Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/52—Purines, e.g. adenine
  • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/22—Anxiolytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/24—Antidepressants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P5/00—Drugs for disorders of the endocrine system

Definitions

• MCH Melanin Concentrating Hormone Receptor- 1
• MCH mRNA is upregulated both in hyperphagic obese mice (ob/ob), and fasted animals.
• Targeted disruption of the gene for MCH peptide results in hypophagia and leanness.
• Disruption of the MCHRl gene causes leanness, altered metabolism, and hyperlocomotion accompanied by mild hyperphagia.
• over-expression of MCH peptide results in hyperphagia, obesity and diabetes.
• Small molecule MCHRl antagonists have been shown to cause weight loss in rodent weight and feeding models after both oral and intraperitoneal administration; Eur. J. Pharmacol., 438, 129-135, 2002, Nat. Med., 8, 825-830, 2002, Eur. J. Pharmacol, 497, 41-47, 2004.
• MCHRl antagonists Numerous non-peptide MCHRl antagonists have been disclosed. The scope of the genus for each reflects a common perception regarding the criteria required for ligand recognition as MCHRl agonists. A recent review of MCHRl patent disclosures emphasized the commonality of these structures by the following description; " Ubiquitous throughout the MCH patent literature are molecules consisting of a central scaffold to which linkers to an aryl or heteroaryl group and a basic amino functionality are attached" (T. J. Kowalski and M. D. MacBriar, Expert Opin. t ⁇ vestig. Drugs 13, 1113 - 1122, 2004).
• the present application provides compounds, including all stereoisomers, solvates, prodrugs and pharmaceutically acceptable forms thereof according to Formulae I and II. Additionally, the present application provides pharmaceutical compositions containing at least one compound according to Formula I or II and optionally at least one additional therapeutic agent. Finally, the present application provides methods for treating a patient suffering from an MCHR-I modulated disease or disorder such as, for example, obesity, diabetes, depression or anxiety by administration of a therapeutically effective dose of a compound according to Formula I or II:
• R 1 is independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, aryl, CF 3 , CN, NR 7 R 7 , OR 6 and SR 6 ;
• R 2 is selected from the group consisting of hydrogen and lower alkyl
• R J is independently selected from the group consisting of hydrogen, halogen, lower alkyl
• R 4 is selected from the group consisting of hydroxyl or G-D 2 -Z n , wherein R 4 and R 5 may be taken together to form a ring of 4 to 7 atoms;
• R 5 is selected from the group consisting of hydrogen, hydroxyl, halogen, lower alkyl, lower cycloalkyl, CF 3 , SR 6 , lower alkoxy, lower cycloalkoxy, CN, CONR 7 R 7 , SOR 6 , SO 2 R 6 , NR 7 COR 7 , NR 7 CO 2 R 7 , CO 2 R 6 , heteroaryl, NR 7 SO 2 R 6 and COR 6 ;
• m is an integer from O to 1 ;
• n is an integer from 1 to 3;
• G is selected from the group consisting of a direct bond, O, S and CR 7 R 7 ;
• D 2 is selected from the group consisting of a direct bond, lower alkyl, lower cycloalkyl and a 4 to 6-membered non-basic heterocycle;
• Z is selected from the group consisting of hydrogen, halogen, hydroxyl, lower alkoxy, lower cycloalkyl, lower cycloalkoxy, OCOR 6 , OCONR 7 R 7 , CN, CONR 7 R 7 , OSO 2 R 6 , SR 6 , SOR 6 , SO 2 R 6 , NR 7 COR 7 , NR 7 CONR 7 R 7 , NR 7 CO 2 R 7 , CO 2 R 7 , heterocycle, heteroaryl, OPO(OR 6 ) 2 , NR 7 SO 2 R 6 and COR 6 ;
• R 6 is independently selected from the group consisting of lower alkyl, lower cycloalkyl, heterocycle and heteroaryl;
• R 7 is independently selected from the group consisting of hydrogen, lower alkyl, lower cycloalkyl and heterocycle, wherein two R 7 and the atom to which they are attached may optionally form a ring of 4 to 7 atoms;
• A is selected from the group consisting of phenyl and a monocyclic heteroaryl
• D is selected from the group consisting of CH 2 and a direct bond
• R 1 is independently selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, CF 3 , OR 6 and SR 6 ;
• R 2 is selected from the group consisting of hydrogen and lower alkyl
• R 4 is selected from the group consisting of hydroxyl or G-D 2 -Z n
• n is an integer from 1 to 3;
• R 5 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower cycloalkyl, CF 3 , SR 6 , lower alkoxy, lower cycloalkoxy, CN, CONR 7 R 7 , SOR 6 , SO 2 R 6 , NR 7 COR 7 , NR 7 CO 2 R 7 , CO 2 R 6 , heteroaryl, NR 7 SO 2 R 6 and COR 6 ;
• G is selected from the group consisting of O, S and CR 7 R 7 ;
• D 2 is selected from the group consisting of a direct bond, lower alkyl, lower cycloalkyl and a 4 to 6-membered non-basic heterocycle;
• Z is selected from the group consisting of hydrogen, hydroxyl, lower alkoxy, lower cycloalkoxy, OCONR 7 R 7 , CN, CONR 7 R 7 , SOR 6 , SO 2 R 6 , NR 7 COR 7 , NR 7 CO 2 R 7 , CO 2 R 6 , heteroaryl, NR 6 SO 2 R 6 and COR 6 ;
• R 6 is independently selected from the group consisting of lower alkyl and lower cycloalkyl
• R 7 is independently selected from the group consisting of hydrogen, lower alkyl and lower cycloalkyl, wherein two R 7 and the atom to which they are attached may optionally form a ring of 4 to 7 atoms.
• lower alkyl as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing 1 to 8 carbons
• alkyl and alk as employed herein alone or as part of another group includes both straight and branched chain hydrocarbons containing.1 to 20 carbons, preferably 1 to 10 carbons, more preferably 1 to 8 carbons, in the normal chain, such as methyl, ethyl, propyl, isopropyl, butyl, t- butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4- trimethylpentyl, nonyl, decyl, undecyl, dodecyl, the various branched chain isomers thereof, and the like as well as such groups including 1 to 4 substituents such as hal
• cycloalkyl as employed herein alone or as part of another group includes saturated or partially unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon groups containing 1 to 3 rings, any one of which may optionally be a spiro substituted cycolalkyl, including monocyclicalkyl, bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20 carbons forming the rings, preferably 3 to 10 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryl, which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl and cyclododecyl, cyclohexenyl,
• any of which groups maybe optionally substituted with 1 to 4 substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and/or alkylthio and/or any of the alkyl substituents.
• substituents such as halogen, alkyl, alkoxy, hydroxy, aryl, aryloxy, arylalkyl, cycloalkyl, alkylamido, alkanoylamino, oxo, acyl, arylcarbonylamino, nitro, cyano, thiol and/or alkylthio and/or any of the alkyl substituents.
• heterocyclo represents an unsubstituted or substituted stable 4 to 7- membered monocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms, with one to four heteroatoms selected from nitrogen, oxygen or sulfur, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
• the heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure.
• heterocyclic groups include, but is not limited to, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopyrrolidinyl, oxoazepinyl, azepinyl, pyrrolyl, pyrrolidinyl, furanyl, thienyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isooxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, thiadiazolyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl,
• alkanoyl as used herein alone or as part of another group refers to alkyl linked to a carbonyl group.
• halogen or "halo” as used herein alone or as part of another group refers to chlorine, bromine, fluorine, and iodine, with chlorine or fluorine being preferred.
• metal ion refers to alkali metal ions such as sodium, potassium or lithium and alkaline earth metal ions such as magnesium and calcium, as well as zinc and aluminum.
• aryl or “Aryl” as employed herein alone or as part of another group refers to monocyclic and bicyclic aromatic groups containing 6 to 10 carbons in the ring portion (such as phenyl or naphthyl including 1- naphthyl and 2-naphthyl) and may optionally include one to three additional rings fused to a carbocyclic ring or a heterocyclic ring (such as aryl, cycloalkyl, heteroaryl or cycloheteroalkyl rings for example
• heteroaryl refers to a 5- or 6- membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms such as nitrogen, oxygen or sulfur. Such rings may be fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl and include possible N-oxides as described in Katritzky, A. R. and Rees, C. W., eds. Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Uses of Heterocyclic Compounds 1984, Pergamon Press, New York, NY; and Katritzky, A. R., Rees, C. W., Scriven, E.
• heteroaryl as defined herein, may optionally be substituted with one or more substituents such as the substituents included above in the definition of "substituted alkyl” and “substituted aryl".
• substituents include the following:
• lower alkoxy As employed herein alone or as part of another group includes any of the above alkyl, aralkyl or aryl groups linked to an oxygen atom.
• lower alkylthio alkylthio
• alkylthio alkylthio
• arylthio aralkylthio
• polyhaloalkyl refers to an "alkyl” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF 3 CH 2 , CF 3 or CF 3 CF 2 CH 2 .
• halo substituents such as F or Cl
• preferably F such as CF 3 CH 2 , CF 3 or CF 3 CF 2 CH 2 .
• polyhaloalkyloxy refers to an "alkoxy" or “alkyloxy” group as defined above which includes from 2 to 9, preferably from 2 to 5, halo substituents, such as F or Cl, preferably F, such as CF 3 CH 2 O, CF 3 O or CF 3 CF 2 CH 2 O.
• Ph phenyl
• TBS tert-butyldimethylsilyl
• THF tetrahydrofuran
• NaBH 4 sodium borohydride n-BuLi - n-butyllithium
• NaHCO 3 sodium bicarbonate
• Ar argon
• HPLC high performance liquid chromatography
• LC/MS high performance liquid chromatography/mass spectrometry
• compounds of formula I may be prepared by either condensing compounds of formula 2 with compounds of formula 3 to generate the thiophenopyrimidone central bicyclic moiety in situ or via alkylation/arylation of compounds of formula 18 with alkylating agents of formula 19 or arylating agents such as borates of formula 24.
• R 4 can either be fully completed or elaborated after assemblage of the core structure of formula I.
• compounds of formula I may be prepared by condensing compounds of formula 2 with compounds of formula 3 in a solvent such as hot EtOH (Scheme 2).
• Compounds of formula 2 can be prepared as described in WO2003/033476 by heating compounds of formula 4 with dimethylformamide dimethyl acetal. Preparation of compounds of formula 4 is described in WO 1998/49899.
• Amines of formula 3 for which D is a bond may be prepared by reduction of nitro aromatics of formula 5 either by catalytic hydrogenation using a catalyst such as Pd/C in a solvent such as EtOH or by reduction with SnCl 2 in a solvent such EtOAc.
• compounds of formula 5 can be prepared by heating alkali metal salts of compounds of formula 6 with epoxides of formula 7a thermally or preferably by microwave in a solvent such as 15% H 2 OZMeCN containing NaH 2 PO 4 .
• Compounds of formula 5 can be also prepared by heating compounds of formula 8 with preformed sodium salts of compounds of formula 9 in a solvent such as DMF.
• Compounds of formula 6 and 8 are either commercially available or can be readily prepared in the case of formula 6 from the corresponding un-nitrated phenol by sequential acylation, nitration or sulfonalation using methods known to those skilled in the arts
• Compounds of formula 5 ' can be prepared by derivitization of amines of formula 9 or alcohols of formula 10 employing procedures readily known to those skilled in the art.
• Amines of formula 9 and alcohols of formula 10 can be prepared by BH 3 mediated reduction of amides and acids respectively of formula 11 in a solvent such as THF.
• Compounds of formula 11 can be prepared by nitration of commercially available aryl acetic and hydrocinnamic acids of formula 12 followed by conversion to the corresponding amide if appropriate.
• Compounds of formula 13 can be prepared by demethylation of compounds of formula 14 with a reagent such as BBr 3 in a solvent such as CH 2 Cl 2 .
• Compounds of formula 14 can be prepared by condensation of compounds of formula 15 with compounds of formula 2.
• Compounds of formula 15 which are not commercially available can be obtained reduction of aryl nitriles or primary carboxamides of formula 16 with a reducing agent such LiAlH 4 or BH 3 in a solvent such as THF.
• Compounds of formula 16 can be prepared from commercially available benzoic acids by procedures known to those skilled in the arts.
• SCHEME 4
• Aryl borates of formula 24 are commercially available or can be formed by treating commercially compounds of formula 25 either with n-BuLi in a solvent such as THF followed by sequential addition BCl 3 followed by MeOH or alternatively stirring 25 with borate 26 in the presence of a Pd catalyst.
• prodrug encompasses both the term “prodrug esters” and the term “prodrug ethers”.
• prodrug esters as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of formula I with either alkyl, alkoxy, or aryl substituted acylating agents or phosphorylating agent employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates, amino acid esters, phosphates and the like.
• Examples of such prodrug esters include
• prodrug ethers include both phosphate acetals and O- glucosides. Representative examples of such prodrug ethers include
• the compounds of formula I can be present as salts, which are also within the scope of this invention. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred. If the compounds of formula I have, for example, at least one basic center, they can form acid addition salts.
• organic carboxylic acids such as alkanecarboxylic acids of 1 to 4 carbon atoms, for example acetic acid, which are unsubstituted or substituted, for example, by halogen as chloroacetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic acid or lysine or arginine), or benzoic acid, or with organic sulfonic acids, such as (C 1 -C 4 ) alkyl or arylsulfonic acids which are unsubstituted or substituted, for example, by halogen as chloroacetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic,
• Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center.
• the compounds of formula I having at least one acid group can also form salts with bases.
• Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morpholine, thiomorpholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl, tert-butyl, diethyl, diisopropyl, triethyl, tributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower alkylamine, for example mono, di or triethanolamine.
• Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for example, for the isolation or purification of free compounds of formula I or their pharmaceutically acceptable salts, are also included.
• Preferred salts of the compounds of formula I which contain a basic group include monohydrochloride, hydrogensulfate, methanesulfonate, phosphate, nitrate or acetate.
• Preferred salts of the compounds of formula I which contain an acid group include sodium, potassium and magnesium salts and pharmaceutically acceptable organic amines.
• reaction was heated for 1 hr at 90 0 C.
• nitrated aryl ether was reduced to the desired aniline by 10% Pd/C catalyzed hydrogenation (50 psi H 2 ) in EtOH.
• Route B base promoted phenol alkylation entailed heating a mixture of the potassium or sodium salt of the nitrophenol with a alkyl halide in DMF for 2-4 hr at 90 °C. After isolation and purification by silica gel chromatography, the product was reduced to the desired aniline as previously described.
• Route C base promoted phenol alkylation
• routes A or B were not feasible.
• a concentrated suspension of the potassium or sodium salt of the phenol, NaH 2 PO 4 and the appropriate epoxide in 9:1 MeCN/H 2 O was heated to 120 -180 0 C for 30 - 90 minutes with a microwave or 1-8 hr in steel bomb.
• Buffering with NaH 2 PO 4 is essential to prevent reversion of the product to starting phenol as the pH increases during the reaction.
• Method 1 Phenomenex Luna Cl 8 S5 column 4.6 x 50 mm, 4 min gradient at 4 mL/min, 10% MeOH/90% H 2 O/0.2% H 3 PO 4 to 90% MeOH/10% H 2 O/0.2% H 3 PO 4 with 1 min hold at the end of the gradient.
• Method 2. YMC S5 Cl 8 4.6X50 mm column, 4 min gradient at 4 mL/min, 10% MeOH/90% H 2 O/0.2% H 3 PO 4 to 90% MeOH/10% H 2 O/0.2% H 3 PO 4 with 1 min hold at the end of the gradient.
• Method 4 Phenomenex S5 Cl 8 4.6X30 mm column, 2 min gradient at 4 mL/min, 10% MeCN/90% H 2 O/0.1% TFA to 90% MeCN/10% H 2 O/0.1% TFA with 1 min hold at the end of the gradient.
• Method 5. Phenomenex Luna Cl 8 S5 column 4.6 x 50 mm, 4 min gradient at
• TFA to 90% MeOH/10% H 2 O/0.1% TFA. On occasion, mixtures of 10% MeCN/90% H 2 O/0.1 % TFA and 90% MeCN/10% H 2 OA).1 % TFA were employed. If the molecule contained an acid sensitive component, the TFA was omitted.
• Mass spectral data were obtained using a Waters ZMD single quadrapole mass spectrometer.
• Typical conditions were Phenomenex reverse phase Cl 8 column 4.6 x 50 mm, 4 min gradient, 10% MeOH/90% H 2 O/0.1 % TFA to 90% MeOH/10% H 2 O/0.1 %
• N-(2-(4-amino-2- methoxyphenoxy)ethyl)pivalamide (316 mg, 1.2 mmol) was condensed with methyl 5-(4-chlorophenyl)-3-((dimethylamino)methyleneamino)thiophene-2-carboxylate (355 mg, 1.1 mmol) by heating an EtOH solution (3 mL) of the two components to reflux for 15 hr. Upon cooling and filtration, the title compound was isolated as a white solid.
• the title compound (560 mg) was obtained by filtering the solid that formed upon standing at 20 0 C after heating a mixture of tert-butyl 2-(4-amino-2- methoxyphenoxy)ethylcarbamate (700 mg) and methyl 5-(4-chlorophenyl)-3- ((dimethylamino)methyleneamino)thiophene-2-carboxylate (800 mg, 2.5 mmol) in EtOH (3 mL) at reflux for 15 hr.
• Solvent A 10/90 AcetonitrileAVater containing 0.1% TFA
• Solvent B 90/10 Acetonitrile/Water containing 0.1% TFA UV @ 22OnM; MS @ ESI+
• Solvent A 10/90 Methanol/Water containing 0.1% TFA
• Solvent B 90/10 Methanol/Water containing 0.1% TFA
• a steel bomb, fitted with an internal thermocouple, pressure gauge and safety release valve rated at 3000 psi, with ⁇ 55 mL capacity was charged with the potassium salt of 2-methoxy-4-nitrophenol (6g, 29 mrnol), NaH 2 PO 4 (3.3g, 27.7mmol), isobutylene oxide (2.8 g, 35 mmol) and 30 mL of 15% H 2 O/MeCN.
• the sealed bomb was heated at 170 °C for three hr. Following cooling, HPLC revealed all starting phenol had been converted to product.
• the biphasic solution was concentrated using a rotary evaporator before being partitioned between CH 2 Cl 2 and H 2 O.
• the aqueous phase was extracted 3x with CH 2 Cl 2 ; the combined CH 2 Cl 2 fractions were washed 3x with aq KHCO 3 /K 2 CO 3 and once with H 2 O. After drying over Na 2 SO 4 , concentration under vacuum yielded 6.9g of desired product as a tan solid.
• the mixture was transferred to a second flask containing 2-bromo-4-nitroanisole (1.29 g, 5.45 mmol) and tetrakis(triphenylphosphine)palladium (0) (187 mg, 0.16 mmol) in THF (8.0 mL). After heating at 60 °C for 14h, the reaction mixture was quenched with water (15 mL) and extracted with ether (3 x 40 mL). The combined organic extracts wee washed with 2MNaOH (3 x20 mL) and water (3 x 20 mL), dried (Na 2 SO 4 ) and concentrated.
• Part B compound 84.0 mg, 0.47 mmol
• potassium carbonate 195 mg, 1.41 mmol
• CH 3 CN 4.0 mL
• water 0.4 mL
• isobutylene oxide 0.26 mL, 2.84 mmol
• the final mixture was evaporated and, the residue was partitioned between EtOAc (50 mL) and water (8.0 mL). The organic layer was washed with brine (8.0 mL), dried (Na 2 SO 4 ) and concentrated.
• ethyl (dimethylamino)acrylate (0.56 mL, 3.91 mmol) was added followed by addition of a solution Et 3 N (0.30 mL, 2.15 mmol) in 1,2-DCE (3.0 mL) over a 40 min period. Stirring was then continued at 50 °C for 1.5 h and at 20 °C overnight. The mixture was diluted with EtOAc (100 mL) and, washed with 0.5 M KH 2 PO (30 mL) and brine (30 mL). The organic layer was dried (Na 2 SO 4 ) and concentrated.
• Trituration of the chromatographed products with methanol was used to remove traces of 1 -(4-oxo-thieno [3 ,2-d]pyrimidin-3 (4H)-yl)-2-methoxyphenoxy)-2-methyl-2- propanol.
• chromatography mixtures of MeOH/CH 2 Cl 2 , EtO Ac/CH 2 C1 2 or EtOAc/hexanes were used as the solvents.
• Mg turnings (1.38g, 57 mmol) were added to a well dried N 2 flushed round bottom flask equipped with a condenser, magnetic stirbar and addition funnel which was charged with THF (70 mL) and chloromethyldimethylisopropoxysilane (9.5g, 57 mmol). After adding ⁇ 10 mL of the THF solution and 1,2-dibromoethane (30 ⁇ L), the solution above the Mg became cloudy and warm. The remaining solution was added over 30 min at a rate that maintained a gentle reflux.
• a 3Mmethylmagnesium iodide/ether solution (6.9 mL, 20.7 mmol) was diluted with ether (7.0 mL) and cooled to 0 °C. To the resulting solution was added dropwise a solution of Part D compound (1.90 g, 4.42 mmol) in ether (5.0 mL). After stirring at 0 °C for 35 min, IMHCl (15 mL) was slowly added and the aqueous mixture pH was adjusted to 6.5 by further addition of IMHCl. The mixture was extracted with CH 2 Cl 2 (3x40 mL) and the combined extracts were dried (Na 2 SO 4 ) and evaporated. Chromatography (SiO 2 230-400 mesh, 3/2 tol/1 hexanes/EtOAc) gave the desired tertiary alcohol as a 3/2 BOC- carbamate/amine mixture (1.75 g, colorless oil).
• Prodrugs were prepared of selected secondary and tertiary alcohols to improve solubility and exposure. Standard conditions, employed to generate amino acid esters of all but the glycine ester of the tertiary alcohols, are exemplified in
• Example 167 Preparation of the glycine ester of the tertiary alcohols is exemplified in Example 168.
• the respective half-esters of oxalic, malonic, succinic and glutaric acids are exemplified in Examples 169 to 172.
• Example 173 exemplifies preparation of an O-glucoside prodrug;
• Example 174 exemplifies preparation of a mono- phosphate ester.
• the suspension was heated at reflux for 1 h and additional N-(tert-butoxycarbonyl)glycine (0.55 g, 3.17 mmol) was added followed by diisopropylcarbodiimide (0.55 mL, 3.17 mmol) over 2 hrs via syringe pump.
• the suspension heated at reflux for 1 h and cooled to rt. Hydrazine monohydrate (0.34 mL, 7.01 mmol) was added and the suspension stirred at rt for 2 h.
• the suspension was cooled to O 0 C, filtered and the filtrate washed with cold, IN HCl, cold, dilute NaHCO 3 solution, dried over anhydrous MgSO 4 , filtered and the filtrate concentrated under reduced pressure.
• Example 82 To a mixture of Example 82 (140 mg, 0.306 mmol) and DMAP (56 mg, 0.459 mmol.) in DMA (0.6 mL) at 140 0 C was added succinic anhydride (183 mg, 1.83 mmol) over 5 hours. The reaction mixture was stirred at 140 °C for additional 2 h and was then cooled to room temperature. The mixture was diluted with DCM and was loaded onto a silica gel column. Elution with DCM to DCM:ACN:HOAc (90:5:5) afforded partially purified product which was recrystallized from EtOH giving the title compound (90 mg, 53% yield) as an off-white solid.
• Example 104 A solution of Example 104 (100 mg, 0.225 mmol) in DMF (1 mL) was added to a solution of sodium hydride (8.1 mg, 0.338 mmol) in DMF (2 mL). The reaction was stirred at room temperature for 30 minutes. Glutaric anhydride (129 mg, 1.128 mmol) was then added and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into a solution of 1.0N HCl (40 mL) and extracted with EtOAc (30 mL). The EtOAc layer was dried over sodium sulfate and concentrated.
• Example 104 To a mixture of Example 104 (100 mg, 0.225 mmol), silver carbonate (311 mg, 1.12 mmol) and 4 A molecular sieves (500 mg) in chloroform (7 mL) was slowly added a solution of acetobromo-a-D-glucose (232 mg, 0.564 mmol) in chloroform (3 mL). The reaction mixture was stirred at reflux for 48 hours. The precipitated material was filtered and the filtrate was concentrated and subjected to ISCO flash chromatography (silica gel/hexane-EtOAc 100:0 to 0:100 gradient) to give the title compound (139 mg, 80% yield) as a brown gum.
• ISCO flash chromatography sica gel/hexane-EtOAc 100:0 to 0:100 gradient
• Membranes from stably transfected HEK-293 cells expressing a mutated (E4Q, A5T) hMCHRl receptor were prepared by dounce homogenization and differential centrifugation. Binding experiments were carried out with 0.5 -1.0 ug of membrane protein incubated in a total of 0.2 ml in 25 mM HEPES (pH 7.4) with 10 mM MgCl 2 , 2 mM EGTA, and 0.1% BSA (Binding Buffer) for 90 min.
• reaction were carried out in the presence of with 0.06 - 0.1 nM [Phe 13 , [ 125 I]TyT 19 J-MCH and increasing concentrations of unlabeled test molecules. Reactions were terminated by rapid vacuum filtration over 96 well-GFC Unifilter plates pre-coated with 0.075 ml binding buffer containing 1% BSA, and washed 3 times with 0.4 ml of Phospho-buffered Saline (pH 7.4) containing 0.01% TX-100. Filters were dried, 0.05 ml microscint 20 was added to each well and radioactivity was subsequently quantified by scintillation counting on a TopCountTM microplate scintillation counter (Packard). Inhibitory constants were determined by nonlinear least squares analysis using a four parameter logistic equation.
• the compounds of the present application can be administered to mammals, preferably humans, for the treatment of a variety of conditions and disorders, including, but not limited to metabolic and eating disorders as well as conditions associated with metabolic disorders (e.g., obesity, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, impaired glucose hemostasis, insulin resistance, hypercholesterolemia, hypertriglyceridemia, choletithiasis, dislipidemic conditions, bulimia nervosa and compulsive eating disorders); sleep disorders; and psychiatric disorders, such as depression, anxiety, schizophrenia, substance abuse, cognition-enhancement and Parkinson's disease.
• metabolic disorders e.g., obesity, diabetes, arteriosclerosis, hypertension, polycystic ovary disease, cardiovascular disease, osteoarthritis, dermatological disorders, impaired glucose hemostasis, insulin resistance, hypercholesterolemia, hypertriglyceridemia, choletithiasis,
• the compounds described in the present application could be used to enhance the effects of cognition-enhancing agents, such as acetylcholinesterase inhibitors (e.g., tacrine), muscarinic receptor-1 agonists (e.g., milameline), nicotinic agonists, glutamic acid receptor (AMPA and NMDA) modulators, and nootropic agents (e.g., piracetam, levetiracetam).
• cognition-enhancing agents such as acetylcholinesterase inhibitors (e.g., tacrine), muscarinic receptor-1 agonists (e.g., milameline), nicotinic agonists, glutamic acid receptor (AMPA and NMDA) modulators, and nootropic agents (e.g., piracetam, levetiracetam).
• Suitable therapies for treatment of Alzheimer's disease and cognitive disorders for use in combination with the compounds of the present application include donepezil, tacrine, revastigraine, 5HT6, gamma secretase inhibitors, beta secretase inhibitors, SK channel blockers, Maxi-K blockers, and KCNQs blockers.
• the compounds described in the present application could be used to enhance the effects of agents used in the treatment of Parkinson's Disease.
• agents used to treat Parkinson's Disease include: levadopa with or without a COMT inhibitor, antiglutamatergic drugs (amantadine, riluzole), alpha-2 adrenergic antagonists such as idazoxan, opiate antagonists, such as naltrexone, other dopamine agonists or transportor modulators, such as ropinirole, or pramipexole or neurotrophic factors such as glial derived neurotrophic factor (GDNF).
• antiglutamatergic drugs amantadine, riluzole
• alpha-2 adrenergic antagonists such as idazoxan
• opiate antagonists such as naltrexone
• other dopamine agonists or transportor modulators such as ropinirole, or pramipexole
• neurotrophic factors such as glial derived neurotrophic factor (GDNF).
• GDNF glial derived neurotrophic factor
• compositions comprising, as an active ingredient, a therapeutically effective amount of at least one of the compounds of formula I, alone or in combination with a pharmaceutical carrier or diluent.
• compounds of the present application can be used alone, in combination with other suitable therapeutic agents useful in the treatment of the aforementioned disorders including: anti-obesity agents; anti-diabetic agents, appetite suppressants; cholesterol/lipid-lowering agents, HDL-raising agents, cognition enhancing agents, agents used to treat neurodegeneration, agents used to treat respiratory conditions, agents used to treat bowel disorders, anti-inflammatory agents; anti-anxiety agents; anti-depressants; anti-hypertensive agents; cardiac glycosides; and anti-tumor agents.
• Such other therapeutic agent(s) may be administered prior to, simultaneously with, or following the administration of the melanin-concentrating hormone receptor (MCHR) antagonists in accordance with the application.
• MCHR melanin-concentrating hormone receptor
• Suitable anti-obesity agents for use in combination with the compounds of the present application include melanocortin receptor (MC4R) agonists, cannabinoid receptor modulators, growth hormone secretagogue receptor (GHSR) antagonists, galanin receptor modulators, orexin antagonists, CCK agonists, GLP-I agonists, and other Pre-proglucagon-derived peptides; NPYl or NPY5 antagonsist, NPY2 and NPY4 modulators, corticotropin releasing factor agonists, histamine receptor-3 (H3) modulators, aP2 inhibitors, PPAR gamma modulators, PPAR delta modulators, acetyl-CoA carboxylase (ACC) inhibitors, 11- ⁇ -HSD-l inhibitors, adinopectin receptor modulators; beta 3 adrenergic agonists, such as AJ9677 (Takeda/Dainippon), L750355 (Merckokergic
• Suitable anti-diabetic agents for use in combination with the compounds of the present application include: insulin secretagogues or insulin sensitizers, which may include biguanides, sulfonyl ureas, glucosidase inhibitors, aldose reductase inhibitors, PPAR ⁇ agonists such as thiazolidinediones, PPAR ⁇ agonists (such as fibric acid derivatives), PPAR ⁇ antagonists or agonists, PPAR oc/ ⁇ dual agonists, 11- ⁇ -HSD-l inhibitors, dipeptidyl peptidase IV (DP4) inhibitors, SGLT2 inhibitors including tapagliflozin and seraglifozin, glycogen phosphorylase inhibitors, and/or meglitinides, as well as insulin, and/or glucagon-like peptide- 1 (GLP- 1 ), GLP- 1 agonist, and/or a PTP- 1 B inhibitor (protein
• the antidiabetic agent may be an oral antihyperglycemic agent preferably a biguanide such as metformin or phenformin or salts thereof, preferably metformin HCl. Where the antidiabetic agent is a biguanide, the compounds of the present application will be employed in a weight ratio to biguanide within the range from about 0.001:1 to about 10:1, preferably from about 0.01:1 to about 5:1. [00159]
• the antidiabetic agent may also preferably be a sulfonyl urea such as glyburide (also known as glibenclamide), glimepiride (disclosed in U.S. Patent No.
• the oral antidiabetic agent may also be a glucosidase inhibitor such as acarbose (disclosed in U.S. Patent No. 4,904,769) or miglitol (disclosed in U.S. Patent No. 4,639,436), which maybe administered in the same or in a separate oral dosage forms.
• the compounds of the present application may be employed in combination with a PPAR ⁇ agonist such as a tliiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Patent No.
• a PPAR ⁇ agonist such as a tliiazolidinedione oral anti-diabetic agent or other insulin sensitizers (which has an insulin sensitivity effect in NIDDM patients) such as rosiglitazone (SKB), pioglitazone (Takeda), Mitsubishi's MCC-555 (disclosed in U.S. Patent No.
• Glaxo-Wellcome's GL-262570 englitazone (CP-68722, Pfizer) or darglitazone (CP-86325, Pfizer, isaglitazone (MIT/J&J), JTT- 501 (JPNT/P&U), L-895645 (Merck), R-119702 (Sankyo/WL), NN-2344 (Dr. Reddy/NN), or YM-440 (Yamanouchi), preferably rosiglitazone and pioglitazone.
• the compounds of the present application may be employed with a PPAR ⁇ / ⁇ dual agonist such as MK-767/KRP-297 (Merck/Kyorin; as described in , K. Yajima, et. si., Am. J. Physiol. Endocrinol. Metab., 284: E966-E971 (2003)), AZ-242 (tesaglitazar; Astra-Zeneca; as described in B. Ljung, et. al, J. Lipid Res., 43, 1855- 1863 (2002)); muraglitazar; or the compounds described in US patent 6,414,002.
• MK-767/KRP-297 Merck/Kyorin; as described in , K. Yajima, et. si., Am. J. Physiol. Endocrinol. Metab., 284: E966-E971 (2003)
• AZ-242 tesaglitazar; Astra-Zeneca; as
• the compounds of the present application may be employed in combination with anti-hyperlipidemia agents, or agents used to treat arteriosclerosis.
• An example of an hypolipidemic agent would be an HMG CoA reductase inhibitor which includes, but is not limited to, mevastatin and related compounds as disclosed in U.S. Patent No. 3,983,140, lovastatin (mevinolin) and related compounds as disclosed in U.S. Patent No. 4,231,938, pravastatin and related compounds such as disclosed in U.S. Patent No. 4,346,227, simvastatin and related compounds as disclosed in U.S. Patent Nos. 4,448,784 and 4,450,171.
• HMG CoA reductase inhibitors which may be employed herein include, but are not limited to, fluvastatin, disclosed in U.S. Patent No. 5,354,772, cerivastatin disclosed in U.S. Patent Nos. 5,006,530 and 5,177,080, atorvastatin disclosed in U.S. Patent Nos. 4,681,893, 5,273,995, 5,385,929 and 5,686,104, pravastatin (Nissan/Sankyo's nisvastatin (NK- 104) or itavastatin), disclosed in U.S. Patent No.
• phosphinic acid compounds useful in inhibiting HMG CoA reductase suitable for use herein are disclosed in GB 2205837.
• the squalene synthetase inhibitors suitable for use herein include, but are not limited to, ⁇ -phosphono-sulfonates disclosed in U.S. Patent No. 5,712,396, those disclosed by Biller, et al., J. Med.
• Chem., 31, 1869-1871 (1998) including isoprenoid (phosphinyl-methyl)phosphonates as well as other known squalene synthetase inhibitors, for example, as disclosed in U.S. Patent No. 4,871,721 and 4,924,024 and in Biller, S.A., Neuenschwander, K., Ponpipom, M.M., and Poulter, CD., Current Pharmaceutical Design, 2, 1-40 (1996).
• squalene synthetase inhibitors suitable for use herein include the terpenoid pyrophosphates disclosed by P. Ortiz de Montellano, et al., J. Med. Chem., 20, 243-249 (1977), the farnesyl diphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs as disclosed by Corey and Volante, J. Am. Chem. Soc, 98, 1291-1293 (1976), phosphinylphosphonates reported by McClard, R.W. et al., J. Am. Chem.
• hypolipidemic agents suitable for use herein include, but are not limited to, fibric acid derivatives, such as fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate, clinofibrate and the like, probucol, and related compounds as disclosed in U.S. Patent No. 3,674,836, probucol and gemfibrozil being preferred, bile acid sequestrants such as cholestyramine, colestipol and DEAE-Sephadex
• the other hypolipidemic agent may be an ACAT inhibitor (which also has anti-atherosclerosis activity) such as disclosed in, Drugs of the Future, 24, 9-15 (1999), (Avasimibe); "The ACAT inhibitor, Cl-IOl 1 is effective in the prevention and regression of aortic fatty streak area in hamsters", Nicolosi et al., Atherosclerosis (Shannon, Irel), 137 (1), 77-85 (1998); "The pharmacological profile of FCE 27677: a novel ACAT inhibitor with potent hypolipidemic activity mediated by selective suppression of the hepatic secretion of ApoB 100-containing lipoprotein", Ghiselli, Giancarlo, Cardiovasc.
• ACAT inhibitor which also has anti-atherosclerosis activity
• the hypolipidemic agent may be an upregulator of LDL receptor activity such as MD-700 (Taisho Pharmaceutical Co. Ltd) and LY295427 (Eli Lilly).
• the hypolipidemic agent may be a cholesterol absorption inhibitor preferably Schering- Plough's SCH48461 (ezetimibe) as well as those disclosed in Atherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998).
• the other lipid agent or lipid-modulating agent may be a cholesteryl transfer protein inhibitor (CETP) such as Pfizer's CP-529,414 as well as those disclosed in WO/0038722 and in EP 818448 (Bayer) and EP 992496, and Pharmacia's SC-744 and SC-795, as well as CETi-I and JTT-705.
• CETP cholesteryl transfer protein inhibitor
• the hypolipidemic agent may be an ileal NaVbile acid cotransporter inhibitor such as disclosed in Drugs of the Future, 24, 425-430 (1999).
• the ATP citrate lyase inhibitor which may be employed in the combination of the application may include, for example, those disclosed in U.S. Patent No. 5,447,954.
• the other lipid agent also includes a phytoestrogen compound such as disclosed in WO 00/30665 including isolated soy bean protein, soy protein concentrate or soy flour as well as an isoflavone such as genistein, daidzein, glycitein or equol, or phytosterols, phytostanol or tocotrienol as disclosed in WO 2000/015201; a beta-lactam cholesterol absorption inhibitor such as disclosed in EP 675714; an HDL upregulator such as an LXR agonist, a PPAR ⁇ -agonist and/or an FXR agonist; an LDL catabolism promoter such as disclosed in EP 1022272; a sodium-proton exchange inhibitor such as disclosed in DE 19622222; an LDL-receptor inducer or a steroidal glycoside such as disclosed in U.S.
• a phytoestrogen compound such as disclosed in WO 00/30665 including isolated soy bean protein, soy protein concentrate or soy flour as well as
• Patent No. 5,698,527 and GB 2304106 an anti-oxidant such as beta-carotene, ascorbic acid, ⁇ -tocopherol or retinol as disclosed in WO 94/15592 as well as Vitamin C and an antihomocysteine agent such as folic acid, a folate, Vitamin B6, Vitamin B12 and Vitamin E; isoniazid as disclosed in WO 97/35576; a cholesterol absorption inhibitor, an HMG-CoA synthase inhibitor, or a lanosterol demethylase inhibitor as disclosed in WO 97/48701; a PPAR ⁇ agonist for treating dyslipidemia; or a sterol regulating element binding protein-I (SREBP-I) as disclosed in WO 2000/050574, for example, a sphingolipid, such as ceramide, or neutral sphingomyelenase (N-SMase) or fragment thereof.
• an anti-oxidant such as beta-carotene
• Preferred hypolipidemic agents are pravastatin, lovastatin, simvastatin, atorvastatin, fluvastatin, pravastatin and rosuvastatin, as well as niacin and/or cholestagel.
• the compounds of the present application may be employed in combination with anti-hypertensive agents.
• suitable anti-hypertensive agents for use in combination with the compounds of the present application include beta adrenergic blockers, calcium channel blockers (L-type and/or T-type; e.g.
• diltiazem verapamil, nifedipine, amlodipine and mybefradil
• diuretics e.g., chlorothiazide, hydrochlorothiazide, fiuniethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide, ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine, bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors, ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, lis
• Dual ET/AH antagonist e.g., compounds disclosed in WO 00/01389
• neutral endopeptidase (NEP) inhibitors neutral endopeptidase (NEP) inhibitors
• vasopepsidase inhibitors dual NEP-ACE inhibitors
• MCHRl antagonists could be useful in treating other diseases associated with obesity, including sleep disorders. Therefore, the compounds described in the present application could be used in combination with therapeutics for treating sleep disorders.
• Suitable therapies for treatment of sleeping disorders include melatonin analogs, melatonin receptor antagonists, ML 1 B agonists, GABA receptor modulators; NMDA receptor modulators, histamine-3 (H3) receptor modulators, dopamine agonists and orexin receptor modulators.
• MCHRl antagonists may reduce or ameliorate substance abuse or addictive disorders. Therefore, combination of cannabinoid receptor modulators with agents used to treat addictive disorders may reduce the dose requirement or improve the efficacy of current addictive disorder therapeutics. Examples of agents used to treat substance abuse or addictive disorders are: selective serotonin reuptake inhibitors (SSRI), methadone, buprenorphine, nicotine and bupropion.
• SSRI selective serotonin reuptake inhibitors
• methadone methadone
• buprenorphine nicotine and bupropion.
• MCHRl antagonists may reduce anxiety or depression; therefore, the compounds described in this application may be used in combination with antianxiety agents or antidepressants.
• Suitable anti-anxiety agents for use in combination with the compounds of the present application include benzodiazepines (e.g., diazepam, lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam, chlorazepate, halazepam and prazepam), 5HTl A receptor agonists (e.g., buspirone, flesinoxan, gepirone and ipsapirone), and corticotropin releasing factor (CRF) antagonists.
• benzodiazepines e.g., diazepam, lorazepam, oxazepam, alprazolam, chlordiazepoxide, clonazepam, chlorazepate, halazepam and prazepam
• 5HTl A receptor agonists e.g., buspirone, flesinoxan, gepirone and ipsapirone
• anti-depressants for use in combination with the compounds of the present application include norepinephrine reuptake inhibitors (tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs) (fluoxetine, fluvoxamine, paroxetine and sertraline), monoamine oxidase inhibitors (MAOIs) (isocarboxazid, phenelzine, tranylcypromine, selegiline), reversible inhibitors of monoamine oxidase (RTMAs) (moclobemide), serotonin and norepinephrine reuptake inhibitors (SNRIs) (venlafaxine), corticotropin releasing factor (CRF) receptor antagonists, alpah-adrenoreceptor antagonists, and atypical antidepressants (bupropion, lithium, nefazodone, trazodone and viloxazine).
• SSRIs selective seroton
• the combination of a conventional antipsychotic drug with a MCHRl antagonist could also enhance symptom reduction in the treatment of psychosis or mania. Further, such a combination could enable rapid symptom reduction, reducing the need for chronic treatment with antipsychotic agents. Such a combination could also reduce the effective antipsychotic dose requirement, resulting in reduced • probability of developing the motor dysfunction typical of chronic antipsychotic treatment.
• Suitable antipsychotic agents for use in combination with the compounds of the present application include the phenothiazine (chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine), thioxanthine (chlorprothixene, thiothixene), heterocyclic dibenzazepine (clozapine, olanzepine and aripiprazole), butyrophenone (haloperidol), dipheyylbutylpiperidine .
• schizophrenic disorders include paranoid, disorganized, catatonic, undifferentiated and residual schizophrenia, schizophreniform disorder, shcizoaffective disorder, delusional disorder, brief psychotic disorder and psychotic disorder not specified.
• Suitable antipsychotic drugs for combination with the compounds in the present application include the antipsychotics mentioned above, as well as dopamine receptor antagonists, muscarinic receptor agonists, 5HT2A receptor antagonists and 5HT2A/dopamine receptor antagonists or partial agonists (e.g., olanzepine, aripiprazole, risperidone, ziprasidone).

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