Pharmaceutical uses for fluoroalkoxybenzylamino derivatives of nitrogen containing heterocycles

A method of treating a disorder or condition selected from sleep disorders;

• autism;
• pervasive development disorder;
• rheumatoid arthritis;
• osteoarthritis;
• fibromyalgia;
• human immunodeficiency virus (HIV) infections;
• dissociative disorders such as body dysmorphic disorders;
• eating disorder such as anorexia and bulimia;
• ulcerative colitis;
• Crohn's disease;
• irritable bowel syndrome;
• functional abdominal pain;
• chronic fatigue syndrome;
• sudden infant death syndrome (SIDS);
• overactive bladder;
• chronic cystitis;
• chemotherapy induced cystitis;
• cough, angiotensin converting enzyme (ACE) induced cough;
• itch;
• hiccups;
• premenstrual syndrome:
• premenstrual dysphoric disorder;
• schizophrenia;
• schizoaffective disorder;
• delusional disorder;
• substance-induced psychotic disorder;
• brief psychotic disorder;
• shared psychotic disorder;
• psychotic disorder due to a general medical condition;
• schizophreniform disorder;
• amenorrheic disorders such as desmenorrhea;
• obesity;
• epilepsy:
• movement disorders such as primary movement disorders, spasticities, Scott's syndrome, Tourette's syndrome, palsys, amyolateral sclerosis (ALS), akinetic-rigid disorders, akinesias, dyskinesias, restless leg syndrome and movement disorders associated with Parkinson's disease or Huntington's disease;
• mastalgia syndromes;
• motion sickness;
• immune dysfunctions;
• generalized anxiety disorder;
• panic disorder;
• phobias, including social phobia, agoraphobia, and specific phobias;
• obsessive-compulsive disorder;
• post-traumatic stress disorder;
• depression including major depression, single episode depression, recurrent depression, child abuse induced depression, postpartum depression and dysthemia;
• cyclothymia;
• bipolar disorder;
• neurocardiac disorders such as neurocardiac syncope, neurogenic syncope, hypersensitive Carotid sinus, neurovascular syndrome and arrythmias including arrythmias secondary to gastrointestinal disturbances;
• addiction disorders involving addictions to behaviors;
• HIV-1 associated dementia, AIDS dementia complex, HIV encephalopathy, HIV related neuralgias;
• AIDS related neuralgias;
• epilepsy;
• and attention deficit hyperactivity disorder in a mammal, comprising administering to said mammal an amount of a compound of the formula I,
• 12
• wherein
• X1 is hydrogen, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms or (C1-C10) alkyl optionally substituted with from one to three fluorine atoms;
• X2 and X3 are independently selected from halo, hydrogen, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, (C1-C6)-alkylamino, di-(C1-C6)alkylamino, —C(═O)—NH—(C1-C6)alkyl, (C1-C6)alkyl-C(═O)—NH—(C1-C6)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, —NHC(═O)H and —NHC(═O)—(C1-C6)alkyl;
• and
• Q is a group of the formula
• 13
• wherein
• R1 is a radical selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl optionally substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C1-C3) alkoxy-carbonyl;
• R13 is selected from (C3-C4) branched alkyl, (C5-C6) branched alkenyl, (C5-C7) cycloalkyl, and the radicals named in the definition of R1;
• R2 is hydrogen or (C1-C6) alkyl;
• R3 is phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl or furyl, and R3 may optionally be substituted with from one to three substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms;
• Y is (CH2)I wherein I is an integer from one to three, or Y is a group of the formula
• 14
• Z is oxygen, sulfur, amino, (C1-C3)alkylamino or (CH2)n wherein n is zero, one or two;
• o is two or three;
• p is zero or one;
• x is an integer from zero to four;
• y is an integer from zero to four;
• z is an integer from one to six, and the ring in formula VIII containing (CH2)z may contain from zero to three double bonds, and one of the carbons of said (CH2)z may optionally be replaced by oxygen, sulphur or nitrogen;
• R4 is furyl, thienyl, pyridyl, indolyl, biphenyl, or phenyl optionally substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, (C1-C3) alkoxy-carbonyl and benzyloxycarbonyl;
• R5 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms and (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms;
• X is (CH2)q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH2)q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R8, and wherein any one of the carbon atoms of said (CH2)q may optionally be substituted with R9;
• m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH2)m may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH2)m having an available bonding site may optionally be substituted with R11;
• R6 is a radical selected from hydrogen, (C1-C6) straight or branched alkyl, (C3-C7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur;
• aryl selected from biphenyl, phenyl, indanyl and naphthyl;
• heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl;
• phenyl (C2-C6) alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl (C2-C6) alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C1-C10) alkyl optionally substituted with from one to three fluorine atoms, (C1-C10) alkoxy optionally substituted with from one to three fluorine atoms, amino, hydroxy-(C1-C6)alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)-alkylamino, (C1-C6)alkyl-O—C(═O)—, (C1-C6) alkyl-O—C(═O)—(C1-C6)alkyl, (C1-C6)alkyl-C(═O)—O—, (C1-C6)alkyl-C(═O)—(C1-C6)alkyl-O—, (C1-C6)alkyl-C(═O)—, (C1-C6)alkyl-C(═O)—(C1-C6)alkyl-, di-(C1-C6)alkylamino, —C(═O)NH—(C1-C6)alkyl,(C1-C6)-alkyl-C(═O)—NH—(C1-C6)alkyl, —NHC(═O)H and —NHC(═O)—(C1-C6) alkyl;
• and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;
• R7 is hydrogen, phenyl or (C1-C6)alkyl;
• or R6 and R7, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;
• R8 and R9 are each independently selected from hydrogen, hydroxy, halo, amino, oxo (═O), nitrile, hydroxy-(C1-C6)-alkyl, (C1-C6)alkoxy-(C1-C6)alkyl, (C1-C6)alkylamino, di-(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkyl-O—C(═O)—, (C1-C6)alkyl-O—C(═O)—(C1-C6)alkyl, (C1-C6)alkyl-C(═O)—O—, (C1-C6)alkyl-C(═O)—(C1-C6)alkyl-O—, (C1-C6)alkyl-C—, (C1-C6)alkyl-C(═O)—(C1-C6)alkyl-, and the radicals set forth in the definition of R6;
• R10 is NHC(═O)R12, NHCH2R12, NHSO2R12 or one of the radicals set forth in any of the definitions of R6, R8 and R9;
• R11 is oximino (═NOH) or one of the radicals set forth in any of the definitions of R6, R8 and R9;
• and
• R12 is (C1-C6)alkyl, hydrogen, phenyl(C1-C6)alkyl or phenyl optionally substituted with (C1-C6)alkyl;
• with the proviso that (a) when m is 0, R11 is absent, (b) neither R8, R9, R10 nor R11 can form, together with the carbon to which it is attached, a ring with R7, (c) when Q is a group of the formula VIII, R8 and R9 cannot be attached to the same carbon atom, (d) when R8 and R9 are attached to the same carbon atom, then either each of R8 and R9 is independently selected from hydrogen, fluoro, (C1-C6) alkyl, hydroxy-(C1-C6)alkyl and (C1-C6)alkoxy-(C1-C6)alkyl, or R8 and R9, together with the carbon to which they are attached, form a (C3-C6) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached, (e) when neither X1, X2 nor X3 is a fluorinated alkoxy group, at least one of R1, R3, R4, R5, R6, R7 and R13 is an aryl group substituted with a fluorinated alkoxy group;
• or a pharmaceutically acceptable salt thereof,
• or a compound selected from the group consisting of:
• (2S,3S)-3-(6-methoxy-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl)methylamino-2-phenylpiperidine;
• (2S,3S)-3-(6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl)methylamino-2-phenylpiperidine;
• (2S,3S)-3-(6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl)methylamino-2-phenylpiperidine;
• (2S,3S)-3-(6-methoxy-3-phenyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl)methylamino-2-phenylpiperidine;
• (2S,3S)-3-[1-(6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl)ethylamino]-2-phenylpiperidine;
• (2S,3S)-3-[(1R)-6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl]methylamino-2-phenylpiperidine;
• (2S,3S)-3-[(3R)-6-methoxy-3-methyl-3-trifluoromethyl-1,3-dihydroisobenzofuran-5-yl)methylamino-2-phenylpiperidine;
• (2S,3S)-N-(5-ethyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabi-cyclo[2.2.2]octan-3-amine;
• (2S,3S)-N-(5-isopropyl-2-methoxyphenyl)methyl-2-di-phenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
• (2S,3S)-N-(5-sec-butyl-2-methoxyphenyl)-methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
• (2S,3S)-N-(5-tert-butyl-2-methoxyphenyl)-methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
• and
• (2S,3S)-N-(5-methyl-2-methoxyphenyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octan-3-amine;
• or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder or condition.