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US-20260124201-A1 - CYCLOPENTANE COMPOUND

US20260124201A1US 20260124201 A1US20260124201 A1US 20260124201A1US-20260124201-A1

Abstract

The present invention aims to provide a novel compound which has an OX2R agonist activity. The present invention relates to a cyclopentane compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof. The compound of the present invention or a pharmaceutically acceptable salt thereof has an agonist activity on OX2R and is useful as an agent for the treatment of sleep disorders involving OX2R (for example, narcolepsy, idiopathic hypersomnia, Kleine-Levin syndrome, hypersomnia due to physical diseases, hypersomnia due to psychiatric disorders, hypersomnia due to drugs or substances, circadian rhythm sleep-wake disorder, insufficient sleep syndrome and long sleep) or the like.

Inventors

  • Atsushi Kondo
  • Masako Yoshida
  • Tsutomu Matsumoto
  • Akihiro SHIOGAI
  • Tomoya OKI

Assignees

  • KISSEI PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260507
Application Date
20231006
Priority Date
20221007

Claims (12)

  1. 1 . A compound represented by the formula (I): [in the formula, ring A is C 6-10 aryl, 5- or 6-membered heteroaryl, or 9- or 10-membered heteroaryl; R 1 is a group selected from the group consisting of the following (a) to (c): (a) —NR a R a ′, R a and R a ′ are each independently a hydrogen atom, a hydroxy group, C 1-6 alkyl, C 1-6 alkoxy, hydroxy C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or halo C 1-6 alkyl; R b is a hydrogen atom, a halogen atom, C 1-6 alkyl, C 1-6 alkoxy, or halo C 1-6 alkyl; p is an integer number of 1 to 3; when p is 2 or 3, these R b are the same or different from each other; q is an integer number of 1 to 3; r is 1 or 2; R 2 is C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl which may be substituted by 1 to 3 C 1-6 alkyl, 3- to 8-membered heterocycloalkyl which may be substituted by 1 to 3 C 1-6 alkyl, halo C 1-6 alkyl, or C 1-6 alkylamino; R 3 and R 4 are each independently a hydrogen atom, a halogen atom, C 1-6 alkyl, or C 1-6 alkoxy; R 5 and R 6 are each independently a hydrogen atom or a halogen atom; R 7 is a hydrogen atom, a halogen atom, a hydroxy group, an amino group, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, or C 1-6 alkylamino; R 8 is a hydrogen atom, a halogen atom, a hydroxy group, a cyano group, C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkyl, or C 1-6 alkylamino; n is 1 or 2; when n is 2, these R 7 are the same or different from each other; and m is 1 or 2; when m is 2, these R 8 are the same or different from each other]; or a pharmaceutically acceptable salt thereof.
  2. 2 . The compound according to claim 1 ; wherein ring A is C 6-10 aryl or 5- or 6-membered heteroaryl; R 5 and R 6 are hydrogen atoms; R 7 is a hydrogen atom, a halogen atom, a hydroxy group, C 1-6 alkyl, halo C 1-6 alkyl, or C 1-6 alkoxy; and n is 1; or a pharmaceutically acceptable salt thereof.
  3. 3 . The compound according to claim 2 ; wherein R a and R a ′ are each independently a hydrogen atom, a hydroxy group, C 1-6 alkyl, or C 1-6 alkoxy; R b is C 1-6 alkyl; p is 1; q is 2; r is 1; and R 3 and R 4 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
  4. 4 . The compound according to claim 3 : wherein R 1 is —NR a R a ′; and R a and R a ′ are each independently C 1-6 alkyl or C 1-6 alkoxy; or a pharmaceutically acceptable salt thereof.
  5. 5 . The compound according to claim 4 ; wherein ring A is 5- or 6-membered heteroaryl; or a pharmaceutically acceptable salt thereof.
  6. 6 . The compound according to claim 5 ; wherein R 2 is C 1-6 alkyl, C 3-8 cycloalkyl which may be substituted by 1 to 3 C 1-6 alkyl, 3- to 8-membered heterocycloalkyl which may be substituted by 1 to 3 C 1-6 alkyl, or halo C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
  7. 7 . The compound according to claim 6 which is represented by the formula (II): [in the formula, R 2 is C 1-6 alkyl, C 3-8 cycloalkyl which may be substituted by 1 to 3 C 1-6 alkyl, 3- to 8-membered heterocycloalkyl which may be substituted by 1 to 3 C 1-6 alkyl, or halo C 1-6 alkyl; R 3 and R 4 are each independently a hydrogen atom, a halogen atom, or C 1-6 alkyl; R 7 is a hydrogen atom, a halogen atom, a hydroxy group, or C 1-6 alkyl; and R is a hydrogen atom, a halogen atom, or C 1-6 alkyl]; or a pharmaceutically acceptable salt thereof.
  8. 8 . A compound selected from the group consisting of the following compounds: or a pharmaceutically acceptable salt thereof.
  9. 9 . A compound selected from the group consisting of the following compounds: or a pharmaceutically acceptable salt thereof.
  10. 10 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutical additive.
  11. 11 . The pharmaceutical composition according to claim 10 which is a pharmaceutical composition for use in the treatment of a sleep disorder involving OX2R.
  12. 12 . The pharmaceutical composition according to claim 11 wherein the sleep disorder involving OX2R is narcolepsy.

Description

TECHNICAL FIELD The present invention relates to cyclopentane compounds useful as medicaments. More particularly, the present invention relates to cyclopentane compounds or pharmaceutically acceptable salts thereof which have an orexin 2 receptor (OX2R) agonist activity and are useful as agents for the treatment of sleep disorders involving OX2R. BACKGROUND ART Orexin is a neuropeptide produced and secreted by orexin neurons in the hypothalamus and contains two subtypes, orexin A and orexin B. Projections of orexin neurons are distributed throughout the central nervous system except for the cerebellum, with prominent projections to monoaminergic nerves and cholinergic nerves in the brainstem, the paraventricular nucleus in the thalamus, and the like, which are involved in sleep-wake mechanisms. Orexin receptors are expressed corresponding to the projection targets, and two kinds of subtypes, orexin 1 receptors (OX1R) and orexin 2 receptors (OX2R), are present in different topography. Orexin nervous system plays an important role in maintenance of wakefulness, and its dysfunction is considered to be the cause of the onset of narcolepsy. Narcolepsy is one of sleep disorders and is a chronic neurologic disease whose main symptoms are excessive daytime sleepiness and paroxysmal sleep. There are two types of narcolepsy according to symptoms: a case with cataplexy (a seizure in which the body suddenly loses strength triggered by strong emotions) is classified as Type 1 (NT1); and a case without cataplexy is classified as Type 2 (NT2). Currently, in treatment of narcolepsy, Modafinil, Methylphenidate and Pemoline, which are central nerve stimulators, are used for hypersomnia, but all of them can cause paradoxical reaction, and Methylphenidate and Pemoline have strong side effects, including dependency and the like. On the other hand, on cataplexy, antidepressants are used because no therapeutic effect is observed by the above agents, but it is difficult to use them because of their strong side effect, and there are problems such as exacerbation due to a rebound phenomenon that is characteristic of antidepressants when the drugs are discontinued. In this way, it is present situation of narcolepsy treatment that there are only symptomatic therapies for any symptom, and therapeutic agents based on the etiology of narcolepsy are desired. In research using the postmortem brains of narcolepsy patients, it is reported that orexin neurons in the hypothalamus have decreased in comparison with healthy subjects (Non-patent literature 1). In addition, it is reported that the gene responsible for narcolepsy is the gene encoding OX2R in a canine model of hereditary narcolepsy (Non-patent literature 2) and that, while OX1R deficient mice don't develop narcolepsy symptoms, OX2R deficient mice develop the symptoms (Non-patent literature 3). In view of this background, it is strongly indicated that OX2R signaling is important in the maintenance of wakefulness and that its reduction is related to the onset of narcolepsy, and OX2R agonists are expected as therapeutic agents of narcolepsy or other sleep disorders. As an OX2R agonist, for instance, TAK-925 is known, and prolonging of wake time by subcutaneous administration of TAK-925 was observed in wild-type mice (Non-patent literature 4). In addition, in a clinical study, it is reported that TAK-925 showed the effects of maintaining wakefulness and reducing daytime sleepiness in NT1 patients (Patent literature 1). Compounds having an OX2R agonist activity are disclosed in Patent literatures 1 to 14 and Non-patent literature 4. In addition, compounds including cyclopentane substituted by sulfonamide as a substructure are disclosed in Patent literature 15 and Non-patent literature 5. However, the cyclopentane compounds of the invention of the present application are not described in any of Patent literatures 1 to 15, Non-patent literature 4 and Non-patent literature 5. CITATION LIST Patent Literature Patent literature 1: WO 2021/048822Patent literature 2: WO 2021/166934Patent literature 3: WO 2021/142083Patent literature 4: WO 2021/048821Patent literature 5: U.S. Published Application No. 2020/0247747Patent literature 6: U.S. Published Application No. 2019/0040010Patent literature 7: U.S. Published Application No. 2020/0385346Patent literature 8: U.S. Published Application No. 2017/0226137Patent literature 9: WO 2022/109117Patent literature 10: U.S. Published Application No. 2022/0056017Patent literature 11: WO 2022/040058Patent literature 12: WO 2021/026047Patent literature 13: U.S. Published Application No. 2020/0255403Patent literature 14: U.S. Published Application No. 2022/0144771Patent literature 15: U.S. Published Application No. 2007/0149532 Non-Patent Literature Non-patent literature 1: Thomas C. Thannickal et al., “Neuron” 2000, Vol. 27, No. 3, pp. 469-474Non-patent literature 2: Ling Lin et al., “Cell” 1999, Vol. 98, No. 3, pp. 365-376Non-patent literature 3: Michihiro Mied