Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • 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
  • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
• • 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
  • A61P25/06—Antimigraine agents
• • 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
  • A61P25/20—Hypnotics; Sedatives
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to novel quinoline derivatives, to intermediates used in their preparation, to pharmaceutical compositions containing them and to their medicinal use.
• the compounds of the present invention are agonists of serotonin 7 (5HT7) receptors. They are useful in treating CNS disorders, including depression and disorders that can be treated by modulating circadian rhythms. Examples of such disorders and conditions are seasonal affective disorder, bipolar disorder, jet lag, sleep disorders such as circadian sleep rhythm disorder, sleep deprivation, REM sleep disorders, hypersomnia, parasomnias, sleep-wake cycle disorders, narcolepsy, sleep disorders associated with blindness, sleep disorders associated with obesity, and sleep disorders associated with shift work or irregular work schedules; nocturnal enuresis, and restless leg syndrome.
• Serotonin 7 receptors are present in the suprachiasmatic nucleus (SCN), the brain region that contains the biological clocks, and their activation leads to a resetting of the clocks as a function of dose and timing of treatment.
• SCN suprachiasmatic nucleus
• Such a mechanistic link is evident in numerous paradigms - in in vitro electrophysiological studies of SCN neuronal activity, and in light induced changes in wheel running behavior and nighttime melatonin suppression - in each case activation of 5HT7 receptors having the potential to modulate both clock function and the clock resetting ability of light.
• Full agonists and partial agonists of the 5HT7 receptor therefore offer a wide range of clinically useful therapeutics.
• Behavioral Reviews, 14, 35-47 (1990) refers to the pharmacological effects associated with serotonin receptors including appetite suppression, thermoregulation, cardiovascular/hypotensive effects, sleep, psychosis, anxiety, depression, nausea, emesis, Alzheimer's disease, Parkinson's disease and Huntington's disease.
• R 1 , R 2 and R 3 are independently selected from hydrogen, halo, (C ⁇ -C 6 )alkyl optionally substituted with from one to three halo (i.e., chloro, fluoro, bromo or iodo) atoms; and (C C 6 )alkoxy optionally substituted with from one to three halo atoms;
• R 4 is hydrogen or (C C 3 ) alkyl; and n is one or two; and to the pharmaceutically acceptable salts thereof.
• Compounds of Formula I and their pharmaceutically acceptable salts are potent agonists of 5HT7 receptors.
• non-quinoline ring refers to the ring containing the nitrogen to which R 4 is attached, i.e.,
• the present invention provides compounds of Formula I wherein n is 1. In another embodiment, the present invention provides compounds of Formula I wherein either R 1 and R 2 are both hydrogen or one of R 1 and R 2 is hydrogen and the other is attached at position 5. In another embodiment, n is 1, and either R 1 and R 2 are both hydrogen or one of R and R 2 is hydrogen and the other is attached at position 5.
• the invention provides compounds of Formula I wherein the non-quinoline ring is attached at position 7 or 8.
• compounds of Formula I are provided wherein n is 1 , and either R 1 and R 2 are both hydrogen or one of R 1 and R 2 is hydrogen and the other is attached at position 5, and the non-quinoline ring is attached at position 7.
• R 4 , R 1 and R 3 are defined as above.
• Examples of preferred compounds of the Formula I of the invention are: R and S - (3-Ethyl-7-methyl-8-piper idin-3-yl-quinoline);
• the present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
• the present invention also provides a method for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, comprising administering to a mammal requiring such treatment a serotonin 7 receptor agonizing effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
• the present invention also provides a pharmaceutical composition for treating a condition or disorder that can be treated by modulating serotonergic neurotransmission in a mammal, comprising: a) a pharmaceutically acceptable carrier; b) an amount of a first compound of Formula I or a pharmaceutically acceptable salt thereof; and c) an amount of a second compound selected from the group consisting of a
• the present invention also provides a method for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, comprising administering to a mammal requiring such treatment: a) an amount of a compound of Formula I or a pharmaceutically acceptable salt thereof; and b) an amount of a second compound selected from the group consisting of 5HT reuptake inhibitor, a 5HT7 receptor antagonist and an NK1 receptor antagonist or pharmaceutically acceptable salt thereof; wherein the amounts of (a) and (b) are together effective in treating such disorder or condition.
• the present invention also provides a method for treating a disorder or condition selected from depression, anxiety, avoidant personality disorder, premature ejaculation, eating disorders, migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, jet lag, sleep disorder, nocturnal enuresis, and restless leg syndrome in a mammal, comprising administering to a mammal in need of such treatment an amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, which amount is (a) effective in treating such disorder or condition, or (b) effective in agonizing 5HT7 receptors.
• a disorder or condition selected from depression, anxiety, avoidant personality disorder, premature ejaculation, eating disorders, migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, jet lag, sleep disorder, nocturnal enuresis, and restless leg syndrome in a mammal
• the sleep disorder is circadian sleep rhythm disorder, sleep deprivation, REM sleep disorder, hypersomnia, parasomnia, sleep-wake cycle disorder, sleep disorder associated with blindness, sleep disorder associated with obesity, narcolepsy or sleep disorder associated with shift work or irregular work schedules.
• the present invention also provides a method of treating a disorder or condition selected from depression, anxiety, avoidant personality disorder, premature ejaculation, eating disorders, migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder, jet lag, sleep disorder, nocturnal enuresis, and restless leg syndrome in a mammal, comprising administering to a mammal requiring such treatment: (a) and amount of a first compound of Formula I or pharmaceutically acceptable salt thereof; and (b) an amount of a second compound selected from the group consisting of a 5HT7 receptor antagonist, a NK1 receptor antagonist and an a 5HT7 receptor antagonist or pharmaceutically acceptable salts of said second compound; wherein the amounts of (a) and (b) are together effective in treating such disorder or condition.
• a disorder or condition selected from depression, anxiety, avoidant personality disorder, premature ejaculation, eating disorders, migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal affective disorder, bipolar disorder,
• the sleep disorder is circadian sleep rhythm disorder, sleep deprivation, REM sleep disorder, hypersomnia, parasomnia, sleep-wake cycle disorders, sleep disorder associated with blindness, sleep disorder associated with obesity, narcolepsy, or sleep disorder associated with shift work or irregular work schedules.
• the present invention also provides compounds of the Formula
• R 1 , R 2 and R 3 are independently selected from hydrogen, halo, (CrC 6 )alkyl optionally substituted with from one to three halo atoms; and (Cr C 6 )alkoxy optionally substituted with from one to three halo atoms.
• R 1 , R 2 and R 3 are independently selected from hydrogen, halo, (CrC 6 )alkyl optionally substituted with from one to three halo atoms; and (Cr C 6 )alkoxy optionally substituted with from one to three halo atoms.
• the present invention also provides a method for synthesizing a compound of the
• R 1 , R 2 and R 3 are independently selected from hydrogen, halo, (C C 6 )alkyl optionally substituted with from one to three halo atoms; and (C C 6 )alkoxy optionally substituted with from one to three halo atoms; which method comprises reacting a compound of the Formula
• R— OH wherein R is as recited above, wherein said reaction is in the presence of an aqueous acid and 3- nitrobenzenesulfonic acid or a salt thereof, and wherein said reaction is at a temperature of from about 100°C to about 140°C.
• the present invention also provides a method for synthesizing a compound of the
• R 1 , R 2 and R 3 are independently selected from hydrogen, halo, (d-C- ⁇ Jalkyl optionally substituted with from one to three halo atoms; and (C C- ⁇ Jal oxy optionally substituted with from one to three halo atoms; which method comprises reacting a compound of the Formula
• R is as recited above, or, preferably, with a compound
• R 3 — OH wherein R 3 is as recited above, wherein said reaction is in the presence of an aqueous acid and 3- nitrobenzenesulfonic acid or a salt thereof, and wherein said reaction is at a temperature of from about 100°C to about 140°C.
• the aqueous acid is in one embodiment sulfuric acid.
• Compounds of Formula I may contain chiral centers and therefore may exist in different enantiomeric and diastereomeric forms.
• This invention relates to all optical isomers and all stereoisomers of compounds of the Formula I, both as racemic mixtures and as individual enantiomers and diastereoisomers of such compounds, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment defined above that contain or employ them, respectively.
• Individual isomers can be obtained by known methods, such as optical resolution, optically selective reaction, or chromatographic separation in the preparation of the final product or its intermediate.
• Individual enantiomers of the compounds of Formula I may have advantages, as compared with the racemic mixtures of these compounds, in the treatment of various disorders or conditions.
• the compounds of Formula I of this invention are basic compounds, they are capable of forming a wide variety of different salts with various inorganic and organic acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bi-tartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1 ,1'-methylene-bis-(2-hydroxy-3- naphthoate)
• the present invention also includes isotopically labelled compounds, which are identical to those recited in Formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
• isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 0, 17 0, 31 P, 32 P, S, F, and CI, respectively.
• Isotopically labelled compounds of Formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples below, by substituting a readily available isotopically labelled reagent for a non- isotopically labelled reagent.
• “Serotonin 7 agonists” are useful for the treatment of depression.
• depression includes major depressive disorder; single episode or recurrent major depressive episodes; recurrent depression; dysthymia; cyclothymia; depressive disorders not otherwise specified; seasonal affective disorder; and bipolar disorders, for example, bipolar I disorder, bipolar II disorder and bipolar disorder not otherwise specified.
• mood disorders encompassed within the term “depression”, as used herein, include dysthymic disorder with early or late onset and with or without atypical features; dementia of the Alzheimer's type, with early or late onset, with depressed mood; vascular dementia with depressed mood; mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics or other substances; schizoaffective disorder of the depressed type; and adjustment disorder with depressed mood.
• depression is: depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, child abuse induced depression, and post partum depression.
• Major depression is characterized by feelings of intense sadness and despair, mental slowing and loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical changes also occur, especially in severe or "melancholic" depression. These include insomnia or hypersomnia, anorexia and weight loss (or sometimes overeating), decreased energy and libido, and disruption of normal circadian rhythms of activity, body temperature, and many endocrine functions.
• the Serotonin 7 agonists of Formula I of the invention are also useful for the treatment of anxiety.
• anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalized anxiety disorders.
• Generalized anxiety is typically defined as an extended period (e.g., at least six months) of excessive anxiety or worry with symptoms on most days of that period. The anxiety and worry is difficult to control and may be accompanied by restlessness, being easily fatigued, difficulty concentrating, irritability, muscle tension, and disturbed sleep.
• “Panic disorder” is defined as the presence of recurrent panic attacks followed by at least one month of persistent concern about having another panic attack.
• a “panic attack” is a discrete period in which there is a sudden onset of intense apprehension, tearfulness or terror. During a panic attack, the individual may experience a variety of symptoms including palpitations, sweating, trembling, shortness of breath, chest pain, nausea and dizziness. Panic disorder may occur with or without agoraphobia.
• Phobias includes agoraphobia, specific phobias and social phobias.
• Agoraphobia is characterized by an anxiety about being in places or situations from which escape might be difficult or embarrassing or in which help may not be available in the event of a panic attack. Agoraphobia may occur without history of a panic attack.
• a "specific phobia” is characterized by clinically significant anxiety provoked by a feared object or situation.
• Specific phobias include the following subtypes: animal type, cued by animals or insects; natural environment type, cued by objects in the natural environment, for example storms, heights or water; blood- injection-injury type, cued by the sight of blood or an injury or by seeing or receiving an injection or other invasive medical procedure; situational type, cued by a specific situation such as public transportation, tunnels, bridges, elevators, flying, driving or enclosed spaces; and other type, where fear is cued by other stimuli.
• Specific phobias may also be referred to as simple phobias.
• a "social phobia” is characterized by clinically significant anxiety provoked by exposure to certain types of social or performance circumstances. Social phobia may also be referred to as social anxiety disorder.
• anxiety disorders encompassed within the term “anxiety” include anxiety disorders induced by alcohol, amphetamines, caffeine, cannabis, cocaine, hallucinogens, inhalants, phencyclidine, sedatives, hypnotics, anxiolytics and other substances, and adjustment disorders with anxiety or with mixed anxiety and depression.
• Anxiety may be present with or without other disorders, such as depression in mixed anxiety and depressive disorders.
• the compositions of the present invention are therefore useful in the treatment of anxiety with or without accompanying depression.
• alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
• alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, iso- sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbomyl, and the like.
• alkoxy as used herein, unless otherwise indicated, means “alkyl-O-", wherein “alkyl” is as defined above.
• alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and pentoxy.
• alkenyl as used herein, unless otherwise indicated, includes unsaturated hydrocarbon radicals having one or more double bonds connecting two carbon atoms, wherein said hydrocarbon radical may have straight, branched or cyclic moieties or combinations thereof.
• alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and dimethylpentyl, and include E and Z forms where applicable.
• aryl as used herein, unless otherwise indicated, includes an aromatic ring system with no heteroatoms, which can be either unsubstituted or substituted with one, two or three substituents selected from the group consisting of halo, (C ⁇ -C )alkyl optionally substituted with from one to three fluorine atoms and (C C 4 )alkoxy optionally substituted with from one to three fluorine atoms.
• heteroaryl includes an aromatic heterocycle containing five or six ring members, of which from 1 to 4 can be heteroatoms selected, independently, from N, S and O, and which rings can be unsubstituted, monosubstituted or disubstituted with substituents selected, independently, from the group consisting of halo, (C C )alkyl, and (C-
• substituents refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites.
• halo and halogen, as used herein, unless otherwise indicated, include, fluoro, chloro, bromo and iodo.
• treating refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or preventing one or more symptoms of such condition or disorder.
• treatment refers to the act of treating, as “treating” is defined immediately above.
• Modemating serotonergic neurotransmission refers to increasing or improving, or decreasing or retarding the neuronal process whereby serotonin is released by a pre-synaptic cell upon excitation and crosses the synapse to stimulate or inhibit the post- synaptic cell.
• active compounds and “active agents” are synonymous and are therefore interchangeable.
• This term refers to the compounds of Formula I or its pharmaceutically acceptable salts thereof either alone or in combination with one or more of the compounds selected from the group consisting of 5HT1D receptor antagonists, NK1 receptor antagonists, 5HT7 receptor antagonists or pharmaceutically acceptable salts of any of the compounds identified herein.
• Scheme 1 illustrates the synthesis of compounds of the Formula I wherein R 4 is hydrogen, n is two, and the saturated nitrogen containing ring is piperidin-3-yl and is attached to position "7" of the quinoline nucleus.
• a compound of Formula X is reacted with a compound of the Formula XI and 3-nitrobenzenesufonic acid or salt thereof, such as the Group IA salt, e.g., sodium salt thereof in aqueous acid, e.g., sulfuric acid, at a temperature from about 100°C, to about 140°C, preferably at 110°C, to form the corresponding quinoline derivative of Formula XII.
• the Group IA salt e.g., sodium salt thereof in aqueous acid, e.g., sulfuric acid
• R 3 -OH An alcohol, R 3 -OH, may be used instead of the reactant XI.
• THF tetrahydrofuran
• 1 ,4,-dioxane or 1 ,2,- dichloroethane preferably THF
• Reduction of the pyridine derivative of Formula XIII using lithium triethylborohydride in tetrahydrofuran (THF) yields the corresponding piperidine derivative of Formula XIV.
• This reaction is typically carried out at a temperature from about 0°C to about 70°C, preferably at about room temperature.
• Alternate reducing agents and solvents can be used. These are well known to those of ordinary skill in the art (e.g., lithium tri-isobutylborohydride, lithium triphenyl borohydride, and the like.). Lithium triphenyl borohydride in THF is preferred.
• the piperidine derivative of Formula XIV is then converted into the corresponding ester of Formula XV by reacting it with di-t-butyldicarbonate in the presence of a tertiary amine base such as triethylamine, 4-methyl morpholine, or DBU (1 ,8 - diazabicyclo[5.4.0. ] undec - 7 -ene preferably triethylamine.
• a tertiary amine base such as triethylamine, 4-methyl morpholine, or DBU (1 ,8 - diazabicyclo[5.4.0. ] undec - 7 -ene preferably triethylamine.
• Suitable solvents for this reaction include chloro alkanes (e.g., methylene chloride), 1 ,4-dioxane, THF and 1 ,2,-dichIoroethane. Methylene chloride is preferred.
• the reaction temperature can range from about 0 °C to about
• Chiral column chromatography can be used to separate the enantiomers that comprise the racemic compound of Formula XV.
• Each enantiomer ester can then be deprotected using methods well known to those of skilled in the art, for example, by hydrolysis with a strong acid such as hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid, in a solvent such as methanol, methylene chloride, dioxane, ethyl ether, or ethyl acetate, to form the corresponding enantiomeric acid salt of a compound of the Formula IA.
• hydrochloric acid is used. This reaction is typically carried out at a temperature from about 0°C to about 70°C, and is preferably carried out at about room temperature.
• Scheme 1 can also be used to prepare compounds identical to those of Formula IA but for the piperidine ring is being attached to the quinoline nucleus at position "8". This can be accomplished by replacing the starting material of Formula X with the analogous compound wherein the bromo and amino groups are ortho to each other.
• synthesizing intermediates analogous to intermediate XII having the bromine in position "8" according to Scheme 1 use of an alcohol R 3 -OH instead of a compound of formula XI is preferred.
• Scheme 2 illustrates the synthesis of compounds of the Formula I wherein n is 2, R 4 is hydrogen, R 3 is attached to position "4" of the quinoline nucleus, and the saturated nitrogen containing ring of Formula l is a piperidin-3-yl ring that is attached to position "8" of such nucleus.
• a compound of the Formula XVI is reacted with palladium triphenylphosphine dichloride and [diethyl (3-pyridyl) borane] in the presence of an inorganic base, e.g., metal carbonates such as sodium carbonate potassium carbonate, calcium carbonateor cesium carbonate, and the like, preferably sodium carbonate, in an organicsolvent such as THF, 1 ,4,-dioxaneor 1 ,2,-dichloroethane, preferably THF, at a temperature from about 80 °C to about 120°C, preferably at about 90°C, to form the corresponding compound of Formula XVII.
• an inorganic base e.g., metal carbonates such as sodium carbonate potassium carbonate, calcium carbonateor cesium carbonate, and the like, preferably sodium carbonate
• organicsolvent such as THF, 1 ,4,-dioxaneor 1 ,2,-dichloroethane, preferably THF, at
• Reduction of the nitrobenzene derivative of Formula XVII yields the corresponding aniline derivative of Formula XVIII.
• This reduction can be accomplished using methods well known to those of skill in the art, e.g., reaction with hydrogen gas at a pressure of 50 psi, in a methanol solvent, in the presence of a platinum oxide catalyst.
• This reaction is typically conducted at a temperature from about zero to about 40°C, and is preferably conducted at about room temperature.
• the resulting pyridine derivative of Formula XVIII is then reduced to form the corresponding piperidine derivative of Formula XIX using the methods described above, in the description of the reactions in Scheme I, for reducing compounds of the Formula XIII.
• the racemic compound of Formula IB can be separated into its enantio
• Scheme 3 illustrates the preparation of compounds of the Formula I wherein n is 2, R 4 is hydrogen, R 3 is attached to position “3" of the quinoline nucleus, and the saturated nitrogen containing ring of Formula I is a piperidin-3-yl ring that is attached to position "8" of such nucleus.
• the compound of Formula XXI is reacted with palladium triphenylphosphine dichloride and [diethyl (3-pyridyl) borane] in the presence of sodium carbonate or another inorganic base such as potassium carbonate, calcium carbonate or cesium carbonatein an organic solvent such as tetrahydrofuran (THF), 1 ,4,-dioxaneor 1,2,- dichloroethane, preferably THF, at a temperature from about 80 °C to about 120°C, preferably at about 90°C, to form the corresponding compound of Formula XVIII.
• THF tetrahydrofuran
• an organic solvent such as an alcohol of 1-6 carbon atoms, e.g., ethanol,
• Reduction of the pyridine substituted quinoline derivative of Formula XXII using lithium triethylborohydride in tetrahydrofuran (THF) yields the corresponding piperidine substituted quinoline derivative of Formula IC.
• This reaction is typically carried out at a temperature from about 0°C to about 70°C, preferably at about 25°C.
• Alternate reducing agents and solvents can be used. These are well known to those of ordinary skill in the art.
• the racemic compound of Formula IC can be separated into its enantiomers as illustrated in Schemes 1 , 2 and 3 and described above for the preparation of the enantiomers of compounds of the Formula IA.
• Scheme 4 illustrates the syntheses of compounds of the Formula I wherein n is 1 , R 4 and R 2 are hydrogen, and R 1 is attached to position "5" of the quinoline nucleus.
• the compound of Formula IVA is reacted with [3-oxo-pyrrolidine-1 -carboxylic acid tert-butyl ester] and n-butyl lithium in an organic solvent such as tetrahydrofuran (THF), diethyl ether or 1 ,4-dioxane, preferably THF, at a temperature from about -77°C to about -100°C, preferably at about -77°C, to form the corresponding compound of Formula XXIII.
• THF tetrahydrofuran
• diethyl ether diethyl ether
• 1 ,4-dioxane preferably THF
• the resulting compound of Formula XXIV can be reduced to form the corresponding racemic compound of Formula ID.
• This reduction can be accomplished using methods well known to those of ordinary skill in the art, e.g., reaction with hydrogen gas at a pressure of 50 psi, in a solvent such as acetic acid, methanol or ethanol, in the presence of a platinum oxide catalyst.
• Acetic acid is preferred for reduction of the free base pyrrolene to the free base pyrrolidine, while methanol or ethanol is preferred for reducing the hydrochloride salt of the pyrrolene to the hydrochloride salt of the pyrrolidine.
• This reaction is typically conducted at a temperature from about zero to about 40°C, and is preferably conducted at about room temperature.
• Scheme 4 can also be used to prepare compounds identical to those of Formula ID but for the fact that the pyrrolidine ring is attached to the quinoline nucleus at position "7". This can be accomplished by replacing the starting material of Formula IVA with the analogous compound wherein the bromo group is attached to the quinoline ring at position "7".
• Scheme 5 illustrates the formation of compounds of the Formula I wherein R 4 is other than hydrogen from the corresponding compounds of the Formula I wherein R 4 is hydrogen.
• the procedure illustrated in Scheme 5 can be used generally to convert compounds of the Formula I wherein R 4 is other than hydrogen into the corresponding compounds wherein R 4 is hydrogen.
• racemic compounds of Formula ID, ID', IE and IE" can be separated into its enantiomers as illustrated in Schemes 1 , 2 and 3 and described above for the preparation of the enantiomers of compounds of the Formula IA.
• the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).
• the compounds of Formula I that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the Formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt.
• the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
• the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3- naphthoate)] salts.
• non-toxic acid addition salts i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate,
• any of the combination methods of the present invention referred to above, whichever components (a) and (b) that are utilized, i.e., whichever combination of a compound of Formula I or pharmaceutically acceptable salt thereof and 5HTID receptor antagonist or salt, NK1 receptor antagonist or salt or sertonin reuptake inhibitor or salt, the combination will be administered to a patient within a reasonable period of time.
• the compounds may be in the same pharmaceutically acceptable carrier and therefore administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms that are taken simultaneously.
• the term combination as used above, also refers to the case where the pharmaceutically active compounds are provided in separate dosage forms and are administered sequentially.
• the NK1 receptor antagonist may be administered as a tablet and then, within a reasonable period of time, the compound of the Formula I may be administered either as an oral dosage form such as a tablet or a fast-dissolving oral dosage form.
• a fast dissolving oral formulation is meant, an oral delivery form which when placed on the tongue of a patient, dissolves within about seconds.
• serotonin reuptake inhibitors examples include sertraline, fluoxetine and paroxetine.
• Sertraline, (1S-cis)-4- (3,4-dichlorophenyl)-1 ,2,3,4-tetrahydro-N-methyl-1-naphthalenamine has the chemical formula C 17 H 17 NCI 2 and the following structural formula
• Sertraline hydrochloride is useful as an antidepressant and anorectic agent, and is also useful in the treatment of depression, chemical dependencies, anxiety obsessive compulsive disorders, phobias, panic disorder, post traumatic stress disorder, and premature ejaculation.
• NK-1 receptor antagonists that may be used in the methods and pharmaceutical compositions of this invention are compounds of the Formula
• X 1 is hydrogen, (C C-io) alkoxy optionally substituted with from one to three fluorine atoms or (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms;
• R 1 is a radical selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl optionally substituted with one or two substituents independently selected from halo,
• (C-i-Cio) alkyl optionally substituted with from one to three fluorine atoms, (CrC 0 ) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C 1 -C 3 ) alkoxy-carbonyl;
• R 13 is selected from (C 3 -C ) branched alkyl, (C 5 -C 6 ) branched alkenyl, (C 5 -C 7 ) cycloalkyl, and the radicals named in the definition of R 1 ;
• R 2 is hydrogen or (C ⁇ -C 6 ) alkyl
• R 3 is phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl or furyl, and R 3 may optionally be substituted with from one to three substituents independently selected from halo, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms and (C C ⁇ 0 ) alkoxy optionally substituted with from one to three fluorine atoms;
• Y is (CH 2 ) ⁇ wherein I is an integer from one to three, or Y is a group of the Formula
• Z is oxygen, sulfur, amino, (C C 3 )alkylamino or (CH 2 ) 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 (CH 2 ) Z may contain from zero to three double bonds, and one of the carbons of said (CH ) Z may optionally be replaced by oxygen, sulphur or nitrogen;
• R 4 is furyl, thienyl, pyridyl, indolyl, biphenyl, or phenyl optionally substituted with one or two substituents independently selected from halo, (C ⁇ C- t o) alkyl optionally substituted with from one to three fluorine atoms, (C C ⁇ 0 ) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, (C ⁇ -C 3 ) alkoxy-carbonyl and benzyloxycarbonyl;
• R 5 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C C 10 ) alkyl optionally substituted with from one to three fluorine atoms and (CrC 10 ) alkoxy optionally substituted with from one to three fluorine atoms;
• X is (CH 2 ) q wherein q is an integer from 1 to 6, and wherein any one of the carbon- carbon single bonds in said (CH 2 ) q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 8 , and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 9 ;
• m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH 2 ) m may optionally be replaced by a carbon-carbon double bond or a carbon
• R 6 is a radical selected from hydrogen, (C C 6 ) straight or branched alkyl, (C 3 -C 7 ) 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
• R 7 is hydrogen, phenyl or (C C 6 )alkyl; or R 6 and R 7 , 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;
• R 8 and R 9 are each independently selected from hydrogen, hydroxy, halo, amino, oxo
• R 10 is NHCR 12 , NHCH 2 R 12 , NHS0 2 R 12 or one of the radicals set forth in any of the definitions of R 6 , R 8 and R 9 ;
• R 12 is (CrCe)alkyl, hydrogen, phenyl(C C 6 )alkyl or phenyl optionally substituted with (C C 6 ) alkyl; and with the proviso that (a) when m is 0, R 11 is absent, (b) neither R 8 , R 9 , R 10 nor R 11 can form, together with the carbon to which it is attached, a ring with R 7 , (c) when Q is a group of the Formula VIII, R 8 and R 9 cannot be attached to the same carbon atom, (d) when R 8 and R 9 are attached to the same carbon atom, then either each of R 8 and R 9 is independently selected from hydrogen, fluoro, (C C 6 ) alkyl, hydroxy-(C C 6 )alkyl and or R 8 and R 9 , together with the carbon to which they are attached, form a (C 3 -C 6 ) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached
• Preferred methods of this invention include the above combination methods wherein the an NK1 receptor antagonist that is employed in such method is a compound of the Formula IX wherein R 1 , R 4 , R 5 and R 7 are phenyl, R 2 is hydrogen, R 3 is phenyl optionally substituted with chlorine, fluorine, (C C 6 ) alkyl optionally substituted with from one to three fluorine atoms or (C r
• NK1 receptor antagonist is a compound of the Formula IX selected from:
• NK1 receptor antagonists useful in the present invention are selected from:
• NK1 receptor antagonist that is employed in such methods is a compound of the Formula IX wherein o is two or three and each of R 1 and R 13 is phenyl or substituted phenyl.
• NK1 receptor antagonist that is employed in such methods is a compound of the Formula IX wherein Q is a group of the Formula III, R 2 is hydrogen and R 3 is phenyl or substituted phenyl.
• the NK1 receptor antagonist that is employed in such methods is a compound of the Formula IX wherein Q is a group of the Formula V wherein n is zero or one and each of R 4 and R 5 is phenyl or substituted phenyl.
• NK1 receptor antagonist that is employed in such methods is a compound of the Formula IX wherein Q is a group of the Formula VI wherein p is one and each of R 4 and R 5 are phenyl or substituted phenyl.
• NK1 receptor antagonist that is employed in such methods is a compound of the Formula IX wherein Q is a group of the Formula VII wherein q is two, three or four, m is zero and R 6 is phenyl or substituted phenyl.
• NK1 receptor antagonist that is employed in such methods is selected from:
• NK1 receptor antagonists useful in the present invention include: 5-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiazolidine-2,4-dione;
• NK-1 receptor antagonists of the Formula IX can be prepared as described in the following patents and patent applications, all of which are referred to above and incorporated herein by reference in their entirety: WO 93/00331, WO 92/21677, WO 92/15585, WO 92/01688, WO 93/06099, WO 91/18899, United States Patent 5,162,339, and United States Patent 5,232,929.
• NK1 receptor antagonists that can be used, together with the 5HT7 agonists of the Formula I, for the treatment of anxiety or depression in accordance with the methods and pharmaceutical compositions of the present invention are those compounds and pharmaceutically acceptable salts described in the following references: European Patent Application EP 499,313, published August 19, 1992; European Patent Application EP 520,555, published December 30, 1992; European Patent Application EP 522,808, published January 13, 1993, European Patent Application EP 528,495, published February 24, 1993, PCT Patent Application WO 93/14084, published July 22, 1993, PCT Patent Application WO 93/01169, published January 21 , 1993, PCT Patent Application WO 93/01165, published January 21 , 1993, PCT Patent Application WO 93/01159, published January 21 , 1993, PCT Patent Application WO 92/20661, published November 26, 1992, European Patent Application EP 517,589, published December 12, 1992, European Patent Application EP 428,434, published May 22, 1991 , and European Patent Application EP 360,390, published March 28, 1990.
• the appropriate dose regimen, the amount of each dose of an active agent administered, and the specific intervals between doses of each active agent will depend upon the subject being treated, the specific active agent being administered and the nature and severity of the specific disorder or condition being treated.
• the active compounds of this invention when used as a single active agent or in combination with another active agent, will be administered to an adult human in an amount from about 0.05 to about 1500 mg per day, in single or divided doses, preferably from about 5 to about 200 mg/day.
• Such compounds may be administered on a regimen of up to 6 times per day, preferably 1 to 4 times per day, especially 2 times per day and most especially once daily. Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
• a proposed daily dose of a 5HT reuptake inhibitor, preferably sertraline, in the combination methods and compositions of this invention, for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above, is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the 5HT reuptake inhibitor per unit dose, which could be administered, for example, 1 to 4 times per day.
• a proposed daily dose of a 5HT1D receptor antagonist in the combination methods and compositions of this invention, for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above, is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the 5HT1 D receptor antagonist per unit dose, which could be administered, for example, 1 to 4 times per day.
• a proposed daily dose of an NK1 receptor antagonist in the combination methods and compositions, for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above, is from about 0.1 mg to about 2000 mg, preferably from about 1 mg to about 200 mg of the NK1 receptor antagonist per unit dose which could be administered, for example, 1 to 4 times per day.
• the 5HT7 receptor agonists, the NK1 receptor antagonists, the serotonin reuptake inhibitors and the 5HT1D receptor antagonists, and their pharmaceutically acceptable salts, that are employed in the pharmaceutical compositions and methods of this invention are hereinafter also referred to as "therapeutic agents".
• the therapeutic agents can be administered via either the oral, buccal, nasal or parenteral route.
• Compositions containing both a 5HT7 receptor agonist and an NK1 receptor antagonist, a 5HT1 D receptor antagonist or a serotonin reuptake inhibitor will generally be administered orally or parenterally daily, in single or divided doses, so that the total amount of each active agent administered falls within the above guidelines.
• the therapeutic agents may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the therapeutic agents of this invention, when administered separately (i.e., not in the same pharmaceutical composition) are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
• the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate).
• binding agents e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
• fillers e.g., lactose, microcrystalline cellulose or calcium phosphate
• lubricants e.g., magnesium stearate, talc or silica
• disintegrants e.g., potato starch or sodium
• Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
• Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
• suspending agents e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats
• emulsifying agents e.g., lecithin or acacia
• non-aqueous vehicles e.g., almond oil, oily esters or ethyl alcohol
• the principal active ingredient is mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a therapeutic agent, or a non-toxic pharmaceutically acceptable salt thereof.
• a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water
• a pharmaceutical carrier e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, di
• This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing, typically, from 0.05 to about 500 mg of each of the therapeutic agents contained in the composition.
• the tablets or pills of the composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
• the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
• the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
• enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac acetyl alcohol and cellulose acetate.
• the composition may take the form of tablets or lozenges formulated in conventional manner.
• the therapeutic agents may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion.
• Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
• the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Solutions of a therapeutic agent in either sesame or peanut oil or in aqueous propylene giycol may be employed.
• aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes.
• the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
• the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
• the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
• the dosage unit may be determined by providing a valve to deliver a metered amount.
• the pressurized container or nebulizer may contain a solution or suspension of the active compound.
• Capsules and cartridges for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
• Aerosol formulations of the active compounds of this invention for treatment of the conditions referred to above in the average adult human are preferably arranged so that each metered dose or "puff" of aerosol contains 20 ⁇ g to 1000 ⁇ g of active compound.
• the overall daily dose with an aerosol will be within the range 100 ⁇ g to 10 mg.
• Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1 , 2 or 3 doses each time.
• the compounds of Formula I may advantageously be used in conjunction with one or more other therapeutic agents, for instance, different antidepressant agents such as tricyclic antidepressants (e.g., amitriptyline, dothiepin, doxepin, trimipramine, butripyline, clomipramine, desipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline), or monoamine oxidase inhibitors (e.g., isocarboxazid, phenelzine or tranylcyclopramine), and/or with antiparkinsonian agents such as dopaminergic antiparkinsonian agents (e.g., levodopa, preferably in combination with a peripheral decarboxylase inhibitor e.g., benserazide or carbidopa, or with a dopamine agonist e.g., bromocriptine, lysuride or pergolide).
• the present invention covers the use of a compound of general Formula I or a physiologically acceptable salt or solvate thereof in combination with one or more other therapeutic agents.
• the affinities of the active compounds for 5HT7 receptors can be determined using standard radioligand binding assays as described in the literature.
• the 5HT7 affinity can be measured using the following procedure.
• Betaplate scintillation counter (Wallac/LKB) Tissue Preparation:
• HEK-293 cells expressing 5HT7 receptors are grown according to standard cell culture techniques. Cells are harvested by removing the media, rinsing the flasks out with phosphate buffered saline (PBS) and then allowed to sit for 2-3 minutes with PBS containing 2.5 mM EDTA. Cells are dislodged and poured into a RcappableS centrifuge tube. Flasks are rinsed with PBS and added to a centrifuge tube. The cells are centrifuged for ten minutes at 40,000 x g (20,000 rpm in a Sorvall SS34 rotor).
• PBS phosphate buffered saline
• Pellets fresh or frozen are homogenized in 50 mM Tris HCI buffer (pH 7.4 at 4 degrees C) using a Polytron homogenizer (setting 15,000 rpm) for ten seconds in a biologcial hood certified for use with human tissues. The homogenate is centrifuged for ten minutes at 40,000 x g. The supernatant is discarded and the pellet resuspended with the Polytron in a fresh ice-cold 50 mM Tris HCI (pH 7.4 at 4 degrees) buffer and centrifuged again.
• the final pellet is resuspended in assay buffer (50 mM Tris HCI buffer (pH 7.7 at 25 degrees) containing 0.5 mM EDTA, 10 mM MgS0 , 2 mM CaCI 2 ) for a final tissue concentration of 5-15 mg wet weight of original pellet per mL buffer (2X final concentration).
• Receptor Binding Incubation is initiated by the addition of tissue to V-bottom polypropylene plates (in triplicate). Incubation is at 25 degrees C for 2 hours. Each tube receives:
• tissue suspension 5-15mg/mL original wet weight
• 50 uL 3 H-5-CT** 0.4 nM final concentration
• 50 uL drug or buffer ** 3 H-5-CT is made up in assay buffer that contains 40 uM pargyline & 0.4% ascorbic acid (for final concentrations of 10 uM pargyline & 0.1 % ascorbic acid).
• Nonspecific binding is determined using 1 uM 5-HT creatinine sulfate. Incubation is ended by rapid filtration under vacuum through fire-treated Whatman GF/B glass fiber filters (presoaked in 0.3% PEI for two hours and dried) using a 96 well Skatron Harvester (3 sec prewet; 20 seconds wash; 15 seconds dry). Filters are put into LKB sample bags with 10 mL BetaScint. Radioactivity is quantified by liquid scintillation counting using a BetaPlate counter (LKB). The percent inhibition of specific binding is calculated for each concentration of test compound. An IC 50 value (the concentration which inhibits 50% of the specific binding) is determined by linear regression of the concentration-response data (log concentration vs. logit percent values).
• L the concentration of the radioligand used in the experiment
• Kd value the dissociation constant for the radioligand determined in separate saturation experiments.
• the binding activities to 5HT7 receptors of approximately 40 compounds of the invention that were assayed as described above ranged from about 3.5 nM to about 5 ⁇ M.
• the title compound of Example 8 showed a Ki of about 7.6 nM
• the title compound of Example 10, below showed a Ki of about 500 nM.
• the following assay can be used to evaluate the functional activity of compounds at 5HT7 receptors:
• Cells are grown according to standard cell culture techniques. Cells are harvested by replacing the media with phosphate-buffered saline containing 2.5 mM EDTA. The cells are homogenized using a hand-held glass-teflon homogenizer. The homogenate is centrifuged at 35,000 x g for 10 minutes at 4 degrees C. The pellet is resuspended in 100 mM HEPES buffer containing 1 mM EGTA (pH 7.5) to a final protein concentration of 40 microgram protein per tube.
• reaction Mix is prepared so that the following agents will be at these final concentrations in tube: 4.0mM MgCI 2 , 0.5m MATP, 1.0m McAMP, 0.5mM lBMX, 10mM, phosphocreatine, 0.31 mg/mL creatine phosphokinase, and 100uM GTPO.5-1 microcuries a- [ 32 P]-ATP per tube.
• Incubation is initiated by the addition of tissue to siliconized microfuge tubes (in triplicate). Incubation is at 37'C for 15 minutes.
• Each tube receives: 20uL tissue, 20uL drug or buffer (at 5X final concentration), 20 uL 100 nM agonist or buffer (at 5X final concentration), and 40 uL "Reaction Mix”.
• the maximal effect of agonists is defined in terms of the maximal effect of serotonin (5-HT). Antagonists are evaluated by their ability to inhibit 5HT-stimulated adenylate cyclase activity. IC 50 values are converted to apparent Ki values by the following equation: IC 50 / (1 + ([agonist]/EC 50 of agonist)).
• Activity of a combination of active compounds to produce an antidepressant effect and related pharmacological properties can be determined by methods (1 )-(4) below, which are described in Koe, B. et al., Journal of Pharmacology and Experimental Therapeutics, 226 (3), 686-700 (1983), which is incorporated herein by reference in its entirety.
• activity can be determined by studying (1) their ability to affect the efforts of mice to escape from a swim-tank (Porsoit mouse "behavior despair” test), (2) their ability to potentiate 5HT - induced behavioral symptoms in mice in vivo, (3) their ability to antagonize the serotonin- depleting activity of p-chloroamphetamine hydrochloride in rat brain in vivo, and (4) their ability to block the uptake of serotonin, norepinephrine and dopamine by synaptosomal rat brain cells in vitro.
• the ability of the active combination to counteract reserpine hypothermia in mice in vivo can be determined according to the methods described in U.S. Pat. No. 4,029,731 , which is incorporated herein by reference in its entirety.
• the aqueous phase of the biphasic reaction mixture is separated and extracted with three 50 ml portions of ethyl acetate.
• the solvent of the organic phase of the reaction mixture is removed in vacuo, and the residue is extracted with two 50 ml portions of ethyl acetate.
• the combined organic extracts are dried (anhydrous sodium sulfate) and concentrated in vacuo, yielding a viscous syrup.
• Step l 3-(2-Methyl-6-nitro-phenyl.-pyridine
• 2-bromo-3-nitrotoluene 5.0 g (23 mmol) in tetrahydrofuran (180 ml)
• diethyl-3-pyridyl borane (3.89 g, 26 mmol)
• bis-triphenylphosphine palladium (II) chloride 2.42 g, 3.45 mmol
• sodium carbonate (12.19 g, 115 mmol) in water (60 ml) were sequentially added.
• the resulting well-stirred reaction mixture was then heated at 75°C for 18 hours.
• Step 3 3-Ethyl-7-methyl-8-pyridin-3-yl-quinoline
• a reaction mixture prepared by combining the title compound of the previous step (800 mg, 4.3 mmol), concentrated sulfuric acid (660 ⁇ l, 12 mmol), and sodium meta- nitrobenzene sulfonate (544 mg, 24 mmol) in water (450 ⁇ l) was well stirred and heated to 100°C while 2-ethyl acrolein (1.26 ml, 13 mmol) was added dropwise over 4 minutes. The reaction mixture was heated at 100°C; then at 120°C for two hours.
• Step l 3-(2-Methyl-6-nitro-phenyl)-pyridine
• 2-bromo-3-nitrotoluene 5.0 g, 23 mmol
• diethyl-3-pyridyl borane 3.89 g, 26 mmol
• bis (triphenylphosphine) palladium (II) chloride 2.42 g, 3.45 mmol
• sodium carbonate (12.19 g, 115 mmol) in water was added.
• the well-stirred reaction mixture was heated at 75°C for 18 hours.
• Step 2 3-Methyl-2-pyridin-3-yl-phenylamine
• the title compound from the previous step (1.87 g, 8.7 mmol) dissolved in ethanol (40 ml) was hydrogenated (40 psi; 200 mg platinum oxide catalyst) for 4 hours.
• the catalyst was removed by filtration through celite.
• the filtrate was concentrated in vacuo to afford an amber oil (1.2 g).
• Step 4 Racemic 3,7-Dimethyl-8-piperidin-3-yl-quinoline To a solution of the title compound from the previous step (328 mg, 1.4 mmol) in anhydrous tetrahydrofuran (10 ml), a 1.0M solution of lithium triethylborohydride in tetrahydrofuran (4.90 ml, 4.9 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 3 hours. After dropwise addition of a second portion of 1.0 M lithium triethylborohydride in tetrahydrofuran (1.40 ml, 1.4 mmol), ambient temperature stirring was continued for an additional 1.5 hours. The reaction was quenched by cautious dropwise addition of methanol (1 ml).
• reaction temperature was again elevated to 140°C and maintained at that temperature for 1.5 hours.
• the mixture was then extracted with 75 ml of methylene chloride. The organic extract was dried (anhydrous sodium sulfate) and concentrated in vacuo, yielding a dark oil.
• Step 2 2-Pyridin-3-yl-phenylamine A solution of the title compound from the previous step (16.3 g, 81 mmol) in methanol (300 ml) was hydrogenated (50 psi; 1.65 g of platinum oxide catalyst) for 3.5 hours. The catalyst was filtered, and the filtrate was concentrated in vacuo to afford a viscous amber oil. Flash chromatography of the entire sample (silica gel, 47-61 micron mesh; elution with ethyl acetate) afforded the title compound 13.5 g, (94.6% yield) as an amber oil. MS m/z 171 (M+ 1). 1 H NMR (400 MHz, CDCI 3 ) ⁇ 8.71 (1 H, m), 8.58 (1 H, m), 7.80 (1H, m), 7.37 (1 H, m),
• Step 4 Racemic 4-Methyl-8-piperidin-3-yl-quinoline To a well-stirred slurry of the title compound from the previous step (254 mg, 1.49 mmol) in ethanol, 0.12 ml of 12 N hydrochloric acid was added, affording a clear solution. Ferric chloride hexahydrate (557 mg, 2.06 mmol) and zinc chloride (24 mg, 10.18 mmol) were added, and the reaction mixture was heated to 60°C. Methyl vinyl ketone (0.016 ml, 0.19 mmol) was added, and the reaction temperature was maintained at 60°C for 1 hour, during which time, additional 0.016 ml portions of methyl vinyl ketone were added at 10 minute intervals.
• Step 5 Racemic 3-(4-Methyl-quinolin-8-yl-piperidine-1 -carboxylic acid tert-butyl ester Utilizing the method of Example 1, Step 6, the entire 131 mg (0.58 mmol) of the racemic free base title compound from the previous step was converted into the corresponding N-tert-butyloxycarbonyl functional ized title compound of this step (yielding 120 mg, 63.4%o yield, as a colorless oil). MS m/z ( M+1).
• Step 7 Enantiomeric 4-Methyl-8-piperidin-3-yl-quinoline (both enantiomers)
• the entire 31 mg and 17 mg samples respectively of the faster and slower eluting enantiomeric title compounds prepared in the previous step were dissolved in 0.5 ml of chloroform.
• a hydrogen chloride saturated diethyl ether solution (1 ml) was added to each. Both reaction mixtures were stirred for 18 hours at ambient temperature.
• Solvent removal in vacuo afforded 15 mg and 9.5 mg respectively of the title compound enantiomers derived from the faster and slower elution Step 6 enantiomeric compounds as colorless amorphous solids.
• the organic extract was dried (anhydrous sodium sulfate) and concentrated in vacuo to afford an amber syrup. Flash chromatography of the entire sample (silica gel, 47-61 micron mesh; elution with ethyl acetate) yielded the title compound (790 mg, 19.1 % yield) as a viscous colorless syrup.
• Step 3 Enantiomeric 3-(3-Methyl-quinolin-8-yl-piperidine-1 -carboxylic acid tert-butyl ester
• methylene chloride 20 ml
• 436 mg 2.0 mmol
• di-tert-butyl dicarbonate was added, and the resulting reaction mixture was stirred for 48 hours at ambient temperature.
• Aqueous saturated sodium bicarbonate (20 ml) was added with efficient stirring. The mixture was then extracted with two 20 ml portions of methylene chloride.
• Step ⁇ Enantiomeric 3-Methyl-8-piperidin-3-yl-quinoline (both enantiomers)
• a 90 mg sample of the faster eluting title compound enantiomer isolated in the previous step was dissolved in 1 ml of methanol.
• a saturated hydrogen chloride solution in diethyl ether was added, and the reaction mixture was stirred at ambient temperature for 18 hours. Solvents and excess hydrochloric acid were removed in vacuo, affording a colorless glass.
• the free base of the enantiomeric title compounds of this step was prepared by the method of Example 1 , Step 6.
• the mass spectra and 1 H NMR spectra of the enantiomeric title compound free bases are identical in all respects to the racemic title compound free base of Step 2, this Example.
• Step 1 To a well-stirred solution of the title compound of Example 1 , Step 1 (2.10 g, 8.9 mmol) in 30 ml of anhydrous tetrahydrofuran chilled to and maintained at -77°C, a 2.5 M solution of n-butyl lithium in hexanes (3.60 ml, 8.9 mmol; Aldrich Chemical Co.) is added dropwise over a 10 minute period. The reaction was stirred at -77°C for 15 minutes before adding a solution of 3-oxo-pyrrolidine-1 -carboxylic acid tert-butyl ester (1.65 g, 8.9 mmol) in anhydrous tetrahydrofuran (10 ml).
• Step 6 Enantiomeric (Both Enantiomers) 3-Ethyl-8-pyridin-3-yl-quinoline
• the racemic title compound of the previous step of this example was converted to the corresponding racemic nitrogen substituted tert-butoxycarbonyl compound, the separated/purified enantiomers of which were then isolated by the methodology of Step 5/Example 1.
• the enantiomers of the title compound of the previous step of this example were prepared in both mono-hydrochloride and free base form.
• the aqueous phase of the biphasic reaction mixture is separated and extracted with an equal volume of ethyl acetate.
• the solvent of the organic phase of the reaction mixture was removed in vacuo and the residue is extracted with ethyl acetate (25 ml).
• the combined organic extracts are dried (anhydrous sodium sulfate) and concentrated in vacuo, yielding a dark viscous oil. Flash chromatography of the entire sample (silica gel, 47-61 micron mesh; elution with ethyl acetate) afford the title compound (807 mg, 58% yield) as a viscous yellow syrup.
• Step 4 Racemic 3-(3-Ethyl-quinolin-7-yl)-piperidine-1 -carboxylic acid tert-butyl ester
• a reaction mixture consisting of the free base title compound from the previous step (390 mg, 1.63 mmol), triethylamine (0.45 ml, 3.25 mmol), and di-tert-butyl dicarbonate (530 mg, 2.44 mmol) in methylene chloride (15 ml) was stirred at ambient temperature for 18 hours. Saturated aqueous sodium bicarbonate (20 ml) was added with efficient stirring. The mixture was then extracted with two 10 ml portions of methylene chloride.

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