WO2008087611A2 - Dérivés de pyrrolidine et de piperidine - Google Patents

Dérivés de pyrrolidine et de piperidine Download PDF

Info

Publication number
WO2008087611A2
WO2008087611A2 PCT/IB2008/050192 IB2008050192W WO2008087611A2 WO 2008087611 A2 WO2008087611 A2 WO 2008087611A2 IB 2008050192 W IB2008050192 W IB 2008050192W WO 2008087611 A2 WO2008087611 A2 WO 2008087611A2
Authority
WO
WIPO (PCT)
Prior art keywords
thiazole
methyl
carboxylic acid
imidazo
phenyl
Prior art date
Application number
PCT/IB2008/050192
Other languages
English (en)
Other versions
WO2008087611A3 (fr
Inventor
Hamed Aissaoui
Christoph Boss
Markus Gude
Ralf Koberstein
Thierry Sifferlen
Original Assignee
Actelion Pharmaceuticals Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Publication of WO2008087611A2 publication Critical patent/WO2008087611A2/fr
Publication of WO2008087611A3 publication Critical patent/WO2008087611A3/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to selected pyrrolidine- and piperidine-derivatives of formula (I), generically covered but not specifically exemplified by WOO 1/96302 and WO03/051368 and their use as pharmaceuticals.
  • the invention also concerns related aspects including processes for the preparation of the compounds, pharmaceutical compositions containing one or more compounds of formula (I), and especially their use as orexin receptor antagonists.
  • Orexins orexin A or OX-A and orexin B or OX-B
  • Orexins are novel neuropeptides found in 1998 by two research groups, orexin A is a 33 amino acid peptide and orexin B is a 28 amino acid peptide (Sakurai T. et al., Cell, 1998, 92, 573-585).
  • Orexins are produced in discrete neurons of the lateral hypothalamus and bind to G-protein-coupled receptors (OXi and OX 2 receptors).
  • the orexin- 1 receptor (OXi) is selective for OX-A
  • the orexin-2 receptor (OX 2 ) is capable to bind OX-A as well as OX-B.
  • Orexins are found to stimulate food consumption in rats suggesting a physiological role for these peptides as mediators in the central feedback mechanism that regulates feeding behaviour (Sakurai T. et al., Cell, 1998, 92, 573-585).
  • Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies as known from the literature.
  • the present invention provides pyrrolidine- and piperidine-derivatives, which are non- peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of e.g. eating disorders, drinking disorders, sleep disorders, or cognitive dysfunctions in psychiatric and neurologic disorders.
  • pyrrolidine- and piperidine-derivatives which are non- peptide antagonists of human orexin receptors. These compounds are in particular of potential use in the treatment of e.g. eating disorders, drinking disorders, sleep disorders, or cognitive dysfunctions in psychiatric and neurologic disorders.
  • Piperidine derivatives useful as orexin receptor antagonists are disclosed in WO01/96302 and WO03/051368.
  • the present invention describes for the first time the exemplification of superior selected compounds not exemplified but generically disclosed and described in WOO 1/96302 and WO03/051368 as orexin receptor antagonists. i) In a first embodiment the invention relates to pyrrolidine- and piperidine-derivatives of formula (I)
  • Y represents (CH 2 ) n ; nrepresents 0 or 1;
  • R 1 represents an imidazothiazole-group selected from:
  • R 2 represents (C 1-4 )alkyl, bromine or -NH 2 ; and R 3 represents hydrogen or (d_ 4 )alkyl.
  • a dotted line shows the point of attachment of the radical drawn.
  • halogen means fluorine, chlorine, or bromine; preferably it means fluorine or chlorine.
  • (Ci_ 4 )alkyl alone or in combination, means a straight-chain or branched- chain alkyl group with 1 to 4 carbon atoms.
  • Examples of (Ci_ 4 )alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec. -butyl or tert.-butyl. Preferred are methyl and ethyl.
  • (Ci_ 4 )alkyl has the above meaning; preferably it means methyl.
  • (Ci_ 4 )alkyl has the above meaning; preferably it means methyl.
  • (Ci_ 4 )alkyl has the above meaning; preferably it means methyl and ethyl, especially methyl.
  • (Ci_4)alkoxy alone or in combination, means a group of the formula
  • (Ci_4)alkyl-O- in which the term "(Ci_4)alkyl” has the previously given significance, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.-butoxy or tert.-butoxy. Preferred are methoxy and ethoxy, most preferred is methoxy.
  • the combination “A-B” preferably means a biphenyl group which is unsubstituted or substituted with (Ci_4)alkyl for "A” (preferred: unsubstituted for "A”) and unsubstituted or mono-, di- or trisubstituted for "B", wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy, trifluoromethyl, cyano and halogen.
  • the biphenyl group is unsubstituted or mono- or disubstituted for "B", wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy, trifluoromethyl and halogen.
  • a biphenyl group which is unsubstituted or mono- or disubstituted for "B", wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy, and halogen.
  • biphenyl group which is unsubstituted or mono- or disubstituted for "B", wherein the substituents are independently from each other (Ci_ 4 )alkyl.
  • a biphenyl group which is unsubstituted or mono- or disubstituted for "B", wherein the substituents are methyl.
  • the biphenyl group is preferably unsubstituted or mono-substituted for "B”, wherein the substituent is selected from methyl, trifluoromethyl and halogen. Examples of the combination "A-B", wherein "A" and “B” both represent a "phenyl"-group are:
  • preferred examples are:
  • B as substituent for the above thiazolyl-group (wherein “B” is attached in position 5) represents phenyl, wherein the phenyl-ring is unsubstituted or mono- or di- or tri-substituted (preferably unsubstituted or mono- or di-substituted), wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl,
  • B as substituent for the above thiazolyl-group (wherein “B” is attached in position 4) represents phenyl, wherein the phenyl-ring is unsubstituted or mono- or di- or tri- substituted (preferably unsubstituted or mono- or di-substituted), wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy, trifluoromethyl, cyano, and halogen.
  • Preferred substituents are (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy, trifluoromethyl and halogen, especially (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy and halogen. Most preferred substituents are selected from halogen.
  • group "A” may be unsubstituted or monosubstituted, wherein the substituent is (Ci_4)alkyl.
  • the oxazolyl-group is monosubstituted, wherein the substituent is (Ci_ 4 )alkyl (preferred: methyl).
  • "B" as substituent for the oxazolyl- group represents phenyl, wherein the phenyl-ring is unsubstituted or mono- or di- or tri- substituted, wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy, trifluoromethyl, cyano, and halogen.
  • Preferred substituents are (Ci_ 4 )alkyl and halogen.
  • a further embodiment of the invention comprises compounds of formula (I) according to embodiment i), which are also compounds of formula (Ia), wherein the stereogenic center is in (S)-configuration
  • a further embodiment of the invention comprises compounds of formula (I) according to embodiments i) or ii), wherein B represents phenyl, wherein the phenyl- ring is unsubstituted or mono- or disubstituted, wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl, (d_ 4 )alkoxy, trifluoromethyl, and halogen.
  • a further embodiment of the invention comprises compounds of formula (I) according to embodiments i) or ii), wherein B represents phenyl, wherein the phenyl- ring is unsubstituted or mono- or disubstituted, wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl and halogen, v)
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to iv), wherein n represents 0.
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to iv), wherein n represents 1.
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to vi), wherein A represents a thiazolyl group selected from
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to vii), wherein A represents
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to vii), wherein A represents
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to vi), wherein A represents xi)
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to vi), wherein A represents xii)
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to xi), wherein R 1 represents an imidazothiazole-group selected from:
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to xii), wherein R 1 represents
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to xii), wherein R 1 represents
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to xi), wherein R 1 represents
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to xi), wherein R 1 represents
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to viii) and xii) to xvi), wherein R 2 represents (Ci_ 4 )alkyl.
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to viii) or xii) to xvi), wherein R 2 represents methyl.
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to viii) or xii) to xvi), wherein R 2 represents bromine.
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to viii) or xii) to xvi), wherein R 2 represents -NH 2 .
  • a further embodiment of the invention comprises compounds of formula (I) according to any one of embodiments i) to vii) or ix) to xvi), wherein R 3 represents (Ci_4)alkyl, preferably methyl.
  • R represents hydrogen.
  • the compounds of formula (I) and/or (Ia) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
  • the compounds of formula (I) and/or (Ia) may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
  • a further embodiment of the invention relates to compounds according to embodiment i) or ii), which are selected from the group consisting of:
  • 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid ((S)-I -[5-(3 ,4-dimethyl-phenyl)-2- methyl-thiazole-4-carbonyl]-piperidin-2-ylmethyl ⁇ -amide; 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid ((S)-l-[5-(3-bromo-4-fluoro- phenyl)-2-methyl-thiazole-4-carbonyl]-piperidin-2-ylmethyl ⁇ -amide;
  • 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid ((S)-I -[5-(2-chloro-phenyl)-2- methyl-thiazole-4-carbonyl]-piperidin-2-ylmethyl ⁇ -amide; 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid [(S)-l-(2-methyl-5-p-tolyl-thiazole-
  • 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid ((S)-I -[5-(2-methoxy-phenyl)-2- methyl-thiazole-4-carbonyl]-piperidin-2-ylmethyl ⁇ -amide; 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid ⁇ (S)-l-[5-(3-chloro-phenyl)-2- methyl-thiazole-4-carbonyl]-pyrrolidin-2-ylmethyl ⁇ -amide;
  • Imidazo[2, 1 -b]thiazole-5-carboxylic acid ((S)- 1 -[5-(3-fluoro-phenyl)-2-methyl- thiazole-4-carbonyl]-pyrrolidin-2-ylmethyl ⁇ -amide; Imidazo[2,l-b]thiazole-5-carboxylic acid [(S)-l-(2-methyl-5-phenyl-thiazole-4- carbonyl)-pyrrolidin-2-ylmethyl]-amide;
  • 6-Methyl-imidazo[2, 1 -b]thiazole-5-carboxylic acid ((S)- 1 -[2-methyl-5-(3- trifluoromethyl-phenyl)-thiazole-4-carbonyl]-piperidin-2-ylmethyl ⁇ -amide; 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid ((S)-l-[5-(4-fluoro-phenyl)-2- methyl-thiazole-4-carbonyl]-piperidin-2-ylmethyl ⁇ -amide;
  • 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid [(S)-l-(biphenyl-2-carbonyl)- piperidin-2-ylmethyl] -amide
  • 6-Methyl-imidazo[2, 1 -b]thiazole-5-carboxylic acid ((S)- 1 -[4-(3-fluoro-phenyl)-2- methyl-thiazole-5-carbonyl]-piperidin-2-ylmethyl ⁇ -amide;
  • 6-Methyl-imidazo[2, 1 -b]thiazole-5-carboxylic acid ((S)- 1 -[4-(4-fluoro-phenyl)-2- methyl-thiazole-5-carbonyl]-piperidin-2-ylmethyl ⁇ -amide; 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid [(S)-l-(4'-chloro-biphenyl-2- carbonyl)-pyrrolidin-2-ylmethyl]-amide;
  • 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid ((S)-I -[4-(4-chloro-phenyl)-2- methyl-thiazole-5-carbonyl]-pyrrolidin-2-ylmethyl ⁇ -amide; 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid ((S)-l-[4-(3-chloro-phenyl)-2- methyl-thiazole-5-carbonyl]-pyrrolidin-2-ylmethyl ⁇ -amide; and
  • 6-Methyl-imidazo[2, 1 -b]thiazole-5-carboxylic acid ((S)- 1 -[4-(3-fluoro-phenyl)-2- methyl-thiazole-5-carbonyl]-pyrrolidin-2-ylmethyl ⁇ -amide; wherein the first 15 compounds, in another embodiment the first 24 compounds, of the above list are especially preferred.
  • a further embodiment of the invention relates to compounds according to embodiment i) or ii), which are selected from the group consisting of:
  • any reference to a compound of formula (I) and/or (Ia) is to be understood as referring also to salts (especially pharmaceutically acceptable salts) of a compound of formula (I) and/or (Ia), respectively, as appropriate and expedient.
  • pharmaceutically acceptable salts refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.
  • the compounds of formula (I) and/or (Ia) and their pharmaceutically acceptable salts can be used as medicaments, e.g. in the form of pharmaceutical compositions for enteral or parenteral administration.
  • a further aspect of the invention is a pharmaceutical composition containing at least one compound according to formula (I) and/or (Ia), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier material.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the described compounds of formula (I) and/or (Ia) and their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • the compounds according to formula (I) and/or (Ia) may be used for the preparation of a medicament and are suitable for the prevention or treatment of diseases selected from the group consisting of dysthymic disorders including major depression and cyclothymia, affective neurosis, all types of manic depressive disorders, delirium, psychotic disorders, schizophrenia, catatonic schizophrenia, delusional paranoia, adjustment disorders and all clusters of personality disorders; schizoaffective disorders; anxiety disorders including generalized anxiety, obsessive compulsive disorder, posttraumatic stress disorder, panic attacks, all types of phobic anxiety and avoidance; separation anxiety; all psychoactive substance use, abuse, seeking and reinstatement; all types of psychological or physical addictions, dissociative disorders including multiple personality syndromes and psychogenic amnesias; sexual and reproductive dysfunction; psychosexual dysfunction and addiction; tolerance to narcotics or withdrawal from narcotics; increased anaesthetic risk, anaesthetic responsiveness; hypothalamic-adrenal dysfunctions; disturbed biological and circa
  • Compounds of formula (I) and/or (Ia) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of dysthymic, mood, psychotic and anxiety disorders; diabetes and appetite, taste, eating, or drinking disorders; hypothalamic diseases; disturbed biological and circadian rhythms; all types of sleep disorders; sleep disturbances associated with diseases such as neurological disorders including neuropathic pain and restless leg syndrome; insomnias related to psychiatric disorders; sleep apnea; narcolepsy; idiopathic insomnias; parasomnias; stress-related syndromes; benign prostatic hypertrophy; all types of psychoactive substance use and abuse; all dementias and cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders; and other diseases related to general orexin system dysfunctions.
  • diseases or disorders selected from the group consisting of dysthymic, mood, psychotic and anxiety disorders; diabetes and appetite, taste, eating, or drinking disorders; hypothalamic diseases; disturbed biological and circadian rhythms; all types of
  • Compounds of formula (I) and/or (Ia) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of all types of sleep disorders, of stress-related syndromes, of psychoactive substance use and abuse, of cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders, of eating or drinking disorders.
  • Eating disorders may be defined as comprising metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • Pathologically modified food intake may result from disturbed appetite (attraction or aversion for food); altered energy balance (intake vs.
  • Drinking disorders include polydipsias in psychiatric disorders and all other types of excessive fluid intake.
  • Sleep disorders include all types of parasomnias, insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias; restless leg syndrome; sleep apneas; jet- lag syndrome; shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • Insomnias are defined as comprising sleep disorders associated with aging; intermittent treatment of chronic insomnia; situational transient insomnia (new environment, noise) or short-term insomnia due to stress; grief; pain or illness.
  • Insomnia also include stress-related syndromes including post-traumatic stress disorders as well as other types and subtypes of anxiety disorders such as generalized anxiety, obsessive compulsive disorder, panic attacks and all types of phobic anxiety and avoidance; psychoactive substance use, abuse, seeking and reinstatement are defined as all types of psychological or physical addictions and their related tolerance and dependence components.
  • Cognitive dysfunctions include deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • compounds of formula (I) and/or (Ia) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of sleep disorders that comprises all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias, restless leg syndrome, sleep apneas, jet-lag syndrome, shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • sleep disorders that comprises all types of insomnias, narcolepsy and other disorders of excessive sleepiness, sleep-related dystonias, restless leg syndrome, sleep apneas, jet-lag syndrome, shift-work syndrome, delayed or advanced sleep phase syndrome or insomnias related to psychiatric disorders.
  • compounds of formula (I) and/or (Ia) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of cognitive dysfunctions that comprise deficits in all types of attention, learning and memory functions occurring transiently or chronically in the normal, healthy, young, adult or aging population, and also occurring transiently or chronically in psychiatric, neurologic, cardiovascular and immune disorders.
  • compounds of formula (I) and/or (Ia) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of eating disorders that comprise metabolic dysfunction; dysregulated appetite control; compulsive obesities; emeto-bulimia or anorexia nervosa.
  • compounds of formula (I) and/or (Ia) are particularly suitable for use in the treatment of diseases or disorders selected from the group consisting of psychoactive substance use and abuse that comprise all types of psychological or physical addictions and their related tolerance and dependence components.
  • the present invention also relates to a method for the prevention or treatment of a disease or disorder mentioned herein comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) and/or (Ia).
  • X plus 10% of X and preferably to an interval extending from X minus 5% of X to X plus 5% of X.
  • the term "about” placed before a temperature "Y” refers in the current application to an interval extending from the temperature Y minus 1O 0 C to Y plus 1O 0 C, and preferably to an interval extending from Y minus 5 0 C to Y plus 5 0 C.
  • a further aspect of the invention is a process for the preparation of compounds of formula (I).
  • Compounds according to formula (I) of the present invention can be prepared according to the general sequence of reactions outlined in the schemes below wherein A, B, Y, R 1 , R 2 and R 3 are as defined in the description of formula (I).
  • the compounds obtained may also be converted into pharmaceutically acceptable salts thereof in a manner known per se.
  • Scheme I Synthesis of compounds of formula (I) wherein A, Y and R 1 are as defined above.
  • Pathway 1 The synthesis of the final compounds started from N-Boc-protected-2- aminomethylazacycloalkane derivatives 1 (commercially available in racemic or enatiomerically pure form), which were coupled with carboxylic acid derivatives 2 (either commercially available or prepared as described in scheme 5 below, and in I-Chemistry, Section A.1.9.1 to A.1.9.4) under standard peptide coupling reaction conditions in the presence of an activating reagent (e.g. TBTU) and a base (e.g. DIPEA) to give the mono-amide intermediates 3.
  • an activating reagent e.g. TBTU
  • DIPEA e.g. DIPEA
  • the bis-amide final compounds 6 were prepared by a second amide bond formation reaction under comparable conditions as described above by using the carboxylic acid derivatives 5 (either commercially available or prepared as described in Schemes 2 to 4 and in I-Chemistry, Section A.1.1 to A.1.8).
  • Pathway 2 The sequence can be inverted by starting from the template 7 (commercially available in racemic or enatiomerically pure form), Boc-protected at the exocyclic N- atom by first introducing the substituent at the endocyclic N-atom in a standard peptide bond forming reaction with the carboxylic acid derivatives 5 (either commercially available or prepared as described in Schemes 2 to 4 and in I-Chemistry, Section A.1.1 to A.1.8) to give compound 8 which after deprotection to 9 led in a final amide bond forming step with carboxylic acid derivatives 2 to the final compounds 6.
  • the template 7 commercially available in racemic or enatiomerically pure form
  • Boc-protected at the exocyclic N- atom by first introducing the substituent at the endocyclic N-atom in a standard peptide bond forming reaction with the carboxylic acid derivatives 5 (either commercially available or prepared as described in Schemes 2 to 4 and in I-Chemistry, Section A.1.1 to
  • Carboxylic acid derivatives A-COOH if not commercially available, were for example synthesized according to scheme 2 to scheme 4.
  • Cyclization to the oxazole was achieved under dehydrating conditions (e.g. SOCl 2 in chloroform) to give the oxazole-derivative 23, which was transformed to the 5-aryl-oxazole-4-carboxylic acid derivative 24 by esterhydrolyis under basic conditions with e.g. NaOH in EtOH/water-mixtures.
  • dehydrating conditions e.g. SOCl 2 in chloroform
  • Biphenyl-carboxylic acid derivatives such as the following examples used to prepare final compounds:
  • the enantiomers can be separated using methods known to one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m) or AD-H (5 ⁇ m) column.
  • a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m) or AD-H (5 ⁇ m) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as triethylamine, diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
  • 3-chloro-3-(4-ethyl-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 4-ethyl-benzaldehyde with methyl dichloroacetate.
  • 3-chloro-3-(3-fluoro-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 3-fluoro-benzaldehyde with methyl dichloroacetate.
  • 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 4-fluoro-benzaldehyde with methyl dichloroacetate.
  • 3-chloro-3-(4-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 4-trifluoromethyl-benzaldehyde with methyl dichloro-acetate.
  • 3-chloro-3-(2-fluoro-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 2-fluoro-benzaldehyde with methyl dichloro-acetate.
  • 3-chloro-3-(2-chloro-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 2-chloro-benzaldehyde with methyl dichloro-acetate.
  • 3-chloro-3-(3-chloro-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 3-chloro-benzaldehyde with methyl dichloro-acetate.
  • 3-chloro-2-oxo-3-o-tolyl-propionic acid methyl ester prepared by reaction of 2-methyl-benzaldehyde with methyl dichloro-acetate.
  • 3-chloro-3-(2-methoxy-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 2-methoxy-benzaldehyde with methyl dichloro-acetate.
  • 3-chloro-3-(3-methoxy-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 3-methoxy-benzaldehyde with methyl dichloro-acetate.
  • 3-chloro-2-oxo-3-(2-trifluoromethyl-phenyl)-propionic acid methyl ester prepared by reaction of 2-trifluoromethyl-benzaldehyde with methyl dichloro-acetate.
  • 3-chloro-2-oxo-3-(3-trifluoromethyl-phenyl)-propionic acid methyl ester prepared by reaction of 3-trifluoromethyl-benzaldehyde with methyl dichloro-acetate.
  • 2-amino-5-m-tolyl-thiazole-4-carboxylic acid prepared by saponification of 2-amino-5-m-tolyl-thiazole-4-carboxylic acid methyl ester.
  • 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid prepared by saponification of 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid methyl ester.
  • 2-methyl-4-aryl-thiazole-5-carboxylic acid ethyl ester derivative (0.42 mmol, 1 eq) was dissolved in EtOH (1 ml) and water (0.26 ml) followed by the addition of KOH (0.84 mmol, 2 eq). The mixture was stirred at reflux temperature for 3 h, concentrated under reduced pressure followed by the addition of ice/water. The solution was acidified to pH ca. 3 by the addition of aq. HCl (1 M). The product precipitated and was filtered off, washed with water and dried under high vacuum.
  • STEP 2 The oxime derivative (4.36 mmol, 1 eq) prepared in STEP 1 was dissolved in a mixture of acetic anhydride (1.25 ml) and acetic acid (1.65 ml) followed by the addition of sodium acetate (0.266 mmol, 0.061 eq), mercury(II)chloride (0.009 mmol, 0.002 eq) and zinc powder (13.1 mmol, 3 eq). The resulting reaction mixture was refluxed for 1 h, cooled again to rt and filtered. The cake was washed with ether. The organic filtrate was washed with water and 1 M K2CO3 solution and dried over magnesium sulphate, filtered and concentrated under reduced pressure. The product was purified by FC (heptane / EtOAc 9/1 to 2/3).
  • STEP 3 The acetamide derivative (1.84 mmol, 1 eq) prepared in STEP 2 was dissolved in chloroform (1.1 ml) and cooled to 0 0 C, followed by the addition of thionyl chloride (2.21 mmol, 1.2 eq). Stirring at 0 0 C was continued for 30 min. Then the reaction mixture was heated to reflux for 1 h, cooled again to rt and 1 M K2CO3 solution (5 ml) was added. The product was extracted with ether (2x 5 ml). The combined organic layers were washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure. The oxazole-ethylester derivatives were used in STEP 4 without further purification.
  • the oxazole-ethylester derivative (0.975 mmol, 1 eq) prepared in STEP 3 was dissolved in EtOH (1.1 ml) followed by the addition of 2 N NaOH solution (1.1 ml). Stirring at rt was continued for 2 h followed by the addition of water to the reaction mixture and extraction with ether. The aq. phase was then acidified to pH 2 to 3 by the addition of cone, hydrochloric acid and extracted with ether. The combined organic layers were dried over magenisum sulphate, filtered and concentrated under reduced pressure to give the oxazole-carboxylic acid as solid material.
  • 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid (2.0 g, 10.975 mmol) was dissolved in MeCN (35 ml), TBTU (3.52 g, 10.975 mmol) was added followed by the addition of DIPEA (2.82 ml, 16.462 mmol) and a solution of (S)-2-aminomethyl-piperidine-l- carboxylic acid tert-butyl ester (2.35 g, 10.975 mmol) in MeCN (20 ml). Stirring at rt was continued for 20 h. The reaction mixture was concentrated under reduced pressure, again diluted with EtOAc and subsequently washed with a sat.
  • Example 2 By applying the same reaction sequence and varying the substituents, Examples 2 to 19 could be prepared:
  • 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid (1.73 g, 9.5 mmol) were dissolved in DMF (20 ml) followed by the addition of PyBOP (4.94 g, 9.5 mmol) and DIPEA (2.82 g, 22 mmol). Stirring was continued for 30 min at rt.
  • (S)-2-Aminomethyl- pyrrolidine- 1-carboxylic acid tert-butyl ester (1.94 g, 9.5 mmol) was added and stirring was continued at rt for 20 h.
  • the reaction mixture was diluted with EtOAc (110 ml) and subsequently extracted with 1 M hydrochloric acid (30 ml), sat.
  • 6-Methyl-imidazo[2,l-b]thiazole-5-carboxylic acid 29 mg, 0.159 mmol was dissolved in DMF (0.5 ml).
  • TBTU 56 mg, 0.175 mmol
  • DIPEA 31 mg, 0.239 mmol
  • a solution of (S)-(2-aminomethyl- pyrrolidin-l-yl)-(2-methyl-5-phenyl-thiazol-4-yl)-methanone 48 mg, 0.159 mmol
  • DMF 0.5 ml
  • the mixture was concentrated under reduced pressure.
  • Examples 21 to 65 could be prepared:
  • the orexin receptor antagonistic activity of the compounds of formula (I) is determined in accordance with the following experimental method.
  • Chinese hamster ovary (CHO) cells expressing the human orexin- 1 receptor and the human orexin-2 receptor, respectively, are grown in culture medium (Ham F- 12 with L- Glutamine) containing 300 ⁇ g/ml G418, 100 U/ml penicillin, 100 ⁇ g/ml streptomycin and 10 % inactivated fetal calf serum (FCS).
  • FCS fetal calf serum
  • the cells are seeded at 80O00 cells / well into 96-well black clear bottom sterile plates (Costar) which have been precoated with 1% gelatine in Hanks' Balanced Salt Solution (HBSS). All reagents are from Gibco BRL.
  • the seeded plates are incubated overnight at 37°C in 5% CO 2 .
  • Human orexin- A as an agonist is prepared as 1 mM stock solution in MeOH: water (1 :1), diluted in HBSS containing 0.1 % bovine serum albumin (BSA) and 2 mM HEPES for use in the assay at a final concentration of 10 nM.
  • BSA bovine serum albumin
  • Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 96-well plates, first in DMSO, then in HBSS containing 0.1 % bovine serum albumin (BSA) and
  • BSA bovine serum albumin
  • the 96-well plates are incubated for 60 min at 37° C in 5% CO 2 .
  • the loading solution is then aspirated and cells are washed 3 times with 200 ⁇ l HBSS containing 2.5 mM probenecid, 0.1% BSA, 2 mM HEPES. 100 ⁇ l of that same buffer is left in each well.
  • antagonists are added to the plate in a volume of 50 ⁇ l, incubated for 20 min and finally 100 ⁇ l of agonist is added. Fluorescence is measured for each well at 1 second intervals, and the height of each fluorescence peak is compared to the height of the fluorescence peak induced by 10 nM orexin-A with buffer in place of antagonist. For each antagonist, IC 50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined.
  • Antagonistic activities (IC 50 values) of all exemplified compounds are in the range of 1.0-682 nM with an average of 22 nM with respect to the OXl receptor and in the range of 1.5-343 nM with an average of 21 nM with respect to the OX2 receptor. Antagonistic activities of selected compounds are displayed in Table 1.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

L'invention concerne des dérivés de pyrrolidine et de piperidine représentés par la formule (I), dans laquelle Y représente (CH2)n ; n représente 0 ou 1; A représente (Ibis); B représente phényle, où le noyau phényle est non substitué ou monosubstitué ou bisubstitué ou trisubstitué, les substituants étant sélectionnés indépendamment du groupe constitué par (C1-4)alkyle, (C1-4)alcoxy, trifluorométhyle, cyano, et halogène; R1 représente un groupe imidazothiazole sélectionné dans le groupe constitué par (IIbis); R2 représente (C1-4)alkyle, bromure ou -NH2; et R3 représente hydrogène ou (C1-4)alkyle; et l'utilisation de ces dérivés. L'invention concerne également des sels pharmaceutique mentacceptables de ces dérivés, lesditsdérivés étant utilisés comme médicaments et, en particulier, comme antagonistes des récepteurs de l'orexine.
PCT/IB2008/050192 2007-01-19 2008-01-18 Dérivés de pyrrolidine et de piperidine WO2008087611A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IBPCT/IB2007/050180 2007-01-19
IB2007050180 2007-01-19

Publications (2)

Publication Number Publication Date
WO2008087611A2 true WO2008087611A2 (fr) 2008-07-24
WO2008087611A3 WO2008087611A3 (fr) 2009-06-04

Family

ID=39636451

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2008/050192 WO2008087611A2 (fr) 2007-01-19 2008-01-18 Dérivés de pyrrolidine et de piperidine

Country Status (1)

Country Link
WO (1) WO2008087611A2 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011073316A1 (fr) * 2009-12-18 2011-06-23 Novartis Ag 4-aryl-butane-1,3-diamides
WO2013182972A1 (fr) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Dérivés de benzimidazole-proline
WO2014057435A1 (fr) 2012-10-10 2014-04-17 Actelion Pharmaceuticals Ltd Antagonistes des récepteurs de l'orexine, qui sont des dérivés [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone
WO2014141065A1 (fr) 2013-03-12 2014-09-18 Actelion Pharmaceuticals Ltd Dérivés d'amide d'azétidine en tant qu'antagonistes des récepteurs d'oréxine
JP2015506382A (ja) * 2012-02-07 2015-03-02 エオラス セラピューティクス， インコーポレイテッド オレキシンレセプターアンタゴニストとしての置換プロリン／ピペリジン
WO2015083071A1 (fr) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Forme de sel cristalline de (s)-(2-(6-chloro-7-méthyl-1 h-benzo[d]imidazol- 2-yl)-2-méthylpyrrolidin-1-yl)(5-méthoxy-2-(2h-1,2,3-triazol-2-yl)phényl)méthanone comme antagoniste des récepteurs à l'oréxine
WO2015083070A1 (fr) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Forme cristalline de (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone et utilisation de celle-ci en tant qu'antagonistes des recepteurs de l'orexine
WO2015083094A1 (fr) 2013-12-04 2015-06-11 Actelion Pharmaceuticals Ltd Utilisation de dérivés de benzimidazole-proline
JP2015522622A (ja) * 2012-07-18 2015-08-06 モラスキ，ギャレット ５，５−ヘテロ芳香族抗感染症化合物
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
WO2020007964A1 (fr) 2018-07-05 2020-01-09 Idorsia Pharmaceuticals Ltd Dérivés de 2-(2-azabicyclo [3.1.0] hexan-1-yl)-1h-benzimidazole
WO2020099511A1 (fr) 2018-11-14 2020-05-22 Idorsia Pharmaceuticals Ltd Dérivés de benzimidazole-2-méthyl-morpholine
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
WO2023218023A1 (fr) 2022-05-13 2023-11-16 Idorsia Pharmaceuticals Ltd Dérives d'hydrazine-n-carboxamide cycliques substitués par thiazoloaryl-méthyle

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096302A1 (fr) * 2000-06-16 2001-12-20 Smithkline Beecham P.L.C. Piperidines utiles en tant qu'antagonistes du recepteur d'orexine
WO2003041711A1 (fr) * 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives bis-amide de piperazine et leur utilisation en tant qu'antagonistes du recepteur d'orexine
WO2003051368A1 (fr) * 2001-12-19 2003-06-26 Smithkline Beecham Plc Derives d'amine cyclique n-aroyle utilises en tant qu'antagonistes du recepteur d'orexine
WO2004041791A1 (fr) * 2002-11-06 2004-05-21 Glaxo Group Limited Derives d'amine cyclique n-aryle acetyle utilises comme antagonistes de l'orexine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001096302A1 (fr) * 2000-06-16 2001-12-20 Smithkline Beecham P.L.C. Piperidines utiles en tant qu'antagonistes du recepteur d'orexine
WO2003041711A1 (fr) * 2001-11-10 2003-05-22 Smithkline Beecham P.L.C. Derives bis-amide de piperazine et leur utilisation en tant qu'antagonistes du recepteur d'orexine
WO2003051368A1 (fr) * 2001-12-19 2003-06-26 Smithkline Beecham Plc Derives d'amine cyclique n-aroyle utilises en tant qu'antagonistes du recepteur d'orexine
WO2004041791A1 (fr) * 2002-11-06 2004-05-21 Glaxo Group Limited Derives d'amine cyclique n-aryle acetyle utilises comme antagonistes de l'orexine

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011073316A1 (fr) * 2009-12-18 2011-06-23 Novartis Ag 4-aryl-butane-1,3-diamides
EP2811997A4 (fr) * 2012-02-07 2015-07-22 Eolas Therapeutics Inc Pipéridines/prolines substituées en tant qu'antagonistes du récepteur de l'orexine
US9440982B2 (en) 2012-02-07 2016-09-13 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
JP2015506382A (ja) * 2012-02-07 2015-03-02 エオラス セラピューティクス， インコーポレイテッド オレキシンレセプターアンタゴニストとしての置換プロリン／ピペリジン
US9896452B2 (en) 2012-02-07 2018-02-20 Eolas Therapeutics, Inc. Substituted prolines/piperidines as orexin receptor antagonists
US9499517B2 (en) 2012-02-07 2016-11-22 Eolas Therapeutics, Inc. Substituted prolines / piperidines as orexin receptor antagonists
US9732075B2 (en) 2012-06-04 2017-08-15 Idorsia Pharmaceuticals Ltd Benzimidazole-proline derivatives
US10329287B2 (en) 2012-06-04 2019-06-25 Idorsia Pharmaceuticals Ltd Benzimidazole-proline derivatives
WO2013182972A1 (fr) 2012-06-04 2013-12-12 Actelion Pharmaceuticals Ltd Dérivés de benzimidazole-proline
US11040966B2 (en) 2012-06-04 2021-06-22 Idorsia Pharmaceuticals Ltd Benzimidazole-proline derivatives
JP2015522622A (ja) * 2012-07-18 2015-08-06 モラスキ，ギャレット ５，５−ヘテロ芳香族抗感染症化合物
EP2875029A4 (fr) * 2012-07-18 2016-03-02 Garrett Moraski Composés anti-infectieux 5,5-hétéroaromatiques
US9605002B2 (en) 2012-07-18 2017-03-28 University Of Notre Dame Du Lac 5,5-heteroaromatic anti-infective compounds
US9493446B2 (en) 2012-10-10 2016-11-15 Actelion Pharmaceuticals Ltd. Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
WO2014057435A1 (fr) 2012-10-10 2014-04-17 Actelion Pharmaceuticals Ltd Antagonistes des récepteurs de l'orexine, qui sont des dérivés [ortho bi (hetero )aryl]-[2-(meta bi (hetero )aryl)-pyrrolidin-1-yl]-methanone
US9403813B2 (en) 2013-03-12 2016-08-02 Actelion Pharmaceuticals Ltd. Azetidine amide derivatives as orexin receptor antagonists
WO2014141065A1 (fr) 2013-03-12 2014-09-18 Actelion Pharmaceuticals Ltd Dérivés d'amide d'azétidine en tant qu'antagonistes des récepteurs d'oréxine
US10023560B2 (en) 2013-12-03 2018-07-17 Idorsia Pharmaceuticals Ltd Crystalline salt form of (S)-(2-(6 chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone as orexin receptor antagonist
US9790208B2 (en) 2013-12-03 2017-10-17 Idorsia Pharmaceuticals Ltd Crystalline salt form of (S)-(2-(6-chloro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone as orexin receptor antagonist
US9914720B2 (en) 2013-12-03 2018-03-13 Idorsia Pharmaceuticals Ltd Crystalline form of (S)-(2-(6-chloro-7-methyl-1H-benzo[D]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and its use as orexin receptor antagonists
WO2015083070A1 (fr) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Forme cristalline de (s)-(2-(6-chloro-7-methyl-1h-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1 -yl)(5-methoxy-2-(2h-1,2,3-triazol-2-yl)phenyl)methanone et utilisation de celle-ci en tant qu'antagonistes des recepteurs de l'orexine
WO2015083071A1 (fr) 2013-12-03 2015-06-11 Actelion Pharmaceuticals Ltd Forme de sel cristalline de (s)-(2-(6-chloro-7-méthyl-1 h-benzo[d]imidazol- 2-yl)-2-méthylpyrrolidin-1-yl)(5-méthoxy-2-(2h-1,2,3-triazol-2-yl)phényl)méthanone comme antagoniste des récepteurs à l'oréxine
US9914721B2 (en) 2013-12-04 2018-03-13 Idorsia Pharmaceuticals Ltd Use of benzimidazole-proline derivatives
WO2015083094A1 (fr) 2013-12-04 2015-06-11 Actelion Pharmaceuticals Ltd Utilisation de dérivés de benzimidazole-proline
US10221170B2 (en) 2014-08-13 2019-03-05 Eolas Therapeutics, Inc. Difluoropyrrolidines as orexin receptor modulators
US10894789B2 (en) 2016-02-12 2021-01-19 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
US11434236B2 (en) 2016-02-12 2022-09-06 Astrazeneca Ab Halo-substituted piperidines as orexin receptor modulators
WO2020007964A1 (fr) 2018-07-05 2020-01-09 Idorsia Pharmaceuticals Ltd Dérivés de 2-(2-azabicyclo [3.1.0] hexan-1-yl)-1h-benzimidazole
WO2020099511A1 (fr) 2018-11-14 2020-05-22 Idorsia Pharmaceuticals Ltd Dérivés de benzimidazole-2-méthyl-morpholine
WO2023218023A1 (fr) 2022-05-13 2023-11-16 Idorsia Pharmaceuticals Ltd Dérives d'hydrazine-n-carboxamide cycliques substitués par thiazoloaryl-méthyle

Also Published As

Publication number Publication date
WO2008087611A3 (fr) 2009-06-04

Similar Documents

Publication Publication Date Title
EP2155739B1 (fr) Dérivés de 2-cyclopropyl-thiazole
US8133901B2 (en) 3-heteroaryl (amino or amido)-1-(biphenyl or phenylthiazolyl) carbonylpiperidine derivatives as orexin receptor inhibitors
EP2318367B1 (fr) Composés de pipéridine et de pyrrolidine
WO2008087611A2 (fr) Dérivés de pyrrolidine et de piperidine
US8288411B2 (en) Pyrrolidines and piperidines as orexin receptor antagonists
EP2164847B1 (fr) Composés 3-aza-bicyclo[3.3.0]octane
US8288429B2 (en) 2-aza-bicyclo[3.3.0]octane derivatives
US8236964B2 (en) Thiazolidine derivatives as orexin receptor antagonists
EP2185512B1 (fr) Dérivés de trans-3-aza-bicyclo[3.1.0]hexane
EP2188282B1 (fr) Dérivés du 1,2-diamido-éthylène comme antagonistes d'orexine
CA2669821A1 (fr) Derives 2-aza-bicyclo[3.1.0]hexane
WO2009104155A1 (fr) Dérivés de 2-aza-bicyclo[2.2.1]heptane
EP2069332A2 (fr) Composés d'azétidine en tant qu'antagonistes du recepteur orexin

Legal Events

Date Code Title Description
NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08702467

Country of ref document: EP

Kind code of ref document: A2