclic compound and use thereof
US7897595B2 (en) 2006-05-26 2011-03-01 Forest Laboratories Holdings Limited Pyridoazepine derivatives
JP2010509201A (en) * 2006-11-03 2010-03-25 グレンマーク・ファーマシューティカルズ・エスエー Novel cannabinoid receptor ligands, pharmaceutical compositions containing them, and methods for their preparation
WO2009063992A1 (en) 2007-11-15 2009-05-22 Takeda Pharmaceutical Company Limited Condensed pyridine derivative and use thereof
EP2789338A2 (en) 2007-11-15 2014-10-15 Takeda Pharmaceutical Company Limited Condensed pyridine derivate and use thereof
WO2011071136A1 (en) 2009-12-11 2011-06-16 アステラス製薬株式会社 Therapeutic agent for fibromyalgia
JP2013523790A (en) * 2010-04-08 2013-06-17 アジェンデ・キミケ・リウニテ・アンジェリニ・フランチェスコ・ア・チ・エレ・ア・エフェ・ソシエタ・ペル・アチオニ Tricyclic indazole compound, preparation method thereof and pharmaceutical composition containing the same
CN102812028A (en) * 2010-04-08 2012-12-05 方济各安吉利克化学联合股份有限公司 Tricyclic indazole compound, method of preparation and pharmaceutical composition containing it
WO2011124430A1 (en) * 2010-04-08 2011-10-13 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Tricyclic indazole compound, method of preparation and pharmaceutical composition containing it
CN102812028B (en) * 2010-04-08 2014-11-12 方济各安吉利克化学联合股份有限公司 Tricyclic indazole compound, method of preparation and pharmaceutical composition containing it
EA021417B1 (en) * 2010-04-08 2015-06-30 Ацьенде Кимике Рьюните Анджелини Франческо А.К.Р.А.Ф. С.П.А. Tricyclic indazole compound, method of preparation and pharmaceutical composition containing it
US9120801B2 (en) 2010-04-08 2015-09-01 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Tricyclic indazole compound, method of preparation and pharmaceutical composition containing it
AU2011238054B2 (en) * 2010-04-08 2016-06-23 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Tricyclic indazole compound, method of preparation and pharmaceutical composition containing it
US9655906B2 (en) 2010-04-08 2017-05-23 Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. S.P.A. Tricyclic indazole compound, method of preparation and pharmaceutical composition containing it
WO2019131902A1 (en) 2017-12-27 2019-07-04 武田薬品工業株式会社 Therapeutic agent for stress urinary incontinence and fecal incontinence

Also Published As

Publication number Publication date
AU2002360819A8 (en) 2003-07-24
WO2003057213A3 (en) 2004-02-19
AU2002360819A1 (en) 2003-07-24

Similar Documents

Publication Publication Date Title
EP0731802B1 (en) N-substituted azabicycloalkane derivatives as neuroleptics etc.
AU662960B2 (en) N-sulphonyl-2-oxoindole derivatives having affinity for vasopressin and/or ocytocin receptors
JP5139307B2 (en) Prolinamide derivatives as sodium channel modulators
EP0923581B1 (en) 4-substituted beta-carbolines as immunomodulators
JP5384659B2 (en) Alkylcyclohexyl ether of dihydrotetraazabenzoazulene
JP2010518026A (en) Pyridopyrimidinone compounds useful for the treatment of diseases or conditions mediated by sodium channels
JPH08333363A (en) Indole derivative
BRPI0617166A2 (en) 5-amino-4-hydroxy-7- (imidazo [1,2-a] pyridin-6-ylmethyl) -8-methyl-nonamidia derivatives and related compounds as renin inhibitors for the treatment of hypertension
ZA200603181B (en) 3-(4-aminophenyl) thienopyrimid-4-one derivatives as MCH R1 antagonists for the treatment of obesity, diabetes, depression and anxiety
US5300512A (en) Benzimidazole compounds
WO2003057161A2 (en) 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
US7928099B2 (en) Pyrimido [4,5-D] azepine derivatives as 5-HT2c agonists
WO2003057213A2 (en) Cyclohexano- and cycloheptapyrazole derivative compounds, for use in diseases associated with the 5-ht2c receptor
JPWO2007032371A1 (en) Oxindole derivatives as feeding regulators
WO2006044762A2 (en) Tetrahydro-5h-pyrimido[4,5-d]azepine derivatives useful for the treatment of diseases associated with the 5-ht2c receptor
JP2024501641A (en) Substituted Macrocycles and Related Treatment Methods
US20060128781A1 (en) Flavaxate derivatives as muscarinic receptor antagonists
JP2023554282A (en) SUBSTITUTED PIPERIDINO COMPOUNDS AND RELATED TREATMENT METHODS
US5521193A (en) Benzimidazole compounds
JPWO2007007890A1 (en) N-dihydroxyalkyl-substituted 2-oxoimidazole derivatives
US5534521A (en) Benzimidazole compounds
JP2006525309A (en) Pyrrolo (1,2-b) pyridazine compounds and their use as CRF-1 receptor antagonists
WO2009034028A2 (en) Novel compounds
US20090176836A1 (en) Cyclic Ketal Beta-Secretase Inhibitors for the Treatment of Alzheimer's Disease
US8828989B2 (en) Oxy-cyclohexyl-4H,6H-5-oxa-2,3,10b-triaza-benzo[E]azulenes as V1A antagonists

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SC SD SE SG SK SL TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR IE IT LU MC NL PT SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP

DPE2 Request for preliminary examination filed before expiration of 19th month from priority date (pct application filed from 20040101)