JP2012509910A - New compounds - Google Patents

Abstract

  The present invention relates to imidazopyrazine substituted piperidine derivatives and their use as pharmaceuticals.

Description

  The present invention relates to imidazopyrazylmethyl substituted piperidine derivatives and their use as pharmaceuticals.

  Many medically significant biological processes are mediated by proteins involved in signal transduction pathways including G proteins and / or second messengers.

  Polypeptides and polynucleotides encoding the human 7-transmembrane G protein-coupled neuropeptide receptor orexin-1 (HFGAN72) have been identified and disclosed in EP875565, EP875556, and WO 96/34877. Polypeptides and polynucleotides encoding a second human orexin receptor orexin-2 (HFGANP) have been identified and are disclosed in EP893498.

  Polypeptides that are ligands for the orexin-1 receptor, eg orexin-A (Lig72A) and polynucleotides that encode the polypeptides are disclosed in EP 899361.

  Orexin ligand and receptor systems have been well characterized since their discovery (eg, Sakurai, T. et al (1998) Cell, 92 p. 573-585; Smart et al (1999) British Journal of Pharmacology). 128 p.1-3; Willie et al (2001) Ann.Rev. Neurosciences 24 p.429-458; Sakurai (2007) Nature Reviews in pours 171-181; 70-87). From these studies, orexin and orexin receptors play a number of important physiological roles in mammals, opening up the potential for the development of new therapeutic treatments for various diseases and disorders described below. It is clear that

  Experiments have shown that central administration of the ligand orexin-A stimulated food intake in freely fed rats for 4 hours. This increase was approximately 4 times that of control rats receiving vehicle. These data suggest that orexin-A may be an endogenous regulator of appetite (Sakurai, T. et al (1998) Cell, 92 p. 573-585; Peyron et al ( 1998) J. Neurosciences 18 p. 9996-10015; Willie et al (2001) Ann. Rev. Neurosciences 24 p. 429-458). Therefore, orexin-A receptor antagonists may be useful in the treatment of obesity and diabetes. To prove this, the orexin receptor antagonist SB334867 strongly reduced pleasure eating in rats (White et al (2005) Peptides 26 p. 2231-2238) and high fat pellet self-administration in rats. (Nair et al (2008) British Journal of Pharmacology, published online 28 January 2008). The search for new therapies to treat obesity and other eating disorders is an important endeavor goal. According to the definition of WHO, in the westernized society, an average of 35% of subjects in 39 studies were overweight and an additional 22% were clinically obese. It is estimated that 5.7% of total health care in the United States is the result of obesity. About 85% of type 2 diabetes is obese. Diet and exercise are valuable in all obese people. The incidence of diabetes diagnosed in Western countries is typically 5%, and it is estimated that an equal number has not been diagnosed. The incidence of both diseases is rising, indicating inadequate current treatment that may either be ineffective, including cardiovascular effects, or may be at risk of toxicity. Treatment of diabetes with sulfonylureas or insulin can result in hypoglycemia, whereas metformin produces GI side effects. There is no drug treatment for the disease that has been shown to reduce the long-term complications of type 2 diabetes. Insulin sensitizers may be useful for many diabetics but do not have an anti-obesity effect.

  Similar to having a role in feeding, the orexin system is also involved in sleep and wakefulness. Rat sleep / electroencephalography studies have shown that, when central administration of orexin-A, an orexin receptor agonist, is administered at the beginning of the normal sleep phase, it produces a dose-related increase in arousal, paradoxical sleep and slow wave sleep 2 (Hagan et al (1999) Proc. Natl. Acad. Sci. 96 p. 10911-10916). The role of the orexin system in sleep and wakefulness is now well established (Sakurai (2007) Nature Reviews Neuroscience 8 p.171-181; Ohno and Sakurai (2008) Fronto Neurocricol. et al (1999) Cell 98 p. 437-451; Lee et al (2005) J. Neuroscience 25 p. 6716-6720; Piper et al (2000) European J Neuroscience 12 p. 726-730 and Sr. 2002) Pharmacology and Ther peutics 94 p.51~61). Orexin receptor antagonists may therefore be useful in the treatment of sleep disorders, including insomnia. Studies using orexin receptor antagonists such as rats (see, eg, Smith et al (2003) Neuroscience Letters 341 p. 256-258) and more recently dogs and humans (Brisbare-Roch et al (2007) Nature Medicine 13 ( 2) SB334867 in p.150-155) further supports this.

  In addition, recent studies have suggested a role for orexin antagonists in the treatment of ambitious disorders, such as disorders associated with reward-seeking behavior, such as drug addiction and drug abuse (Borgland et al (2006) Neuron 49 (4). P. 589-601; Boutre et al (2005) Proc. Natl. Acad. Sci. 102 (52) p. 19168-19173; Harris et al (2005) Nature 437 p. 556-559).

  International patent applications WO99 / 09024, WO99 / 58533, WO00 / 47577, and WO00 / 47580 disclose phenylurea derivatives, and WO00 / 47576 discloses quinolinylcinnamide derivatives as orexin receptor antagonists. is doing. WO 05/118548 discloses substituted 1,2,3,4-tetrahydroisoquinoline derivatives as orexin antagonists.

  WO 01/96302, WO 02/44172, WO 02/89800, WO 03/002559, WO 03/002561, WO 03/032991, WO 03/037847, WO 03/041711, and WO 08/038251 all disclose cyclic amine derivatives.

  WO 03/002561 discloses N-aroyl cyclic amine derivatives as orexin antagonists. Compounds disclosed in WO 03/002561 include piperidine derivatives substituted at the 2-position with a bicyclic heteroarylmethyl group. The inventors have reported that some piperidine derivatives substituted at the 2-position with an imidazopyrazinylmethyl group have, for example, higher oral bioavailability and physiologically relevant media compared to conventional compounds. It has now been found to have beneficial properties including significantly higher solubility in Due to these properties, these imidazopyrazinylmethyl-substituted piperidine derivatives are obese, including obesity observed in patients with type 2 (non-insulin dependent) diabetes, sleep disorders, anxiety, depression, schizophrenia, It has become very attractive as a pharmaceutical agent that may be useful in the prevention or treatment of drug addiction or compulsive behavior. In addition, these compounds may be useful in the treatment of stroke, especially ischemic or hemorrhagic stroke, and / or in the treatment of blocking emetic responses, i.e. useful in the treatment of nausea and vomiting. unknown.

（ここで、Ａｒは、式：

からなる群から選択され；
Ｒ_１が、（Ｃ_１−４）アルキル、ハロ、ハロ（Ｃ_１−４）アルキル、（Ｃ_１−４）アルコキシ、ハロ（Ｃ_１−４）アルコキシ、（Ｃ_１−４）アルキル−Ｏ−（Ｃ_１−４）アルキル、ＣＮ、ＮＲ^５Ｒ^６であり、式中、Ｒ^５は、Ｈまたは（Ｃ_１−４）アルキルであり、かつＲ^６は、Ｈまたは（Ｃ_１−４）アルキルであり；
Ｒ_２が、（Ｃ_１−４）アルキル、ハロ、ハロ（Ｃ_１−４）アルキル、（Ｃ_１−４）アルコキシ、ハロ（Ｃ_１−４）アルコキシ、（Ｃ_１−４）アルキル−Ｏ−（Ｃ_１−４）アルキル、ＣＮ、ＮＲ^７Ｒ^８であり、式中、Ｒ^７は、Ｈまたは（Ｃ_１−４）−アルキルであり、かつＲ^８はＨまたは（Ｃ_１−４）−アルキルであり；
Ｒ_３が、（Ｃ_１−４）アルキル、ハロ、ハロ（Ｃ_１−４）アルキル、（Ｃ_１−４）アルコキシ、ハロ（Ｃ_１−４）アルコキシ、（Ｃ_１−４）アルキル− Ｏ −（Ｃ_１−４）アルキル、ＣＮ、ＮＲ^９Ｒ^１０であり、式中、Ｒ^９は、Ｈまたは（Ｃ_１−４）−アルキルであり、かつＲ^１０は、Ｈまたは（Ｃ_１−４）−アルキルであり；
ｎが、０または１であり；
ｐが、０または１であり；かつ
ｑが、０または１であり；
但し、ｐおよびｑが両方とも０ではないという条件付きである。）
の化合物またはその医薬として許容し得る塩を提供する。 Accordingly, the present invention provides a compound of formula (I)

(Where Ar is the formula:

Selected from the group consisting of:
R ₁ is (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O—. (C _1-4 ) alkyl, CN, NR ⁵ R ⁶ , wherein R ⁵ is H or (C _1-4 ) alkyl, and R ⁶ is H or (C _1-4 ) alkyl. Is;
R ₂ is (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O—. (C _1-4 ) alkyl, CN, NR ⁷ R ⁸ , wherein R ⁷ is H or (C _1-4 ) -alkyl, and R ⁸ is H or (C _1-4 ) — Is alkyl;
R ₃ is (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O −. (C _1-4 ) alkyl, CN, NR ⁹ R ¹⁰ , wherein R ⁹ is H or (C _1-4 ) -alkyl, and R ¹⁰ is H or (C _1-4 ). -Alkyl;
n is 0 or 1;
p is 0 or 1; and q is 0 or 1;
However, there is a condition that both p and q are not 0. )
Or a pharmaceutically acceptable salt thereof.

  In one embodiment, Ar is a group of formula (II).

  In another embodiment, Ar is a group of formula (III).

  In one embodiment, Ar is a group of formula (II) and n is 0.

In one embodiment, Ar is a group of formula (II), n is 0, p is 1, q is 0, and R ₂ is (C _1-4 ) alkyl.

In another embodiment, Ar is a group of formula (II), n is 0, p is 1, q is 0, and R ₂ is methyl.

In one embodiment, Ar is a group of formula (II), n is 0, p is 0, q is 1 and R ₃ is (C _1-4 ) alkyl.

In another embodiment, Ar is a group of formula (II), n is 0, p is 0, q is 1 and R ₃ is methyl.

In one embodiment, Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is (C _1-4 ) alkyl, and R ₃ Is (C _1-4 ) alkyl.

In another embodiment, Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is methyl, and R ₃ is methyl.

  In one embodiment, n is 0.

In one embodiment, Ar is a group of formula (III), n is 0, p is 1, q is 0, and R ₂ is (C _1-4 ) alkyl.

In another embodiment, Ar is a group of formula (III), n is 0, p is 1, q is 0, and R ₂ is methyl.

In one embodiment, Ar is a group of formula (III), n is 0, p is 0, q is 1 and R ₃ is (C _1-4 ) alkyl.

In another embodiment, Ar is a group of formula (III), n is 0, p is 0, q is 1 and R ₃ is methyl.

In one embodiment, Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is (C _1-4 ) alkyl, and R ₃ Is (C _1-4 ) alkyl.

In another embodiment, Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is methyl, and R ₃ is methyl.

  Examples of compounds of the present invention include 6,8-dimethyl-2-({(2S) -1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl) carbonyl] -2- Piperidinyl} methyl) imidazo [1,2-a] pyrazine.

When the compound contains a (C _1-4 ) alkyl group, whether alone, to form a larger group, for example a (C _1-4 ) alkoxy moiety, the alkyl group may be linear, branched, or cyclic Or a combination thereof. Examples of (C _1-4 ) alkyl are methyl or ethyl. An example of (C _1-4 ) alkoxy is methyloxy.

Examples of halo (C _1-4 ) alkyl include trifluoromethyl (ie, —CF ₃ ).

Examples of (C _1-4 ) alkoxy include methyloxy and ethyloxy.

Examples of halo (C _1-4 ) alkoxy include trifluoromethyloxy (ie, —OCF ₃ ).

Halogen or “halo” (eg when used in halo (C _1-4 ) alkyl) means fluoro, chloro, bromo, or iodo.

  It is to be understood that the invention extends to all combinations of the specific groups and substituents described herein above.

  It will be appreciated that for use in medicine, salts of the compounds of formula (I) should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include Berge, Bigley and Monkhouse J. et al. Pharm. Sci (1977) 66, p. 1-19 are included. Such pharmaceutically acceptable salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, or phosphoric acid, and organic acids such as succinic acid, maleic acid, acetic acid, fumaric acid, citric acid. Examples include acid addition salts formed using acids, tartaric acid, benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, or naphthalenesulfonic acid. Other salts, such as oxalate or formate, may be used, for example, in the isolation of compounds of formula (I) and are included within the scope of the present invention.

  Certain compounds of formula (I) may form acid addition salts with one or more equivalent acids. The present invention includes within its scope all possible stoichiometric and non-stoichiometric forms.

  The compounds of formula (I) may be prepared in crystalline or amorphous form, and in the case of crystals, optionally solvated, for example as hydrates. The present invention includes within its scope compounds that contain a stoichiometric solvate (eg, hydrate) and a variable amount of solvent (eg, water).

  It will be understood that the present invention includes pharmaceutically acceptable derivatives of compounds of formula (I) and these are within the scope of the present invention.

  As used herein, “pharmaceutically acceptable derivative” refers to a compound of formula (I) or an active metabolite or residue thereof (directly or indirectly) upon administration to a recipient. ) Any pharmaceutically acceptable ester of a compound of formula (I) that can be provided or a salt of such an ester is included.

  The compound of formula (I) is the S enantiomer. When additional chiral centers are present in the compounds of formula (I), the present invention includes within its scope all possible enantiomers and diastereoisomers, including mixtures thereof. Different isomeric forms may be separated or resolved from one another by conventional methods, or any given isomer may be obtained by conventional synthetic methods, or by stereospecific or asymmetric synthesis. . The invention also extends to any tautomeric form or mixtures thereof.

The present invention also includes isotopically labeled compounds that are identical to those listed in Formula (I), with the exception that one or more atoms are the most universally recognized atomic masses in nature. Or the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the mass number. Examples of isotopes that can be incorporated into the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, fluorine, iodine, and chlorine, such as ³ H, ¹¹ C, ¹⁴ C, ¹⁸ F, ¹²³ I, or ¹²⁵ I Isotopes.

Compounds of the present invention and pharmaceutically acceptable salts of such compounds that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present invention. Isotopically labeled compounds of the invention, for example those into which radioactive isotopes such as ³ H or ¹⁴ C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritium labeled isotopes, ie ³ H, and carbon-14 isotopes, ie ¹⁴ C, are particularly preferred for ease of preparation and detectability. ^{The 11} C and ¹⁸ F isotopes are particularly useful in PET (Positron Emission Tomography).

  Since the compounds of formula (I) are intended for use in pharmaceutical compositions, they are in substantially pure form, such as at least 60% pure, more suitably at least 75% pure, preferably at least 85%, in particular at least It will be readily appreciated that each is suitably provided in 98% pure form (% refers to weight on a weight basis). Impure preparations of the compounds may be used to prepare more pure forms for use in pharmaceutical compositions.

  According to a further aspect of the invention, there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following scheme details several synthetic routes to the compounds of the present invention. In the scheme below, the reactive group is protected using a protecting group and can be deprotected according to well-established techniques.

Scheme According to a further feature of the present invention, there is provided a process for the preparation of compounds of formula (I) and derivatives thereof. The following is an example of a synthetic scheme that may be used to synthesize the compounds of the present invention.

  It will be appreciated by those skilled in the art that certain compounds of the present invention can be converted to other compounds of the present invention according to standard chemical methods.

  Starting materials for use in the scheme are commercially available, known in the literature, or can be prepared by known methods.

  The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in human or veterinary medicine.

  A compound of formula (I) or a pharmaceutically acceptable salt thereof is a primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy where an antagonist of the human orexin receptor is required. (347), breathing-related sleep disorders (780.59), circadian rhythm sleep disorders (307.45), and sleep disorders such as unspecified sleep disorders (307.47); Primary sleep disorders such as concomitant (307.47), night-surprise disorder (307.46), sleepwalking disorder (307.46), and unspecified parasomnia (307.47); Sleep disorders associated with another mental disorder, such as insomnia associated with other mental disorders (307.42) and hypersomnia associated with another mental disorder (307.44); sleep with general medical conditions Disability Sleep disorders associated with diseases such as neurological disorders, neuropathic pain, restless legs syndrome, heart disease and lung disease; and insomnia, hypersomnia, parasomnia, and mixed subs Substance-induced sleep disorders including types; may be for use for the treatment or prevention of diseases or disorders such as sleep disorders selected from the group consisting of sleep apnea and jet lag syndrome.

  In addition, the compounds of the present invention or pharmaceutically acceptable salts thereof include depression and major depression, manic, mixed seizures and hypomania, which require an antagonist of the human orexin receptor. Mood disorders; major depression, dysthymic disorder (300.4), depressive disorders including other unspecified depression disorders (311); bipolar I disorder, bipolar II disorder (hypomania) Recurrent major depressive seizures with seizures) (296.89), circulatory temperament disorders (301.13); and bipolar disorders including other unspecified bipolar disorders (296.80); depressive Other mood disorders, including mood disorders due to general medical conditions (298.83), including subtypes with features, major depression-like seizures, manic features, and mixed features, drug-induced mood Disability (depressive Including subtypes with symptom, mania characteristics, and mixed characteristics), and use for the treatment or prevention of diseases or disorders such as mood disorders (296.90) not otherwise specified Also good.

  Further, the compound of formula (I) or a pharmaceutically acceptable salt thereof is an anxiety disorder, including panic attacks, where an antagonist of the human orexin receptor is required; a panic disorder without agoraphobia (300.01 ) And panic disorder with agoraphobia (300.21); agoraphobia; agoraphobia with no history of panic disorder (300.22), animal type, natural environment type, blood injection damage Specific phobia (300.29, former single fear), social phobia (social anxiety disorder, 300.23), obsessive compulsive disorder (300.3), including types, contextual types, and other types of subtypes Post-traumatic stress disorder (309.81), acute stress disorder (308.3), generalized anxiety disorder (300.02), general medical condition anxiety disorder (293.84), drug For the treatment or prevention of diseases or disorders such as onset anxiety disorder, separation anxiety disorder (309.21), coordinating disorder with anxiety (309.24), and anxiety disorder not otherwise specified (300.00) It may be related to the use of.

In addition, a compound of formula (I) or a pharmaceutically acceptable salt thereof is a drug use disorder such as drug dependence, drug dependence, and drug abuse, where an antagonist of the human orexin receptor is required; Drug withdrawal, drug-induced delirium, drug-induced persistent dementia, drug-induced persistent amnesia, drug-induced mental disorder, drug-induced mood disorder, drug-induced anxiety disorder, drug-induced dysfunction, Substance-induced sleep disorders, and drug-induced disorders such as hallucinogen persistent sensory disturbances (flashback); alcohol dependence (303.90), alcohol abuse (305.00), alcohol addiction (303.00), alcohol abuse Drugs (292.81), alcohol addiction delirium, alcohol withdrawal delirium, alcohol-induced persistent dementia, alcohol-induced persistent amnesia, ARCO Alcohol-related disorders such as alcohol-induced mental disorders, alcohol-induced mood disorders, alcohol-induced anxiety disorders, alcohol-induced dysfunction, alcohol-induced sleep disorders, and alcohol-related disorders not otherwise specified (291.9) Disorders: amphetamine dependence (304.40), amphetamine abuse (305.70), amphetamine addiction (292.89), amphetamine blockade (292.0), amphetamine addiction delirium, amphetamine-induced mental disorder, amphetamine-induced mood disorder Amphetamine (or amphetamine-like) related disorders, such as amphetamine-induced anxiety disorder, amphetamine-induced dysfunction, amphetamine-induced sleep disorder, and unspecified amphetamine-related disorders (292.9); 3 5.90), caffeine-related disorders such as caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorders not otherwise specified (292.9); cannabis dependence (304.30), Cannabis abuse (305.20)
Cannabis-related disorders, such as cannabis poisoning (292.89), cannabis poisoning delirium, cannabis-induced psychiatric disorders, cannabis-induced anxiety disorder, and other unspecified cannabis-related disorders (292.9); .20), cocaine abuse (305.60), cocaine addiction (292.89), cocaine withdrawal (292.0), cocaine addiction delirium, cocaine-induced mental disorder, cocaine-induced mood disorder, cocaine-induced anxiety disorder Cocaine-induced disorders such as cocaine-induced dysfunction, cocaine-induced sleep disorder, and cocaine-related disorders not otherwise specified (292.9); hallucinogen dependence (304.50), hallucinogen abuse (305. 30), hallucinogen addiction (292.89), hallucinogen persistent sensory impairment (flashback) (292.89), hallucinogen addiction delirium, hallucinogen induced Hallucinogen-related disorders such as psychiatric disorders, hallucinogen-induced mood disorders, hallucinogen-induced anxiety disorders, and other unspecified hallucinogen-related disorders (292.9); inhalant dependence (304.60), inhalation Drug abuse (305.90), inhaled drug addiction (292.89), inhaled drug intoxication delirium, inhaled drug-induced persistent dementia, inhaled drug-induced mental disorder, inhaled drug-induced mood disorder, inhaled drug-induced anxiety Disorders, and inhalant-related disorders such as unspecified inhalant-related disorders (292.9); nicotine dependence (305.1), nicotine withdrawal (292.0), nicotine-related not otherwise specified Nicotine-related disorders such as disorders (292.9); opioid dependence (304.00), opioid abuse (305.50), opioid addiction (292.89), opioid withdrawal (292.0), opioid Opioid-related disorders such as toxic delirium, opioid-induced mental disorders, opioid-induced mood disorders, opioid-induced dysfunction, opioid-induced sleep disorders, and opioid-related disorders not otherwise specified (292.9); Cyclidine dependence (304.60), phencyclidine abuse (305.90), phencyclidine poisoning (292.89), phencyclidine poisoning delirium, phencyclidine-induced mental disorder, phencyclidine-induced mood disorder Phencyclidine (or phencyclidine-like) related disorders such as phencyclidine-induced anxiety disorder, and phencyclidine-related disorder (292.9) not otherwise specified; sedative, hypnotic, or anxiolytic Drug addiction (304.10), sedative, hypnotic, or anxiolytic abuse (305.40) Sedative, hypnotic, or anxiolytic addiction (292.89), sedative, hypnotic, or anxiolytic withdrawal (292.0), sedative, hypnotic, or anxiolytic addiction delirium, sedation Drugs, hypnotics, or anxiolytics withdrawal delirium, sedatives, hypnotics, or anxiolytics persistent dementia, sedatives, hypnotics, or anxiolytics persistent amnesia, sedatives, hypnotics, or Anxiolytic-induced psychosis, sedative, hypnotic, or anxiolytic-induced mood disorder, sedative, hypnotic, or anxiolytic-induced anxiety disorder, sedative, hypnotic, or anxiolytic-induced Sedatives, hypnotics, such as sexual dysfunction, sedatives, hypnotics, or anxiolytic-induced sleep disorders, and sedatives, hypnotics, or anxiolytic-related disorders not otherwise specified (292.9) Or anxiolytic-related disorders; many such as multidrug dependence (304.80) Related disorders; and anabolic steroids, may be related to the use for the treatment or prevention of a disease or disorder, such as other (or unknown) substance-related disorders, such as nitric inhalants, and nitrous oxide.

  In addition, a compound of formula (I) or a pharmaceutically acceptable salt thereof requires an antagonist of the human orexin receptor. Eating disorders such as bulimia nervosa, distraction eating, etc., for use in the treatment or prevention of diseases or disorders such as obesity, including obesity observed in patients with type 2 (non-insulin dependent) diabetes You can. Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof is of a disease or disorder such as an ischemic or hemorrhagic stroke and / or emetic which requires an antagonist of the human orexin receptor. It may relate to a response or use for treatment or prevention in blocking nausea and vomiting.

  The numbers in parentheses after the listed diseases refer to the classification codes in DSM-IV: Diagnostic and Statistical Manual Mental Disorders, 4th edition, published by American Psychiatric Association. The various subtypes of disorders described herein are considered as part of the present invention.

  The invention also provides a method of treating or preventing a disease or disorder for which an antagonist of a human orexin receptor is required, eg, the above-mentioned diseases and disorders, which requires treating or preventing the disease or disorder. Also provided is a method comprising administering to a subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

  The invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of diseases or disorders in which an antagonist of human orexin receptor is required, eg, the aforementioned diseases and disorders Salt is also provided.

  The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of diseases or disorders in which an antagonist of human orexin receptor is required, eg, the above diseases and disorders. The use of possible salts is also provided.

  For use in therapy, the compounds of the present invention are usually administered as a pharmaceutical composition. The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

  The compound of formula (I) or a pharmaceutically acceptable salt thereof can be obtained by any convenient method, for example, oral administration, parenteral administration, buccal administration, sublingual administration, nasal administration, rectal administration, or transdermally. It may be administered by administration and by a suitable pharmaceutical composition accordingly.

  The active compound of formula (I) or pharmaceutically acceptable salt thereof, when given orally, as a liquid or solid, for example as a syrup, suspension, emulsion, tablet, capsule or lozenge. Can be formulated.

  Liquid formulations will generally consist of a suspension or solution of the active ingredient in a suitable liquid carrier, for example, an aqueous solvent such as water, ethanol, or glycerin, or a non-aqueous solvent such as polyethylene glycol or oil. The formulation may also include suspending agents, preservatives, seasonings, and / or coloring agents.

  A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier conventionally used to prepare solid formulations such as magnesium stearate, starch, lactose, sucrose, and cellulose.

  Compositions in the form of capsules can be prepared using conventional encapsulation means, for example, pellets containing the active ingredient are prepared using standard carriers and then filled into hard gelatin capsules. Alternatively, the dispersion or suspension may be prepared using any suitable pharmaceutical carrier such as aqueous gum, cellulose, silicate, or oil and the dispersion or suspension then soft gelatin Can be filled into capsules.

  Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil such as polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil, or sesame oil. Alternatively, the solution can be administered immediately after lyophilization and immediately after reconstitution with a suitable solvent.

  Compositions for nasal administration may be conveniently formulated as aerosols, nasal drops, gels, and powders. Aerosol formulations typically include a solution of the active ingredient or a fine suspension of particles in a pharmaceutically acceptable aqueous or non-aqueous solvent and take the form of a cartridge or refill for use with a spray device. It is usually presented in a sterilized single dose or multiple doses in a sealed container capable. Alternatively, the sealed container may be a disposable dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a dose setting valve. Where the dosage form comprises an aerosol distributor, it will contain a propellant which may be a compressed gas, for example air or an organic propellant such as fluorochlorohydrocarbon or hydrofluorocarbon. The aerosol dosage form can also take the form of a pump sprayer.

  Compositions suitable for buccal or sublingual administration include tablets, lozenges, and pastels where the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth or gelatin, and glycerin.

  Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

  Compositions suitable for transdermal administration include ointments, gels, and patches.

  In one embodiment, the composition is in unit dose form such as a tablet, capsule, or ampoule.

  The dosage of the compound of formula (I) or a pharmaceutically acceptable salt thereof used in the treatment or prevention of the above disorders or diseases will depend on the particular disorder or disease being treated, the weight of the subject, and other similar factors And will vary in the usual way. However, as a general rule, a suitable unit dose may contain from 0.1% to 100%, eg 10% to 60% by weight of active material, depending on the method of administration. The composition may comprise 0% to 99%, eg 40% to 90%, by weight of carrier, depending on the method of administration. The composition may contain from 0.05 mg to 1000 mg, such as from 1.0 mg to 500 mg of active material, depending on the method of administration. The composition may comprise from 50 mg to 1000 mg, such as from 100 mg to 400 mg, depending on the method of administration. The dose of the compound used in the treatment of the above disorders will vary in a conventional manner, along with the severity of the disorder, the weight of the affected person, and other similar factors. However, as a general rule, a suitable unit dose may be 0.05 to 1000 mg, more suitably 1.0 to 500 mg, and such unit dose may be more than once a day, for example one day. May be administered two or three times. Such treatment may extend over weeks or months.

  The compounds of the invention may be identified and characterized using screening procedures and assays including, for example, activity assays and functional assays. Orexin-A (Sakurai, T. et al (1998) Cell, 92 p. 573-585) is employed in screening procedures for compounds that inhibit the activation of orexin-1 receptor or orexin-2 receptor ligands can do.

  In general, such screening procedures involve providing appropriate cells that express orexin-1 receptor or orexin-2 receptor on the cell surface. Such cells include cells derived from mammals, yeast, Drosophila, or E. coli. In particular, cells are transfected with a polynucleotide encoding orexin-1 receptor or orexin-2 receptor to express the receptor. The expressed receptor is then contacted with the test compound and orexin-1 receptor ligand or orexin-2 receptor ligand, and the inhibition of the functional response is observed as appropriate. One such screening procedure involves the use of a melanophore transfected to express orexin-1 or orexin-2 receptor as described in WO 92/01810.

  Another screening procedure involves introducing RNA encoding the orexin-1 receptor or orexin-2 receptor into Xenopus oocytes to transiently express the receptor. Receptor oocytes are then contacted with a receptor ligand and a test compound, followed by detection of signal inhibition when screening for compounds that are believed to inhibit receptor activation by the ligand.

  Another method is to determine the inhibition of binding of labeled orexin-1 receptor ligand or orexin-2 receptor ligand to cells having (if appropriate) orexin-1 receptor or orexin-2 receptor on the cell surface. Screening for compounds that inhibit receptor activation. The method comprises transfecting a eukaryotic cell with an orexin-1 receptor or orexin-2 receptor such that the cell expresses the receptor on its surface, and an orexin-1 receptor ligand or orexin-2 receptor. Contacting the cell or cell membrane preparation with the compound in the presence of a labeled form of the body ligand. The ligand may include a radioactive label. The amount of labeled ligand bound to the receptor is determined, for example, by measuring radioactivity.

  Yet another screening technique involves the appropriate influence on the interaction between orexin-1 receptor ligand or orexin-2 receptor ligand and orexin-1 receptor or orexin-2 receptor, thereby allowing intracellular calcium ions or other Use of the FLIPR instrument for high-throughput screening of test compounds that inhibit the movement of ions.

  Unless the context requires otherwise, throughout the following specification and claims, variations such as the word “comprising” and “including” and “comprising” are stated integers or classes or integers It will be understood that other integers or classes or groups of integers or classes are not excluded.

  All publications, including but not limited to patents and patent applications cited herein, are specifically and individually indicated to be incorporated by reference as if each individual publication was fully presented. As if incorporated herein by reference.

  The following examples illustrate the preparation of pharmacologically active compounds of the invention. Descriptions 1 and 2 illustrate the preparation of intermediates leading to the compounds of the present invention.

Examples In the procedures below, a citation for the description is typically provided after each starting material. This is provided merely as an aid to those skilled in the art. The starting material may not necessarily have been prepared from the cited batch.

  All compounds described in the examples described hereinafter were prepared as a first step from stereochemically pure methyl 5-oxo-L-prophosphate or ethyl 5-oxo-D-prophosphate. Yes. The stereochemistry of the compounds of the description and examples is given under the assumption that the pure configuration of 5-oxo-prolinate is maintained.

  The compounds are named using ACD / Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

  Proton magnetic resonance (NMR) spectra were recorded either on a Varian instrument at 300, 400, or 500 MHz, or on a Bruker instrument at 300 and 400 MHz. Chemical shifts are reported in ppm (δ) using a residual solvent line as an internal standard. The splitting pattern is designed as s, single line; d, double line; t, triple line; q, quadruple line; m, multiple line; b, wide.

  NMR spectra were recorded at a temperature in the range of 25-90 ° C. If more than one conformer is detected, the chemical shift for the highest amount of conformer is reported.

  Rt (HPLC): HPLC analysis indicated by X min was performed on an Agilent 1100 series instrument using a Luna 3u C18 (2) 100A (50 × 2.0 mm) column (mobile phase: 100% [water + 0. 05% TFA] to 95% [acetonitrile + 0.05% TFA], 8 minutes, flow rate = 1 mL / min, detection wavelength 220 nm).

Mass spectra (MS) are coupled in 4II triple quadrupole Mass Spectrometer (Micromass UK) operating in ES (+) ionization mode and ES (−) ionization mode or in Agilent MSD 1100 Mass Spectrometer, or with HPLC instrument Agilent 1100 Series. Obtained on an Agilent LC / MSD 1100 Mass Spectrometer operating in the ES (+) ionization mode and ES (−) ionization mode. [LC / MS-ES (+): analysis performed in Supelcosil ABZ + Plus (33 × 4.6 mm, 3 μm) (mobile phase: 100% [water + 0.1% HCO ₂ H] for 1 minute, then 100 % [Water + 0.1% HCO ₂ H] to 5% [water + 0.1% HCO ₂ H] and 95% [CH ₃ CN] for 5 minutes and finally under these conditions for 2 minutes); T = 40 ° C; flow rate = 1 mL / min; LC / MS-ES (-): Supelcosil ABZ + Plus (33 × 4.6 mm, 3 μm) analysis (mobile phase: 100% [water + 0.05% NH ₃ ]) 1 minute, then 100% [water + 0.05% NH ₃ ] to 5% [water + 0.05% NH ₃ ] and 95% [CH ₃ CN] for 5 minutes, and finally 2 minutes under these conditions); T = 40 ° C .; flow rate = 1 m / Min]. In the mass spectrum, only one peak in the ion cluster of the molecule is reported.

  For reactions involving microwave irradiation, Personal Chemistry Emrys ™ Optimizer was used.

  Flash silica gel chromatography was performed on silica gel 230-400 mesh (supplied by Merck AG Darmstadt, Germany) or through a Varian Mega Be-Si pre-filled cartridge or pre-filled Biotage silica cartridge.

  The SPE-SCX cartridge is an ion exchange solid phase extraction column supplied by Varian. The eluent used with the SPE-SCX cartridge is methanol followed by 2N ammonia solution in methanol.

  In some preparations, purification was performed using either a Biotage manual flash chromatography (Flash +) or automated flash chromatography (Horizon) system. All these instruments work with Biotage Silica cartridges.

  The SPE-Si cartridge is a silica solid phase extraction column supplied by Varian.

The table below lists the abbreviations used in the text:

２５０ｍＬの丸底フラスコに、（（２Ｓ）−１−｛［（１，１−ジメチルエチル）オキシ］カルボニル｝−２−ピペリジニル）酢酸（１．００ｇ、４．１１ｍｍｏｌ）、ＤＭＦ（２５ｍＬ）、ＤＩＰＥＡ（２．１５ｍＬ、１２．３３ｍｍｏｌ）、およびＴＢＴＵ（１．９８ｇ、６．１７ｍｍｏｌ）を加えた。混合物を室温で２０分間撹拌し、褐色を形成した。この時点の後、ＭｅＯＨ（０．２５ｍＬ、６．１７ｍｍｏｌ）を添加し、得られた溶液を室温で３０分間撹拌した。次に、これを、鹹水を含む分離漏斗に移し、ＥｔＯＡｃ（２０ｍＬ×２）で抽出し、組み合わせた有機層を水／氷（５×２０ｍＬ）で洗浄した。有機層を乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、濃縮した。得られた粗物をカラムクロマトグラフィー（Ｂｉｏｔａｇｅ ＳＰ１， Ｃｙ−ＥｔＯＡｃ１００／０〜８５／１５）によって精製した。 回収した画分によって、表題化合物（１．０１ｇ、３．９２ｍｍｏｌ、９５％収率）が無色の油として与えられた。^１Ｈ−ＮＭＲ （５００ ＭＨｚ， ＣＤＣｌ_３） δ（ｐｐｍ）： ４．６７ − ４．７５ （ｍ， １ Ｈ）， ３．９６ − ４．０５ （ｍ， １ Ｈ）， ３．６７ （ｓ， ３ Ｈ）， ２．７９ （ｔ， １ Ｈ）， ２．６１ （ｄｄ， １ Ｈ）， ２．５３ （ｄｄ， １ Ｈ）， １．６０ − １．７０ （ｍ， ６ Ｈ）， １．４６ （ｓ， ９ Ｈ）。 Description Description 1: (2S) -2- [2- (Methyloxy) -2-oxoethyl] -1-piperidinecarboxylic acid 1,1-dimethylethyl (D1)

A 250 mL round bottom flask was charged with ((2S) -1-{[(1,1-dimethylethyl) oxy] carbonyl} -2-piperidinyl) acetic acid (1.00 g, 4.11 mmol), DMF (25 mL), DIPEA. (2.15 mL, 12.33 mmol), and TBTU (1.98 g, 6.17 mmol) were added. The mixture was stirred at room temperature for 20 minutes to form a brown color. After this point, MeOH (0.25 mL, 6.17 mmol) was added and the resulting solution was stirred at room temperature for 30 minutes. This was then transferred to a separatory funnel containing brine, extracted with EtOAc (20 mL × 2), and the combined organic layers were washed with water / ice (5 × 20 mL). The organic layer was dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting crude was purified by column chromatography (Biotage SP1, Cy-EtOAc 100/0 to 85/15). The collected fractions afforded the title compound (1.01 g, 3.92 mmol, 95% yield) as a colorless oil. ¹ H-NMR (500 MHz, CDCl ₃ ) δ (ppm): 4.67 to 4.75 (m, 1 H), 3.96 to 4.05 (m, 1 H), 3.67 (s, 3 H), 2.79 (t, 1 H), 2.61 (dd, 1 H), 2.53 (dd, 1 H), 1.60-1.70 (m, 6 H), 46 (s, 9 H).

室温における窒素下の５００ｍＬの丸底フラスコに、Ｄ１（１１．１ｇ、４３．１ｍｍｏｌ）をＴＨＦ（１００ｍＬ）に溶解し、淡黄色の溶液を与えた。この溶液を−７８℃に冷却し、テッベ試薬（トルエンにおける０．５Ｍ溶液１０４ｍＬ、５１．８ｍｍｏｌ）を滴下して添加した。粘稠な混合物をさらなる無水トルエン７０ｍＬで希釈した。得られた褐色−橙色混合物をこの温度で３０分間撹拌した後、室温までゆっくりと加温し、撹拌下で２時間放置しておいた。反応混合物を滴下漏斗へと負荷した後、０℃に冷却したＮａＯＨの１Ｍ水溶液を最大で４００ｍＬ含む２Ｌの丸底フラスコに滴下して添加した。クエンチの終了時に、得られた灰色の懸濁液をＥｔＯＡｃ（２５０ｍＬ）で希釈し、一晩撹拌しておいた（機械的撹拌）。次に、得られた黄色の懸濁液を、Ｇｏｏｃｈ漏斗（Ｓｔｅｒｉｍａｔを用いる）で濾過し：塩をＥｔＯＡｃ（最大５００ｍＬ）で洗浄した。次に、相を分離し、有機層を鹹水（２×５００ｍＬ）で洗浄した。組み合わせた有機相を乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、濃縮して、濃橙色の油を与えた。この材料を最大５００ｍＬのＥｔ_２Ｏで希釈し：いくらかの塩が沈殿したので、得られた懸濁液をＧｏｏｃｈ漏斗（Ｓｔｅｒｉｍａｔを用いる）で濾過した。濾液を真空下で濃縮して１２．４ｇの粗物（２Ｓ）−２−［２−（メチルオキシ）−２−プロペン−１−イル］−１−ピペリジンカルボン酸１，１−ジメチルエチル１２．４ｇを橙色−褐色の油として与えた。（回収された全体量が、理論値より高かったので）材料はいくらかの残余塩を含んでいた。次の反応において材料をさらに精製せずに用い、８９重量％で純粋であると想定した。室温における窒素下の１Ｌ丸底フラスコにおいて、（２Ｓ）−２−［２−（メチルオキシ）−２−プロペン−１−イル］−１−ピペリジンカルボン酸１，１−ジメチルエチル（１２．４ｇ、４３．１ｍｍｏｌ）をＴＨＦ（１２５ｍＬ）および水（３５ｍＬ）に溶解して、淡黄色の溶液を与えた。次に、ＮＢＳ（７．６７ｇ、４３．１ｍｍｏｌ）を添加して、最大１００ｍＬのＴＨＦに溶解した。得られた灰色の混合物を室温で１時間撹拌した。次に、５０ｍＬのＴＨＦに溶解した追加的なＮＢＳ（０．２等量、１．５ｇ）を添加し、反応混合物を室温で１時間撹拌した。混合物を真空下で濃縮して、ＴＨＦを除去した後、ＥｔＯＡｃ（最大５００ｍＬ）および水（２００ｍＬ）で希釈した。相を分離し、水性層をＥｔＯＡｃ（２５０ｍＬ）で溶媒相抽出した。組み合わせた有機層を乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、濃縮して、１７．８ｇの褐色の油を与えた。この材料をフラッシュクロマトグラフィー（Ｂｉｏｔａｇｅ ７５Ｌ、Ｃｙ−ＥｔＯＡｃ、１００−０〜９０−１０）によって精製して、表題化合物（６．０ｇ、１８．７ｍｍｏｌ、Ｄ１からの４３％収率、２工程）をわずかに黄色の油として与え、静置して凝固させた。ＵＰＬＣ： ｒｔ ＝ ０．７９， 観察されたピーク： ３４４ ［Ｍ＋Ｎａ， １００％］， ３４２ ［Ｍ＋Ｎａ， １００％］， ２６６ ［Ｍ−ｔＢｕ，１００％］および２６４ ［Ｍ−ｔＢｕ，１００％］。^１Ｈ ＮＭＲ （５００ ＭＨｚ， ＣＤＣｌ_３） δ（ｐｐｍ）： ４．７２ − ４．７９ （ｍ， １ Ｈ）， ３．９１ − ４．１０ （ｍ， ３ Ｈ）， ２．７７ − ２．９７ （ｍ， ３ Ｈ）， １．４９ − １．７５ （ｍ， ６ Ｈ）， １．４６ （ｓ， ９ Ｈ）。 Description 2: 1,2-dimethylethyl (D2) (2S) -2- (3-bromo-2-oxopropyl) -1-piperidinecarboxylic acid

In a 500 mL round bottom flask under nitrogen at room temperature, D1 (11.1 g, 43.1 mmol) was dissolved in THF (100 mL) to give a pale yellow solution. The solution was cooled to −78 ° C. and Tebbe reagent (104 mL of 0.5 M solution in toluene, 51.8 mmol) was added dropwise. The viscous mixture was diluted with an additional 70 mL of anhydrous toluene. The resulting brown-orange mixture was stirred at this temperature for 30 minutes, then slowly warmed to room temperature and left under stirring for 2 hours. After loading the reaction mixture into a dropping funnel, it was added dropwise to a 2 L round bottom flask containing up to 400 mL of 1 M NaOH aqueous solution cooled to 0 ° C. At the end of the quench, the resulting gray suspension was diluted with EtOAc (250 mL) and allowed to stir overnight (mechanical stirring). The resulting yellow suspension was then filtered through a Gooch funnel (using Sterimat): the salt was washed with EtOAc (500 mL maximum). The phases were then separated and the organic layer was washed with brine (2 × 500 mL). The combined organic phases were dried (Na ₂ SO ₄ ), filtered and concentrated to give a dark orange oil. This material was diluted with a maximum of 500 mL Et ₂ O: some salt precipitated, and the resulting suspension was filtered through a Gooch funnel (using Sterimat). The filtrate was concentrated under vacuum to 12.4 g of crude (2S) -2- [2- (methyloxy) -2-propen-1-yl] -1-piperidinecarboxylate 1,1-dimethylethyl 12. 4 g was given as an orange-brown oil. The material contained some residual salt (since the total amount recovered was higher than the theoretical value). The material was used in the next reaction without further purification and assumed 89% pure by weight. In a 1 L round bottom flask under nitrogen at room temperature, 1,2-dimethylethyl (12.4 g, (2S) -2- [2- (methyloxy) -2-propen-1-yl] -1-piperidinecarboxylic acid 43.1 mmol) was dissolved in THF (125 mL) and water (35 mL) to give a pale yellow solution. NBS (7.67 g, 43.1 mmol) was then added and dissolved in a maximum of 100 mL of THF. The resulting gray mixture was stirred at room temperature for 1 hour. Then additional NBS (0.2 eq, 1.5 g) dissolved in 50 mL THF was added and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to remove THF, then diluted with EtOAc (500 mL max) and water (200 mL). The phases were separated and the aqueous layer was solvent phase extracted with EtOAc (250 mL). The combined organic layers were dried (Na ₂ SO ₄ ), filtered and concentrated to give 17.8 g of a brown oil. This material was purified by flash chromatography (Biotage 75L, Cy-EtOAc, 100-0 to 90-10) to give the title compound (6.0 g, 18.7 mmol, 43% yield from D1, 2 steps). It was given as a slightly yellow oil and allowed to solidify on standing. UPLC: rt = 0.79, observed peaks: 344 [M + Na, 100%], 342 [M + Na, 100%], 266 [M-tBu, 100%] and 264 [M-tBu, 100%]. ¹ H NMR (500 MHz, CDCl ₃ ) δ (ppm): 4.72 to 4.79 (m, 1 H), 3.91 to 4.10 (m, 3 H), 2.77 to 2.97 (M, 3H), 1.49-1.75 (m, 6H), 1.46 (s, 9H).

ＤＭＦ（２ｍＬ）における（２Ｓ）−２−（３−ブロモ−２−オキソプロピル）−１−ピペリジンカルボン酸１，１−ジメチルエチルＤ２（０．１４０ｇ、０．４４ｍｍｏｌ）の溶液に、３，５−ジメチル−２−ピラジンアミン（０．０５４ｇ、０．４４ｍｍｏｌ）を添加し、混合物を１５０℃で３０分間撹拌した。反応混合物をＳＣＸカラムに負荷し、メタノールおよびメタノールにおける２Ｍアンモニアで溶出した。回収した画分によって、所望の６，８−ジメチル−２−［（２Ｓ）−２−ピペリジニルメチル］イミダゾ［１，２−ａ］ピラジンを含む０．１１５ｇの粗物が与えられた。ＵＰＬＣ： ｒｔ＝０．３４， 観察されたピーク： ２４５ （Ｍ＋１）。Ｃ_１４Ｈ_２０Ｎ_４は２４４を要する。７ｍＬのねじキャップつきバイアルへと、２−メチル−５−フェニル−１，３−チアゾール−４−カルボン酸（０．１１４ｇ、０．５２ｍｍｏｌ）をＤＣＭ（１ｍＬ）に溶解し、塩化オキサリル（０．１００ｍＬ、１．１４ｍｍｏｌ）、次いでＤＭＦ（０．０３６ｍＬ、０．４７ｍｍｏｌ）を添加し、得られた混合物を室温で３０分間撹拌した。溶媒を減圧下で除去し、得られた黄色の固体をＤＣＭ（１ｍＬ）に溶解し、粗物６，８−ジメチル−２−［（２Ｓ）−２−ピペリジニルメチル］イミダゾ［１，２−ａ］ピラジンおよびＤＣＭ（１ｍＬ）におけるＴＥＡ（０．１９７ ｍｌ、０．４７ ｍｍｏｌ）を含む０℃に冷却した溶液に滴下して添加した。氷槽を除去し、反応混合物を室温で撹拌下で１時間放置した。ＤＣＭ（１ｍＬ）を添加し、混合物を飽和ＮａＨＣＯ_３水溶液で洗浄し、有機相を分離し、乾燥させ（Ｎａ_２ＳＯ_４）、濾過し、濃縮した。残留物をシリカゲル上でのカラムクロマトグラフィーによって（Ｂｉｏｔａｇｅ ２５ Ｍ、ＤＣＭ／ＭｅＯＨ ９０／０１）、およびｆｒａｃｔｉｏｎ ｌｙｎｘ（基本法）によって精製した。表題化合物の遊離塩基（０．０３９ｇ、０．０７９ ｍｍｏｌ、Ｄ２から２０％収率、３工程）を黄色の固体として得た。ＵＰＬＣ： ｒｔ ＝０．５８， 観察されたピーク： ４４６ （Ｍ＋１）。Ｃ_２５Ｈ_２７Ｎ_５ＯＳは４４５を要する。^１Ｈ ＮＭＲ ［本生成物は、配座異性体の混合物（ｃ比約６０／４０）として存在する。］ （５００ ＭＨｚ， ＤＭＳＯ−ｄ^６）。遊離塩基（０．０３７ｇ、０．０８ｍｍｏｌ）を、無水ＤＣＭ（１ｍＬ）の入った７ｍＬのねじキャップつきバイアルに移し、溶液を０℃に冷却した。ＨＣｌ（Ｅｔ_２Ｏにおける１Ｍ溶液０．１２５ｍＬ、０．１３ｍｍｏｌ）を滴下して添加し、混合物を１５分間撹拌した。溶媒を減圧下で除去し、得られた固体を無水Ｅｔ_２Ｏで倍散した。表題化合物を白色の固体として得た（０．０４１ｇ、０．０８ｍｍｏｌ、９８％収率）。ＵＰＬＣ： ｒｔ＝０．５８分、観察されたピーク：４４６（Ｍ＋１−ＨＣｌ）。Ｃ_２５Ｈ_２８ＣｌＮ_５ＯＳは４８２を要する。 Example 1: 6,8-dimethyl-2-({(2S) -1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl) carbonyl] -2-piperidinyl} methyl) imidazo [1,2-a] pyrazine (HCl salt) (E1):

To a solution of (2S) -2- (3-bromo-2-oxopropyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl D2 (0.140 g, 0.44 mmol) in DMF (2 mL), 3,5 -Dimethyl-2-pyrazinamine (0.054 g, 0.44 mmol) was added and the mixture was stirred at 150 ° C. for 30 minutes. The reaction mixture was loaded onto an SCX column and eluted with methanol and 2M ammonia in methanol. The collected fractions gave 0.115 g of crude containing the desired 6,8-dimethyl-2-[(2S) -2-piperidinylmethyl] imidazo [1,2-a] pyrazine. UPLC: rt = 0.34, observed peak: 245 (M + 1). C ₁₄ H ₂₀ N ₄ requires 244. To a 7 mL vial with a screw cap, 2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (0.114 g, 0.52 mmol) was dissolved in DCM (1 mL) and oxalyl chloride (0. 100 mL, 1.14 mmol) was added followed by DMF (0.036 mL, 0.47 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the resulting yellow solid was dissolved in DCM (1 mL) and the crude 6,8-dimethyl-2-[(2S) -2-piperidinylmethyl] imidazo [1,2 -A] Added dropwise to a solution cooled to 0 ° C. containing TEA (0.197 ml, 0.47 mmol) in pyrazine and DCM (1 mL). The ice bath was removed and the reaction mixture was left under stirring at room temperature for 1 hour. DCM (1 mL) was added and the mixture was washed with saturated aqueous NaHCO ₃ and the organic phase was separated, dried (Na ₂ SO ₄ ), filtered and concentrated. The residue was purified by column chromatography on silica gel (Biotage 25 M, DCM / MeOH 90/01) and by fraction lynx (basic method). The free base of the title compound (0.039 g, 0.079 mmol, 20% yield from D2, 3 steps) was obtained as a yellow solid. UPLC: rt = 0.58, observed peak: 446 (M + 1). C ₂₅ H ₂₇ N ₅ OS requires 445. ¹ H NMR [This product exists as a mixture of conformers (c ratio about 60/40). ] (500 MHz, DMSO-d ⁶ ). The free base (0.037 g, 0.08 mmol) was transferred to a 7 mL screw-capped vial with anhydrous DCM (1 mL) and the solution was cooled to 0 ° C. HCl (0.125 mL of 1M solution in Et ₂ O, 0.13 mmol) was added dropwise and the mixture was stirred for 15 minutes. The solvent was removed under reduced pressure and the resulting solid was triturated with anhydrous Et ₂ O. The title compound was obtained as a white solid (0.041 g, 0.08 mmol, 98% yield). UPLC: rt = 0.58 min, observed peak: 446 (M + 1-HCl). C ₂₅ H ₂₈ ClN ₅ OS requires 482.

Example 2: Determination of antagonist affinity at human orexin-1 receptor and 2 receptor using FLIPR Cell culture Recombinant recombinant human orexin-1 receptor (hOX1) or human orexin-2 receptor (hOX2) Adherent Chinese hamster ovary (CHO) cells expressed in 10% fetal calf serum (Life Technologies, catalog number 10106-078) and 400 μg / mL geneticin G418 (Calbiochem, catalog number 345810) without complement. Maintained in culture in alpha minimal essential medium supplemented with (Gibco / Invitrogen, catalog number; 22571-020). Cells were grown as monolayers at 37 ° C. under 95%: 5% air: CO ₂ and passaged every 3-4 days. The highest passage used was 25 times.

  The sequences of human orexin 1 receptor and human orexin 2 receptor used in this example are described in Sakurai, T .; et al (1998) Cell, 92 p. The exception was that the human orexin 1 receptor sequence used had the amino acid residue alanine at position 280, as described in Sakurai et al. It was not glycine reported in

Measurement of [Ca ²⁺ ] _i using FLIPR ™ Seed CHO-hOX1 or CHO-hOX2 cells in a black clear bottom 384 well plate at a density of 20,000 per well in the above medium, Maintained overnight (95% at 37 ° C .: 5% air: CO ₂ ).

On the day of the experiment, the medium was discarded and the cells were washed with standard buffer supplemented with 2.5 mM Probenecid (NaCl, 145 mM; KCl, 5 mM; HEPES, 20 mM; glucose, 5.5 mM; MgCl ₂ , 1 mM; CaCl ₂ , 2 mM ) 3 times.

  The plate is then incubated with 1 μM FLUO-4AM dye for 60 minutes in the dark at room temperature to allow FLUO-4AM to be taken up by the cells and then converted to FLUO-4 that cannot remain in the cells by intracellular esterases. did.

  After incubation, the cells were washed 3 times with standard buffer to remove extracellular dye, and 30 μL of buffer was left in each well after washing. The compounds of the invention were tested at final assay concentrations ranging from 1.66E-05M to 1.58E-11M.

  The compounds of the invention were dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 10 mM. These solutions were serially diluted with DMSO in a 384 compound plate and 1 μL of each dilution was transferred to the test compound plate. Just prior to compound addition to cells, buffer (50 μL / well) was added to 1 μL compound copy plate.

  Immediately after preparing an agonist-stimulated 384-well plate containing 50 μL / well human orexin A (hOrexinA), use by diluting the stock plate with buffer: final concentration is equivalent to EC80 calculated for hOrexinA is there. This value was obtained by testing hOrexinA in a concentration response curve (at least 16 replicates) on the same day of the experiment.

The loaded cells were then incubated with the test compound at 37 ° C. for 10 minutes. The plates were then placed on FLIPR ™ (Molecular Devices, UK) and cell fluorescence (λ _ex = 488 nm, λ _EM = 540 nm) was monitored (Sullivan E, Tucker EM, Dale IL. Measurement of [Ca ²⁺ ] _i using the fluometric imaging reader (FLIPR). Labeled DG (eds.), Calcium Signaling Protocols. New Jersey: Humana Press, 1999, 125-136). After baseline fluorescence readings were taken for 5-10 seconds, 10 μL of EC80 hOrexin A solution was added. The fluorescence was then read for 4-5 minutes.

Data Analysis Functional response using FLIPR was measured as peak fluorescence intensity-baseline fluorescence and expressed as a percentage of the response induced by uninhibited orexin A on the same plate. Iterative curve fitting and parameter estimation was performed using a four parameter logistic model and Microsoft Excel (Bowen WP, Jerman JC. Nonlinear regression using spreadsheets. Trends Pharmacol. Sci. 1995: 16: 1995); Antagonist affinity values (IC ₅₀ ) were converted to functional pK _i values using a modified Cheng-Prusoff correction (Cheng YC, Prusoff WH. Relationship between the inhibint constant (K _i ). 50 percent inhibition (IC ₅₀ ) of an enzymatic reaction. Biochem. Pharmacol. 1973, 22: 3099-3108).

Where [agonist] is the agonist concentration, EC ₅₀ is the concentration of agonist that gives 50% activity from the agonist dose response curve, and n = slope of the dose response curve. When n = 1, the equation is folded into the more familiar Cheng-Prusoff equation.

  The fpKi value of the compound of Example 1 tested according to this method is 8.3 at the human cloned orexin-1 receptor (having the amino acid residue alanine at position 280, not glycine), and human cloned orexin. -2 receptor was 8.2.

Claims (32)

A compound of formula (I) or a pharmaceutically acceptable salt thereof:

(In the above formula, Ar represents the formula:

Selected from the group consisting of
R ₁ is (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O—. (C _1-4 ) alkyl, CN, NR ⁵ R ⁶ , wherein R ⁵ is H or (C _1-4 ) alkyl, and R ⁶ is H or (C _1-4 ) alkyl. And
R ₂ represents (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O—. (C _1-4 ) alkyl, CN, NR ⁷ R ⁸ , wherein R ⁷ is H or (C _1-4 ) -alkyl, and R ⁸ is H or (C _1-4 ) — Alkyl,
R ₃ is (C _1-4 ) alkyl, halo, halo (C _1-4 ) alkyl, (C _1-4 ) alkoxy, halo (C _1-4 ) alkoxy, (C _1-4 ) alkyl-O −. (C _1-4 ) alkyl, CN, NR ⁹ R ¹⁰ , wherein R ⁹ is H or (C _1-4 ) -alkyl, and R ¹⁰ is H or (C _1-4 ). -Alkyl,
n is 0 or 1,
p is 0 or 1, and q is 0 or 1,
However, both p and q are not 0).   2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is a group of formula (II).   2. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ar is a group of formula (III).   The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ar is a group of the formula (II) and n is 0. Ar, which is a group of formula (II), n is 0, p is 1, q is 0, and R ₂ is (C _1-4 ) alkyl. Or a pharmaceutically acceptable salt thereof. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein Ar is a group of formula (II), n is 0, p is 1, q is 0, and R ₂ is methyl. Get salt. Ar, which is a group of formula (II), n is 0, p is 0, q is 1 and R ₃ is (C _1-4 ) alkyl. 4. The compound according to 4, or a pharmaceutically acceptable salt thereof. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein Ar is a group of formula (II), n is 0, p is 0, q is 1 and R ₃ is methyl. Get salt. Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is (C _1-4 ) alkyl, and R ₃ is (C _{1- 4} ) The compound according to claim 1, 2, or 4, or a pharmaceutically acceptable salt thereof, which is alkyl. 10. Ar according to claim 9, wherein Ar is a group of formula (II), n is 0, p is 1, q is 1, R ₂ is methyl and R ₃ is methyl. A compound or a pharmaceutically acceptable salt thereof.   The compound according to claim 1 or 3, or a pharmaceutically acceptable salt thereof, wherein Ar is a group of the formula (III) and n is 0. Ar, is a group of formula (III), n is 0, p is 1, q is 0, and R ₂ is (C _1-4 ) alkyl. 11. The compound according to 11, or a pharmaceutically acceptable salt thereof. 13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein Ar is a group of formula (III), n is 0, p is 1, q is 0, and R ₂ is methyl. Get salt. Ar, is a group of formula (III), n is 0, p is 0, q is 1 and R ₃ is (C _1-4 ) alkyl. 11. The compound according to 11, or a pharmaceutically acceptable salt thereof. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein Ar is a group of formula (III), n is 0, p is 0, q is 1 and R ₃ is methyl. Get salt. Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is (C _1-4 ) alkyl, and R ₃ is (C _{1- 4} ) The compound according to claim 1, 3 or 11, or a pharmaceutically acceptable salt thereof, which is alkyl. 17. Ar according to claim 16, wherein Ar is a group of formula (III), n is 0, p is 1, q is 1, R ₂ is methyl and R ₃ is methyl. A compound or a pharmaceutically acceptable salt thereof.   6-8-dimethyl-2-({(2S) -1-[(2-methyl-5-phenyl-1,3-thiazol-4-yl) carbonyl] -2-piperidinyl} methyl) imidazo [1,2 -A] A compound that is pyrazine or a pharmaceutically acceptable salt thereof.   19. A compound as defined in any one of claims 1-18 or a pharmaceutically acceptable salt thereof for use in therapy.   19. A compound as defined in any one of claims 1-18 or a pharmaceutically acceptable salt thereof for the treatment of a disease or disorder in which an antagonist of human orexin receptor is required.   21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is sleep disorder, depression or mood disorder, anxiety disorder, substance related disorder, or eating disorder.   22. A compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein the disease or disorder is a sleep disorder.   The sleep disorders include primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory-related sleep disorder (780.59), circadian rhythm sleep disorder (307.45). ), And sleep abnormalities such as sleep abnormalities (307.47) not otherwise specified; sleep-related complications such as nightmare disorder (307.47), night-surprise disorder (307.46), sleepwalking disorder (307.47) 46), and primary sleep disorders such as unspecified parasomnia (307.47); insomnia associated with another mental disorder (307.42) and hypersomnia associated with another mental disorder Sleep disorders associated with another mental disorder, such as symptom (307.44); sleep disorders with general medical conditions, especially neurological disorders, neuropathic pain, restless legs syndrome, heart disease and lung disease, etc. Associated with other diseases Claims selected from the group consisting of sleep disorders; and substance-induced sleep disorders including insomnia, hypersomnia, parasomnia, and mixed subtypes; sleep apnea and jet lag syndrome Item 22. The compound according to Item 22 or a pharmaceutically acceptable salt thereof.   Use of a compound as defined in any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder in which an antagonist of human orexin receptor is required.   25. Use according to claim 24, wherein the disease or disorder is a sleep disorder, depression or mood disorder, anxiety disorder, substance-related disorder, or eating disorder.   26. Use according to claim 25, wherein the disease or disorder is a sleep disorder.   The sleep disorders include primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory-related sleep disorder (780.59), circadian rhythm sleep disorder (307.45). ), And sleep abnormalities such as sleep abnormalities (307.47) not otherwise specified; sleep-related complications such as nightmare disorder (307.47), night-surprise disorder (307.46), sleepwalking disorder (307.47) 46), and primary sleep disorders such as unspecified parasomnia (307.47); insomnia associated with another mental disorder (307.42) and hypersomnia associated with another mental disorder Sleep disorders associated with another mental disorder, such as symptom (307.44); sleep disorders with general medical conditions, especially neurological disorders, neuropathic pain, restless legs syndrome, heart disease and lung disease, etc. Associated with other diseases Claims selected from the group consisting of sleep disorders; and substance-induced sleep disorders including insomnia, hypersomnia, parasomnia, and mixed subtypes; sleep apnea and jet lag syndrome Item 27. Use according to Item 26.   19. A method of treating or preventing a disease or disorder in which an antagonist of human orexin receptor is needed, in a subject in need thereof, an effective amount of a compound as defined in any one of claims 1-18. Or administering a pharmaceutically acceptable salt thereof.   30. The method of claim 28, wherein the disease or disorder is a sleep disorder, depression or mood disorder, anxiety disorder, substance-related disorder, or eating disorder.   30. The method of claim 29, wherein the disease or disorder is a sleep disorder.   The sleep disorders include primary insomnia (307.42), primary hypersomnia (307.44), narcolepsy (347), respiratory-related sleep disorder (780.59), circadian rhythm sleep disorder (307.45). ), And sleep abnormalities such as sleep abnormalities (307.47) not otherwise specified; sleep-related complications such as nightmare disorder (307.47), night-surprise disorder (307.46), sleepwalking disorder (307.47) 46), and primary sleep disorders such as unspecified parasomnia (307.47); insomnia associated with another mental disorder (307.42) and hypersomnia associated with another mental disorder Sleep disorders associated with another mental disorder, such as symptom (307.44); sleep disorders with general medical conditions, especially neurological disorders, neuropathic pain, restless legs syndrome, heart disease and lung disease, etc. Associated with other diseases Claims selected from the group consisting of sleep disorders; and substance-induced sleep disorders including insomnia, hypersomnia, parasomnia, and mixed subtypes; sleep apnea and jet lag syndrome Item 30. The method according to Item 30.   A pharmaceutical composition comprising: a) a compound as defined in any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof; and b) a pharmaceutically acceptable carrier.