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  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Definitions

• This invention relates to compounds which have a good affinity to the trace amine associated receptors (TAARs), especially for TAAR1.
• TAARs trace amine associated receptors
• These compounds are useful in the treatment or prevention of, inter alia, disorders of the central nervous system, for example, the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and/or attention deficit hyperactivity disorder (ADHD).
• disorders of the central nervous system for example, the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and/or attention deficit hyperactivity disorder (ADHD).
• ADHD attention deficit hyperactivity disorder
• the invention relates also to processes for preparing such compounds and a pharmaceutical composition comprising such a compound.
• a second class of endogenous amine compounds the so-called trace amines (TAs) significantly overlap with the classical biogenic amines regarding structure, metabolism and subcellular localization.
• the TAs include p-tyramine, ⁇ -phenylethylamine, tryptamine and octopamine, and they are present in the mammalian nervous system at generally lower levels than classical biogenic amines.
• Usdin, E. and Sandler, M. eds. (1984) Trace Amines and the brain , Dekker.
• Their disregulation has been linked to various psychiatric diseases like schizophrenia and depression and for other conditions like attention deficit hyperactivity disorder, migraine headache, Parkinson's disease, substance abuse and eating disorders. Lindemann, L. and Hoener, M.
• TA-specific receptors had only been hypothesized based on anatomically discrete high-affinity TA binding sites in the central nervous system of humans and other mammals. Mousseau, D. D. and Butterworth, R. F. (1995), Prog. Brain Res. 106, 285-291; McCormack, J. K. et al. (1986), J. Neurosci. 6, 94-101. Accordingly, the pharmacological effects of TAs were believed to be mediated through the well known machinery of classical biogenic amines, by either triggering their release, inhibiting their reuptake or by “crossreacting” with their receptor systems. Premont, R. T. et al. (2001), Proc. Natl. Acad. Sci.
• TAAR genes there are 9 TAAR genes in human (including 3 pseudogenes) and 16 genes in mouse (including 1 pseudogene).
• the TAAR genes do not contain introns (with one exception, TAAR2 contains 1 intron) and are located next to each other on the same chromosomal segment.
• the phylogenetic relationship of the receptor genes in agreement with an in-depth GPCR pharmacophore similarity comparison and pharmacological data suggest that these receptors form three distinct subfamilies. Lindemann, L. and Hoener, M. (2005), Trends in Pharmacol. Sci. 26, 274-281; Lindemann, L. et al. (2005), Genomics 85, 372-385.
• TAAR1 is in the first subclass of four genes (TAAR1-4) highly conserved between human and rodents. TAs activate TAAR1 via G ⁇ s. Disregulation of TAs was shown to contribute to the aetiology of various diseases like depression, psychosis, attention deficit hyperactivity disorder, substance abuse, Parkinson's disease, migraine headache, eating disorders, metabolic disorders and therefore TAAR1 ligands have a high potential for the treatment of these diseases.
• the compounds are useful in the treatment or prevention of disorders of the central nervous system, for example, the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and/or attention deficit hyperactivity disorder (ADHD).
• the present invention is directed to a compound according to formula I,
• the present invention also relates to a pharmaceutically-suitable acid-addition salt of such a compound.
• the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.
• the present invention is also directed to processes for the preparation of the above compound.
• the present invention is also directed to a pharmaceutical composition
• a pharmaceutical composition comprising the above compound or a pharmaceutically-suitable acid-addition salt thereof.
• Compounds according to the present invention have a good affinity to the TAARs, especially for TAAR1.
• Such compounds are useful in the treatment or prevention of illnesses such as depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder, stress-related disorders, psychotic disorders such as schizophrenia, neurological diseases such as Parkinson's disease, neurodegenerative disorders such as Alzheimer's disease, epilepsy, migraine, hypertension, substance abuse and metabolic disorders such as eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, disorders of energy consumption and assimilation, disorders and malfunction of body temperature homeostasis, disorders of sleep and circadian rhythm, and cardiovascular disorders.
• the compounds of the present invention are useful in the treatment or prevention of disorders of the central nervous system, for example, the treatment or prevention of depression, psychosis, Parkinson's disease, anxiety and/or attention deficit hyperactivity disorder (ADHD).
• ADHD attention deficit hyperactivity disorder
• the present invention is directed to a compound according to formula I,
• the present invention also relates to a pharmaceutically-suitable acid-addition salt of such a compound.
• the invention includes all racemic mixtures, all their corresponding enantiomers and/or optical isomers.
• the present invention is also directed to processes for the preparation of the above compound.
• halogen refers to chlorine, iodine, fluorine or bromine.
• lower alkyl denotes a saturated straight- or branched-chain hydrocarbon group containing from 1 to 7 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like.
• Preferred lower alkyl groups are groups with 1 to 4 carbon atoms.
• lower alkyl substituted by halogen denotes a lower alkyl group as defined above, wherein at least one hydrogen atom is replaced by halogen, for example —CF 3 , —CHF 2 , —CH 2 F, —CH 2 CF 3 , —CH 2 CH 2 CF 3 , —CH 2 CF 2 CF 3 and the like.
• lower alkoxy denotes a substituent wherein the alkyl residue is attached to the remainder of the molecule via an oxygen group.
• pharmaceutically-suitable acid-addition salt embraces salts of a compound of formula I with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like, the salt not being toxic and not interfering with the ability of the compound of formula I to elicit the biological or medical response of a tissue system, animal or human, that is being sought by the researcher, veterinarian, medical doctor or other clinician.
• inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the
• Preferred compounds of the present invention are those of formula I wherein X and Y are both —CH 2 —.
• Such compounds include:
• compounds of the present invention are those of formula I wherein X is —CH 2 — and Y is —CH (lower alkyl), for example the following compounds:
• Still another preferred embodiment of the present invention are compounds of formula I, wherein X is —CH 2 — and Y is —S—, for example the following compounds:
• present compounds of formula I and their pharmaceutically-suitable acid-addition salts can be prepared by various processes, for example, by a process comprising
• R 2 is hydrogen, lower alkyl or lower alkoxy, or c) alkylating a compound of formula
• R is lower alkyl and Ar is as described above, or g) reacting a compound of formula
• the above produced compounds of formula I may be converted into pharmaceutically-suitable acid-addition salts.
• the starting materials are either commercially available (e.g., from one or more of the following chemical suppliers such as Aldrich, Fluka, Acros, Maybridge, Avocado, TCI, or additional suppliers as indicated in databases such as Chemical Abstracts [American Chemical Society, Columbus, Ohio] or Available Chemicals Director [Elsevier MDL, San Ramon, Calif.]), are otherwise known in the chemical literature, or may be prepared in accordance with methods well known in the art.
• R 2 is lower alkyl or hydrogen.
• Step A The Wittig reaction between an aldehyde or a ketone of formula III and (1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester (IV) can be accomplished by using a base such as NaH, KO-tert-butyl (KOtBu), NaOCH 3 , NaOCH 2 CH 3 , n-butyllithium, LiHMDS, NaHMDS, KHMDS, and LDA in a solvent such as tetrahydrofuran (THF), dioxane, acetonitrile, 1,2-dimethoxyethan, DMF, benzene, toluene or mixtures thereof at temperatures from ⁇ 78° C.-80° C.
• a base such as NaH, KO-tert-butyl (KOtBu), NaOCH 3 , NaOCH 2 CH 3 , n-butyllithium, LiHMDS, NaHMDS, KHMDS, and LDA
• the base, the carbonyl compound and the optional crown ether can be added to the reaction mixture at the same time without preformation of the ylide at temperatures from ⁇ 78° C.-80° C.
• Preferred conditions for reactions with aryl ketones are ylide formation at room temperature using KOtBu as the base and THF as the solvent, reacting the phosphonic acid ester for 15 minutes at room temperature, and then condensation with the carbonyl component at 80° C. overnight.
• Preferred conditions for benzaldehydes are ylide formation in the presence of the carbonyl compound using KOtBu as the base and THF as the solvent at 80° C. overnight.
• Step B The reduction of the alkene of formula V can be effected by hydrogenation with hydrogen under normal or elevated pressure or by transfer hydrogenation using ammonium formiate or cyclohexadiene as a hydrogen source with a catalyst such as PtO 2 , Pd—C or Raney nickel in solvents such as methanol (MeOH), ethanol (EtOH), H 2 O, dioxane, THF, HOAc, EtOAc, CH 2 Cl 2 , CHCl 3 , DMF or mixtures thereof.
• the reduction of the alkene can be effected by Mg in MeOH or by LiAlH 4 in THF or diethylether.
• the preferred procedure for trisubstituted alkenes is hydrogenation at normal pressure in MeOH/CH 2 Cl 2 using 10% Pd/C as catalyst.
• the preferred procedure for disubstituted alkenes is hydrogenation at normal pressure in MeOH/CHCl 3 /AcOH using 10% Pd/C as catalyst. Both conditions may lead to partial loss of the trityl protecting group. In this case the mixture of protected and unprotected products is subjected directly to conditions C.
• Step C The cleavage of the trityl group can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or a organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
• a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
• organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid
• a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
• Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hours.
• Step A The formylation of 2-(tert-butyl-dimethyl-silanyl)-imidazole-1-sulfonic acid dimethyl-amide (VII) can be effected by deprotonation with a strong base such as n-butyllithium, s-butyllithium or t-butyllithium and optionally an additive such as tetramethylethylene diamine or pentamethyl diethylene triamine in a solvent such as THF or diethylether at ⁇ 78° C.- ⁇ 40° C., followed by quenching the anion with a formylating electrophile such as DMF at ⁇ 78° to room temperature for 1-24 hours.
• a strong base such as n-butyllithium, s-butyllithium or t-butyllithium and optionally an additive such as tetramethylethylene diamine or pentamethyl diethylene triamine in a solvent such as THF or diethylether at ⁇ 78° C
• Preferred conditions are deprotonation with n-butyllithium at ⁇ 78° C. for 10 minutes, then reaction with DMF at ⁇ 78° C. for 2 hours.
• Step B The Grignard reaction of the protected formyl imidazole (VII) with an aryl magnesium chloride or bromide (VIII) can be effected by adding a solution of the Grignard reagent (commercially available or prepared form a benzyl chloride or bromide and Mg by standard methods) in a solvent such as diethylether, THF or benzene to a solution of the aldehyde in one of the previously mentioned solvents at ⁇ 20° C. to room temperature and letting the two components react at room temperature to reflux temperature for 1-24 hours.
• a solution of the Grignard reagent commercially available or prepared form a benzyl chloride or bromide and Mg by standard methods
• a solvent such as diethylether, THF or benzene
• Preferred conditions involve addition of the Grignard reagent in diethylether to a solution of aldehyde in THF at room temperature and reaction at room temperature overnight.
• Step C The alkylation of the alcohol of formula IX can be accomplished by deprotonation of the hydroxy group with a base such as NaH, KH, n-butyllithium, KOtBu, KOH or aqueous NaOH and KOH in the presence of a phase transfer catalyst (tetraalkylammonium salts) in a suitable solvent such as THF, DMF, DMSO, toluene or 1,2-dimethoxyethane at ⁇ 78° C. to room temperature for 30 minutes-2 hours and subsequent addition of an alkyl halide.
• a base such as NaH, KH, n-butyllithium, KOtBu, KOH or aqueous NaOH and KOH
• a phase transfer catalyst tetraalkylammonium salts
• Preferred conditions are deprotonation with NaH in THF at room temperature for 1 hour and alkylation with an alkyl iodide at room temperature overnight.
• Step D The simultaneous cleavage of both protecting groups (II-2) can be achieved in the presence of a mineral acid such as HCl, HBr or H 2 SO 4 in a solvent such as EtOH, MeOH, H 2 O or THF at room temperature reflux temperature for 1-24 hours.
• a mineral acid such as HCl, HBr or H 2 SO 4
• a solvent such as EtOH, MeOH, H 2 O or THF
• Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hours.
• Step A The alkylation of a substituted phenol with 4-chloromethyl-1-trityl-1H-imidazole (XI) can be accomplished using a base such as K 2 CO 3 , Cs 2 CO 3 , Na 2 CO 3 , NaHCO 3 , aqueous NaOH, KOH, LiOH, NaH, NaOCH 3 , NaOCH 2 CH 3 or triethylamine in a solvent such as acetone, DMF, DMSO, acetonitrile, toluene, EtOH, and MeOH and optionally if appropriate a phase transfer catalyst such as tetrabutylammonium bromide or an additive such as a crown ether, tetrabutylammonium iodide or potassium iodide at room temperature 120° C. for 1-24 hours.
• a base such as K 2 CO 3 , Cs 2 CO 3 , Na 2 CO 3 , NaHCO 3 , aqueous NaOH, KOH,
• Preferred conditions are K 2 CO 3 in DMF at 80° C. for 5 hours.
• Step B The cleavage of the trityl group can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or a organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C. Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hours.
• a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
• a organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid
• a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
• Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hours.
• An appropriate olefin such as aryl-1-butene (XII) can be reacted at lower temperature with a nitrile such as acetonitrile and nitrosonium fluoroborate to form an imidazole-N-oxide according to Scheinbaum et al. (Tetrahedron Lett. 1971, p. 2205).
• a nitrile such as acetonitrile and nitrosonium fluoroborate
• the hydroxyfunction can be removed by various reducing agents such as Red-Al, Titanium(III)-salts, Lithiumaluminiumhydride or others as described by Lipshutz et al. in Tetrahedron Lett. 25, 1984, p. 1319.
• An alpha-bromoketone of formula XIII is reacted with an protected guanidine such as acetylguanidine (XIV) in a solvent such as dimethylformamide followed by deprotection of the amino group to form 2-aminoimidazole I-5.
• This deprotection can be achieved for instance by acid or base catalysed hydrolysis.
• deprotection is preferably achieved by treatment with hydrochloric acid in a polar solvent such as water, alcohols or mixtures of water and alcohols.
• Step A The alkylation of a substituted phenol (X) with 4-chloromethyl-1-trityl-1H-imidazole (XI) can be accomplished using a base such as K 2 CO 3 , Cs 2 CO 3 , Na 2 CO 3 , NaHCO 3 , aqueous NaOH, KOH, LiOH, NaH, NaOCH 3 , NaOCH 2 CH 3 or triethylamine in a solvent such as acetone, DMF, DMSO, acetonitrile, toluene, EtOH or MeOH and optionally if appropriate a phase transfer catalyst such as tetrabutylammonium bromide or an additive such as a crown ether, tetrabutylammonium iodide or potassium iodide at room temperature to 120° C. for 1-24 hours.
• a base such as K 2 CO 3 , Cs 2 CO 3 , Na 2 CO 3 , NaHCO 3 , aqueous NaOH,
• Preferred conditions are K 2 CO 3 in DMF at 80° C. for 5 hrs.
• Step B The cleavage of the trityl group can be effected with a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4 or a organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid in a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
• a mineral acid such as HCl, H 2 SO 4 or H 3 PO 4
• organic acid such as CF 3 COOH, CHCl 2 COOH, HOAc or p-toluonesulfonic acid
• a solvent such as CH 2 Cl 2 , CHCl 3 , THF, MeOH, EtOH or H 2 O at 0 to 60° C.
• Preferred conditions are 2N HCl in EtOH at reflux for 1-3 hrs.
• Step C The oxidation of the thioether (II-4) to the corresponding sulfoxide (II-5) can be accomplished by oxidants such as mCPBA, isopropyl 2-iodoxybenzoate, oxone or natriumperiodate in a solvent such as CH 2 Cl 2 , dichloroethane, toluene, acetonitrile, MeOH at temperatures from 0° C. to reflux.
• oxidants such as mCPBA, isopropyl 2-iodoxybenzoate, oxone or natriumperiodate in a solvent such as CH 2 Cl 2 , dichloroethane, toluene, acetonitrile, MeOH at temperatures from 0° C. to reflux.
• Preferred conditions are 1 equivalent of mCPBA in CH 2 Cl 2 at 0° C. to room temperature for 1-5 hours.
• Step D The oxidation of the thioether (II-4) to the corresponding sulfoxide (II-6) can be accomplished by oxidants such as mCPBA, H 2 O 2 , oxone or sodium wolframate in a solvent such as CH 2 Cl 2 , dichloroethane, toluene, acetonitrile, THF, acetone, or MeOH at temperatures from 0° C. to reflux.
• oxidants such as mCPBA, H 2 O 2 , oxone or sodium wolframate in a solvent such as CH 2 Cl 2 , dichloroethane, toluene, acetonitrile, THF, acetone, or MeOH at temperatures from 0° C. to reflux.
• Preferred conditions are 2 equivalent of mCPBA in CH 2 Cl 2 at 0° C. to room temperature for 1 to 5 hrs.
• Step A The coupling of a substituted arylcarboxylic acid (XVI) with a suitably protected 4-amino-imidazole compound (XVII) to afford an amide compound (IXX) can be accomplished using a coupling agent such as 2-(1h-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) or 2-(1h-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) or o-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU) and a base such as triethylamine or ethyldiisopropylamine in a solvent such as THF, DMF, or dichloromethane.
• a coupling agent such as 2-(1h
• Suitable nitrogen protecting groups include tert-butoxycarbamate (BOC), trityl, dimethylaminosulfonyl and trimethylsilyl-ethyl (SEM). Preferred conditions are TBTU and ethyldiisopropylamine in DMF at 40° C. for 16 hrs, and a preferred protecting group is trityl.
• Step B The coupling of a substituted arylcarboxylic acid chloride (XVIII) with a suitably protected 4-amino-imidazole compound (XVII) to afford an amide compound (IXX) can be accomplished using a base such as pyridine, triethylamine or ethyldiisopropylamine in a solvent such as THF, DMF or dichloromethane and optionally using a catalyst such as N,N-dimethylformamide or 4-N,N-dimethylaminopyridine (DMAP)
• a base such as pyridine, triethylamine or ethyldiisopropylamine in a solvent such as THF, DMF or dichloromethane
• a catalyst such as N,N-dimethylformamide or 4-N,N-dimethylaminopyridine (DMAP)
• Preferred conditions are triethylamine in dichloromethane at room temperature for 1 hour, and a preferred protecting group is trityl.
• Step C The reduction of an amide (IXX) to an amine (II-7) can be accomplished using a metal hydride reducing agent such as lithium aluminium hydride or a borane reagent such as borane-tetrahydrofuran complex in a solvent such as dioxane, ether or tetrahydrofuran at elevated temperature.
• a metal hydride reducing agent such as lithium aluminium hydride or a borane reagent such as borane-tetrahydrofuran complex in a solvent such as dioxane, ether or tetrahydrofuran at elevated temperature.
• Preferred conditions are lithium aluminium hydride in tetrahydrofuran at reflux temperature for 16 hours.
• Step D The deprotection conditions depend on the nature of the protecting group employed and many methods are well known in the art.
• preferred deprotection conditions are 4 M aqueous hydrochloric acid in dioxane at room temperature for 1-2 hours.
• Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures.
• suitable separation and isolation procedures can be had by reference to the preparations and examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used. Racemic mixtures of chiral compounds of formula I can be separated using chiral HPLC.
• the compounds of formula I are basic and may be converted to a corresponding acid-addition salt.
• the conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
• an appropriate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
• organic acids such as acetic acid, propionic acid, glyco
• the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent.
• an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like.
• the temperature is maintained between 0° C. and 50° C.
• the resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
• the acid-addition salts of the basic compounds of formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
• a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
• Another aspect of the present invention is a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula I, or a pharmaceutically-suitable acid-addition salt thereof, and a therapeutically-inert carrier.
• Processes for the production of such a composition are also aspects of the present invention.
• Such a process comprises bringing one or more compounds of formula I and/or a pharmaceutically-suitable salt(s) thereof and, if desired, one or more other therapeutically-valuable substances into a galenical administration form together with one or more therapeutically-inert carriers.
• therapeutically-inert carrier means that the carrier is not toxic and does not interfere with the ability of the active compound(s) to elicit the biological or medical response of a tissue system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
• the therapeutically-inert carrier for use in the composition of the present invention may be inorganic or organic. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules.
• Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like.
• Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like.
• Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
• the pharmaceutical composition can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants.
• the composition can also contain still other therapeutically valuable substances.
• the pharmaceutical composition of the present invention can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions.
• the administration can, however, also be effected rectally, e.g. in the form of suppositories, and parenterally, e.g. in the form of injection solutions.
• the present invention relates also to a method for treating or preventing a disease or disorder in a patient comprising administering a therapeutically-effective amount of a compound of the present invention to a patient.
• a “therapeutically-effective amount” is the amount of the subject compound that will elicit the biological or medical response of a tissue system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician.
• the above method may involve the administration of a composition which comprises a therapeutically-effective amount of the compound such as the composition described above.
• the therapeutically-effective amount can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case.
• the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula I or of the corresponding amount of a pharmaceutically-suitable salt thereof.
• the daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
• telomere sequences of human, rat and mouse TAAR 1 were amplified from genomic DNA essentially as described by Lindemann et al. (2005) Genomics 85, 372-385.
• the Expand High Fidelity PCR System (Roche Diagnostics) was used with 1.5 mM Mg 2+ and purified PCR products were cloned into pCR2.1-TOPO cloning vector (Invitrogen) following the instructions of the manufacturer. PCR products were subcloned into the pIRESneo2 vector (BD Clontech, Palo Alto, Calif.), and expression vectors were sequence verified before introduction in cell lines.
• HEK293 cells (ATCC # CRL-1573) were cultured essentially as described in Lindemann et al. (2005) Genomics 85, 372-385.
• HEK293 cells were transfected with the pIRESneo2 expression plasmids containing the TAAR coding sequences (described above) with Lipofectamine 2000 (Invitrogen) according to the instructions of the manufacturer, and 24 hours post transfection, the culture medium was supplemented with 1 mg/ml G418 (Sigma, Buchs, Switzerland).
• Cells at confluence were rinsed with ice-cold phosphate buffered saline without Ca 2+ and Mg 2+ containing 10 mM EDTA and pelleted by centrifugation at 1000 rpm for 5 minutes at 4° C. The pellet was then washed twice with ice-cold phosphate buffered saline and the cell pellet was frozen immediately by immersion in liquid nitrogen and stored until use at ⁇ 80° C. The cell pellet was then suspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 10 mM EDTA, and homogenized with a Polytron (PT 3000, Kinematica) at 10,000 rpm for 10 seconds.
• PT 3000, Kinematica Polytron
• the homogenate was centrifuged at 48,000 ⁇ g for 30 minutes at 4° C. and the pellet resuspended in 20 ml HEPES-NaOH (20 mM), pH 7.4 containing 0.1 mM EDTA (buffer A), and homogenized with a Polytron at 10,000 rpm for 10 seconds. The homogenate was then centrifuged at 48,000 ⁇ g for 30 minutes at 4° C. and the pellet resuspended in 20 ml buffer A, and homogenized with a Polytron at 10,000 rpm for 10 seconds. Protein concentration was determined by the method of Pierce (Rockford, Ill.).
• the homogenate was then centrifuged at 48,000 ⁇ g for 10 minutes at 4° C., resuspended in HEPES-NaOH (20 mM), pH 7.0 including MgCl 2 (10 mM) and CaCl 2 (2 ml) (buffer B) at 200 ⁇ g protein per ml and homogenized with a Polytron at 10,000 rpm for 10 seconds.
• Binding assay was performed at 4° C. in a final volume of 1 ml, and with an incubation time of 30 minutes.
• the radioligand [ 3 H]-rac-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline was used at a concentration equal to the calculated K d value of 60 nM to give a total binding at around 0.1% of the total added radioligand concentration, and a specific binding which represented approximately 70-80% of the total binding.
• Non-specific binding was defined as the amount of [ 3 H]-rac-2-(1,2,3,4-tetrahydro-1-naphthyl)-2-imidazoline bound in the presence of the appropriate unlabelled ligand (10 ⁇ M).
• Competing ligands were tested in a wide range of concentrations (10 pM-30 ⁇ M). The final dimethylsulphoxide concentration in the assay was 2%, and it did not affect radioligand binding. Each experiment was performed in duplicate. All incubations were terminated by rapid filtration through UniFilter-96 plates (Packard Instrument Company) and glass filter GF/C, pre-soaked for at least 2 hours in polyethylenimine 0.3%, and using a Filtermate 96 Cell Harvester (Packard Instrument Company). The tubes and filters were then washed 3 times with 1 ml aliquots of cold buffer B. Filters were not dried and soaked in Ultima gold (45 ⁇ l/well, Packard Instrument Company) and bound radioactivity was counted by a TopCount Microplate Scintillation Counter (Packard Instrument Company).
• the preferred compounds show a Ki value ( ⁇ M) in mouse on TAAR1 in the range of ⁇ 0.1 ⁇ M as shown in the table below.
• Ki ( ⁇ M) Example mouse Example Ki 1 0.0609 20 0.043 5 0.0059 35 0.0889 8 0.0843 36 0.0227 11 0.0025 37 0.0802 12 0.0097 39 0.0684 13 0.0106 42 0.0041 14 0.0606 46 0.0146 16 0.0172 47 0.0103 17 0.0019
• Tablet Formulation mg/tablet Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Lactose Anhydrous DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. Microcrystalline Cellulose 30 30 30 150 5. Magnesium Stearate 1 1 1 1 Total 167 167 167 831 Manufacturing Procedure 1. Mix items 1, 2, 3 and 4 and granulate with purified water. 2. Dry the granules at 50° C. 3. Pass the granules through suitable milling equipment. 4. Add item 5 and mix for three minutes; compress on a suitable press.
• Capsule Formulation mg/capsule Item Ingredients 5 mg 25 mg 100 mg 500 mg 1. Compound of formula I 5 25 100 500 2. Hydrous Lactose 159 123 148 — 3. Corn Starch 25 35 40 70 4. Talc 10 15 10 25 5. Magnesium Stearate 1 2 2 5 Total 200 200 300 600 Manufacturing Procedure 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes. 2. Add items 4 and 5 and mix for 3 minutes. 3. Fill into a suitable capsule.

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