JP2006508113A - Quinoline derivatives - Google Patents

Abstract

（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、及びｎは定義したとおりである）の化合物、及び該化合物の薬学的許容塩に関する。式Ｉの化合物は５ＨＴ７受容体に作動する活性を有し、例えば概日リズムを調整することにより治療することが出来る障害を治療するのに有用である。The present invention provides compounds of formula I:
[Chemical 1]

Wherein R1, R2, R3, R4, and n are as defined, and a pharmaceutically acceptable salt of the compound. The compounds of formula I have activity acting on 5HT7 receptors and are useful for treating disorders that can be treated, for example, by modulating circadian rhythm.

Description

  The present invention relates to novel quinoline derivatives, intermediates used in their production, pharmaceutical compositions containing them, and their medical use. The compounds of the present invention are agonists of serotonin 7 (5HT7) receptors. They are useful for the treatment of CNS disorders, including depression and disorders that can be treated by modulating circadian rhythm. Examples of such disorders and symptoms include seasonal morbidity disorder, bipolar nerve cell disorder, jet lag, circadian sleep rhythm disorder, sleep deprivation, REM sleep disorder, hypersomnia, loss of response to stimuli, sleep-wake cycle disorder, Sleep disorders such as narcolepsy, sleep disorders associated with blindness, sleep disorders associated with obesity, 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 area of the brain that contains the biological clock, and their activation resets the clock as a function of dose and treatment timing Guide you to. Such mechanistic linkages are evident in many exemplary cases—in vivo electrophysiological studies of SCN neuronal activity, and light-induced changes in wheel rotation behavior and nocturnal melatonin inhibition—in each case the activity of the 5HT7 receptor The control has the ability to adjust both the clock function and the light clock reset capability. Thus, full and partial agonists of the 5HT7 receptor provide a wide range of clinically useful treatments.

Non-Patent Document 1 relates to serotonin receptors, including appetite suppression, temperature regulation, cardiovascular / hypertensive effects, sleep, psychosis, anxiety, depression, nausea, vomiting, Alzheimer's disease, Parkinson's disease and Huntington's disease Mention pharmacological effects.
Glennon, “Serotonin Receptors: Clinical Implications”, Neuroscience and Behavioral Reviews, 14, 35-47 (1990).

（式中、
Ｒ¹、Ｒ²及びＲ³は独立して、水素、ハロゲン、場合によっては１〜３個のハロゲン（即ち、クロロ、フルオロ、ブロモ又はヨード）原子で置換されていてもよい（Ｃ₁−Ｃ₆
）アルキル、及び場合によっては１〜３個のハロゲン原子で置換されていてもよい（Ｃ₁−Ｃ₆）アルコキシから選ばれ；
Ｒ⁴は水素又は（Ｃ₁−Ｃ₃）アルキルであり；そして
ｎは１又は２である）
の化合物、及びその薬学的許容塩に関する。 The present invention has the formula:

(Where
R ¹ , R ² and R ³ are independently hydrogen, halogen, and optionally substituted with 1 to 3 halogen (ie, chloro, fluoro, bromo or iodo) atoms (C ₁ -C ₆
) Alkyl and optionally selected from (C ₁ -C ₆ ) alkoxy optionally substituted with 1 to 3 halogen atoms;
R ⁴ is hydrogen or (C ₁ -C ₃ ) alkyl; and n is 1 or 2)
And a pharmaceutically acceptable salt thereof.

を云う。 The compounds of formula I and their pharmaceutically acceptable salts (collectively referred to herein as “active compounds of the invention”) are potent agonists of the 5HT7 receptor.
As used herein, a non-quinoline ring is a ring containing a nitrogen to which R ⁴ is attached, ie

Say.

In one embodiment, the present invention provides a compound of formula I, wherein n is 1. In another embodiment, the invention provides that R ¹ and R ² are both hydrogen, or ^one of R ¹ and R ² is hydrogen and the other is attached to the 5-position. In another embodiment, n is 1 and R ¹ and R ² are both hydrogen, or ^one of R ¹ and R ² is hydrogen and the other is bonded to the 5-position.
In another aspect, the present invention provides a compound of formula I wherein the non-quinoline ring is attached at the 7 or 8 position.

In another embodiment, n is 1 and R ¹ and R ² are both hydrogen, or ^one of R ¹ and R ² is hydrogen and the other is bonded to the 5-position, and non- Compounds of formula I are provided in which the quinoline ring is attached at the 7-position.

（式中、Ｒ⁴、Ｒ¹及びＲ³は前に定義した通りである）
を有する式Ｉの化合物を提供する。 In another embodiment, the invention provides a compound of formula:

(Wherein R ⁴ , R ¹ and R ³ are as previously defined)
A compound of formula I having the formula

Examples of preferred compounds of formula I according to the invention are as follows:
R and S- (3-ethyl-7-methyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3-ethyl-7-methyl-8-piperidin-3-yl-quinoline);
R and S- (3,6-dimethyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3,6-dimethyl-8-piperidin-3-yl-quinoline);
R and S- (3,7-dimethyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3,7-dimethyl-8-piperidin-3-yl-quinoline);
R and S- (3,5-dimethyl-8-piperidin-3-yl-quinoline);
R and S- (3,5-dimethyl-8-piperidin-3-yl-quinoline);
R and S- (6-chloro-3-methyl-8-piperidin-3-yl-quinoline);
R , S- (6-Chloro-3-methyl-8-piperidin-3-yl-quinoline);
R and S- (3-ethyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3-ethyl-8-piperidin-3-yl-quinoline);
R and S- (4-methyl-8-piperidin-3-yl-quinoline);
R 1 , S- (4-Methyl-8-piperidin-3-yl-quinoline);
R and S- (3-methyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3-methyl-8-piperidin-3-yl-quinoline);
R and S- (3-ethyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3-ethyl-8-piperidin-3-yl-quinoline);
R and S- (ethyl-7-piperidin-3-yl-quinoline);
R , S- (ethyl-7-piperidin-3-yl-quinoline);
R and S- [3-methyl-8- (1-methyl-piperidin-3-yl) -quinoline]; and
R 1 , S- [3-Methyl-8- (1-methyl-piperidin-3-yl) -quinoline];
And pharmaceutically acceptable salts thereof.

Other examples of specific compounds of formula I according to the invention are as follows:
3-ethyl-7-methyl-8- (1-methyl-piperidin-3-yl) -quinoline;
3-ethyl-8-methyl-8- (1-ethyl-piperidin-3-yl) -7-methyl-quinoline;
3,6-dimethyl-8- (1-methyl-piperidin-3-yl) -quinoline;
8- (1-ethyl-piperidin-3-yl) -3,6-dimethyl-quinoline;
3,7-dimethyl-8- (1-methyl-piperidin-3-yl) -quinoline;
8- (1-ethyl-piperidin-3-yl) -3,7-dimethyl-quinoline;
3,5-dimethyl-8- (1-methyl-piperidin-3-yl) -quinoline;
8- (1-ethyl-7-piperidin-3-yl) -3,5-dimethyl-quinoline;
6-chloro-3-methyl-8- (1-methyl-piperidin-3-yl) -quinoline;
6-chloro-8- (1-ethyl-piperidin-3-yl) -3-methyl-quinoline;
3-ethyl-8- (1-methyl-piperidin-3-yl) -quinoline;
3-ethyl-8- (1-ethyl-piperidin-3-yl) -quinoline;
4-methyl-8- (1-methyl-piperidin-3-yl) -quinoline;
8- (1-ethyl-piperidin-3-yl) -4-methyl-quinoline;
3-methyl-8- (1-methyl-piperidin-3-yl) -quinoline;
8- (1-ethyl-piperidin-3-yl) -3-methyl-quinoline;
3-ethyl-8- (1-methyl-pyrrolidin-3-yl) -quinoline;
3-ethyl-8- (1-ethyl-pyrrolidin-3-yl) -quinoline;
3-ethyl-7- (1-methyl-piperidin-3-yl) -quinoline;
3-ethyl-7- (l-ethyl-piperidin-3-yl) -quinoline;
3-ethyl-7-pyrrolidin-3-yl) -quinoline;
3-ethyl-7- (1-methyl-pyrrolidin-3-yl) -quinoline; and 3-ethyl-7- (1-ethyl-pyrrolidin-3-yl) -quinoline;
And pharmaceutically acceptable salts thereof.

  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 is also a method of treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, acting on a serotonin 7 receptor in a mammal in need of such treatment ( a method comprising administering an 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 disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, comprising:
a) a pharmaceutically acceptable carrier;
b) the amount of the first compound of formula I or a pharmaceutically acceptable salt thereof; and c) a 5HT reuptake inhibitor, a 5HT7 receptor antagonist or an NK1 receptor antagonist or a pharmaceutically acceptable salt thereof. The amount of the second compound;
Wherein the amounts of (b) and (c) are together effective amounts for treating such a disorder or symptom.

The invention also provides a method of treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, wherein the mammal in need of such treatment comprises:
a) an amount of a compound of formula I or a pharmaceutically acceptable salt thereof; and b) a second selected from the group consisting of 5HT reuptake inhibitors, 5HT7 receptor antagonists and NK1 receptor antagonists or pharmaceutically acceptable salts thereof. Amount of compound;
Wherein the amounts of (a) and (b) are together effective amounts for treating such a disorder or symptom are provided.

  The present invention also includes depression, anxiety, avoidance personality disorder, premature ejaculation, eating disorder, migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal emotional disorder, bipolar nerve cell disorder, time difference in mammals A method of treating a disorder or symptom selected from bokeh, sleep disorders, nocturnal enuresis, and restless leg syndrome, comprising administering an amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment And a method of treatment wherein the amount is (a) effective in treating such a disorder or condition, or (b) effective in agonizing the 5HT7 receptor.

  In another embodiment of the method described in the previous paragraph, the sleep disorder is circadian sleep rhythm disorder, sleep deprivation, REM sleep disorder, hypersomnia, loss of stimulus response, sleep-wake cycle disorder, sleep disorder associated with blindness Sleep disorders associated with obesity, narcolepsy, or sleep disorders associated with shift work or irregular work schedules.

  The present invention also includes depression, anxiety, avoidance personality disorder, premature ejaculation, eating disorder, migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal emotional disorder, bipolar nerve cell disorder, time difference in mammals A method of treating a disorder or symptom selected from bokeh, sleep disorders, nocturnal enuresis, and restless leg syndrome, wherein (a) an amount of a first compound of formula I or a pharmaceutical thereof in a mammal in need of such treatment An acceptable salt; and (b) an amount of a second compound selected from the group consisting of a 5HT7 receptor antagonist, an NK1 receptor antagonist, and a 5HT7 receptor antagonist, or a pharmaceutically acceptable salt of the second compound. A method comprising administering, wherein the amounts of (a) and (b) are effective together to treat such a disorder or symptom.

  In another embodiment of the method described in the previous paragraph, the sleep disorder is circadian sleep rhythm disorder, sleep deprivation, REM sleep disorder, hypersomnia, loss of stimulus response, sleep-wake cycle disorder, sleep disorder associated with blindness Sleep disorders associated with obesity, narcolepsy, or sleep disorders associated with shift work or irregular work schedules.

の化合物、及び式：

の化合物を提供し、上記二つの式のそれぞれで、Ｒ¹、Ｒ²及びＲ³は独立して水素、ハロゲン、場合によっては１〜３個のハロゲン原子で置換されていてもよい（Ｃ₁−Ｃ₆）アルキル、及び場合によっては１〜３個のハロゲン原子で置換されていてもよい（Ｃ₁−Ｃ₆）アルコキシから選ばれる。これらの二つの式の化合物は式Ｉの化合物を合成するための中間体として有用である。 The present invention also has the formula:

And a compound of the formula:

In each of the above two formulas, R ¹ , R ² and R ³ are independently hydrogen, halogen, and optionally substituted with 1 to 3 halogen atoms (C ₁ -C ₆₎ alkyl, and optionally selected from 1-3 may be substituted with a halogen atom (C ₁ -C ₆₎ alkoxy. These two compounds of formula are useful as intermediates for the synthesis of compounds of formula I.

（式中、Ｒ¹、Ｒ²及びＲ³は独立して水素、ハロゲン、場合によっては１〜３個のハロゲン原子で置換されていてもよい（Ｃ₁−Ｃ₆）アルキル、及び場合によっては１〜３個のハロゲン原子で置換されていてもよい（Ｃ₁−Ｃ₆）アルコキシから選ばれる）の化合物を合成する方法であって；
該方法は、式：

（式中、Ｒ¹及びＲ²は前に記載した通りである）の化合物を、式：

（式中、Ｒ³は前に記載した通りである）の化合物と反応させるか、又は化合物：
Ｒ³−ＯＨ
（式中、Ｒ³は前に記載した通りである）と反応させることを含み、ここで上記反応は水性酸及び３−ニトロベンゼンスルホン酸又はその塩の存在下で行われ、そして上記反応は約１００℃〜約１４０℃の温度で行われる方法を提供する。 The present invention also has the formula:

Wherein R ¹ , R ² and R ³ are independently hydrogen, halogen, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 3 halogen atoms, and optionally A method of synthesizing a compound (selected from (C ₁ -C ₆ ) alkoxy) optionally substituted with 1 to 3 halogen atoms;
The method has the formula:

Wherein R ¹ and R ² are as previously described, the compound of formula:

Reacting with a compound of the formula (wherein R ³ is as previously described) or a compound:
R ³ —OH
Wherein R ³ is as previously described, wherein the reaction is carried out in the presence of an aqueous acid and 3-nitrobenzenesulfonic acid or salt thereof, and the reaction is about A method is provided that is performed at a temperature of 100 ° C to about 140 ° C.

（式中、Ｒ¹、Ｒ²及びＲ³は独立して水素、ハロゲン、場合によっては１〜３個のハロゲン原子で置換されていてもよい（Ｃ₁−Ｃ₆）アルキル、及び場合によっては１〜３個のハロゲン原子で置換されていてもよい（Ｃ₁−Ｃ₆）アルコキシから選ばれる）の化合物を合成する方法であって；
該方法は、式：

（式中、Ｒ¹及びＲ²は前に記載した通りである）の化合物を、式：

（式中、Ｒ³は前に記載した通りである）の化合物と反応させるか、又は好ましくは化合物：
Ｒ³−ＯＨ
（式中、Ｒ³は前に記載した通りである）と反応させることを含み、ここで上記反応は水性酸及び３−ニトロベンゼンスルホン酸又はその塩の存在下で行われ、そして上記反応は約１００℃〜約１４０℃の温度で行われる方法を提供する。 The present invention also has the formula:

Wherein R ¹ , R ² and R ³ are independently hydrogen, halogen, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 3 halogen atoms, and optionally A method of synthesizing a compound (selected from (C ₁ -C ₆ ) alkoxy) optionally substituted with 1 to 3 halogen atoms;
The method has the formula:

Wherein R ¹ and R ² are as previously described, the compound of formula:

Reacted with a compound of formula (wherein R ³ is as previously described) or preferably a compound:
R ³ —OH
Wherein R ³ is as previously described, wherein the reaction is carried out in the presence of an aqueous acid and 3-nitrobenzenesulfonic acid or salt thereof, and the reaction is about A method is provided that is performed at a temperature of 100 ° C to about 140 ° C.

In any of the above synthetic methods, the aqueous acid is sulfuric acid in one embodiment.
The compounds of formula I may contain chiral centers and therefore may exist in various enantiomeric and diastereomeric forms. The present invention relates to all optical isomers and stereoisomers of compounds of the formula I as racemic mixtures of the compounds of the formula I and as individual enantiomers and diastereomers and mixtures thereof and to the pharmaceuticals containing them. It relates to compositions and methods of treatment using them. Individual isomers can be obtained by known methods, such as optical resolution, optical selective reaction, or chromatographic separation in the preparation of the final product or its intermediate. The individual enantiomers of the compounds of formula I may have advantages in the treatment of various disorders or symptoms compared to racemic mixtures of these compounds.

  As long as the compounds of formula I of the present invention are basic compounds, they can be selected from the various inorganic and organic acids used to prepare pharmaceutically acceptable acid addition salts of the aforementioned basic compounds of the present invention. A wide variety of salts can be formed. The inorganic and organic acids are non-toxic acid addition salts, i.e. hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acidic phosphate, acetic acid. Salt, lactate, citrate or acid citrate, tartrate or bitartrate, oxalate, maleate, fumarate, gluconate, saccharide, benzoate, methanesulfonate, Pharmaceutically acceptable, such as ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (ie, 1,1′-methylene-bis- (2-hydroxy-3-naphthoate) salt An acid that forms a salt containing an anion.

The invention also includes isotope-labeled compounds. The isotope-labeled compound is the same as the compound of formula I, but one or more atoms have an atomic mass or mass number different from the atomic mass or mass number normally found in nature. It has been replaced by an atom. Examples of isotopes that can be included in the compounds of the present invention include ² H, ³ H, ¹³ C, ¹¹ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as ¹⁸ F and ³⁶ Cl are included. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of the compounds or prodrugs that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. A compound of the invention labeled with an isotope, for example ³
Compounds contaminated with radioactive isotopes such as H and ¹⁴ C are useful for drug and / or substrate tissue distribution assays. Tritiated, ie ³ H, and carbon-14, ie ¹⁴ C, isotopes are particularly preferred due to their ease of production and detection. In addition, replacement with heavy isotopes such as deuterium, i.e. ² H, has certain therapeutic benefits due to its high metabolic stability, e.g., high in vivo half-life or low dose requirements. Can be given and may therefore be preferred in certain situations. The isotope-labeled compounds of formula I and their prodrugs of the present invention generally perform the procedures disclosed in the following schemes or examples, replacing non-isotopically labeled reagents with readily available isotope-labeled reagents. Can be manufactured.

  “Serotonin” and “5HT7” are used interchangeably in this application unless otherwise indicated. Serotonin 7 agonists are useful in the treatment of depression.

  As used herein, the term “depression” refers to major depressive disorder; single episode or recurrent major depressive episode; recurrent depression; dysthymia; circulatory disease; unspecified depression disorder; seasonal emotional disorder; Polar nerve cell disorders, such as bipolar neuron I disorder, bipolar neuron II disorder, and bipolar neuron disorder not otherwise specified.

  Other mood disorders encompassed within the term “depression” as used in this application include mood modulation disorders with early or late signs and with or without atypical features; with early or late signs; Alzheimer's dementia with depressive mood; Vascular dementia with depressive mood; Induced by alcohol, amphetamine, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics or other substances Mood disorders; depression-type schizophrenic disorders; and dysregulation with mood.

  Included within the term “depression” as used herein are depression in cancer patients, depression in Parkinson's disease patients, depression after myocardial infarction, depression with symptoms of subsyndrome, depression in infertile women, childhood depression Child abuse-induced depression, and postpartum depression.

  Major depression is characterized by a strong sense of sadness and despair, mental retardation and loss of concentration, pessimistic worry, agitation, and self-denial. Physical changes also occur in particularly strong or “depressed” depression. These include insomnia or hypersomnia, anorexia and weight loss (or sometimes overeating), reduced energy and sexual impulses, and normal circadian rhythms of activity, body temperature, and disruption of many endocrine functions.

  The serotonin 7 agonists of formula I of the present invention are also useful for the treatment of anxiety. As used herein, the term “anxiety” includes panic disorder with or without agoraphobia, agoraphobia with no history of panic disorder, certain phobias, such as certain animal phobias, social phobias Stress disorders, including post-traumatic stress disorder and acute stress disorder, and anxiety disorders such as generalized anxiety disorder.

  “Generalized anxiety” is typically defined as excessive anxiety or anxiety over a long period of time (eg, at least 6 months), with indications on most days during that period. Anxiety or anxiety is difficult to control and can involve emotional anxiety, fatigue, difficulty concentrating, irritability, muscle tone, and disturbed sleep.

  A “panic disorder” is defined by persistent concern that there is a recurrent panic attack and then another panic attack for at least one month. A “panic attack” is a clear period in which strong anxiety, fear or horror begins suddenly. During a panic attack, each person may experience a variety of signs including palpitations, sweating, tremors, short breaths, chest pains, nausea and dizziness. Panic disorder can occur with or without agoraphobia.

  “Phobias” includes agoraphobia, specific phobias, and social phobias. “Plaphobia” is characterized by a place or position that is difficult or troublesome to escape, or anxiety about having a panic attack, inability to get help, or being in a position. Agoraphobia can occur without a history of panic attacks. “Specific phobia” is characterized by clinically significant anxiety caused by the object or location of fear. Specific phobias include the following subtypes: animal types that are triggered by animals or insects; natural environment types that are triggered by objects in the natural environment, such as storms, altitudes or waters; blood Or blood-injection-injury types that are triggered by seeing or receiving medical treatments that see or receive injections or other tissues; public transport, tunnels, bridges, elevators, flying, driving or trapped Situation types that are triggered by specific circumstances, such as open spaces; and other types where fear is triggered by other incentives. Specific phobia is also called simple phobia. “Social phobia” is characterized by clinically significant anxiety caused by exposure to certain types of social or acting situations. Social phobia is also called social anxiety disorder.

  Other anxiety disorders encompassed within the term “anxiety” include alcohol, amphetamine, caffeine, cannabis, cocaine, hallucinogens, inhalants, phencyclidine, sedatives, hypnotics, anxiolytics or other Substance-induced anxiety disorders and adaptation disorders with anxiety or mixed anxiety and depression are included.

  Anxiety may be present with or without other disorders, such as disorders such as mixed anxiety and depressive disorders. Thus, the compositions of the present invention are useful for the treatment of anxiety with or without depression.

  The term “alkyl” as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon groups having straight chain, branched chain or cyclic groups, or combinations thereof. Examples of “alkyl” groups include methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, hexyl, heptyl, 3-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Norbonyl and the like are included, but are not limited thereto.

  The term “alkoxy” as used herein, unless otherwise indicated, means “alkyl-O—”, where “alkyl” is as previously defined. Examples of “alkoxy” groups include, but are not limited to, methoxy, ethoxy, propoxy, butoxy and pentoxy.

  The term “alkenyl” as used herein, unless otherwise indicated, includes unsaturated hydrocarbon groups having one or more double bonds connecting two carbon atoms, where the hydrocarbon group Can have a linear, branched or cyclic group, or combinations thereof. Examples of “alkenyl” include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, and dimethylpentyl, and include E and Z forms where applicable.

The term “aryl”, as used herein, unless otherwise indicated, includes aromatic ring systems that do not contain heteroatoms, which aromatic ring is unsubstituted or halogen, optionally 1-3. substituted with fluorine atoms (C ₁ -C ₄₎ alkyl, and optionally substituted with 1-3 fluorine atoms (C ₁ -C ₄₎ 1, 2 or selected from the group consisting of alkoxy It can be substituted with 3 substituents.

The term “heteroaryl” as used herein, unless otherwise indicated, includes aromatic heterocycles containing 5 or 6 ring members, and 1-4 of 5 or 6 ring members are independently It can be a heteroatom selected from N, S and O and the ring is unsubstituted or independently substituted with halogen, optionally 1 to 3 fluorine atoms (C ₁ -C ₄₎ alkyl, and optionally can be monosubstituted or di-substituted with 1-3 fluorine atoms are substituted with (C ₁ -C ₄₎ substituents selected from the group consisting of alkoxy .

  The term “one or more substituents” as used herein refers to the number of substituents equal to the maximum number of possible substituents based on the number of available binding sites, unless otherwise indicated. say.

  The terms “halo” and “halogen” as used herein include fluorine, chlorine, bromine and iodine, unless otherwise indicated.

  As used herein, the term “treating” refers to reversing, alleviating, preventing or preventing the progression of symptoms or disorders to which such terms apply, or one or more of such symptoms or disorders, unless otherwise indicated. It means preventing the above symptoms. As used herein, the term “treatment” refers to the act of treating, and “treating” was defined immediately before.

  As used herein, “modulating serotonergic neurotransmission” refers to increasing or improving, or decreasing or degenerating neuronal processes, unless otherwise indicated, whereby serotonin is pre-synaptic by excitation. Released by cells and prevents synapses from stimulating or inhibiting post-synaptic cells.

  Unless otherwise indicated, the terms “active compound” and “active agent” as used herein are synonymous and are therefore interchangeable. The term is derived from a pharmaceutically acceptable salt of a compound of formula I or a pharmaceutically acceptable salt thereof alone or a 5HTID receptor antagonist, NK1 receptor antagonist, 5HT7 receptor antagonist or any of the compounds described herein. A compound of formula I or a pharmaceutically acceptable salt thereof in combination with one or more compounds selected from the group consisting of:

Compounds of formula I can be prepared according to the following reaction schemes or discussion. Unless otherwise stated, the following reaction schemes or R ¹ , R ² , R ³ , R ⁴ and n and the structural formulas I to IX in discussion are as defined above.

Scheme 1 shows the synthesis of a compound of formula I wherein R ⁴ is hydrogen, n is 2, and the saturated nitrogen-containing ring is piperidin-3-yl and is attached to the “7” position of the quinoline nucleus. . Referring to Scheme 1, a compound of formula I is about 100 in a compound of formula XI and its salt, such as 3-nitrobenzenesulfonic acid or its Group IA salt, such as the sodium salt, and an aqueous acid, such as sulfuric acid. Reaction at from about 140 ° C. to about 140 ° C., preferably 110 ° C., to form the corresponding quinoline derivative of formula XII. Alcohol, R ³ —OH, may be used in place of reactant XI. The resulting compound of formula XII and triphenylphosphine palladium dichloride and diethyl (
3-pyridyl) borane in the presence of a sodium carbonate salt or other inorganic base such as potassium carbonate, calcium carbonate, or cesium carbonate, an organic solvent such as tetrahydrofuran (THF), 1,4-dioxane or 1,2 Reaction in dichloroethane and the like, preferably THF, at a temperature of about 80 ° C. to about 120 ° C., preferably about 90 ° C., produces the corresponding compound of formula XIII.

  Reduction of the pyridine derivative of formula XIII in tetrahydrofuran (THF) with lithium triethylborohydride produces the corresponding piperidine derivative of formula XIV. This reaction is typically carried out at a temperature of about 0 ° C. to about 70 ° C., preferably about room temperature. Other reducing agents and solvents can be used. These are well known to those skilled in the art (eg lithium triisobutylborohydride, lithium triphenylborohydride, etc.). Preference is given to lithium triphenylborohydride in THF.

  The piperidine derivative of formula XIV is then followed by di-tert-butyl carbonate and a tertiary amine such as triethylamine, 4-methylmorpholine, or DBU (1,8-diazabicyclo [5.4.0.] Undec-7-ene. ), Preferably by reaction in the presence of triethylamine, to the corresponding ester of formula XV. Suitable solvents for this reaction include chloroalkanes (eg methylene chloride), 1,4-dioxane, THF and 1,2-dichloroethane. Methylene chloride is preferred. The reaction temperature can range from about 0 ° C to about 50 ° C, preferably about 25 ° C.

  Chiral column chromatography can be used to separate enantiomers including racemic compounds of formula XV. Each enantiomer ester is then used in a manner well known to those skilled in the art, such as methanol, methylene chloride, dioxane, ethyl ether, or ethyl acetate, using a strong acid such as hydrochloric acid, sulfuric acid, acetic acid or trifluoroacetic acid. Deprotection using a method of hydrolysis in a solvent to form the corresponding enantiomer salt of the compound of formula IA. Preferably hydrochloric acid is used. This reaction is typically carried out at a temperature from about 0 ° C. to about 70 ° C., preferably at about room temperature.

Scheme 1 can also be used to prepare compounds that are identical to compounds of formula IA, but with the piperidine ring attached to the "8" position of the quinoline nucleus. This can be done by replacing the starting material of formula X with similar compounds in which the bromo and amino groups are ortho to each other. In synthesizing intermediates similar to those having a bromine in the “8” position according to Scheme 1, it is preferred to use the alcohol R ³ —OH instead of the compound of formula XI.

Scheme 2 is a compound of formula I wherein n is 2, R ⁴ is hydrogen, R ³ is bonded to the “4” position of the quinoline nucleus, and the saturated nitrogen-containing ring of formula I is in the “8” position of the nucleus. 1 shows the synthesis of a compound that is piperidin-3-yl linked to. Referring to Scheme 2, the compound of formula XVI is converted to triphenylphosphine palladium dichloride and diethyl (3-pyridyl) borane with an inorganic base such as a metal carbonate such as sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, Preferably, in the presence of sodium carbonate, in an organic solvent such as THF, 1,4-dioxane or 1,2-dichloroethane, preferably THF, about 80 ° C. to about 120 ° C., preferably about 90 ° C. When reacted at temperature, the corresponding compound of formula XVII is formed. Reduction of the nitrobenzene derivative of formula XVII produces the corresponding aniline derivative of formula XVIII. This reaction is performed using methods well known to those skilled in the art, for example, reaction in the presence of a platinum oxide catalyst in 50 psi hydrogen gas and methanol solvent. This reaction is typically carried out at a temperature of about 0 ° C. to about 40 ° C., preferably at about room temperature.

The resulting pyridine derivative of formula XVIII is then reduced using the method described for reducing the compound of formula XIII in the description of the reaction of Scheme 1 to form the corresponding piperidine derivative of formula XIX. The desired compound of formula IB is a compound of formula XIX, a compound of formula R ³ (C═CH) CHO and 3-nitrobenzenesulfonic acid sodium salt or ferrous chloride hexahydrate and zinc chloride, ethanol, n— About 60 ° C. to about 100 ° C., preferably in an organic solvent such as propanol, isopropanol and an acid, for example an inorganic acid such as sulfuric acid or hydrochloric acid, or in an aqueous inorganic acid such as aqueous sulfuric acid, more preferably aqueous hydrochloric acid. Can be produced by reacting at a temperature of about 60 ° C. Racemic compounds of formula IB can be separated into their enantiomers as shown in Scheme 2 and as previously described for the preparation of enantiomers of compounds of formula IA.

Scheme 3 is a compound of formula I wherein n is 2, R ⁴ is hydrogen, R ³ is bonded to the “3” position of the quinoline nucleus, and the saturated nitrogen-containing ring of formula I is in the “8” position of the quinoline nucleus. 1 shows a method for producing a compound that is bound piperidin-3-yl. Referring to Scheme 3, a compound of formula XXI is prepared in the presence of triphenylphosphine palladium dichloride and diethyl (3-pyridyl) borane and other inorganic bases such as sodium carbonate or potassium carbonate, calcium carbonate, cesium carbonate. , Tetrahydrofuran (THF), 1,4-dioxane, or 1,2-dichloroethane, preferably in THF at a temperature of about 80 ° C. to about 120 ° C., preferably about 90 ° C. The corresponding compound of formula XVIII is formed.

Next, the compound of formula XVIII is converted to a compound of formula R ³ (C═CH) CHO and 3-nitrobenzenesulfonic acid or a salt thereof, in particular a metal salt such as a sodium salt, or ferrous chloride hexahydrate and zinc chloride. An organic solvent such as an alcohol having 1 to 6 carbon atoms, such as ethanol, n-propanol and isopropanol, and an acid such as an inorganic acid such as hydrochloric acid, sulfuric acid, preferably aqueous hydrochloric acid, and more preferably an aqueous inorganic such as aqueous sulfuric acid. Racemic pyridine substituted quinoline derivatives of formula XXII can be prepared by reacting in acid at temperatures of about 100 ° C. to about 140 ° C., preferably about 110 ° C. Reduction of the racemic pyridine substituted quinoline derivative of formula XXII in tetrahydrofuran (THF) using lithium triethylborohydride produces the corresponding piperidine substituted quinoline derivative of formula IC. This reaction is typically carried out at a temperature of about 0 ° C to about 70 ° C, preferably about 25 ° C. Other reducing agents and solvents can be used. These are well known to those skilled in the art.

  Racemic compounds of formula IC can be separated into their enantiomers as shown in Schemes 1, 2 and 3 and as previously described for the preparation of enantiomers of compounds of formula IA.

Scheme 4 shows a method for the synthesis of compounds of formula I wherein n is 1, R ⁴ and R ² are hydrogen, and R ¹ is attached to the “5” position of the quinoline nucleus. Referring to Scheme 4, a compound of formula IVA is converted to [3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester] and n-butyllithium, such as tetrahydrofuran (THF), diethyl ether or 1,4-dioxane. Reaction in an organic solvent, preferably THF, at a temperature of about −77 ° C. to about −100 ° C., preferably about −77 ° C., forms the corresponding compound of formula XXIII. Addition of acid to it followed by treatment with base hydrolyzes the amide to form pyrrolene XXIV. The resulting compound of formula XXIV can be reduced to form the corresponding racemic compound of formula ID. This reduction can be performed using methods well known to those skilled in the art, such as 50 psi of hydrogen gas and reaction in a solvent such as acetic acid, methanol or ethanol in the presence of a platinum oxide catalyst. Acetic acid is preferred for reducing the free base pyrrolene to the free base pyrrolidine, while methanol or ethanol is preferred for reducing the pyrrolene hydrochloride to the pyrrolidine hydrochloride. This reaction is typically carried out at a temperature of about 0 ° C. to about 40 ° C., preferably at about room temperature.

  Scheme 4 can also be used to prepare compounds that are identical to compounds of formula ID but with the pyrrolidine ring attached to the “7” position of the quinoline nucleus. This can be done by replacing the starting material of formula IVA with a similar compound in which the bromo group is attached to the quinoline nucleus at the “7” position.

Scheme 5, the compound of formula I R ⁴ is other than hydrogen, indicating the formation of a corresponding compound of formula I R ⁴ is hydrogen. Referring to Scheme 5, a compound of formula IE or IF is of formula HC (═O) R ⁴ and an alkylating agent such as sodium triacetoxyborohydride, sodium cyanoborohydride and the like and an organic solvent, especially ethanol or methanol, preferably Reacts in an alcohol such as methanol at a temperature of about 0 ° C. to about 30 ° C., preferably about 25 ° C., to form the corresponding compound of formula IE ′ or IF ′, respectively. The procedure shown in Scheme 5 can generally be used to convert a compound of Formula I where R ⁴ is other than hydrogen to the corresponding compound where R ⁴ is hydrogen.

  Racemic compounds of formula ID, ID ', IE and IE' can be separated into their enantiomers as shown in Schemes 1, 2 and 3 and as described above for the preparation of enantiomers of compounds of formula IA.

  Unless otherwise indicated, the pressure of each of the above reactions is not critical. Generally, the reaction will be conducted at a pressure of about 1 atmosphere to about 3 atmospheres, preferably ambient pressure (about 1 atmosphere).

  The compounds of formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and basic acids. Such salts must be pharmaceutically acceptable for administration to animals, but in practice, the compound of formula I is first isolated from the reaction mixture as a pharmaceutically unacceptable salt and then pharmaceutically unacceptable. It is often preferred to treat the salt with an alkaline reagent and simply convert it to the free base compound, followed by conversion of the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of the present invention are readily prepared by treating the base compound with a substantially equal amount of a selected mineral or organic acid in an aqueous medium or a suitable organic solvent such as methanol or ethanol. Is done. Upon careful evaporation of the solvent, the desired solid salt is obtained.

The acids used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of the present invention are non-toxic acid addition salts, i.e. salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromic acid. Salt, hydroiodide, nitrate, sulfate or hydrogen sulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, oxalic acid Salt, maleate, fumarate, gluconate, saccharide, benzoate, methanesulfonate and pamoate [ie, 1,1′-methylene-bis- (2-hydroxy-3-naphthoate)] Salt, an acid that forms.

  When using any of the previously mentioned combination methods of the present invention, which component (a) and (b) is utilized, i.e. a compound of formula I or a pharmaceutically acceptable salt thereof and a 5HTID receptor antagonist Or any combination thereof with a salt, NK1 receptor antagonist or salt thereof, or a serotonin intake inhibitor or salt thereof, it will be understood that the combination is administered to the patient within a reasonable time. Let's go. Multiple compounds are in the same pharmaceutically acceptable carrier and may therefore be administered simultaneously. They may be in separate pharmaceutical carriers such as conventional oral dosage forms taken at the same time. The term combination used previously also refers to the case where the pharmaceutically active compounds are given in separate dosage forms and are administered sequentially. Thus, by way of example, an NK1 receptor antagonist may be administered as a tablet and then within a reasonable time the compound of formula I may be administered as a tablet-like dosage form or as a fast dissolving oral dosage form. By “fast dissolving oral formulation” is meant an oral dosage form that dissolves within about a few seconds when placed on the patient's tongue.

Examples of serotonin reuptake inhibitors that can be used in the methods and compositions of the present invention are 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 NC _l2 and structural formula Having:

  The synthesis is described in US Pat. No. 4,536,518, assigned to Pfizer Inc., the contents of which are incorporated herein by reference. Sertraline hydrochloride is useful as an antidepressant and appetite suppressant and is also useful in the treatment of depression, drug addiction, anxiety obsessive compulsive disorder, phobia, panic disorder, post-traumatic stress disorder, and premature ejaculation.

［式中、
Ｘ¹は水素、場合によっては１ないし３個のフッ素原子で置換されていてもよい（Ｃ₁−Ｃ₁₀）アルコキシ、又は場合によっては１ないし３個のフッ素原子で置換されていてもよい（Ｃ₁−Ｃ₁₀）アルキルであり；
Ｘ²及びＸ³は独立して、水素、ハロゲン、ニトロ、場合によっては１ないし３個のフッ素原子で置換されていてもよい（Ｃ₁−Ｃ₁₀）アルキル、場合によっては１ないし３個のフッ素原子で置換されていてもよい（Ｃ₁−Ｃ₁₀）アルコキシ、トリフルオロメチル、ヒドロキシ、フェニル、シアノ、アミノ、（Ｃ₁−Ｃ₆）−アルキルアミノ、ジ−（Ｃ₁−Ｃ₆）−アルキルアミノ、−Ｃ（＝Ｏ）−ＮＨ−（Ｃ₁−Ｃ₆）−アルキル、（Ｃ₁−Ｃ₆）−アルキル−Ｃ（＝Ｏ）−ＮＨ−（Ｃ₁−Ｃ₆）−アルキル、ヒドロキシ（Ｃ₁−Ｃ₄）−アルキル、（Ｃ₁−Ｃ₄）−アルコキシ（Ｃ₁−Ｃ₄）アルキル、−ＮＨＣ（＝Ｏ）Ｈ及び−ＮＨＣ（＝Ｏ）−（Ｃ₁−Ｃ₆）−アルキルから選ばれ；そして Examples of NK1 receptor antagonists that can be used in the methods and pharmaceutical compositions of the present invention include compounds of the formula:

[Where:
X ¹ is hydrogen, (C ₁ -C ₁₀ ) alkoxy optionally substituted with 1 to 3 fluorine atoms, or optionally substituted with 1 to 3 fluorine atoms ( C ₁ -C ₁₀₎ alkyl;
X ² and X ³ are independently hydrogen, halogen, nitro, (C ₁ -C ₁₀ ) alkyl optionally substituted with 1 to 3 fluorine atoms, optionally 1 to 3 ₍₁ -C ₁₀ C) alkoxy, trifluoromethyl, hydroxy, phenyl, cyano, amino, optionally substituted with fluorine atoms (C ₁ -C ₆₎ - alkylamino, di - (C ₁ -C ₆₎ - alkylamino, -C (= O) -NH- ( C 1 -C 6) - alkyl, (C ₁ -C ₆₎ - alkyl -C (= O) -NH- (C 1 -C 6) - alkyl , Hydroxy (C ₁ -C ₄ ) -alkyl, (C ₁ -C ₄ ) -alkoxy (C ₁ -C ₄ ) alkyl, —NHC (═O) H and —NHC (═O) — (C ₁ -C ₆ ) selected from -alkyl; and

（式中、
Ｒ¹はフリル、チエニル、ピリジル、インドリル、ビフェニル、及び場合によっては独立してハロゲン、場合によっては１ないし３個のフッ素原子で置換されていてもよい（Ｃ₁−Ｃ₁₀）アルキル、場合によっては１ないし３個のフッ素原子で置換されていてもよい（Ｃ₁−Ｃ₁₀）アルコキシ、カルボキシ、ベンジルオキシカルボニル、及び（Ｃ₁−Ｃ₃）アルコキシ−カルボニルから選ばれた１又は２個の置換基で置換されてもよいフェニルから選ばれた基であり；
Ｒ¹³は（Ｃ₃−Ｃ₄）分枝鎖アルキル、（Ｃ₅−Ｃ₆）分枝鎖アルケニル、（Ｃ₅−Ｃ₇）シクロアルキル、及びＲ₁の定義で命名した基から選ばれ； Q is a group of the formula:

(Where
R ¹ is furyl, thienyl, pyridyl, indolyl, biphenyl and optionally independently halogen, optionally (C ₁ -C ₁₀ ) alkyl optionally substituted with 1 to 3 fluorine atoms, optionally 1 to 2 selected from (C ₁ -C ₁₀ ) alkoxy, carboxy, benzyloxycarbonyl, and (C ₁ -C ₃ ) alkoxy-carbonyl optionally substituted with 1 to 3 fluorine atoms A group selected from phenyl optionally substituted by a substituent;
R ¹³ is selected from (C ₃ -C ₄ ) branched alkyl, (C ₅ -C ₆ ) branched alkenyl, (C ₅ -C ₇ ) cycloalkyl, and groups named in the definition of R ₁ ;

R ² is hydrogen or (C ₁ -C ₆ ) alkyl;
R ³ is phenyl, biphenyl, naphthyl, pyridyl, benzhydryl or thienyl, and R ³ is optionally independently halogen, optionally substituted with 1 to 3 fluorine atoms (C _1- Optionally substituted with 1 to 3 substituents selected from C ₁₀ ) alkyl, and optionally (C ₁ -C ₁₀ ) alkoxy optionally substituted with 1 to 3 fluorine atoms;

で表される基であり、 Y is (CH ₂ ) _l , where l is an integer from 1 to 3 or Y is a formula:

A group represented by

Z is oxygen, sulfur, amino, (C ₁ -C ₃ ) alkylamino, or (CH ₂ ) _n , where n is 0, 1 or 2;
o is 2 or 3;
p is 0 or 1;
x is an integer from 0 to 4;
y is an integer from 0 to 4;
z is an integer from 0 to 6 and the ring containing (CH ₂ ) _z in formula VIII may contain 0 to 3 double bonds, one of the carbons of (CH ₂ ) _{z being} May be substituted with oxygen, sulfur or nitrogen;

R ⁴ is furyl, thienyl, pyridyl, indolyl, biphenyl, or independently halogen, (C ₁ -C ₁₀ ) alkyl optionally substituted with 1 to 3 fluorine atoms, optionally 1 to In case of 1 or 2 substituents selected from (C ₁ -C ₁₀ ) alkoxy, carboxy, (C ₁ -C ₃ ) alkoxy-carbonyl and benzyloxycarbonyl optionally substituted by 3 fluorine atoms Is optionally substituted phenyl;

R ⁵ is thienyl, biphenyl, or independently halogen, (C ₁ -C ₁₀ ) alkyl optionally substituted with 1 to 3 fluorine atoms, and optionally 1 to 3 fluorine atoms Phenyl optionally substituted with one or two substituents selected from (C ₁ -C ₁₀ ) alkoxy optionally substituted by:

X is (CH ₂ ) _q , where q is an integer from 1 to 6, wherein any one of the carbon-carbon single bonds in the (CH ₂ ) _q is optionally carbon-carbon bis. May be replaced by a heavy bond, wherein any one of the carbon atoms in the (CH ₂ ) _q may optionally be replaced by R ⁸ , and wherein in the (CH ₂ ) _q Any one of the carbon atoms may optionally be substituted with R ⁹ ;
m is an integer of 0 to 8, and any one of (CH ₂ ) _m carbon-carbon single bonds may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, And any one of the (CH ₂ ) _m carbon atoms may be optionally substituted with R ¹¹ ;

R ⁶ is hydrogen, linear or branched (C ₁ -C ₆ ) alkyl, any one of the carbon atoms optionally substituted with nitrogen, oxygen or sulfur (C ₃ -C ₇ ) cyclo. Alkyl; aryl selected from biphenyl, phenyl, indaryl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolinyl, isoxazolinyl, triazolyl, tetrazolyl and quinolyl; phenyl (C ₂ -C ₆₎ alkyl, a group selected from benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups, and said benzyl, phenyl (C ₂ -C ₆₎ phenyl group of alkyl and benzhydryl are independently halogen , Nitro, optionally substituted with 1 to 3 fluorine atoms Which may be (C ₁ -C ₁₀₎ alkyl, optionally substituted with one to three fluorine atoms (C ₁ -C ₁₀₎ alkoxy, amino, hydroxy - (C ₁ -C ₆₎ Alkyl, (C ₁ -C ₆ ) alkoxy- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl-O—C (═O) —, (C ₁ -C ₆₎ alkyl -O-C (= O) - (C 1 -C 6) alkyl, (C ₁ -C ₆₎ alkyl -C (= O) -O -, (C 1 -C 6) alkyl -C (= O) - (C 1 -C 6) alkyl _{-O -, (C 1 -C 6} ) alkyl -C (= O) -, ( C 1 -C6) alkyl -C (= O) - ( C ₁ -C ₆₎ alkyl -, di - (C ₁ -C ₆₎ alkylamino, -C (= O) NH- ( C 1 -C 6) alkyl, (C ₁ -C ₆₎ - alkyl -C In (C ₁ -C _{6) 1} or more substituents selected from alkyl _{- = O) -NH- (C 1} -C 6) alkyl, -NHC (= O) H and -NHC (= O) Optionally substituted; the phenyl group of the benzhydryl may optionally be substituted with naphthyl, thienyl, furyl or pyridyl;

R ⁷ is hydrogen, phenyl or (C ₁ -C ₆ ) alkyl;
Alternatively, R ⁶ and R ⁷ together with the carbon to which they are attached form a saturated carbocyclic ring having 3 to 7 carbon atoms, where one of the carbon atoms is optionally oxygen, May be substituted with nitrogen or sulfur;
R ⁸ and R ⁹ are each independently hydrogen, hydroxy, halogen, amino, oxo (═O), nitrile, hydroxy- (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy- (C _1- C ₆ ) alkyl, (C ₁ -C ₆ ) alkylamino, di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆ ) alkyl-O—C (= O) -, (C ₁ -C ₆₎ alkyl -O-C (= O) - (C 1 -C 6) alkyl, (C ₁ -C ₆₎ alkyl -C (= O) -O -, (C ₁ -C ₆₎ alkyl -C (= O) - (C 1 -C 6) alkyl -O -, (C ₁ -C ₆₎ alkyl -C (= O) -, ( C 1 -C 6) alkyl - C (═O) — (C ₁ -C ₆ ) alkyl- and selected from the groups mentioned in any of the definitions of R ⁶ ;

R ¹⁰ is one of the groups mentioned in any of the definitions of NHCR ¹² , NHCH ₂ R ¹² , NHSO ₂ R ¹² , or R ⁶ , R ⁸ and R ⁹ ;
R ¹¹ is oxyimino (= NOH) or one of the groups mentioned in any of the definitions of R ⁶ , R ⁸ and R ⁹ ; and R ¹² is (C ₁ -C ₆ ) alkyl, hydrogen, phenyl (C ₁ -C ₆₎ alkyl, or optionally phenyl substituted with (C ₁ -C ₆₎ alkyl;

However, when (a) m is 0, R ¹¹ does not exist, and (b) any of R ⁸ , R ⁹ , R ¹⁰ or R ¹¹ forms a ring with R ⁷ together with the carbon to which it is bonded. (C) when Q is a group of formula VIII, R ⁸ and R ⁹ cannot be bonded to the same carbon atom, and (d) R ⁸ and R ⁹ are bonded to the same carbon atom. When attached, each of R ⁸ and R ⁹ is independently hydrogen, fluorine, (C ₁ -C ₆ ) alkyl, hydroxy- (C ₁ -C ₆ ) alkyl, and (C ₁ -C ₆ ) alkoxy- Or selected from (C ₁ -C ₆ ) alkyl, or R ⁸ and R ⁹ together with the carbon to which they are attached form a (C ₃ -C ₆ ) saturated carbocyclic ring, wherein the (C _3- C ₆ ) a saturated carbocyclic ring forms a spiro compound with a nitrogen-containing ring to which R ⁸ and R ⁹ are bonded, and (e) all of X ¹ , X ² , and X ³ are fluorinated alcohols. If not a xoxy group, at least one of R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ¹³ is an aryl group substituted with a fluorinated alkoxy group)]
And pharmaceutically acceptable salts thereof.

Additional examples include the following compounds (hereinafter collectively referred to as “Group A compounds”):
(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-azabicyclo [2.2.2] -octane-3-amine;
(2S, 3S) -N- (5-isopropyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] -octane-3-amine;
(2S, 3S) -N- (5-sec-butyl-2-methoxyphenyl) -methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] -octane-3-amine;
(2S, 3S) -N- (5-tert-butyl-2-methoxyphenyl) -methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] -octane-3-amine; and (2S, 3S ) -N- (5-methyl-2-methoxyphenyl) methyl-2-diphenylmethyl-1-azabicyclo [2.2.2] -octane-3-amine;
And pharmaceutically acceptable salts thereof.

Preferred methods of the invention include the combination methods described above, wherein the NK1 receptor antagonist used in such methods is a compound of formula IX, wherein R ¹ , R ⁴ , R ⁵ and R ⁷ are phenyl, R ² is hydrogen, R ³ is chlorine, fluorine, optionally substituted with (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 3 fluorine atoms, or optionally substituted with 1 to 3 fluorine atoms Optionally substituted (C ₁ -C ₆ ) alkoxy optionally substituted phenyl, m is 0 and n is 3 or 4.

More particularly preferred methods of the present invention are the above combination methods wherein the NK1 receptor antagonist is a compound of formula IX selected from:
(2S, 3S) -3- (5-tert-butyl-2-methoxybenzyl) amino-2- (3-trifluoromethoxyphenyl) piperidine;
(2S, 3S) -3- (2-Isopropoxy-5-trifluoromethoxybenzyl) amino-2-phenyl-piperidine;
(2S, 3S) -3- (2-Ethoxy-5-trifluoromethoxybenzyl) amino-2-phenyl-piperidine;
(2S, 3S) -3- (2-methoxy-5-trifluoromethoxybenzyl) -amino-2-phenylpiperidine;
(2S, 3S) -3 (-5-tert-butyl-2-trifluoromethoxybenzyl) amino-2-phenylpiperidine;
2- (diphenylmethyl) -N- (2-methoxy-5-trifluoromethoxy-phenyl) methyl 1-azabicyclo [2.2.2] octane-3-amine;
(2S, 3S) -3- [5-Chloro-2- (2,2,2-trifluoroethoxy) -benzyl] amino-2-phenylpiperidine;
(2S, 3S) -3- (5-tert-butyl-2-trifluoromethoxybenzyl) amino-2-phenylpiperidine;
(2S, 3S) -3- (2-isopropoxy-5-trifluoromethoxybenzyl) amino-2-phenylpiperidine;
(2S, 3S) -3- (2-difluoromethoxy-5-trifluoromethoxybenzyl) -amino-2-phenylpiperidine;
(2S, 3S) -2-phenyl-3- [2- (2,2,2-trifluoroethoxybenzyl) -aminopiperidine; or (2S, 3S) -2-phenyl-3- (2-trifluoromethoxy) Benzyl)] aminopiperidine;
Or a pharmaceutically acceptable salt thereof.

Other NK1 receptor antagonists useful in the present invention are selected from:
3- [N- (2-methoxy-5-trifluoromethoxybenzyl) -amino] -5,5-dimethyl-2-phenylpyrrolidine;
3- [N- (2-methoxy-5-trifluoromethoxybenzyl) amino] -4,5-dimethyl-2-phenylpyrrolidine;
3- (2-cyclopropyloxy-5-trifluoromethoxybenzyl) amino-2-phenylpiperidine;
3- (2-cyclopropylmethoxy-5-trifluoromethoxybenzyl) amino-2-phenylpiperidine;
3- (2-difluoromethoxy-5-phenylbenzyl) amino-2-phenylpiperidine;
3- (5-cyclopropylmethoxy-2-difluoromethoxybenzyl) amino-2-phenylpiperidine;
3- (2-methoxybenzyl) amino-2- (3-trifluoromethoxyphenyl) -piperidine;
3- (2-methoxy-5-trifluoromethoxybenzyl) amino-2- (3-trifluoromethoxyphenyl) piperidine;
2-phenyl-3- (5-n-propyl-2-trifluoromethoxybenzyl) amino-piperidine;
3- (5-isopropyl-2-trifluoromethoxybenzyl) amino-2-phenylpiperidine;
3- (5-ethyl-2-trifluoromethoxybenzyl) amino-2-phenyl-piperidine;
3- (5-sec-butyl-2-trifluoromethoxybenzyl) amino-2-phenyl-piperidine;
3- (5-difluoromethoxy-2-methoxybenzyl) amino-2-phenyl-piperidine;
3- (2-methoxy-5-trifluoromethoxybenzyl) amino-2-phenylpyrrolidine;
3- (2-methoxy-5-trifluoromethoxybenzyl) amino-2-phenylhomopiperidine;
2-benzhydryl-3- (2-methoxy-5-trifluoromethoxy-benzyl) aminopyrrolidine;
2-benzhydryl-3- (2-methoxy-5-trifluoromethoxy-benzyl) amino homopiperidine;
3- [2,5-bis- (2,2,2-trifluoroethoxy) benzyl] amino-2-phenylpiperidine;
2-phenyl-3- (3-trifluoromethoxybenzyl) aminopiperidine;
2-benzhydryl-3- (2-methoxy-5-trifluoromethoxybenzyl) -aminopiperidine;
1- (5,6-difluorohexyl) -3- (2-methoxy-5-trifluoromethoxy-benzyl) amino-2-phenylpiperidine;
1- (6-hydroxyhexyl) -3- (2-methoxy-5-trifluoromethoxy-benzyl) amino-2-phenylpiperidine;
3-phenyl-4- (2-methoxy-5-trifluoromethoxybenzyl) amino-2-azabicyclo [3.3.0] octane;
4-Benzhydryl-5- (2-methoxy-5-trifluoromethoxybenzyl) -amino-3-azabicyclo [4.1.0] heptane;
4- (2-methoxy-5-trifluoromethoxybenzyl) amino-3-phenyl-2-azabicyclo [4.4.0] decane;
2-phenyl-3- (2-methoxy-5-trifluoromethoxybenzyl) -aminoquinuclidine;
8-Benzhydryl-N- (2-methoxy-5-trifluoromethoxybenzyl) -9-azatricyclo [4.3.1.0 ^4,9 ] decan-7-amine;
9-benzhydryl-N- (2-methoxy-5-trifluoromethoxybenzyl) -10-azatricyclo [4.4.1.0 ^5,10 ] undecan-8-amine;
9-benzhydryl-N- (2-methoxy-5-trifluoromethoxybenzyl) -3-thia-10-azatricyclo- [4.4.1.0 ^5,10 ] undecan-8-amine;
8-Benzhydryl-N- (2-methoxy-5-trifluoromethoxybenzyl) -9-azatricyclo [4.3.1.0 ^4,9 ] decan-7-amine;
5,6-pentamethylene-2-benzhydryl-3- (2-methoxy-5-trifluoromethoxybenzyl) amino-quinuclidine;
5,6-trimethylene-2-benzhydryl-3- (2-methoxy-5-trifluoromethoxybenzyl) amino-quinuclidine;
9-benzhydryl-N-((2-methoxy-5-trifluoromethoxyphenyl) -methyl) -3-oxa-10-azatricyclo- [4.4.1.0 ^5,10 ] undecan-3-amine;
8-benzhydryl-N-((2-methoxy-5-trifluoromethoxyphenyl) -methyl) -7-azatricyclo- [4.4.1.0 ^5,10 ] undecan-9-amine; and 2-benzhydryl- N-((2-methoxy-5-trifluoromethoxyphenyl) -methyl) -1-azabicyclo- [3.2.2] nonane-3-amine;
And pharmaceutically acceptable salts thereof.

Another more specific aspect of this invention is that the NK1 receptor antagonist used in such a method is a compound of formula IX, wherein o is 2 or 3, and each of R ¹ and R ¹³ is phenyl or It relates to the above combination process, which is a compound that is a substituted phenyl.
Another more specific embodiment of this invention is that the NK1 receptor antagonist used in such a method is a compound of formula IX, wherein Q in formula IX is a group of formula III, R ² is hydrogen and R ³ is It relates to the above combination method, which is a compound that is phenyl or substituted phenyl.

Another more specific embodiment of this invention is that the NK1 receptor antagonist used in such a method is a compound of formula IX, wherein Q is a group of formula IV, 1 is 1 or 2, and R ⁴ and R ⁵ It relates to the above combination process, wherein each is a compound that is phenyl or substituted phenyl.

Another more specific aspect of this invention is that the NK1 receptor antagonist used in such a method is a compound of formula IX, wherein Q in formula IX is a group of formula V, n is 0 or 1, and R ⁴ And R ⁵ is a compound wherein each of R ⁵ is phenyl or substituted phenyl.

Another more specific aspect of this invention is that the NK1 receptor antagonist used in such a method is a compound of formula IX, wherein Q in formula IX is a group of formula VI, p is 1, and R ⁴ and R ^{4 The} above combination method wherein each of ⁵ is a compound that is phenyl or substituted phenyl.

Another more specific aspect of this invention is that the NK1 receptor antagonist used in such a method is a compound of formula IX, wherein Q in formula IX is a group of formula VII, q is 2, 3, or 4, m Relates to a combination method as described above, wherein R is 0 and R ⁶ is phenyl or substituted phenyl.

Another more specific aspect of the present invention relates to the above combination method wherein the NK1 receptor antagonist used in such method is selected from:
(2S, 3S) -3- (6-Methoxy-1-methyl-1-trifluoromethylisochroman-7-yl) methylamino-2-phenylpiperidine;
(2S, 3S) -3-[(lR) -6-methoxy-1-methyl-1-trifluoromethylisochroman-7-yl] methylamino-2-phenylpiperidine;
(2S, 3S) -N- (5-isopropyl-2-methoxyphenyl) methyl-2-di-phenylmethyl-1-azabicyclo [2.2.2] -octane-3-amine; and (2S, 3S) -N- (5-tert-butyl-2-methoxyphenyl) -methyl 2-diphenylmethyl-1-azabicyclo [2.2.2] -octane-3-amine;
And pharmaceutically acceptable salts thereof.

Examples of 5HT1D antagonists that can be used in the pharmaceutical compositions and methods of the invention are:
3- (4-chlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidine-2,4-dione;
3- (4-chlorobenzyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidine-2,4-dione;
3- (4-chlorobenzyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione;
4-Benzyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;
4- (3,4-dichlorobenzyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;
3- (4-chlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione;
3- (4-trifluoromethylphenyl) -5- [2- (4-methylpiperazin-I-yl) -benzylidene] -thiazolidine-2,4-dione;
2- [2- (4-Methylpiperazin-1-yl) -benzylidene] -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;
2- [2- (4-Methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- [2-fluoro-6- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -morpholin-3-one;
4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzyl] -thiomorpholin-3-one;
4-methyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one; and 4- (3,4-dichlorophenyl) -2- (2-piperazine-1- Ilbenzylidene) -thiomorpholin-3-one and pharmaceutically acceptable salts thereof.

Other specific NK1 receptor antagonists useful in the present invention include:
5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidine-2,4-dione;
2- [2,4-dibromo-6- (4-methylpiperazin-1-yl) -benzylidene] -4- (3,4-dichlorophenyl) -thiomorpholin-3-one;
4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]-[1,4] oxadiazepan-3-one;
4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]-[1,4,5] oxadiazepan-3-one;
4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]-[1,4] thiazepan-3-one;
4- (3,4-dichlorophenyl) -2- {2- [2-dimethylaminoethyl] -methylamino} -benzylidene} -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- [2- (1-methylpiperidin-4-yl) -benzylidene] -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- [2- (1,4-dimethylpiperidin-4-yl) -benzylidene] -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholine-3,5-dione;
4- (3,4-dichlorophenyl) -2- [2- (2-dimethylaminoethoxy) -benzylidene] -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- [2- (4-isopropylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- [2- (1-methylpyrrolidin-3-ylmethyl) -benzylidene] -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- {2- [methyl (1-methylpyrrolidin-2-ylmethyl) -amino] -benzylidene} -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- [2- (1-methylpyrrolidin-2-ylmethoxy) -benzylidene] -thiomorpholin-3-one;
4- (3,4-dichlorophenyl) -2- {2- [2- (1-methylpyrrolidin-2-yl) -ethyl] -benzylidene} -thiomorpholin-3-one;
1- (3,4-dichlorophenyl) -4-methyl 3- [2- (4-methylpiperazin-1-yl) -benzylidene] -piperazin-2-one;
4-methyl-3- [2- (4-methylpiperazin-1-yl) -benzylidene] -1- (4-trifluoromethylphenyl) -piperazin-2-one;
1- (4-chlorophenyl) -4-methyl 3- [2- (4-methylpiperazin-1-yl) -benzylidene] -piperazin-2-one;
2- [2- (4-Methylpiperazin-1-yl) -benzylidene] -4- (4-trifluoromethylphenyl) -morpholin-3-one;
2- [4-fluoro-2- (4-methylpiperazin-1-yl) -benzylidene] -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;
2- [5-fluoro-2- (4-methylpiperazin-I-yl) -benzylidene] -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;
2- {1- [2- (4-methylpiperazin-1-yl) -phenyl] -ethylidene} -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;
2- [2- (4-methylpiperazin-1-yl) -benzyl] -4- (4-trifluoromethylphenyl) -thiomorpholin-3-one;
4- (4-chlorophenyl) -6-methyl-2- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiomorpholin-3-one;
3- (4-chlorophenyl) -2,2-dimethyl-5- [2- (4-methylpiperazin-1-yl) -benzylidene] -thiazolidin-4-one;
4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene]-[1,4] oxazepan-3-one;
4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -4H- [1,4] thiazin-3-one;
1- (4-chlorophenyl) -4,6,6-trimethyl-3- [2- (4-methylpiperazin-1-yl) -benzylidene] -piperazin-2-one;
1- (4-chlorophenyl) -4-methyl-3- [2- (4-methylpiperazin-I-yl) -benzylidene] -piperazin-2-one;
4- (4-chlorophenyl) -2- [2- (4-methylpiperazin-1-yl) -benzylidene] -morpholin-3-one;
3- (4-chlorophenyl) -5- [2- (4-methylpiperazin-1-yl) -benzylidene] -oxazolidine-4-one;
3- (4-chlorophenyl) -2,2-dimethyl-5- [2- (4-methylpiperazin-1-yl) -benzylidene] -imidazolidin-4-one;
And pharmaceutically acceptable salts thereof.

  The following references show kinolidine, piperidine, ethylenediamine, pyrrolidine and quinuclidine, which exhibit activity as NK1 receptor antagonists and can be used in combination with the 5HT7 receptor partial agonist of formula I in the pharmaceutical compositions and methods of the present invention. Reference is made to azanorbornane derivatives, as well as related compounds and methods for their preparation: US Pat. No. 5,162,339, issued November 11, 1992; US Pat. No. 5,232,929, August 1993 International Patent Application WO 92/20676, published on November 26, 1992; International Patent Application WO 93/00331, published on January 7, 1993; International Patent Application WO 92/21677, published on December 10, 1992; Application WO 93/00330, published January 7, 1993; International patent application WO 93/06099, 1993 Published on April 1, 1992; International patent application WO 93/10073, published on May 27, 1993; International patent application WO 92/06079, published on April 16, 1992; International patent application WO 92/12151, July 23, 1992 Published; International patent application WO 92/15585, published September 17, 1992; International patent application WO 93/10073, published May 27, 1993; International patent application WO 93/19064, Published September 30, 1993; International patent application WO94 / 08997, published on April 28, 1994; International patent application WO94 / 04966, published on March 3, 1994; International patent application WO95 / 07908, published on March 3, 1995; International patent application WO94 / 20500, 1994 Published on September 15, 1994; International patent application WO94 / 13663, June 23, 1994 Open; International patent application WO95 / 16679, published on June 22, 1995; International patent application WO97 / 08144, published on March 6, 1997; International patent application WO97 / 03066, published on January 30, 1997; International patent application WO 99/25714, published May 27, 1999; U.S. Patent Application No. 988,653, filed Dec. 10, 1992; U.S. Patent Application No. 026,382, filed Mar. 4, 1993; U.S. Patent Application No. 123 No. 306, filed September 17, 1993, and U.S. Patent Application No. 072,629, filed June 4, 1993. All said international patent applications designate the United States. The entirety of said patents and patent applications is incorporated herein by reference.

  The NK1 receptor antagonists of formula IX can be prepared as described in the following patents and patent applications, all of which are referred to and are hereby incorporated by reference in their entirety: WO 93/00331 WO92 / 21677, WO92 / 15585, WO92 / 01688, WO93 / 06099, WO91 / 18899, US Pat. No. 5,162,339, and US Pat. No. 5,232,929.

  Other NK1 receptor antagonists that can be used with 5HT7 agonists of Formula I for the treatment of anxiety or depression according to the methods and pharmaceutical compositions of the present invention include the compounds and pharmaceutically acceptable salts described in the references below. There are: EP520,555, published December 30, 1992; European patent application EP522,808, published January 13, 1993; European patent application EP528,495, published February 24, 1993; PCT patent application WO93 / 14084 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, January 1993; published July 22, 1993; Published on 21st; PCT patent application WO92 / 20661, published on 26th November 1992; European patent application EP5 7,589, 1992 December 12, public; European patent application EP428,434, published May 22, 1991; and European Patent Application EP360,390, published March 28, 1990. All of the aforementioned international patent applications designate the United States. The entirety of the aforementioned patents and patent applications are incorporated herein by reference.

For any treatment or pharmaceutical composition of the invention, the appropriate dosing regimen, the dose of active agent to be administered, and the specific interval between administrations of each active agent is the subject being treated, the specific activity being administered It will depend on the nature and severity of the drug and the particular disorder or condition being treated. In general, the active compounds of the present invention, when used as a single active agent or in combination with another active agent, are administered to an adult in a single dose or in an amount of about 0.05 to about 1500 mg / day. It will be administered in a dose, preferably in an amount of about 5 to about 200 mg / day. Such compounds may be administered on a regimen of 6 times per day, preferably 1 to 4 times per day, especially 2 times per day and most especially once per day. Nevertheless, variations will occur depending on the type of animal being treated and the individual response to the medicament, as well as the type of pharmaceutical formulation selected and the duration and interval at which such administration is performed. In some cases, dosages below the lower limit of the above range are not just suitable, while in other examples, larger dosages may be used without causing adverse side effects. However, such a large dose is first divided into several small doses and administered over a day.

  1 day of a 5HT reuptake inhibitor, preferably sertraline, proposed for oral, parenteral or buccal administration to an average adult for the treatment of the above symptoms in the combination methods and compositions of the present invention The dosage is about 0.1 mg to about 2000 mg, preferably about 1 mg to about 200 mg of 5HT reuptake inhibitor per unit dose, which can be administered, for example, 1 to 4 times per day.

  Daily dosage of a 5HTID receptor antagonist proposed for oral, parenteral, rectal or buccal administration to an average adult for the treatment of the above symptoms in the combination methods and compositions of the present invention Is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of 5HTID receptor antagonist per unit dose, which can be administered, for example, 1 to 4 times per day.

  In the combination method and composition of the present invention, the daily dose of the NK1 receptor antagonist proposed for oral, parenteral or buccal administration to the average adult for the treatment of the above symptoms is The NK1 receptor antagonist per dose is about 0.1 mg to about 2000 mg, preferably about 1 mg to about 200 mg, which can be administered, for example, 1 to 4 times per day.

  5HT7 receptor agonists, NK1 receptor antagonists, serotonin reuptake inhibitors and 5HTID receptor antagonists, and pharmaceutically acceptable salts thereof used in the pharmaceutical compositions and methods of the present invention are hereinafter referred to as “therapeutic agents”. Also called. The therapeutic agent can be administered via the oral, buccal, nasal or parenteral routes. A composition comprising both a 5HT7 receptor agonist and an NK1 receptor antagonist, a 5HTID receptor antagonist, or a serotonin reuptake inhibitor is generally administered orally or parenterally daily in a single or divided dose, The total amount of each active agent to be administered will be administered so that it is within the above guidelines.

  The therapeutic agent can be administered alone or in combination with a pharmaceutically acceptable carrier or diluent by any of the routes previously indicated, and such administration can be performed in a single or multiple doses. More particularly, the therapeutic agents of the present invention can be administered in a variety of different dosage forms. That is, the therapeutic agent is combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candy, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups, etc. Also good. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. Furthermore, oral pharmaceutical compositions can be suitably sweetened and / or flavored. In general, the therapeutic agents of the invention are present in such dosage forms at concentration levels in the range of about 5.0 to about 70% by weight when administered separately (ie, not in the same pharmaceutical composition).

  For oral administration, the pharmaceutical composition includes, for example, a binder (eg, pre-gelled corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); a filler (eg, lactose, microcrystalline cellulose or calcium phosphate); a lubricant (eg, Manufactured by conventional means using pharmaceutically acceptable excipients such as disintegrants (eg potato starch or sodium starch glycolate); or wetting agents (eg sodium lauryl sulfate); magnesium stearate, talc or silica); In the form of a tablet or capsule. The tablets can be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or may be presented as a dry product and made up with water or other suitable vehicle before use. Such liquid formulations include suspensions (eg, sorbitol syrup, methylcellulose or hardened edible fat); emulsifiers (eg, lecithin or acacia); non-aqueous vehicles (eg, almond oil, oily esters or ethyl alcohol); and preservatives (eg, p- It may be prepared by conventional means using pharmaceutically acceptable additives such as methyl or propyl hydroxybenzoate, or sorbic acid).

  For preparing solid compositions such as tablets, the principal active ingredient may be a conventional tableting with a pharmaceutical carrier such as corn starch, lactose, sucrose, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum. The ingredients, and other pharmaceutical diluents such as water, are mixed to form a solid pre-blended composition containing a homogeneous mixture of the therapeutic agent or non-toxic pharmaceutically acceptable salt thereof. When these pre-blended compositions are homogeneous, the therapeutic agent is evenly distributed throughout the composition and thus the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills or capsules. Means you can. This solid pre-blended composition is then subdivided into unit dosage forms of the type described above containing typically about 0.05 to 500 mg of each therapeutic agent contained in the composition. Tablets or pills of the composition can be coated or formulated to provide a dosage form that provides extended action benefits. For example, a tablet or pill can include an inner dosage component and an outer dosage component, the latter being in a form that wraps around the former. The two components can be separated by an enteric layer, which helps to resist disintegration in the stomach and delivers the inner component intact into the duodenum or delays the release of the inner component. A variety of materials can be used for such enteric layers or coatings, such materials including many polymeric acids and mixtures of polymeric acids with materials such as shellac acetyl alcohol and cellulose acetate.

  For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.

  The therapeutic agent may be formulated for parenteral administration by injection, including the use of conventional catheter insertion techniques or dip. Injectable formulations may be presented in unit dosage form, ie, ampoules or multiple dose containers, with a preservative added. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain compounding agents such as suspending, stabilizing and / or dispersing agents. Solutions of therapeutic agents in sesame oil or peanut oil or aqueous propylene glycol may be used. Aqueous solutions should be appropriately buffered if necessary and the liquid diluent should first be isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, 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. Alternatively, the active ingredient may be in powder form and reconstituted with a suitable vehicle, such as sterilized pyrogen-free water, before use.

  For intranasal administration or administration by inhalation, the active compounds of the invention are in the form of a solution or suspension, from a pump spray container squeezed or pumped by the patient, or from a pressurized container or nebulizer Are conveniently released as an aerosol spray presentation using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or a suitable gas. In the case of a pressurized aerosol, the dosage unit may be measured by providing a valve to release a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (eg made from gelatin) for use in inhalers or insufflators may be formulated to contain a compound of the invention and a suitable powder-based powder mix such as lactose or starch.

  The active compound aerosols of the present invention used for the treatment of the above conditions in the average adult are preferably prepared so that each metered dose or “puff” of the aerosol contains 20 μg to 1000 μg of the active compound. Let's go. The overall daily dose with an aerosol will be in the range of 100 μg to 10 mg. Administration may be several times a day, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.

  The compound of formula I is one or more therapeutic agents, such as tricyclic antidepressants (eg amitriptyline, dothiepine, doxepin, trimipramine, buttripyline, clomipramine, imipramine, iprindole, lofepramine, nortriptyline or protriptyline) or monoamine oxidase Various antidepressants, such as inhibitors (eg isocarboxazide, phenelzine or tranylcyclopramine), and / or dopaminergic antiparkinsonian agents (eg levodopa, preferably peripheral decarboxylase inhibitors such as benzrazide or carbidopa Or in combination with anti-parkinsonian agents such as dopamine agonists (eg in combination with bromocriptine, lisuride or pergolide). It is to be understood that the present invention encompasses 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 affinity of the active compound for the 5HT5 receptor can be determined using standard radioligand binding assays as described in the literature. 5HT7 affinity can be measured using the following procedure.

Binding of ³ H-5-carboxamide tryptamine ( ³ H-5-CT) to the rat 5HT7 receptor expressed in HEK-293 cells :
Material :
HEK-293 cells expressing rat 5HT7 receptor Brinkman Polytron tissue homogenizer phosphate buffered saline (GIBCO)
Centrifuge tube with lid Centrifuge 50 mM Tris HCI buffer, pH 7.7 (Sigma T-4378)
EDTA (Sigma E-4884)
MgSO ₄ (Sigma M-7506)
CaCl ₂ (MCBCX156)
Pargyline (Sigma P-8013)
Ascorbic acid (Calbiochem1831)
5-HT creatinine sulfate complex (Sigma H-7752)
³ H-5CT (Amersham TRK. 1038)
12 x 75mm borosilicate glass tube 96 hole V-bottom polypropylene plate (NUNC-442587)
Whatman GF / B glass fiber filter (Brandel FP-105) presoaked in Scatron 96-well harvester 0.3% polyethyleneimine (Sigma-P-3143)
Betaplate scintillation counter (Wallac / LKB)

Tissue preparation:
HEK-293 cells expressing the 5HT7 receptor are grown according to standard culture techniques. The medium is removed and the cells are harvested by rinsing the flask with phosphate buffered saline (PBS) and then left for 2-3 minutes with PBS containing 2.5 mM EDTA. Remove cells and pour into RcapableS centrifuge tubes. Rinse flask with PBS and add to centrifuge tube. The cells are centrifuged for 10 minutes at 40,000 xg (20,000 rpm in a Sorvall SS34 rotor). The supernatant can be discarded and the pellet remaining at this point can be weighed and stored frozen (−20 ° C.) until used for binding assays. Pellet (fresh or frozen) in a biological hood certified for use on human tissue using a Polytron homogenizer (setting 15,000 rpm) in 50 mM Tris HCI buffer (pH 7.4 at 4 ° C.) Homogenize for 10 seconds. The homogenate is centrifuged at 40,000 × g for 10 minutes. The supernatant is discarded and the pellet is resuspended in fresh ice-cold 50 mM Tris HCI (pH 7.4 at 4 ° C) buffer using a Polytron and centrifuged again. The final pellet is resuspended in assay buffer (50 mM Tris HCI buffer (pH 7.7 at 25 ° C.) containing 0.5 mM EDTA, 10 mM MgSO ₄ , 2 mM CaCl ₂ ) to give a final tissue concentration of 1 mL buffer. The original pellet wet weight is 5-15 mg (2 × final concentration).

Incubation is initiated by adding receptor connective tissue to the V-bottom polypropylene plate (3 times). Incubation is for 2 hours at 25 ° C.
Each tube contains: 100 μL tissue suspension (original wet weight 5-15 mg / mL), 50 μL ³ H-5-CT ** (final concentration 0.4 μM), and 50 μL drug. Or buffer.
^{** 3} H-5-CT is made in assay buffer (final concentration 10 μM pargyline and 0.1% ascorbic acid) containing 40 μM pargyline and 0.4% ascorbic acid.

  Non-specific binding is determined using 1 μM 5-HT creatinine sulfate. Incubation was pre-soaked in a flame treated Whatman GF / B glass fiber filter (0.3% PEI for 2 hours under vacuum using a 96-well Skatron harvester (3 seconds pre-wet, 20 seconds wash, 15 seconds dry) and Finish by rapid filtration through (dry). Place filter in LKB sample bag 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. IC ₅₀ values (concentration that inhibits 50% of specific binding) are determined by linear regression of concentration-response data (logarithmic concentration versus logit percent value). The Ki value is Cheng & Prusoff Ki = IC ₅₀ / (1+ (L / Kd)), where L is the concentration of radioligand used in the experiment, and the Kd value was determined in a separate saturation experiment. The dissociation constant of the radioligand). Approximately 40 compounds of the present invention assayed as described above ranged from about 3.5 nM to about 5 μM binding activity to the 5HT7 receptor. For example, the title compound of Example 8 below showed a Ki of about 7.6 nM, and the title compound of Example 10 below showed a Ki of about 500 nM.

The following assay can be used to assess the functional activity of a compound at the 5HT7 receptor:
5-HT7 receptor mediated adenylate cyclase activity:
material:
1.5 mL siliconized polypropylene microfuge tube (Costar 3207)
12 × 75 mm of the borosilicate glass tube heated water bath Glass - Teflon ^(R) HEK-293 cells @ 32 P-ATP expressing homogenizer centrifuge 5-HT7 receptor (30 Ci / mmol: NEG-003-New Engl and Nuclear)
3H-cAMP (30 Ci / mmol: NET-275-New Engl and Nuclear)

Method :
Cells are grown according to standard cell culture techniques. Cells are harvested by replacing the medium with phosphate buffered saline containing 2.5 mM EDTA. Cells are homogenized using a hand-held glass-Teflon ^(R) homogenizer. The homogenate is centrifuged at 35,000 × g for 10 minutes at 4 ° 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 / tube.

A “reaction mix” is prepared so that the following drugs are in the tubes to the following final concentrations: 4.0 mM MgCl ₂ , 0.5 mM ATP, 1.0 mM cAMP, 0.5 mM per tube. IBMX, 10 mM phosphocreatine, 0.31 mg / mL creatine phosphokinase, and 100 μM GTP 0.5-1 microcurie [ ³² P] -ATP.
Incubation is initiated by adding tissue to siliconized microphage tubes (3 times). Incubation is 15 minutes at 37 ° C.
Each tube contains: 20 μL tissue, 20 μL drug or buffer (5 × final concentration), 20 μL 100 nM agonist or buffer (5 × final concentration), and 40 μL “reaction mix”.

Incubation is stopped by adding 100 μL of 2% SDS, 1.3 mM cAMP, 45 mM ATP solution containing 40,000 dpm [ ³ H] -cAMp to monitor cAMP recovery from the column. ^[32 P] -ATP and ^[32 P] separation of -cAMP is Salomon outside Analytical Biochemistry 58: 541-548, pp performs using the method of 1974 (incorporated herein by reference in its entirety). Radioactivity is quantified by liquid scintillation counting.

The maximum effect of an agonist is defined in terms of the maximum effect of serotonin (5-HT). Antagonists are evaluated for their ability to inhibit 5HT-stimulated adenylate cyclase activity. IC ₅₀ values are converted to apparent Ki values according to the following formula: IC ₅₀ / (1 + ([agonist] / EC _{50 of} agonist)).

The activity that produces the anti-depressant effect and associated pharmacological properties of the combination of active compounds can be determined by the following methods (1) to (4). Methods (1) to (4) are described by Koe, B. et al. Et al., Journal of Pharmacology and Experimental Therapeutics, 226 (3), 686-700 (1983), which is incorporated herein by reference in its entirety. Specifically, the activity is (1) the ability of mice to affect efforts to escape the swimming tank (Porsolt mouse “behavior despair” test), (2) 5HT-induced behavioral symptoms of mice in vivo (3) the ability to antagonize the serotonin depleting activity of p-chloroamphetamine hydrochloride in the rat brain in vivo, and (4) the ingestion of serotonin, norepinephrine and dopamine by synaptosomal rat brain cells in vivo. It can be determined by studying the ability to stop. The ability of the combination of active compounds to counteract reserpine hypothermia in mice in vivo is described in US Pat. No. 4,022, which is incorporated herein by reference in its entirety.
It can be determined by the method described in US Pat.

  The following examples illustrate the invention. It should be understood, however, that the invention fully described herein and set forth in the claims is not limited by the details of the following examples.

The following examples illustrate the preparation of the compounds of the present invention. Melting points are not corrected. The NMR data is reported in p.p.m. and relates to the deuterium lock signal from the sample solvent (deuterium chloroform unless otherwise specified). Specific rotation was measured using sodium D line (589 nm) at room temperature. Commercial reagents were used without further purification. THF refers to tetrahydrofuran. DMF refers to N, N-dimethylformamide. Chromatography refers to column chromatography performed using 47-61 micron silica gel and performed under nitrogen pressure (flash chromatography) conditions. Room or ambient temperature refers to 20-25 ° C. All non-aqueous reactions were performed under a nitrogen atmosphere to maximize convenience and yield. Concentration under reduced pressure means using a rotary evaporator.

Example 1
Step 1
8-Bromo-3-ethyl-quinoline
Enantiomers (both enantiomers) and racemic 3-ethyl-8-piperidin-3-yl-quinoline 2-bromo-aniline (5.4 g, 31.4 mmol), sodium 3-nitrobenzenesulfonate (4.25 g, 18.9) Mmol), concentrated sulfuric acid (8.5 g, 177 mmol), and water (3.20 ml), and to a well-stirred mixture heated to 100 ° C., was added 2-ethylacrolein (5.0 ml, 51.06 mmol). Was added. After maintaining the reaction temperature at 100 ° C. for 1 hour, the temperature was raised to 110 ° C. An additional portion of 2-ethylacrolein (1.0 ml, 10.2 mmol) was added and the reaction was stirred at 110 ° C. for 1 hour. The reaction temperature was then raised to 120 ° C. before another 1.0 ml (10.2 mmol) portion of 2-ethyl acrolein was added. The reaction was heated at 120 ° C. for 1 hour and then raised to a temperature of 130 ° C. before adding 1.0 ml (10.2 mmol) of 2-ethylacrolein. Finally, after the last portion of 2-ethylacrolein (1.3 ml, 13.3 mmol) was added, the reaction temperature was raised to 140 ° C. and maintained at that temperature for 2 hours. The cooled reaction was quenched with ice (60 g) and the pH of the resulting mixture was adjusted to 14 by addition of 6N aqueous sodium hydroxide. The reaction mixture was then extracted with three 100 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give an amber oil. Flash chromatography of all samples (silica gel, 47-61 micron mesh; eluted with methylene chloride) gave the title compound (3.70 g, 50% yield) as an amber oil.
MS m / z 236, 237, 238, 239 (M + 1).
¹ H NMR (400 MHz, CDCI3) δ 8.9 (1H, m), 7.97 (1H, m), 7.91 (1H, m), 7.74 (1H, m), 7.36 (1H, m), 2.86 (2H, q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz) ppm.

Step 2
The title compound from the previous step (2.36 g, 10 mmol), diethyl (3-pyridyl) borane (1.67 g, 11.0) in 3-ethyl-8-pyridin-3-yl-quinoline tetrahydrofuran (40 ml). Mmol) and bis (triphenylphosphinepalladium (II) chloride (913 mg, 1.3 mmol) to a well stirred mixture was added aqueous sodium carbonate (4.24 g, 40 mmol in 20 ml of water) to give The reaction mixture is heated at reflux for 4 hours, water (50 ml) is added to the well stirred mixture, the aqueous phase of the two-phase reaction mixture is separated and extracted three times with 50 ml portions of ethyl acetate. The solvent is removed in vacuo and the residue is extracted twice with 50 ml portions of ethyl acetate The combined organic extracts are dried (anhydrous sodium sulfate ), Concentrated in vacuo to yield a viscous syrup, which was purified by flash chromatography (silica gel, 47-61 micron mesh; eluted with ethyl acetate) of the title compound (830 mg, 35.4% yield). A second portion (700 mg) of the title compound (700 mg) that was less pure (determined to be approximately 75% pure by NMR inspection) was also produced as an amber syrup.
MS m / z 234 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.93 (1H, m), 8.80 (1H, m), 8.63 (1H, m), 8.10 (1H, m), 7.96 (1H , M), 7.81 (1H, m), 7.66 (1H, m), 7.60 (1H, m), 7.42 (1H, m), 2.84 (2H, q, J = 7.5 Hz), 1.34 (3H, t, J = 7.5 Hz) ppm.

Step 3
3-ethylidene-3-yl-quinoline To a solution of the title compound from the previous step (830 mg, 3.53 mmol) in anhydrous tetrahydrofuran (5.0 ml) was added 28.4 ml of 1.0 M lithium triethylborohydride in tetrahydrofuran ( 28.4 mmol) was added and the resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction was quenched by careful dropwise addition of water (50 ml). Removal of the solvent in vacuo gave a viscous oil that was extracted three times with 25 ml portions of methylene chloride. The organic extract was dried (anhydrous sodium sulfate) and concentrated in vacuo to give a viscous yellow syrup. The procedure just described was repeated using 817 mg (3.49 mmol) and 27.9 ml (27.9 mmol) of the title compound from the previous step and 1.0 N triethylborohydride in tetrahydrofuran, respectively. The crude reaction product (ie viscous yellow syrup) after treatment from both reactions was combined. Flash chromatography of all samples (silica gel, 47-61 micron mesh; methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 90: 9: 1 (volume)) gave the title compound (480 mg) as a viscous yellow oil.
MS m / z 240 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.78 (1H, m), 7.87 (1H, m), 7.58 (1H, m), 7.42-7.50 (2H, overlapping multiplets) ), 4.07 (1H, m), 3.32 (1H, m), 3.16 (1H, m), 2.80 (2H, q, J = 7.5 Hz), 2.73-2. 64 (2H, m), 2.2-2.0 (1H, m), 1.66-1.87 (3H, m), 1.32 (3H, t, J = 7.5 Hz) ppm.
¹³ C NMR (125 MHz, CDCl ³ ) δ 150.9, 145.1, 143.3, 136.7, 134.1, 128.7, 126.6, 125.7, 125.3, 54.0, 47 .1, 38.1, 31.6, 28.0, 26.4, 15.5 ppm.

Separation of enantiomers of racemic title compounds
Step 4
From the previous step dissolved in ethylene chloride (50 ml) containing racemic 3- (3-ethyl-quinolin-8-yl) -piperidine-1-carboxylic acid tert-butyl ester triethylamine (6.7 ml, 47.8 mmol) To a well-stirred solution of racemic title compound (5.40 g, 23.9 mmol) was added di-tert-butyl dicarbonate (7.80 g, 35.8 mmol) and the resulting reaction mixture was at ambient temperature. Stir for 5 hours. Saturated aqueous sodium bicarbonate solution (50 ml) was added with efficient stirring. The mixture was then extracted twice with 20 ml portions of methylene chloride. The organic extracts were combined, washed with the same volume of brine, dried (anhydrous sodium sulfate) and finally concentrated in vacuo to give a viscous syrup. Using a Biotage Flash 401i ™ silica gel flash chromatography module (cartridge pre-packed with silica gel 32-63 micron mesh, manufacturer Dyax Corporation, Biotage Division, Charlottesville, VA), methylene chloride / methanol = 99.5 : Flash chromatography of all samples eluting with 0.5 (volume) gave the title compound (4.24 g, 52% yield) as a colorless solid.
MS m / z 340 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.80 (1H, m), 7.88 (1H, m), 7.62 (1H, m), 7.50-7.43 (2H, overlapping multiplets) , 4.32 (1H, m), 4.18 (1H, m), 4.10 (1H, m), 2.92 (1H, m), 2.85-2.76 (overlapping 1H, m and 2H, 2.80 center quartet, J = 7.5 Hz), 2.12 (1H, m), 1.82-1.71 (3H, m), 1.44 (s, 9H), 1. 33 (3H, t, J = 7.5 Hz) ppm.

Step 5
Enantiomer 3- (3-Ethyl-quinolin-8-yl-piperidine-1-carboxylic acid ter-butyl ester (both enantiomers)
Separation of enantiomers of the title compound of Step 4 :
Waters Prep LC2000 ™ Preparative Chromatography System (Waters Chiracel ™ OD 10 cm × 50 cm preparative column; moving bed: heptane / ethanol containing 0.025% diethylamine modifier = 98: 2 (volume); flow rate 225 ml 4.08 g of the title compound from the previous step dissolved in 10 ml of methylene chloride / methanol = 4: 1 (volume); inject 204 mg of compound in methylene chloride / methanol solution at once; 20 minutes for the enantiomer And the appropriate retention time of 28 minutes) was used to separate the enantiomer of the title compound from Step 4 above as a yellow oil. Mass and ¹ H NMR spectra of both enantiomers was identical to the mass and ¹ H NMR spectra of the racemic compound of Step 4 in all respects. A 1.5 g total sample of the more rapidly eluting enantiomer was eluted with the above Biotage Flash 401i ™ silica gel chromatography module (32-63 micron mesh factory pack cartridge; hexane / ethyl acetate = 8: 2 (volume)) Further purification by flash chromatography using 1.34 g of purified enantiomer was obtained as a colorless syrup.
MS m / z 340 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ

Step 6
Enantiomer 3-ethyl-8-piperidin-3-yl-quinoline (both enantiomers) Any purified compound from the previous step was dissolved in ethyl acetate / saturated hydrogen chloride solution (tert-butyloxycarbonyl functionalized substrate 10 mg). 0.25 ml of saturated ethyl acetate per hydrogen chloride; reaction time of 4 hours at ambient temperature), the corresponding deprotected enantiomer of step 5 was obtained in quantitative yield as the monohydrochloride title compound. The free base of either enantiomer title compound hydrochloride as a colorless amorphous solid in quantitative yield, the salt form dissolved in vigorously stirred (pH 10) aqueous sodium hydroxide / ethyl acetate biphasic mixture, separated and organic extracted Was obtained by drying over anhydrous sodium sulfate and then removing the solvent in vacuo. The mass spectrum and ¹ H NMR spectrum of the enantiomeric free base compound are in all respects the same as those of the racemic counterpart described previously (title compound in Step 3).

Example 2
Enantiomers (both enantiomers) and racemic 3-ethyl-7-methyl 8-piperidin-3-yl-quinoline
Step 1
To a solution of 3- (2-methyl-6-nitro-phenyl) -pyridine 2-bromo-3-nitrotoluene 5.0 g (23 mmol) in tetrahydrofuran (180 ml); diethyl-3-pyridylborane (3.89 g, 26 mmol) ), Bis-triphenylphosphine palladium (II) chloride (2.42 g, 3.45 mmol), and a solution of sodium carbonate (12.19 g, 115 mmol) in water (60 ml) were sequentially added. The resulting well stirred reaction mixture was then heated to 75 ° C. for 18 hours. The separated organic layer was diluted with ethyl acetate (200 ml) and extracted with an equal volume of water. The organic extract was then dried (anhydrous sodium sulfate) and concentrated in vacuo to give a brown oil (9.4 g). Flash chromatography of all samples (silica gel, 47-61 micron mesh; eluting with ethyl acetate / hexane = 1: 1 (volume)) gave the title compound (2.40 g, 48% yield) as an amber oil. It was.
¹ HNMR (400 MHz, CDCl ₃ ) δ 8.66 (m, 1H), 8.47 (m, 1H), 7.80 (m, 1H), 7.61 (m, 1H), 7.55 (m, 1H), 7.42 (m, 2H), 2.11 (5, 3H) ppm.

Step 2
The title compound from the previous step (2.40 g, 12 mmol) dissolved in 3-methyl-2-pyridin-3-yl-phenylamine ethanol (50 ml) was hydrogenated (40 psi; 275 mg platinum oxide catalyst) for 3 hours. ). The catalyst was filtered and the solvent removed in vacuo to give an amber oil (1.4 g). Flash chromatography of all samples (silica gel, 41-67 micron mesh; elution with methylene chloride / methanol = 96: 4 (volume)) gave the title compound (1.40 g, 69% yield) as an amber oil. . TLC Rf (silica gel plate; eluted with methylene chloride / methanol = 96: 4 (volume); UV detection): 0.35.
¹ HNMR (450 MHz, CDCl ₃ ) δ 8.62 (m, 1H), 8.50 (m, 1H), 7.61 (m, 1H), 7.40 (m, 1H), 7.04 (m, 1H), 6.70 (m, 1H), 6.60 (m, 1H), 3.25 (broad s, 2H), 2.00 (s, 3H) ppm.

Step 3
3-ethyl-7-methyl-8-pyridin-3-yl-quinoline The title compound from the previous step (800 mg, 4.3 mmol), concentrated sulfuric acid (660 μl, 12 mmol), and meta in water (450 μl). The reaction mixture prepared by combining sodium nitrobenzenesulfonate (544 mg, 24 mmol) was stirred well and heated to 100 ° C. while 2-ethylacrolein (1.26 ml, 13 mmol) was added dropwise over 4 minutes. did. The reaction mixture was heated to 100 ° C .; then heated to 120 ° C. for 2 hours. The reaction was then cooled to 100 ° C. and an additional 1.26 ml (13 mmol) of 2-ethylacrolein was added dropwise over several minutes. After further heating to 120 ° C. for 2 hours, water (10 ml) was added and the solution was made basic (pH 12) with sodium hydroxide. The solution was then extracted three times with 25 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give an oil (2.36 g). Flash chromatography of all samples (silica gel, 41-67 micron mesh; eluted with methylene chloride / methanol = 97: 3 (volume)) gave the title compound as a colorless oil (567 mg, 53% yield). TLC Rf (silica gel plate, eluted with methylene chloride / methanol = 97: 3 (volume); UV detection): 0.31.
MS m / z 249 (M + l).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 152.0, 151.2, 148.1, 145.8, 138.4, 136.9, 135.7, 135.1, 133.4, 129.6, 127 .4,126.8,123.2,26.3,21.2,15.4 ppm.

Step 4
Racemic 3-ethyl-7-methyl-8-piperidine-3-quinoline To a solution of the title compound from the previous step (567 mg, 2.3 mmol) in anhydrous tetrahydrofuran (20 ml) was added lithium triethylborohydride (1 in anhydrous tetrahydrofuran). A solution of 0.0 M; 8.1 ml, 8.1 mmol; Aldrich Chemical Company) was added dropwise over several minutes. After stirring for 3 hours at ambient temperature, an additional 4.05 ml (4.05 mmol) of 1.0 M triethylborohydride in anhydrous tetrahydrofuran was added dropwise. After stirring for an additional 3 hours at ambient temperature, the reaction was quenched by dropwise addition of methanol. Saturated aqueous sodium carbonate was added and the resulting mixture was extracted three times with 25 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give an oil (670 mg). The title compound (87 mg, 15% yield) was colorless by flash chromatography of all samples (silica gel, 47-61 micron mesh; eluted with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 79: 20: 1 (volume)). Obtained as an oil.
TLC Rf (silica gel plate; eluted with methylene chloride / methanol / concentrated aqueous ammonium hydroxide solution = 58.75: 40: 1.25 (volume); UV detection): 0.14.
MS m / z 255 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (m, 1H), 7.77 (m, 1H), 7.46 (m, 1H), 7.26 (m, 1H), 4.2 (m , 1H), 3.5 (m, 2H), 2.9 (m, 2H), 2.75 (q, 2H, J = 7), 2.52 (s, 3H), 1.70 (m, 4H), 1.30 (t, 3H, J = 7) ppm.

Step 5
Enantiomer (both enantiomers)
Step 4 / Using a procedure similar to that of Example 1, the racemic title compound of the previous step of this example is converted to the corresponding racemic nitrogen substituted tert-butoxycarbonyl compound, which is then separated / purified. The enantiomer was isolated by the method of Step 5 / Example 1. Finally, the enantiomer of the title compound of the previous step of this example was prepared in both monohydrochloride and free base form by the procedure of Step 6 / Example 1.

Example 3
Enantiomers (both enantiomers) and racemic 3,6-dimethyl-8-piperidin-3-yl-quinoline
Step 1
4-Methyl-2-pyridin-3-yl-phenylamine 2-bromo-4-methylaniline (2.67 ml, 21 mmol) in tetrahydrofuran (125 ml), diethyl-3-pyridylborane (3.08 g, 24 mmol) And to a mixture of bis (triphenylphosphine) palladium (II) chloride (2.21 g, 0.32 mmol) was added aqueous sodium carbonate solution (11.13 g in 44 ml water, 10.5 mmol). The well stirred reaction mixture was heated to 75 ° C. for 18 hours. The upper layer of the cooled biphasic mixture was separated, dried (anhydrous sodium sulfate) and then filtered through celite. Removal of the solvent in vacuo gave an oil (6.5 g). Flash chromatography of all samples (silica gel; eluted with methylene chloride / methanol = 95: 5 (volume)) gave the title compound (1.85 g, 48% yield) as a colorless amorphous solid. TLC Rf (silica gel plate; eluted with methylene chloride / methanol = 95: 5; UV detection): 0.53.
MS m / z 185 (M + l).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 150.2, 148.5, 141.5, 136.8, 135.6, 131.2, 130.1, 128.4, 124.0, 123.7, 116 .3, 20.6 ppm.

Step 2
3,6-Dimethyl-8-pyridin-3-yl-quinoline To a solid sample of the title compound from the previous step (1.85 g, 10 mmol) was slowly added concentrated sulfuric acid (18 M, 27.5 mmol, 1.52 ml). In addition, sodium meta-nitrobenzenesulfonate (1.26 g, 56 mmol) and water (1.05 ml) were then added. The well-stirred mixture was heated to 100 ° C. during which time 2-methylacrolein (4.97 m
l, 60 mmol) was added dropwise over 5 minutes. After stirring at 100 ° C. for 1/2 hour, the reaction temperature was raised to 140 ° C. with continuous stirring for 3 hours. After quenching with ice, the reaction mixture was made basic (pH 12) by the addition of 50% aqueous sodium hydroxide. The mixture was then extracted three times with 30 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and the solvent removed in vacuo to give an amber oil. Flash chromatography of all samples (silica gel; 41-67 micron mesh; elution with methylene chloride / methanol = 96: 4 (volume)) gave the title compound (650 mg, 28% yield) as an amorphous solid. TLC Rf (silica gel plate; eluted with methylene chloride / methanol = 96: 4 (volume); UV detection): 0.24.
MS m / z 235 (M + l).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 151.8, 1, 51.0, 148.4, 138.4, 136.7, 136.3, 135.5, 134.5, 131.7, 130.9 , 130.1, 128.9, 126.9, 123.0, 21.8, 18.8 ppm.

Step 3
3,6-Dimethyl-8-piperidin-3-yl-quinoline To a solution of the title compound from the previous step (650 mg, 28 mmol) in anhydrous tetrahydrofuran (20 ml) was added a 1.0 M solution of lithium triborohydride (9.70 ml). 9.7 mmol; Aldrich Chemical Co.) was added over several minutes. After the reaction mixture was stirred for 2 hours at ambient temperature, an additional 2.8 ml (2.8 mmol) of 1.0 M lithium triethylborohydride in tetrahydrofuran was added; stirring at ambient temperature was continued for an additional hour. The reaction was quenched by slow and careful addition of methanol. Saturated aqueous sodium carbonate (15 ml) and methylene chloride were added and the resulting mixture was extracted with 25 ml portions of 3 parts of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give an oil (600 mg). Flash chromatography of all samples (silica gel, 41-67 micron mesh; first eluting with methylene chloride / methanol / concentrated aqueous ammonia = 84: 15: 1 (volume), then methylene chloride / methanol / concentrated aqueous ammonia = 73.75 : 25: 1.25 (volume)) to give the title compound (100 mg, 15% yield) as a colorless oil. TLC Rf (silica gel plate; methylene chloride / methanol / concentrated aqueous ammonium hydroxide solution = 82: 15: 1 (volume); UV detection): 0.25.
MS m / z 241 (M + l).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 150.6, 143.3, 142.6, 136.2, 134.7, 130.4, 128.6, 127.7, 124.5, 53.6, 46 9.9, 37.8, 31.5, 27.7, 22.0, 18.8 ppm.

Step 4
Enantiomer (both enantiomers)
Step 4 / Using a procedure similar to that of Example 1, the racemic title compound of the previous step of this example is converted to the corresponding racemic nitrogen substituted tert-butoxycarbonyl compound, which is then separated / purified. The enantiomer was isolated by the method of Step 5 / Example 1. Finally, the enantiomer of the title compound of the previous step of this example was prepared in both monohydrochloride and free base form by the procedure of Step 6 / Example 1.

Example 4
Enantiomers (both enantiomers) and racemic 3,7-dimethyl-8-piperidin-3-yl-quinoline
Step 1
2-Bromo-3-nitrotoluene (5.0 g, 23 mmol), diethyl-3-pyridylborane (3.89 g, 26 mmol) in 3- (2-methyl-6-nitro-phenyl) -pyridinetetrahydrofuran (180 ml). ) And an aqueous solution of sodium carbonate (12.19 g, 115 mmol) was added to a mixture consisting of bis (triphenylphosphine) palladium (II) chloride (2.42 g, 3.45 mmol).
The well stirred reaction mixture was heated to 75 ° C. for 18 hours. The organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give an oil (9.6 g). Flash chromatography of all samples (silica gel, 41-67 micron mesh; eluting with ethyl acetate / hexane = 1: 1 (volume)) gave the title compound as a pale yellow oil (1.87 g, 38% yield). . TLC Rf (silica gel plate; eluted with ethyl acetate / hexane = 1: 1 (volume); UV detection): 0.50.
MS m / z 215 (M + l).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 171.4, 148.1, 148.0, 139.6, 137.2, 134.7, 133.0, 131.7, 129.2, 123.9, 122 0.0, 21.0 ppm.

Step 2
The title compound from the previous step (1.87 g, 8.7 mmol) dissolved in 3-methyl-2-pyridin-3-yl-phenylamineethanol (40 ml) was hydrogenated (40 psi; platinum oxide catalyst 200 mg) for 4 hours. ). The catalyst was removed by filtration through celite. The filtrate was concentrated in vacuo to give an amber oil (1.2 g). Flash chromatography of all samples (silica gel, 41-67 micron mesh; elution with methylene chloride / methanol = 96: 4 (volume)) gave the title compound (1.17 g, 74% yield) as a sticky solid. TLC Rf (silica gel plate; eluted with methylene chloride / methanol = 96: 4 (volume); UV detection): 0.38.
MS m / z 185 (M + l).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 151.1, 148.8, 144.4, 138.2, 137.4, 134.3, 129.1, 124.2, 123.8, 120.4, 113 .3, 20.9 ppm.

Step 3
3,7-Dimethyl-8-pyridin-3-yl-quinoline To a solid sample of the title compound from the previous step (1.17 g, 6.4 mmol) was added concentrated sulfuric acid (18 M, 17.6 mmol, 980 μl). Slowly added, then sodium meta-nitrobenzenesulfonate (800 mg, 3.6 mmol) and water (680 μl) were added. The well stirred mixture was heated to 100 ° C. during which time 2-methylacrolein (1.59 ml, 19.2 mmol) was added dropwise over 5 minutes. After stirring for 1/2 hour at 100 ° C., a 1.59 ml (19.2 mmol) portion of 2-methylacrolein was added dropwise; and the next well stirred reaction mixture was heated to 140 ° C. for 3 hours. An incomplete reaction was found by thin layer chromatography (TLC) examination of the reaction aliquot. The reaction mixture temperature was lowered to 100 ° C. and a final 1.59 ml (19.2 mmol) portion of 2-methylacrolein was added followed by heating to 140 ° C. for a further 2 hours to complete the reaction. The reaction mixture was poured into ice (50 g), made basic (pH 10) by adding 50% aqueous sodium hydroxide solution and then extracted three times with 50 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give an oil (3.2 g). Flash chromatography of all samples (silica gel plate; 47-61 micromesh; eluted with methylene chloride / methanol = 96: 4 (volume)) gave the title compound (328 mg, 22% yield) as an amber oil. TLC Rf (silica gel plate; eluted with methylene chloride / methanol = 96: 4 (volume), UV detection): 0.34.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.6 (m, 3H), 7.88 (m, 1H), 7.64 (m, 2H), 7.40 (m, 2H), 2.42 (s , 3H), 2.38 (s, 3H) ppm.

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) was added tetrahydrofuran (4.90 ml, 4.9 mmol). ) Was added dropwise in a 1.OM solution of lithium triethylborohydride. The reaction mixture was stirred at ambient temperature for 3 hours. After a second portion of 1.0 M lithium triethylborohydride in tetrahydrofuran (1.40 ml, 1.4 mmol) was added dropwise, stirring at ambient temperature was continued for an additional 1.5 hours. The reaction was quenched by careful dropwise addition of methanol (1 ml). Saturated aqueous sodium carbonate and methylene chloride were added to the well stirred mixture and then it was extracted three times with 30 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give a yellow oil (470 mg). Flash chromatography of all samples (silica gel, 47-61 micron mesh; first eluting with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 84: 15: 1 (volume), then methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 59: 40: 1 (volume)) to give the title compound (45 mg, 13% yield) as an amber amorphous foam.
TLC Rf (silica gel plate; eluted with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 84: 15: 1 (volume), UV detection): 0.28.
MS m / z 241 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (m, 1H), 7.76 (m, 1H
), 7.45 (m, 1H), 7.26 (m, 1H), 4:32 m, 1H), 3.22 (m, 1H), 3.08 (m, 1H), 2.92 (m) , 2H), 2.75 (s, 3H), 2.42 (m, 4H), 1.80 (m, 3H) ppm.

Step 5
Enantiomer (both enantiomers)
Step 4 / Using a procedure similar to that of Example 1, the racemic title compound of the previous step of this example is converted to the corresponding racemic nitrogen-substituted tert-butoxycarbonyl compound, which is then its separated / purified enantiomer. Was isolated by the method of Step 5 / Example 1. Finally, the enantiomer of the title compound of the previous step of this example was prepared in both monohydrochloride and free base form by the procedure of Step 6 / Example 1.

Example 5
Enantiomers (both enantiomers) and racemic 3,5-dimethyl-8-piperidin-3-yl-quinoline
Step 1
4-Bromo-3-nitrotoluene (4.0 g, 18.5 mmol), diethyl-3-pyridylborane (3.12 g, 3- (4-methyl-2-nitro-phenyl) -pyridine tetrahydrofuran (145 ml). 21 mmol) and bis (triphenylphosphine) palladium (II) chloride (1.94 g, 2.8 mmol) to a mixture of sodium carbonate (9.8 g, 92.5 mmol) in water (50 ml). The solution was added. The reaction mixture was heated to 75 ° C. for 18 hours. The organic layer of the biphasic mixture was dried (anhydrous sodium sulfate) and the solvent was removed in vacuo to give an oil (7.0 g). Flash chromatography of all samples (silica gel, 47-61 micron mesh; eluting with ethyl acetate / hexane = 1: 1 (volume)) gave the title compound (2.58 g, 65% yield) as a pale yellow foam. It was. TLC Rf (silica gel plate; eluted with ethyl acetate / hexane = 1: 1 (volume); UV detection): 0.51.
MS m / z 215 (M + l).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 148.4, 147.9, 140.3, 136.4, 134.3, 133.9, 132.1, 130.1, 125.2, 123.6, 21 .1 ppm.

Step 2
The title compound from the previous step (2.58 g, 12 mmol) dissolved in 5-methyl-2-pyridin-3-yl-phenylamine ethanol (65 ml) was hydrogenated for 3 hours (40 psi; platinum oxide catalyst 275 mg) . The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to give an amber oil (2.27 g). Flash chromatography of all samples (silica gel, 47-61 micron mesh; elution with methylene chloride / methanol = 95: 5 (volume)) gave the title compound (1.6 g, 73% yield) as a yellow oil. TLC Rf (silica gel plate; eluted with methylene chloride / methanol = 95: 5 (volume); UV detection): 0.59.
MS m / z 185 (M + l).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 150.2, 148.2, 143.8, 139.7, 135.6, 130.7, 123.8, 121.2, 120.2, 116.7, 21 .4 ppm.

Step 3
3,5-Dimethyl-8-pyridin-3-yl-quinoline To a solid sample of the title compound from the previous step (1.60 g, 8.7 mmol) was added concentrated sulfuric acid (18M, 1.32 ml, 23.9 mmol). ) Was added slowly followed by sodium meta-nitrobenzenesulfonate (1.10 g, 4.9 mmol) and water (1.0 ml). The well-stirred mixture was heated to 100 ° C. while 2-methylacrolein (4.31 ml, 52 mmol) was added dropwise over 5 minutes. After heating at 100 ° C. for 1/2 hour, the reaction was heated to 140 ° C. for 6 hours. The mixture was diluted with water (50 ml) and the pH was adjusted to 10 with 50% aqueous sodium hydroxide. Three successive extractions were performed using a 40 ml portion of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give 1.06 g of an oil. Flash chromatography of all samples (silica gel; 47-61 micromesh; eluting with methylene chloride / methanol = 97: 3 (volume)) gave the title compound as a colorless oil (220 mg, 10.8% yield). TLC
Rf (silica gel plate; eluted with methylene chloride / methanol = 97: 3 (volume), UV detection): 0.20.
MS m / z 235 (M + l).

Step 4
Racemic 3,5-dimethyl-8-piperidin-3-yl-quinoline To a well-stirred anhydrous tetrahydrofuran (7.5 ml) solution of the title compound from the previous step (220 mg, 0.94 mmol) in tetrahydrofuran (3.30 ml). , 3.3 mmol), 1.OM solution of lithium triethylborohydride in a few minutes. The reaction was stirred at ambient temperature for 4 hours and quenched with careful dropwise addition of methanol. Methylene chloride (25 ml) and aqueous sodium carbonate solution (25 ml) were added to the well stirred mixture and then it was extracted with 2 parts of a 30 ml portion of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give an orange oil (440 mg). Elution with flash chromatography of all samples (silica gel, first methylene chloride / methanol / concentrated aqueous ammonium hydroxide solution = 84: 15: 1 (volume), then methylene chloride / methanol / concentrated aqueous ammonium hydroxide solution = 73.75: 25 Elution with 1.25 (volume)) gave the title compound (17 mg, 7.5% yield) as a colorless oil. TLC Rf (silica gel plate; eluted with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 73.75: 25: 1.25 (volume), UV detection): 0.33.
MS m / z 241 (M + l).
¹³ C NMR (125 MHz, CDCl ₃ ) δ 150.9, 144.8, 140.8, 132.1, 131.8, 130.0, 127.7, 127.0, 125.0, 53.4, 46 .7, 37.7, 31.3, 27.4, 19.1, 18.8 ppm.

Step 5
Enantiomer (both enantiomers)
Step 4 / Using a procedure similar to that of Example 1, the racemic title compound of the previous step of this example is converted to the corresponding racemic nitrogen substituted tert-butoxycarbonyl compound, which is then separated / purified. The enantiomer was isolated by the method of Step 5 / Example 1. Finally, the enantiomer of the title compound of the previous step of this example was prepared in both monohydrochloride and free base form by the procedure of Step 6 / Example 1.

Example 6
Enantiomers (both enantiomers) and racemic 6-chloro-3-methyl-8-piperidin-3-yl-quinoline
Step 1
2-Bromo-4-chloroaniline (5.0 g, 24 mmol), diethyl-3-pyridylborane (4.07 g) in 6-chloro-3-methyl-8-pyridin-3-yl-quinoline tetrahydrofuran (180 ml) , 28 mmol), and bis (triphenylphosphine) palladium (II) chloride (2.53 g, 3.6 mmol) to a well stirred mixture of sodium carbonate (12.72 g, 120 mmol) in water (60 ml) The solution was added. The reaction was then heated to 75 ° C. for 18 hours. The organic layer of the biphasic mixture was separated and the aqueous layer was extracted with the same volume of ethyl acetate. The combined original reaction organic phase and ethyl acetate extract were dried and concentrated in vacuo to give an oil (9.4 g). Flash chromatography of all samples (silica gel; first eluting with ethyl acetate / hexane = 8: 2 (volume) and then with pure hexane) gave the title compound as a colorless oil (3.64).
g, yield 74%). TLC Rf (silica gel plate; eluted with ethyl acetate; UV detection): 0.46.

Step 2
6-Chloro-3-methyl-8-pyridin-3-yl-quinoline The title compound from the previous step (3.64 g, 17.8 mmol), sodium 3-nitrobenzenesulfonate (2.33 g, 10 mmol) and To a well stirred mixture consisting of water (1.79 ml) was carefully added 2.72 ml (49 mmol) of concentrated sulfuric acid (18M). The reaction mixture was heated to 100 ° C. and 2-methylacrolein (4.39 ml, 53 mol) was added. The reaction was stirred at 100 ° C. for 20 minutes and then stirred at 140 ° C. for 2 hours. After returning the reaction temperature to 100 ° C., another 4.39 ml (53 mmol) portion of 2-methylacrolein was added dropwise. The reaction temperature was raised again to 140 ° C. and maintained at that temperature for 1.5 hours. The same volume of ice was used to quench the reaction. The resulting mixture was made basic (pH = 12) by the addition of 50% aqueous sodium hydroxide. The mixture was then extracted with 75 ml of methylene chloride. The organic extract was dried (anhydrous sodium sulfate) and concentrated in vacuo to give a dark oil. Flash chromatography of all samples (silica gel, 47-61 micron mesh; first eluting with ethyl acetate / hexane = 8: 2 (volume), steadily increasing the polarity of the eluting solvent and finally pure ethyl acetate To give the title compound as a colorless oil (343 mg, yield 7.6%). TLC Rf (silica gel plate;
Elution with ethyl acetate / hexane = 8: 2 (volume), UV detection): 0.35.
MS m / z 255 (M + l).

Step 3
Racemic 6-chloro-3-methyl-8-piperidin-3-yl-quinoline To a well stirred anhydrous tetrahydrofuran (5 ml) solution of the title compound from the previous step (150 mg, 0.59 mmol) in tetrahydrofuran (2.1 ml). , 2.1 mmol), and a 1.OM solution of lithium triethylborohydride was added and the resulting reaction mixture was stirred at ambient temperature for 4 hours before being quenched by careful addition of 200 μl of methanol. Saturated aqueous sodium carbonate (10 ml) and methylene chloride were added with vigorous stirring. The mixture was then extracted three times with 15 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give a yellow oil (230 mg). Elution with flash chromatography (silica gel, 47-61 micron mesh; first methylene chloride / methanol / concentrated aqueous ammonium hydroxide solution = 97.25: 2.50: 0.25 (volume). The title compound (17 mg, 11% yield) was obtained as a colorless oil by steadily increasing and finally eluting with methylene chloride / methanol / concentrated aqueous ammonium hydroxide solution = 89: 10: 1 (volume). TLC Rf (silica gel plate; eluted with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 89: 10: 1 (volume), UV detection): 0.39.
MS m / z 261 (M + 1).
¹³ C NMR (175 MHz, CDCl ₃ ) δ 151.6, 145.4, 143.2, 134.4, 132.4, 131.6, 129.2, 126.4, 124.1, 53.5 46.8, 37.9, 31.3, 27.5, 18.8 ppm.

Step 4
Enantiomer (both enantiomers)
Step 4 / Using a procedure similar to that of Example 1, the racemic title compound of the previous step of this example is converted to the corresponding racemic nitrogen-substituted tert-butoxycarbonyl compound, which is then its separated / purified enantiomer. Was isolated by the method of Step 5 / Example 1. Finally, the enantiomer of the title compound of the previous step of this example was prepared in both monohydrochloride and free base form by the procedure of Step 6 / Example 1.

Example 7
Enantiomers (both enantiomers) and racemic 4-methyl-8-piperidin-3-yl-quinoline
Step 1
1-Bromo-2-nitrobenzene (2.12 g, 8.7 mmol), diethyl (3-pyridyl) borane (1.47 g, 10.0) in 3- (2-nitro-phenyl) -pyridinetetrahydrofuran (40 ml). Mmol) and bis (triphenylphosphine) palladium (II) chloride (913 mg, 1.3 mmol), sodium carbonate (4.24 g, 40.0 mmol) was added and the resulting reaction mixture was added to 4 Heated at reflux for hours. Water (40 ml) was added to the cooled reaction mixture, and then the mixture was extracted three times with 25 ml portions of ethyl acetate. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give a sticky residue. All the samples were flash chromatographed (silica gel, 47-61 micron mesh; first eluted with methylene chloride and finally eluted with methylene chloride / methanol = 98: 2 (volume)) to give the title compound as a viscous amber oil (713 mg, Yield 41%). The subsequent eluate contained less pure product, which was further purified by similar flash chromatography eluting with methylene chloride / methanol = 99: 1 (volume) to add an additional 488 mg of purified title compound. (Yield 28%) was also obtained as a viscous amber oil.
MS m / z 200 (M + 1).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.65 (1H, M), 8.58 (1H, m), 7.9 (1H, m), 7.60-7.73 (2H, overlapping multiplets) 7.56 (1H, m), 7.43 (1 H, m), 7.36 (1 H, m) ppm.

Step 2
2-Pyridin-3-yl-phenylamine The title compound from the previous step (16.3 g, 81 mmol) in methanol (300 m
l) The solution was hydrogenated for 3.5 hours (50 psi; 1.65 g of platinum oxide catalyst). The catalyst was filtered and the filtrate was concentrated in vacuo to give a viscous amber oil. Flash chromatography of all samples (silica gel, 47-61 micron mesh; eluted with ethyl acetate) gave 13.5 g (94.6% yield) of the title compound as an amber oil.
MS m / z 171 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.71 (1H, m), 8.58 (1H, m), 7.80 (1H, m), 7.37 (1H, m), 7.19 (1H , M), 7.10 (1H, m), 6.84 (1H, m), 6.78 (1H, m), 3.70 (2H, broad s) ppm.

Step 3
Racemic 2-pyridin-3-yl-phenylamine To a well stirred solution of the title compound from the previous step (1.83 g, 10.8 mmol) in tetrahydrofuran (5.0 ml) was added 1M lithium triethylborohydride in tetrahydrofuran. Was added dropwise over 15 minutes. The reaction mixture was then stirred at ambient temperature for 18 hours. The reaction was then quenched by careful dropwise addition of water (100 ml). The solvent was removed in vacuo to give a viscous oil. Chromatography of all samples by flash chromatography (silica gel, 47-61 micron mesh; eluted with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 90: 9: 1 (volume)) 470 mg of a viscous syrup sample (after appropriate combination with the graphy column fraction), which solidifies on standing and is shown to be primarily the title compound by NMR examination, and a sample of the desired compound (600 mg, which is fairly low purity) A viscous oil) was obtained. A 470 mg sample was triturated with methylene chloride (2 ml) to give a 100 mg sample of the title compound (colorless amorphous solid, isolated by suction filtration; no impurities detectable by NMR inspection). A second flash chromatography (same chromatographic conditions) of the above 600 mg impure sample produced an additional 160 mg of purified title compound product (colorless amorphous solid; 260 mg, 14% yield).
MS m / z 177 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.40 (1H, m), 9.33 (1H, m), 9.10 (1H, m), 9.05 (1H, M), 5.60 (2H m), 5.0-5.34 (3H, overlapping multiplets), 4.30 (2H, m), 4.12 (2H, m) ppm.

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 was added 0.12 ml of 12N hydrochloric acid to give a clear A solution was obtained. 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 an additional 0.016 ml portions of methyl vinyl ketone were added at 10 minute intervals. The reaction was then refluxed for 2 hours. The volatiles were removed in vacuo to produce a viscous syrup. The residual syrup was made basic by thoroughly grinding with 10 ml of 3N aqueous sodium hydroxide. The resulting mixture was extracted three times with 10 ml portions of methylene chloride. The combined organic extracts were then extracted with the same volume of brine, dried (anhydrous sodium sulfate) and concentrated in vacuo to produce a viscous oil. Several repeated flash chromatography procedures (silica gel, 47-61 micron mesh; eluting with methylene chloride / methanol = 98: 2 (volume) in the first run) using the whole crude product sample and repeated chromatography The purified product was obtained as a colorless oil (131 mg, 39% yield).
MS m / z 227 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (1H, m), 7.85 (1H, m), 7.58-7.48 (2H, overlapping multiplets), 7.22 (1H, m) 4.14 (1H, m), 3.34 (1H, m), 3.19 (1H, m), 2.68 (3H, s), 2.60-2.
80 (2H, m), 2.1 (1H, m), 1.90-1.6 (3H, m) ppm.

Separation of the enantiomers of the title compound
Step 5
Racemic 3- (4-methyl-quinolin-8-yl-piperidine-1-carboxylic acid tert-butyl ester Using the method of Example 1, Step 6, a total of 131 mg (0 .58 mmol) was converted to the corresponding N-tert-butyloxycarbonyl functionalized title compound of this step (yield 120 mg, 63.4%, as a colorless oil).
MS m / z (M + 1).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.78 (1H, m), 7.87 (1H, m), 7.46-7.60 (2H, overlapping multiplets), 7.23 (1H, m) , 4.34 (1H, m), 4.20 (1H, m), 4.15 (1H, m), 2.91 (1H, m), 2.81 (1H, m), 2.67 ( 3H, s), 2.12 (1H, m), 1.76 (3H, m), 1.44 (9H, s) ppm.

Enantiomer 3- (4-Methyl-quinolin-8-yl) -piperidine-1-carboxylic acid tert-butyl ester (both enantiomers)
Step 6
Separation of enantiomers of the title compound in Step 5 Waters Prep LC2000 ™ preparative chromatography system described in Example 1 (Chiracal ™ OD 2.1 cm × 25 cm preparative column; mobile phase: heptane / ethanol = 98: 2 (volume), using 0.025% diethylamine as a modifier; flow rate 10 ml / min; 134 mg of the title compound from the previous step dissolved in methylene chloride / methanol / mobile phase solution = 1: 1: 1 (volume); The 10 mg of dissolved compound was injected at once; the appropriate retention times 25 and 35 minutes were used to isolate the enantiomer of the title compound from Step 5 above as a colorless oil (31 mg of fast eluting enantiomer, and 17 mg of late eluting enantiomer was obtained). The ¹ H NMR spectra of both enantiomers were identical in all respects to the racemic title compound spectrum of Step 5 of this example.

Step 7
Enantiomer 4-Methyl-8-piperidin-3-yl-quinoline (both enantiomers)
All 31 mg and 17 mg samples of the fast eluting enantiomer title compound and the late eluting enantiomer title compound prepared in the previous step, respectively, were dissolved in 0.5 ml chloroform. Hydrogen chloride saturated diethyl ether solution (1 ml) was added to each. Both reaction mixtures were stirred at ambient temperature for 18 hours. Removal of the solvent in vacuo yielded 15 mg and 9.5 mg of the title compound enantiomer, respectively, as a colorless amorphous solid derived from the fast and slow eluting step 6 enantiomer compounds. NMR obtained with the faster eluting enantiomer monohydrochloride:
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.09 (1H, m), 8.46 (1H, m), 8.18 (1H, m), 7.96-8.09 (2H, overlapping multiplets) , 4.21 (1H, m), 3.65 (1H, m), 3.57 (1H, m), 3.46 (1H, m), 3.18 (1H, m), 3.07 ( 3H, s), 2.08-2.33 (3H, m), 1.93-2.05 (1H, m) ppm.

Example 8
Enantiomers (both enantiomers) and racemic 3-methyl-8-piperidin-3-yl-quinoline
Step 1
3-Methyl-8-pyridin-3-yl-quinoline Example 7, step 2 (3.20 g, 18.8 mmol), sodium 3-nitrobenzenesulfonate 2.51 g (11.1 mmol), concentrated sulfuric acid 5. A well stirred mixture consisting of 1 g (51.9 mmol) and water (1.89 ml) was heated to 100 ° C. 2-Methylacrolein (1.0 ml, 12.1 mmol) was added and the reaction temperature was maintained at 100 ° C. for 1 hour. The reaction temperature was then raised to 110 ° C., an additional 1 ml (12.1 mmol) portion of 2-methylacrolein was added and the reaction temperature of 110 ° C. was maintained for 1 hour. Subsequently, the above continuous procedure of raising the reaction temperature by 10 ° C., then adding 1.0 ml of 2-methylacrolein and heating at the newly set temperature for 1 hour was repeated three more times (reaction temperature 120 ° C., 130 ° C. ° C and finally 140 ° C). The reaction temperature was then lowered to 90 ° C. and maintained at that temperature, resulting in an acidic aqueous phase and a soft sticky gum. The acidic layer was carefully siphoned and the remaining gum was thoroughly ground / pulped with a few 25 ml portions of 1N hydrochloric acid. The combined acidic aqueous extracts were made basic (pH = 14) by the addition of 50% sodium hydroxide and then extracted twice with 50 ml portions of methylene chloride extract. The organic extract was dried (anhydrous sodium sulfate) and concentrated in vacuo to give an amber syrup. Flash chromatography of all samples (silica gel, 47-61 micron mesh; eluted with ethyl acetate) gave the title compound (790 mg, 19.1% yield) as a viscous colorless syrup.
MS m / z 221 (M + 1).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.91 (1H, m), 8.77 (1H, m), 8.63 (1H, m), 8.07 (1H, m), 7.97 (1H , M), 7.66 (1H, m), 7.60 (1H, m), 7.40 (1H, m), 2.52 (3H, s) ppm.

Step 2
Racemic 3-methyl-8-piperidin-3-yl-quinoline To a solution of the title compound from the previous step (590 mg, 2.68 mmol) in tetrahydrofuran (8.0 ml) was added lithium triethylborohydride in tetrahydrofuran (10.72 ml). , 10.72 mmol) 1 M solution was added and the reaction was stirred at ambient temperature for 7 hours. An additional 5.36 ml (5.36 mmol) portion of 1 M lithium triethylborohydride in tetrahydrofuran was added and the reaction mixture was stirred at ambient temperature for 18 hours before being quenched with careful dropwise addition of water (50 ml). . The solvent was then removed in vacuo and the residue was extracted three times with 20 ml portions of methylene chloride. The organic extract was dried (anhydrous sodium sulfate) and concentrated in vacuo to give an amber oil. Flash chromatography of all samples (silica gel, 47-61 micron mesh; elution with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 90: 9: 1 (volume)) gave the title compound (302 mg, 49.8% yield) Was obtained as a pale orange foam.
MS m / z 227 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (1H, m), 7.88 (1H, m), 7.58 (1H, m), 7.40-7.54 (2H, overlapping multiplets) 4.09 (1H, m), 3.33 (1H, m), 3.17 (1H, M), 2.60-2.80 (2H, m), 2.50 (3H, s), 2.09 (1H, m), 1.56-1.93 (3H, m) ppm.

Separation of enantiomers of racemic title compounds
Step 3
The racemic title compound from the previous step (302 mg, 1.33) containing 0.56 ml (4.0 mmol) of the enantiomer 3- (3-methylquinolin-8-yl-piperidine-1-carboxylic acid tert-butyl ester triethylamine To a well-stirred methylene chloride (20 ml) solution was added 436 mg (2.0 mmol) of di-tert-butyl dicarboxylate and the resulting reaction mixture was stirred for 48 hours at ambient temperature. (20 ml) was added with efficient stirring, then the mixture was extracted twice with 20 ml portions of methylene chloride and the combined organic extracts were then extracted with the same volume of brine and dried (anhydrous sulfuric acid Sodium) and finally concentrated in vacuo to give a viscous syrup. Fee (silica gel, 47-61 micron mesh; eluted with methylene chloride / methanol = 99: 1 (volume)) gave the title compound as a colorless oil.
MS m / z 326 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (1H, m), 7.87 (1H, m), 7.40-750 (2H, overlapping multiplets), 7.60 (1H, m), 4 .34 (1H, m), 4.21 (1H, m), 4.09 (1H, m), 2.92 (1H, m), 2.80 (1H, m), 2.50 (3H, s), 2.20 (1H, m), 1.78 (3H, m), 1.44 (9H, s) ppm.

Step 4
Separation of enantiomers of the title compound in Step 2 Waters PrepLC2000 preparative chromatography system described in Example 1 (Chiracal ™ OD 10 cm × 50 cm preparative column; mobile phase: hexane / ethanol = 98: 2 (volume), preparation Using 0.025% diethylamine as the agent; flow rate 225 ml / min; methylene chloride / methanol = 247 mg racemic title compound from the previous step dissolved in 1: 1 (volume); one sample of all 247 mg of dissolved compound The enantiomers were separated using an injection as a packing of; approximate retention times of 25 and 40 minutes). The process produced 119 mg of the enantiomer that elutes quickly. The ¹ H NMR spectrum of the enantiomer is the same as that of the racemic title compound in Step 3 above.

Step 5
Enantiomer 3-Methyl-8-piperidin-3-yl-quinoline (both enantiomers)
A 90 mg sample of the fast eluting title compound enantiomer isolated in the previous step was dissolved in 1 ml of methanol. Saturated hydrogen chloride in diethyl ether was added and the reaction mixture was stirred at ambient temperature for 18 hours. Solvent and excess hydrochloric acid were removed in vacuo to give a colorless glass. Trituration with ethyl acetate (10 ml) produced the enantiomer title compound as an amorphous solid monohydrochloride (61 mg).
Monohydrochloride:
¹ H NMR (400 MHz, CDCl ₃ ) δ 9.15 (1H, m), 9.09 (1H, m), 8.21 (1H, m), 8.12 (1H, m), 7.96 (1H , M), 4.24 (1H, m), 3.66 (1H, m), 3.57 (1H, m), 3.46 (1H, m), 3.20 (1H, m), 2 .75 (3H, s), 2.08-2.34 (3H, m), 1.90-2.08 (1H, m) ppm.
The free base of the enantiomer title compound of this step was prepared by the method of Example 1, Step 6. The mass spectrum and ¹ H NMR spectrum of the free base of the enantiomer title compound are in all respects the same as the racemic title compound free base of Step 2 of this example.

Example 9
Enantiomers (both enantiomers) and racemic 3-ethyl-8-pyrrolidin-3-yl-quinoline
Step 1
3- (3-Ethyl-quinolin-8-yl) -3-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester— cooled and maintained at 77 ° C. The title compound of Example 1, Step 1 (2.10 g , 8.9 mmol) in a well-stirred anhydrous tetrahydrofuran (30 ml) solution of n-butyllithium in 2.5 M hexane (3.60 ml, 8.9 mmol; Aldrich Chemical Co.) is added dropwise over 10 minutes. The reaction was stirred at −77 ° C. for 15 minutes before a solution of 3-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (1.65 g, 8.9 mmol) in anhydrous tetrahydrofuran (10 ml) was added. The reaction mixture was allowed to warm to ambient temperature and stirred at that temperature for 3 hours before being quenched by careful dropwise addition (with cooling) of saturated sodium bicarbonate (total 50 ml). The resulting mixture was sufficiently extracted with 3 parts of 20 ml of ethyl acetate. The combined organic extracts were then extracted with an equal volume of brine, dried (anhydrous sodium sulfate) and finally concentrated in vacuo to give a viscous syrup. Flash chromatography of all samples (silica gel, 47-61 micron mesh; eluting with methylene chloride / methanol = 98: 2 (volume)) gave the title compound (352 mg, 11.5% yield) as a viscous yellow oil. .
MS m / z 343 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.70 (1H, m), 7.96 (1H, m), 7.70 (1H, m), 7.53 (1H, m), 7.44 (1H M), 4.14 (1H, m), 3.93 (1H, m), 3.60-3.76 (2H, m), 3.48-3.60 (1H, m), 2. 83 (2H, m), 2.42 (2H, m), 1.45 and 1.43 (9H, two singlets), 1.34 (3H, m) ppm.

Step 2
8- (2,5-Dihydro-1H-pyrrol-3-yl) -3-ethyl-quinoline The title compound from the previous step (350 mg, 1.02 mmol) was dissolved in concentrated sulfuric acid. The solution was heated to 100 ° C. for 6 hours and then stirred at ambient temperature for 48 hours. The reaction mixture was cooled to ice bath temperature, carefully diluted with water (drop, 25 ml) and made basic (pH = 14) by addition of 50% aqueous sodium hydroxide. The mixture was then extracted twice with 20 ml portions of methylene chloride. The combined organic extracts were then extracted with the same volume of water and then with brine, dried (anhydrous sodium sulfate) and concentrated in vacuo to give a viscous syrup. Flash chromatography of all samples (silica gel, 47-61 micron mesh; eluting with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 90: 9: 1 (volume)) gave the title compound (67 mg, 29.4% yield). ) Was obtained as a viscous light yellow syrup.
MS m / z 225 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.79 (1H, m), 7.88 (1H, m), 7.66 (1H, M), 7.53 (1H, m), 7.44 (1H , M), 6.85 (1H, M0, 4.46 (1H, m), 4.10 (1H, m), 2.82 (2H, q, J = 7.5 Hz), 1.33 (3H , T, J = 7.5 Hz) ppm.
A total 67 mg sample was dissolved in ethyl acetate and then converted to the monohydrochloride salt by adding 0.5 ml of saturated hydrochloric acid in ethyl acetate. The hydrochloride salt immediately precipitated as a pale yellow solid which was isolated in quantitative yield by removing the solvent and excess hydrochloric acid in vacuo. The hydrochloride salt was used in the next manufacturing step (Step 3).

Step 3
Racemic 3-ethyl-8-pyrrolidin-3-yl-quinoline (semi-purified product: purification: step 4/5 below)
The title compound from the previous step (hydrochloride form, 75 mg, 0.29 mmol) was dissolved in methanol (5.0 ml) and hydrogenated (50 psi, platinum oxide catalyst 10 mg). The catalyst was filtered and the filtrate was concentrated in vacuo to give a pale amber residue. The residue was dissolved in 5 ml of water. The solution was extracted with 10 ml of ethyl acetate and then the organic extract was discarded. The aqueous solution was made basic (pH 14) by the addition of 50% aqueous sodium hydroxide and then extracted twice with 10 ml portions of methylene chloride. The combined methylene chloride extracts were then extracted with the same volume of brine, dried (anhydrous sodium sulfate), and finally concentrated in vacuo to give a colorless syrup. Flash chromatography of all samples (silica gel, 47-61 micron mesh; elution with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 90: 9: 1 (volume)) gave the title compound (30 mg, 46.1% yield) Was obtained as a pale yellow amorphous foam.

Final purification of the title compound product The final purification of a 30 mg sample of the title compound just described was followed by tert-butyloxycarbonyl acylation of the pyrrolidine nitrogen (to facilitate further chromatographic purification) followed by tert-butyloxy Performed by acid-catalyzed removal of the carbonyl substituent. This procedure gave the final purified title compound (after basic treatment) in the form of the free base.

Step 4
Racemic 3- (3-ethyl-quinolin-8-yl) -pyrrolidine-1-carboxylic acid tert-butyl ester 15 mg (0.07 mmol) sample of semi-purified title compound product from previous step and triethylamine (0.02 ml) , 0.14 mmol) in well-stirred methylene chloride solution was added di-tert-butyl carbonate (21.8 mg, 0.10 mmol). The reaction was then stirred at ambient temperature for 48 hours. Saturated aqueous sodium bicarbonate (5 ml) was added with efficient stirring. The mixture was then extracted with 2 parts of a 3 ml portion of methylene chloride. The organic extracts were combined and then extracted with the same volume of brine and dried (anhydrous sodium sulfate). Concentration in vacuo gave a viscous syrup. Flash chromatography of all samples (silica gel, 47-61 micron mesh; first elute with methylene chloride / methanol = 99.75: 0.25 (volume), steadily increasing the polarity of the elution system and finally The title compound (15 mg, yield 69.7%) was obtained as a colorless oil by methylene chloride / methanol = 99: 1 (volume).
MS m / z 327 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.78 (1H, m), 7.88 (1H, m), 7.63 (1H, m), 7.40-7.54 (2H, overlapping multiplets) 4.63 (1H, m), 3.96 (1H, m), 3.50 (2H, m), 3.33 (1H, m), 2.82 (2H, q, J = 7.5 Hz) ), 2.34 (1H, m), 2.12 (1H, m), 1.44 and 1.47 (9H, two singlets), 1.33 (3H, t, J = 7.5 Hz) ppm.

Step 5
Racemic 3-ethyl-8-pyrrolidin-3-yl-quinoline To a solution of 15 mg (0.05 mmol) of the title compound from the previous step in methylene chloride / methanol = 9: 2 (volume) 1.0 ml of saturated anhydrous hydrochloric acid / Diethyl ether solution was added and the resulting reaction mixture was stirred at ambient temperature for 18 hours. The solvent was removed in vacuo and the residue was extracted into water. The aqueous extract was then extracted with the same volume of ethyl acetate. Finally, the separated aqueous phase was made basic (pH = 14) by the addition of 50% aqueous sodium hydroxide and then extracted 3 times with 5 ml portions of ethyl acetate. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give the purified title compound (free base form, 10 mg, 96% yield) as a colorless amorphous solid.
MS m / z 227 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (1H, m), 7.89 (1H, m), 7.60 (1H, m), 7.53 (1H, m), 7.44 (1H M), 4.38 (1H, m), 3.46 (1H, m), 3.27 (1H, m), 3.12 (1H, m), 2.97 (1H, m), 2 0.82 (2H, q, J = 7.5 Hz), 2.32 (1H, m), 2.01 (1H, m), 1.33 (3H, t, J = 7.5 Hz) ppm.

Step 6
Enantiomers (both enantiomers) 3-Ethyl-8-pyridin-3-yl-quinoline Step 4 / Using a procedure similar to that of Example 1, the racemic title compound of the previous step of this example was converted to the corresponding nitrogen. Converted to the substituted tert-butoxycarbonyl compound and its separated / purified enantiomer was isolated by the method of Step 5 / Example 1. Finally, the enantiomer of the previous step of this example was prepared in monohydrochloride and free base form by the procedure of Step 6 / Example 1.

Example 10
Enantiomers (both enantiomers) and racemic 3-ethyl-7-piperidin-3-yl-quinoline
Step 1
7-bromo-3-ethyl-quinoline 3-bromo-aniline (5.40 g, 31.4 mmol), sodium 3-nitro-benzenesulfonate (4.25 g, 18.9 mmol), 8.5 g concentrated sulfuric acid ( 2-ethylacrolein (5.0 ml, 51 mmol) was added to a well-stirred mixture of 177 mmol) and 3.2 ml of water heated to 100 ° C. After maintaining the reaction temperature at 100 ° C. for 1 hour, the temperature was raised to 110 ° C. An additional portion of 2-ethylacrolein (1.0 ml, 10.2 mmol) was added and the reaction was stirred at 110 ° C. for 1 hour. The reaction temperature was then raised to 120 ° C. before another 1.0 ml (10.2 mmol) portion of 2-ethylacrolein was added. After the reaction was heated to 120 ° C. for 1 hour, the temperature was raised to 130 ° C. before 1.0 ml (10.2 mmol) of 2-ethylacrolein was added. Finally, after the last portion (1.3 ml, 13.2 mol) of 2-ethylacrolein was added, the reaction temperature was raised to 140 ° C. and maintained at that temperature for 2 hours. The cooled reaction was quenched with ice (50 g) and the pH of the resulting mixture was adjusted by the addition of 6N aqueous sodium hydroxide. The mixture was then extracted twice with 30 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to give an amber oil. Using the Biotage Flash 401i ™ silica gel flash chromatography module described in Example 1, Step 4 and a silica gel cartridge pre-packaged by the manufacturer, and flash chromatography of all samples eluting with methylene chloride, the title The compound (1.46 g, 19.7% yield) was obtained as a viscous pale amber syrup that solidified upon standing.
MS m / z 236, 237, 238, 239 (M + 1).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.77 (1H, m), 8.23 (1H, m), 7.87 (1H, m), 7.54-7.63 (2H, overlapping multiplets) 2.80 (2H, q, J = 7.5 Hz), 1.33 (3H, t, J = 7.5 Hz) ppm.

Step 2
3-Ethyl-7-pyridin-3-yl-quinoline The title compound of this example, Step 1 (1.40 g, 5.93 mmol), diethyl (3-pyridyl) borane (0.96 g, 6.53 mmol) And a well-stirred mixture of bis (triphenylphosphine) palladium (II) chloride (458 mg, 0.65 mmol) in tetrahydrofuran (15 ml) was added 7.5 ml of aqueous sodium carbonate (2.51 g, 23.7 mmol). Was added. The reaction mixture was then stirred at 90 ° C. for 5 hours and then at ambient temperature for 18 hours. The aqueous phase of the biphasic reaction mixture was separated and extracted with the same volume of ethyl acetate. The organic phase solvent of the reaction mixture was removed in vacuo and the residue was extracted with ethyl acetate (25 ml). The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to produce a dark viscous oil. Flash chromatography of all samples (silica gel, 47-61 micron mesh; eluted with ethyl acetate) gave the title compound (807 mg, 58% yield) as a viscous yellow syrup.
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.93 (1H, m), 8.82 (1H, m), 8.62 (1H, m), 8.27 (1H, m), 8.01 (1H M), 7.94 (1H, m), 7.86 (1H, m), 7.74 (1H, m), 7.36-7.49 (2H, overlapping multiplets), 2.84 ( 2H, q, J = 7.5 Hz), 1.35 (3H, t, J = 7.5 Hz) ppm.

Step 3
Racemic 3-ethyl-7-piperidin-3-yl-quinoline To a well stirred solution of the title compound of the previous step (780 mg, 3.33 mmol) in anhydrous tetrahydrofuran (8 ml) was added lithium triethylborohydride (27 mmol). 27.0 ml of 1M tetrahydrofuran solution was added and the resulting reaction mixture was stirred at ambient temperature for 18 hours. The reaction was quenched by careful dropwise addition of water (50 ml). The solvent was removed in vacuo to give a viscous oil that was extracted three times with 20 ml portions of methylene chloride. The combined organic extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to produce a viscous syrup. Flash chromatography of all samples (silica gel, 47-61 micron mesh; elution with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 90: 9: 1 (volume)) gave the title compound (390 mg, yield 48.8%) Was obtained as a yellow gum.
MS m / z 241 (M + l).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.73 (1H, m), 7.86 (2H, overlap multiplet), 7.66 (1H, m), 7.37 (1H, m), 3.27 (1H, m), 3.15 (1H, m), 2.88 (1H, m), 2.7-2.9 (2H, overlapping multiplets), 2.66 (1H, m), 2. 78 (2H, q, J = 7.5 Hz), 1.83 (1H, m), 1.60-1.82 (2H, overlapping multiplets), 1.31 (3H, t, J = 7.5 Hz) ) Ppm.

Separation of enantiomers of racemic title compounds
Step 4
Racemic 3- (3-ethyl-quinolin-7-yl) -piperidine-1-carboxylic acid tert-butyl ester Free base title compound from previous step (390 mg, 1.63 mmol), triethylamine (0.45 ml, 3 .25 mmol) and a reaction mixture consisting of 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 extracted twice with 10 ml portions of methylene chloride. The combined organic extracts were then extracted with the same volume of brine, dried (anhydrous sodium sulfate) and concentrated in vacuo to produce a viscous syrup. Flash chromatography of all samples (silica gel, 47-61 micron mesh; elution with hexane / ethyl acetate = 75: 25 (volume)) gave the title compound (180 mg, 32% yield) as a colorless oil.
MS m / z 341 (M + l).

Step 5
Enantiomer 3- (3-Ethyl-quinolin-7-yl) -piperidine-1-carboxylic acid tert-butyl ester (both enantiomers)
The method of Example 1, Step 5 was used to separate the enantiomers of the racemic title compound of Step 4 of this example.

Step 6
Enantiomer 3-ethyl-7-piperidin-3-yl-quinoline (both enantiomers)
Using the method of Example 1, Step 6, the enantiomer of the previous step of this example was used to prepare the title compound enantiomer of this step in both the monohydrochloride and free base forms.

Example 11
Enantiomers (both enantiomers) and racemic 3-methyl-8- (1-methyl-piperidin-3-yl) quinoline
Step 1
Racemic 3-methyl-8- (1-methyl-piperidin-3-yl) quinoline To a well stirred solution of the title compound of Example 8, Step 2 (30 mg, 0.133 mmol) in 1.0 ml methanol. 0.10 ml of 37% formaldehyde in methanol (1.2 mmol formaldehyde) and 100 mg (0.47 mmol) sodium triacetoxyborohydride were added in succession and the resulting reaction mixture was stirred at ambient temperature for 6 hours. . The solvent was removed in vacuo and the resulting residue was extracted into 10 ml of methylene chloride. The organic extract was then extracted with the same volume of saturated aqueous sodium bicarbonate and then with the same volume of brine. After drying (anhydrous magnesium sulfate), the methylene chloride was removed in vacuo to produce a light amber solid (40 mg). Flash chromatography of all samples (silica gel, 47-61 micron mesh; eluting with methylene chloride / methanol / concentrated aqueous ammonium hydroxide = 90: 9: 1 (volume)) gave the title compound (19 mg, 60% yield) as colorless Obtained as an amorphous solid.
MS m / z 241 (M +).
¹ H NMR (400 MHz, CDCl ₃ ) δ 8.76 (1H, m), 7.86 (1H, m), 7.56 (1H, m), 7.48 (1H, m), 7.43 (1H , M), 4.29 (1H, m), 3.12 (1H, m), 2.97 (1H, m), 2.49 (3H, s), 2.33 (3H, s), 1 .80-2.13 (5H, overlapping multiplets), 1.64 (1H, m) ppm.

Step 2
Enantiomers (both enantiomers) 3-methyl-8- (1-methyl-piperidin-3-yl) quinoline Step 5 / racemic title compound of the previous step using the general method of enantiomeric separation described in Example 1 The enantiomers of were isolated in the form of the free base. The enantiomer monohydrochloride was prepared by the procedure of Step 2 / Example 9.

Claims (15)

formula:

(Where
R ¹ , R ² and R ³ are independently hydrogen, halogen, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 3 halogen atoms, and optionally 1 to 3 halogen atoms. Selected from substituted (C ₁ -C ₆ ) alkoxy;
R ⁴ is hydrogen or (C ₁ -C ₃ ) alkyl; and n is 1 or 2)
A quinoline compound having a non-quinoline ring bonded thereto, or a pharmaceutically acceptable salt thereof. The compound of claim ^1, wherein R ¹ and R ² are both hydrogen, or ^one of R ¹ and R ² is hydrogen and the other is bonded to the 5-position. n is 1 and R ¹ and R ² are both hydrogen, or ^one of R ¹ and R ² is hydrogen and the other is bonded to the 5-position, and the non-quinoline ring is in the 7-position The compound of claim 1, which is bound to following:
R and S- (3-ethyl-7-methyl 8-piperidin-3-yl-quinoline);
R 1 , S- (3-ethyl-7-methyl-8-piperidin-3-yl-quinoline);
R and S- (3,6-dimethyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3,6-dimethyl-8-piperidin-3-yl-quinoline);
R and S- (3,7-dimethyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3,7-dimethyl-8-piperidin-3-yl-quinoline);
R and S- (3,5-dimethyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3,5-dimethyl-8-piperidin-3-yl-quinoline);
R and S- (6-chloro-3-methyl-8-piperidin-3-yl-quinoline);
R , S- (6-Chloro-3-methyl-8-piperidin-3-yl-quinoline);
R and S- (4-methyl-8-piperidin-3-yl-quinoline);
R 1 , S- (4-Methyl-8-piperidin-3-yl-quinoline);
R and S- (3-methyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3-methyl-8-piperidin-3-yl-quinoline);
R and S- (3-ethyl-8-piperidin-3-yl-quinoline);
R 1 , S- (3-ethyl-8-piperidin-3-yl-quinoline);
R and S- (ethyl-7-piperidin-3-yl-quinoline);
R , S- (ethyl-7-piperidin-3-yl-quinoline);
R and S- [3-methyl-8- (1-methyl-piperidin-3-yl) -quinoline];
R 1 , S- [3-Methyl-8- (1-methyl-piperidin-3-yl) -quinoline];
3-ethyl-7-methyl-8- (1-methyl-piperidin-3-yl) -quinoline;
3-ethyl-8-methyl-8- (1-ethyl-piperidin-3-yl) -7-methyl-quinoline;
3,6-dimethyl-8- (1-methyl-piperidin-3-yl) -quinoline;
8- (1-ethyl-piperidin-3-yl) -3,6-dimethyl-quinoline;
3,7-dimethyl-8- (1-methyl-piperidin-3-yl) -quinoline;
8- (1-ethyl-piperidin-3-yl) -3,7-dimethyl-quinoline;
3,5-dimethyl-8- (1-methyl-piperidin-3-yl) -quinoline;
8- (1-ethyl-7-piperidin-3-yl) -3,5-dimethyl-quinoline;
6-chloro-3-methyl-8- (1-methyl-piperidin-3-yl) -quinoline;
6-chloro-8- (1-ethyl-piperidin-3-yl) -3-methyl-quinoline;
3-ethyl-8- (1-methyl-piperidin-3-yl) -quinoline;
3-ethyl-8- (1-ethyl-piperidin-3-yl) -quinoline;
4-methyl-8- (1-methyl-piperidin-3-yl) -quinoline;
8- (1-ethyl-piperidin-3-yl) -4-methyl-quinoline;
3-methyl-8- (1-methyl-piperidin-3-yl) -quinoline;
8- (1-ethyl-piperidin-3-yl) -3-methyl-quinoline;
3-ethyl-8- (1-methyl-pyrrolidin-3-yl) -quinoline;
3-ethyl-8- (1-ethyl-pyrrolidin-3-yl) -quinoline;
3-ethyl-7- (1-methyl-piperidin-3-yl) -quinoline;
3-ethyl-7- (l-ethyl-piperidin-3-yl) -quinoline;
3-ethyl-7-pyrrolidin-3-yl) -quinoline;
3-ethyl-7- (1-methyl-pyrrolidin-3-yl) -quinoline; and 3-ethyl-7- (1-ethyl-pyrrolidin-3-yl) -quinoline;
The compound of Claim 1 selected from these, and those pharmaceutically acceptable salts. formula:

Wherein R ¹ and R ³ are independently hydrogen, halogen, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 3 halogen atoms, and optionally 1 to 3 halogen atoms. Selected from (C ₁ -C ₆ ) alkoxy substituted with and R ⁴ is hydrogen or (C ₁ -C ₃ ) alkyl)
A compound according to claim 1 having   A pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.   A method of treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, claiming an effective amount to act on a serotonin 7 receptor in a mammal in need of such treatment The above-mentioned method comprising administering the compound according to item 1 or a pharmaceutically acceptable salt thereof. A pharmaceutical composition for treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, comprising:
a) a pharmaceutically acceptable carrier;
b) an amount of the first compound according to claim 1 or a pharmaceutically acceptable salt thereof; and c) a 5HT reuptake inhibitor, a 5HT7 receptor antagonist or an NK1 receptor antagonist or a pharmaceutically acceptable salt thereof. The amount of the second compound chosen;
(Wherein the amounts of (b) and (c) are effective together to treat such a disorder or symptom)
A pharmaceutical composition as described above. A method of treating a disorder or condition that can be treated by modulating serotonergic neurotransmission in a mammal, wherein the mammal in need of such treatment comprises:
a) an amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof; and b) a 5HT reuptake inhibitor, a 5HT7 receptor antagonist and an NK1 receptor antagonist or a pharmaceutically acceptable salt thereof. The amount of two compounds;
(Where the amounts of (a) and (b) are effective together to treat such a disorder or symptom)
A method as described above, comprising administering   Depression, anxiety, avoidance personality disorder, premature ejaculation, eating disorder, migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal emotional disorder, bipolar neuropathy disorder, jet lag, sleep disorder, nocturnal enuresis, and A method of treating a disorder or symptom selected from restless leg syndrome, comprising administering to a mammal in need of such treatment an amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. A method of treatment as described above, which is an amount effective for the treatment of the disorder or condition.   Depression, anxiety, avoidance personality disorder, premature ejaculation, eating disorder, migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal emotional disorder, bipolar neuropathy disorder, jet lag, sleep disorder, nocturnal enuresis, and A method of treating a disorder or symptom selected from restless leg syndrome, comprising administering to a mammal in need of such treatment an amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, said amount being 5HT7 A method of treatment as above, which is an amount effective to act on the receptor.   Depression, anxiety, avoidance personality disorder, premature ejaculation, eating disorder, migraine, premenstrual syndrome, premenstrual dysphoric disorder, seasonal emotional disorder, bipolar neuropathy disorder, jet lag, sleep disorder, nocturnal enuresis, and A method of treating a disorder or symptom selected from restless leg syndrome, wherein a mammal in need of such treatment is (a) the amount of the first compound of claim 1 or a pharmaceutically acceptable salt thereof; and (b ) Administering a second compound selected from the group consisting of a 5HT7 receptor antagonist, an NK1 receptor antagonist, and a 5HT7 receptor antagonist, or an amount of a pharmaceutically acceptable salt of the second compound, Wherein the amount of (a) and (b) together is an amount effective to treat such a disorder or symptom. formula:

Wherein R ¹ , R ² and R ³ are independently hydrogen, halogen, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 3 halogen atoms, and optionally 1 to 3 A compound selected from (C ₁ -C ₆ ) alkoxy substituted with ₁ halogen atom, and
formula:

Wherein R ¹ , R ² and R ³ are independently hydrogen, halogen, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 3 halogen atoms, and optionally 1 to 3 A compound selected from the group consisting of (chosen from (C ₁ -C ₆ ) alkoxy) substituted with a halogen atom of formula:

Wherein R ¹ , R ² and R ³ are independently hydrogen, halogen, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 3 halogen atoms, and optionally 1 to 3 A compound selected from (C ₁ -C ₆ ) alkoxy substituted with a halogen atom of
The method has the formula:

A compound of the formula (wherein R ¹ and R ² are as described above) is represented by the formula:

(Wherein R ³ is as defined above) or a compound:
R ³ —OH
(Wherein R ³ is as described above) and
Wherein the reaction is carried out in the presence of an aqueous acid and 3-nitrobenzenesulfonic acid or a salt thereof, and the reaction is carried out at a temperature of about 100 ° C to about 140 ° C.
The above method. formula:

Wherein R ¹ , R ² and R ³ are independently hydrogen, halogen, (C ₁ -C ₆ ) alkyl optionally substituted with 1 to 3 halogen atoms, and optionally 1 to 3 A compound selected from (C ₁ -C ₆ ) alkoxy substituted with a halogen atom of
The method has the formula:

A compound of the formula (wherein R ¹ and R ² are as described above) is represented by the formula:

(Wherein R ³ is as defined above) or a compound:
R ³ —OH
(Wherein R ³ is as described above) and
Wherein the reaction is carried out in the presence of an aqueous acid and 3-nitrobenzenesulfonic acid or a salt thereof, and the reaction is carried out at a temperature of about 100 ° C to about 140 ° C.
The above method.