WO2009133522A1 - Piperidine and pyrrolidine compounds - Google Patents
Piperidine and pyrrolidine compounds Download PDFInfo
- Publication number
- WO2009133522A1 WO2009133522A1 PCT/IB2009/051735 IB2009051735W WO2009133522A1 WO 2009133522 A1 WO2009133522 A1 WO 2009133522A1 IB 2009051735 W IB2009051735 W IB 2009051735W WO 2009133522 A1 WO2009133522 A1 WO 2009133522A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- piperidin
- carbonyl
- methyl
- carboxylic acid
- biphenyl
- Prior art date
Links
- 0 *OC(c1c(B(O)O)cccc1)=O Chemical compound *OC(c1c(B(O)O)cccc1)=O 0.000 description 4
- QARVLSVVCXYDNA-UHFFFAOYSA-N Brc1ccccc1 Chemical compound Brc1ccccc1 QARVLSVVCXYDNA-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D211/56—Nitrogen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Definitions
- the present invention relates to novel piperidine and pyrrolidine compounds of formula (I) 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 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 the 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). On the other hand, it was also observed that orexins regulate states of sleep and wakefulness opening potentially novel therapeutic approaches to narcolepsy as well as insomnia and other sleep disorders (Chemelli R.M. et al, Cell, 1999, 98, 437-451).
- Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as dysthymic, mood, psychotic and anxiety disorders; diabetes and appetite, taste, eating, or drinking disorders; hypothalamic diseases; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; insomnias related to psychiatric disorders; sleep apnea; narcolepsy; idiopathic insomnias; parasomnias; benign prostatic hypertrophy; all dementias and cognitive dysfunctions in the healthy population and in psychiatric and neurologic disorders; and other diseases related to general orexin system dysfunctions.
- pathologies such as dysthymic, mood, psychotic and anxiety disorders; diabetes and appetite, taste, eating, or drinking disorders; hypothalamic diseases; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; insomnias related to psychiatric disorders; sleep apne
- the present invention provides piperidine and pyrrolidine 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 WO01/096302.
- Nitrogenous heterocyclic compounds useful for a disease for which sodium channel inhibition is effective are described in EP 1484327.
- 1,3-Substituted cycloamino derivatives useful as histamine-3 receptor antagonists are described in WO 2006/011042.
- the present invention consists of compounds of formula (I)
- A represents a phenyl-group, wherein the phenyl is unsubstituted, or mono-substituted with (Ci_ 4 )alkyl; or A represents
- B represents phenyl, which is unsubstituted, or mono-, 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;
- n the integer 0 or 1 ;
- X represents -NH-R 1 or -NH-C(O)-R 2 ;
- R 1 represents heteroaryl, wherein said heteroaryl is selected from the group consisting of pyrimidinyl, which is mono-, or di-substituted, wherein the substituents are independently selected from (Ci_ 4 )alkoxy, trifluoromethyl, (Ci_ 4 )alkyl-thio-, and (Ci_ 4 )alkoxy-carbonyl-, or which is di-substituted, wherein one substituent is methyl and the other substituent is selected from (Ci_ 4 )alkoxy, trifluoromethyl, (Ci_ 4 )alkyl- thio-, and (Ci_ 4 )alkoxy-carbonyl-; pyridinyl which is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (Ci_4)alkyl, (Ci_ 4 )alkoxy, trifluoromethyl, halogen, (Ci_ 4 )alky
- R 2 represents heterocyclyl, wherein said heterocyclyl is selected from the group consisting of 2,3-dihydro-benzo[l,4]dioxinyl, 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolyl, 4H-benzo[l,3]dioxinyl, 2H-chromenyl, and chromanyl.
- the compounds of formula (I) may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms.
- the compounds of formula (I) 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.
- an arrow shows the point of attachment of the radical drawn.
- a phenyl group as used for the substituent "B” is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy, trifluoromethyl and halogen.
- the substituents are independently selected from the group consisting of methyl, methoxy, trifluoromethyl, fluorine and chlorine.
- Examples are phenyl, 2-methyl-phenyl, 3-methyl-phenyl, 4-methyl-phenyl, 3,4-dimethylphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 4-fluorophenyl, 3- fluorophenyl, 2-fluorophenyl, 3-fluoro-4-methylphenyl, 3-trifluoromethylphenyl, 3- chlorophenyl, 3-bromophenyl, 3-fluoro-5-trifluoromethylphenyl, and 4-cyanophenyl.
- examples are 3-methyl-phenyl, 3,4-dimethylphenyl, and 4-fluorophenyl.
- the combination “A-B” preferably means a biphenyl group (especially a biphen-2-yl group) which is unsubstituted for "A” and unsubstituted, or mono-, di- or tri-substituted (preferably mono-, or di-substituted) for "B", wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl, (d_ 4 )alkoxy, trifluoromethyl and halogen, especially from (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy and halogen. Further preferred examples of substituents for "B” are methyl and methoxy (notably methyl).
- the 2-cyclopropyl-thiazolyl-group as defined for group "A”, is also substituted by the substituent "B", whereby B is attached in ortho position to the point of attachment of the carbonyl group which links A to the rest of the molecule.
- R 1 represents "heteroaryl” are pyrimidin-2-yl, which is mono-, or di-substituted, wherein the substituents are independently selected from (Ci_ 4 )alkoxy, trifluoromethyl, (Ci_ 4 )alkyl-thio-, and (Ci_ 4 )alkoxy-carbonyl- (notably from (Ci_4)alkoxy and trifluoromethyl), or which is di-substituted, wherein one substituent is methyl and the other substituent is selected from (Ci_ 4 )alkoxy, trifluoromethyl, (Ci_4)alkyl-thio-, and (Ci_4)alkoxy-carbonyl- (notably (Ci_4)alkoxy- carbonyl-); pyridin-2-yl and pyridin-3-yl which groups are unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (Ci_ 4 )al
- R 1 representing "heteroaryl” are selected from:
- R 1 representing "heteroaryl” are selected from:
- R 2 represents "heteroaryl” are pyrazol-3-yl, indol-3-yl, indazol- 3-yl, benzisoxazol-3-yl, quinolin-8-yl, isoquinolin-1-yl, imidazo[l,2-a]pyridine-3-yl, lH-pyrrolo[3,2-b]pyridin-4-yl, lH-pyrrolo[2,3-b]pyridin-4-yl, lH-pyrrolo[2,3-b] pyridin-5-yl, and 2,3-dihydro-thieno[3,4-b][l,4]dioxin-5-yl; wherein the above- mentioned groups are independently unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (Ci_ 4 )alkyl.
- heteroaryl groups as used for the substituent "R 2 " are preferably substituted as follows: pyrazolyl groups are di-substituted, wherein both substituents are independently selected from (Ci_ 4 )alkyl; indolyl and indazolyl groups are mono-substituted (notably on a nitrogen atom) with (Ci_4)alkyl (especially methyl); benzisoxazolyl, quinolinyl, isoquinolinyl, imidazo[l,2-a]pyridyl, pyrrolopyridyl, and 2,3-dihydro-thieno[3,4-b][l,4]dioxinyl groups are unsubstituted.
- R 2 representing "heteroaryl” are selected from:
- R 2 represents "phenyl, which is di-substituted, wherein the substituents are independently selected from (Ci_4)alkyl and halogen" are 3-chloro- 2-methyl-phenyl, 3-fluoro-2-methylphenyl, and 2,3-dimethylphenyl.
- heterocyclyl alone or in combination, means a phenyl ring fused to a saturated or partially unsaturated 5- to 6-membered ring containing 1 or 2 heteroatoms independently selected from oxygen and nitrogen; wherein the phenyl ring carries the point of attachment to the rest of the molecule.
- heterocyclyl as used for the substituent “R 2 " are 2,3-dihydro-benzo[l,4]dioxinyl, 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolyl, 4H-benzo[l,3]dioxinyl, 2H-chromenyl, and chromanyl.
- halogen means fluorine, chlorine, or bromine, preferably fluorine or chlorine.
- (Ci_ 4 )alkyl 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. Most preferred is methyl.
- (Ci_4)alkoxy means a group of the formula (Ci_4)alkyl-0- 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.
- a further embodiment of the invention relates to compounds of formula (I) according to embodiment i) which are also compounds of formula (Ia), wherein the stereogenic center in position 3 of the piperidine or pyrrolidine ring is in absolute (R)-configuration:
- a further embodiment of the invention relates to compounds of formula (I) according to embodiments i) or ii), wherein A represents a phenyl-group, wherein the phenyl is unsubstituted (preferred), or mono-substituted with (Ci_4)alkyl.
- a further embodiment of the invention relates to compounds of formula (I) according to embodiments i) or ii), wherein A represents
- a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments i) to iv), wherein B represents phenyl, which is unsubstituted, or mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy, trifluoromethyl and halogen.
- B represents phenyl, which is mono-, or di- substituted, wherein the substituents are independently selected from the group consisting of methyl and methoxy (notably methyl).
- a further embodiment of the invention relates to compounds of formula (I) according to embodiment iv), wherein B represents phenyl, which is unsubstituted, or (preferred) mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of methyl, methoxy, trifluoromethyl, fluorine and chlorine (notably methyl and fluorine).
- B represents phenyl, which is unsubstituted, or (preferred) mono-, or di-substituted, wherein the substituents are independently selected from the group consisting of methyl, methoxy, trifluoromethyl, fluorine and chlorine (notably methyl and fluorine).
- viii) A further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments i) to vii), wherein n represents the integer 0.
- n represents the integer 1.
- a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments i) to ix), wherein X represents -NH-R 1 .
- a further embodiment of the invention relates to compounds of formula (I) according to any one of embodiments i) to ix), wherein X represents -NH-C(O)-R 2 .
- xii) A further embodiment of the invention relates to compounds of formula (I) according to embodiment x), wherein R 1 is selected from the group consisting of:
- a further embodiment of the invention relates to compounds of formula (I) according to embodiment x), wherein R 1 is selected from the group consisting of:
- a further embodiment of the invention relates to compounds of formula (I) according to embodiment xi), wherein
- R 2 represents phenyl, which is di-substituted (notably in position 2 and 3), wherein the substituents are independently selected from (Ci_ 4 )alkyl and halogen.
- xv) A further embodiment of the invention relates to compounds of formula (I) according to embodiment xi), wherein
- R 2 represents heteroaryl, wherein said heteroaryl is selected from the group consisting of pyrazolyl, indolyl, indazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazo[l,2-a]pyridyl, lH-pyrrolopyridyl (notably lH-pyrrolo[3,2-b]pyridyl and IH- pyrrolo[2,3-b]pyridyl), and 2,3-dihydro-thieno[3,4-b][l,4]dioxinyl; wherein said groups are independently unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (Ci_ 4 )alkyl; or
- R 2 represents heterocyclyl, wherein said heterocyclyl is selected from the group consisting of 2,3-dihydro-benzo[l,4]dioxinyl, 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolyl, 4H-benzo[l,3]dioxinyl, 2H-chromenyl, and chromanyl (notably 2,3-dihydro-benzo[ 1 ,4]dioxinyl).
- heterocyclyl is selected from the group consisting of 2,3-dihydro-benzo[l,4]dioxinyl, 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolyl, 4H-benzo[l,3]dioxinyl, 2H-chromenyl, and chromanyl (notably 2,3-dihydro-benzo[ 1 ,4]dioxinyl).
- a further embodiment of the invention relates to compounds of formula (I) according to embodiment xi) or xv), wherein R 2 represents heterocyclyl, wherein said heterocyclyl is selected from the group consisting of 2,3-dihydro-benzo[l,4]dioxinyl, 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolyl, 4H-benzo[l,3]dioxinyl, 2H-chromenyl, and chromanyl (notably 2,3-dihydro-benzo[ 1 ,4]dioxinyl).
- R 2 represents heterocyclyl, wherein said heterocyclyl is selected from the group consisting of 2,3-dihydro-benzo[l,4]dioxinyl, 2,3-dihydro-benzofuranyl, benzo[l,3]dioxolyl, 4H-benzo[l,3]dioxinyl, 2H
- R 2 represents heteroaryl, wherein said heteroaryl is selected from the group consisting of pyrazolyl, indolyl, indazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazo[l,2-a]pyridyl, l ⁇ -pyrrolopyridyl (notably l ⁇ -pyrrolo[3,2-b]pyridyl and IH- pyrrolo[2,3-b]pyridyl), and 2,3-dihydro-thieno[3,4-b][l,4]dioxinyl; wherein said groups are independently unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (Ci_ 4 )alkyl.
- a further embodiment of the invention relates to compounds of formula (I) according to embodiment xi) in combination with embodiment iv), wherein R 2 is selected from the group consisting of:
- a further embodiment of the invention relates to compounds of formula (I) according to embodiment xi) in combination with embodiment iii), wherein R 2 is selected from the group consisting of:
- a further embodiment of the invention relates to compounds of formula (I) according to embodiment i), which are selected from the group consisting of:
- 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. Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases or the like, this is intended to mean also a single compound, salt, disease or the like.
- the compounds of formula (I) and (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), 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 Remington, The
- the compounds of 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
- 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. expenditure); disturbed perception of food quality (high fat or carbohydrates, high palatability); disturbed food availability (unrestricted diet or deprivation) or disrupted water balance.
- 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 compounds of formula (I) and/or (Ia) are useful for the treatment and/or prevention of the diseases mentioned herein.
- the invention relates to a method for the treatment and/or prevention of the diseases mentioned herein, said method comprising administering to a subject a pharmaceutically active amount of a compound of formula (I) and/or (Ia).
- any preferences indicated for the compounds of formula (I) (whether for the compounds themselves, salts thereof, compositions containing the compounds or salts thereof, uses of the compounds or salts thereof, etc.) apply mutatis mutandis to compounds of formula (Ia).
- the term "about” placed before a numerical value "X” refers in the current application to an interval extending from X minus 10% of X to 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 10 0 C to Y plus 10 0 C, and preferably to an interval extending from Y minus 5 0 C to Y plus 5 0 C.
- room temperature RT as used herein refers to a temperature of about 25°C.
- a further aspect of the invention is a process for the preparation of compounds of formula (I) and (Ia).
- Compounds according to formula (I) and (Ia) of the present invention can be prepared according to the general sequence of reactions outlined in the schemes below wherein A, B, X, n, R 1 and R 2 are as defined in the description for formula (I) and (Ia). Additional generic groups as used in the schemes below are defined as followed: R represents hydrogen or (Ci_4)alkyl; and R represents hydrogen, (Ci_ 4 )alkyl, (Ci_ 4 )alkoxy, trifluoromethyl, cyano or halogen.
- the compounds obtained may also be converted into salts, especially pharmaceutically acceptable salts thereof in a manner known per se.
- the compounds of formula (I) and (Ia) wherein X represents -NH-R 1 may be prepared starting from (+/-)-3-amino-l-N-Boc-piperidine or -pyrrolidine or from enantiomerically pure (R)-3-amino-l-N-Boc-piperidine or -pyrrolidine ((1), all commercially available) by reaction with the corresponding commercially available or well known 2-chloro-heteroaryl, 2-bromo-heteroaryl, or 2-trifluoromethanesulfonyl- heteroaryl derivative under basic conditions such as K2CO3 in presence of DIEA in a solvent such as xylene at reflux.
- reaction conditions are especially successful in case of reactive heteroaryl-chlorides such as 2-chloro-pyrimidines or 2-chloro- pyridines, preferably substituted by electron-withdrawing substituents.
- the Buchwald-Hartwig method may be used for the above coupling reaction (for reaction conditions see the procedures given in eg. J. Med. Chem., 2007, 50, 3497- 3514; J. F. Hartwig, "Modern Animation Methods", A. Ricci (Ed), Wiley- VCH Verlag GmbH, D-69469 Weinheim, 2000; ISBN 3-527-29976-9; Chapter 7, p. 195- 262).
- the resulting amine (2) is transformed to compounds (3) by cleavage of the Boc protecting group under acidic conditions such as TFA in DCM followed by amide formation with the respective carboxylic acid B-A-CO 2 H using standard amide coupling techniques such as PyBOP in presence of DIEA in a solvent such as DMF or TBTU in the presence of DIEA in a solvent such as MeCN (scheme 1).
- the compounds of formula (I) and (Ia), wherein X represents -NH-C(O)-R 2 may be prepared starting from (1) by reaction with the respective carboxylic acid derivative R 2 -C ⁇ 2H using standard amide coupling techniques as above.
- the resulting amide intermediates (4) are transformed to compounds (5) by cleavage of the Boc protecting group as described above, followed by amide formation with the respective carboxylic acid B-A-CO 2 H (scheme 2) as described above.
- Carboxylic acid derivatives B-A-CO 2 H wherein A represents a 2-cyclopropyl- thiazolyl derivative can be synthesised according to scheme 3.
- Carboxylic acid derivatives B-A-CO 2 H, wherein B-A represents a biphen-2-yl derivative, are commercially available or can be synthesized according to scheme 4.
- reaction of commercially available 2-bromo-, or 2- iodo-benzoic acid derivatives (12), or esters thereof, with commercially available phenyl-boronic acid derivatives using the conditions described before provides the corresponding biphenyl-2-carboxylic acid derivatives (11).
- Carboxylic acids of formula R 2 -CO 2 H are commercially available or well known in the art (Lit. e.g. WO2001/96302; T. Eicher, S. Hauptmann "The chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications", 2nd Edition 2003, Wiley, ISBN 978-3-527-30720-3).
- Derivatives of formula R 2 -C ⁇ 2 H wherein R 2 is 2H-chromenyl or chromanyl may be for instance synthesised according to scheme 5.
- the corresponding chroman- 8 -carboxylic acid derivatives may be synthesized by reduction of 4-chromanone (18; commercially available) with zinc in acetic acid and subsequent o/t/zo-metalation of the intermediate chroman derivative (19) with n-BuLi and trapping with carbon dioxide to give the desired acid (20).
- 4-chromanone 18; commercially available
- zinc in acetic acid and subsequent o/t/zo-metalation of the intermediate chroman derivative (19) with n-BuLi and trapping with carbon dioxide to give the desired acid (20).
- n-BuLi n-BuLi and trapping with carbon dioxide
- the enantiomers can be separated using methods known to one skilled in the art: e.g.
- a chiral stationary phase such as a Regis Whelk-01(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.
- FCS Foatal calf serum
- Ph phenyl PyBOP (Benzotriazole- 1 yloxy)-tripyrrolidinophosphonium- hexafluorophosphate i-PrOH Isopropanol
- A.1.1 Synthesis of S-chloro-l-oxo-propionic ester derivatives (general procedure) A solution of the respective aldehyde B-CHO (338 mmol, 1.0 eq) and methyl dichloroacetate (338 mmol, 1.0 eq) in THF (100 mL) is added dropwise to a cold (-60 0 C) suspension of KOtBu (335 mmol, 1.0 eq) in THF (420 mL). After 4 h the mixture is allowed to reach RT, stirred over night and concentrated in vacuo. DCM and ice-cold water are added, the layers are separated and the aqueous layer is extracted twice with DCM. The combined organic layers are washed with ice-cold water and brine, dried over MgSO 4 and concentrated in vacuo to give the desired 2- oxo-propionic acid ester which is used without further purification.
- 3-chloro-2-oxo-3-m-tolyl-propionic acid methyl ester prepared by reaction of 3-methyl-benzaldehyde with methyl dichloroacetate.
- 3-chloro-2-oxo-3-p-tolyl-propionic acid methyl ester prepared by reaction of 4-methyl-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-(3-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 3-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-(3-methoxy-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 3-methoxy-benzaldehyde with methyl dichloro-acetate.
- 3-chloro-3-(3-fluoro-4-methyl-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 3,4-dimethyl-benzaldehyde with methyl dichloro-acetate.
- 3-chloro-3-phenyl-2-oxo-propionic acid methyl ester prepared by reaction of benzaldehyde with methyl dichloro-acetate.
- 3-chloro-3-(3-bromo-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 3-bromo-benzaldehyde with methyl dichloro-acetate.
- 3-chloro-3-(4-cyano-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 4-cyano-benzaldehyde with methyl dichloro-acetate.
- 3-chloro-3-(3-fluoro-5-trifluoromethyl-phenyl)-2-oxo-propionic acid methyl ester prepared by reaction of 3-fluoro-5-trifluoromethyl-benzaldehyde with methyl dichloro-acetate.
- Examples 12 to 14 were prepared according to the description for the preparation of example 11 :
- Examples 16 to 46 were prepared according to the description for the preparation of example 15:
- Examples 47 and 48 were prepared by applying the methods described for the preparation of Example 11 and using a 2-bromopyridine derivative as the arylating agent:
- Examples 49 to 54 were prepared according to the procedures described for the preparation of Example 11 by using R-(3-amino-pyrrolidin-l-yl)-(3'-methyl-biphenyl- 2-yl)-methanone as the amine in the last arylation step.
- Examples 55 and 56 were prepared according to the procedure described for the preparation of example 15 by using R-(3-amino-pyrrolidin-l-yl)-(3'-methyl-biphenyl- 2-yl)-methanone as the amine in the last acylation step.
- Example 55 (R)-l-Methyl-lH-indole-3-carboxylic acid [l-(3'-methyl-biphenyl-2- carbonyl)-pyrrolidin-3-yl]-amide
- 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 % heat inactivated fetal calf serum (FCS).
- the cells are seeded at 20O00 cells / well into 384-well black clear bottom sterile plates (Greiner). 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), NaHCO 3 : 0.375g/l and 20 mM HEPES for use in the assay at a final concentration of 3 nM.
- BSA bovine serum albumin
- NaHCO 3 0.375g/l
- 20 mM HEPES for use in the assay at a final concentration of 3 nM.
- Antagonists are prepared as 10 mM stock solution in DMSO, then diluted in 384-well plates using DMSO followed by a transfer of the dilutions into in HBSS containing 0.1 % bovine serum albumin (BSA), NaHCO 3 : 0.375g/l and 20 mM HEPES.
- BSA bovine serum albumin
- 50 ⁇ l of staining buffer HBSS containing 1% FCS, 20 mM HEPES, NaHCO 3 : 0.375g/l, 5 mM probenecid (Sigma) and 3 ⁇ M of the fluorescent calcium indicator fluo-4 AM (1 mM stock solution in DMSO, containing 10% pluronic) is added to each well.
- the 384-well cell-plates are incubated for 50 min at 37° C in 5% CO 2 followed by equilibration at RT for 30 - 120 min before measurement.
- antagonists are added to the plate in a volume of 10 ⁇ l/well, incubated for 10 min and finally 10 ⁇ l/well 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 3 nM orexin-A with vehicle in place of antagonist. For each antagonist, the IC50 value (the concentration of compound needed to inhibit 50 % of the agonistic response) is determined.
- IC50 values of 47 exemplified compounds are in the range of 6 - 8036 nM with an average of 1388 nM; IC50 values of 9 compounds have been measured > 10000 nM.
- IC50 values of all exemplified compounds are in the range of 8 - 4547 nM with an average of 601 nM.
- Antagonistic activities of selected compounds are displayed in Table 1.
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Anesthesiology (AREA)
- Addiction (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2722347A CA2722347A1 (en) | 2008-04-30 | 2009-04-29 | Piperidine and pyrrolidine compounds |
US12/990,020 US20110039857A1 (en) | 2008-04-30 | 2009-04-29 | Piperidine and pyroolidine compounds |
CN2009801165761A CN102015645B (en) | 2008-04-30 | 2009-04-29 | Piperidine and pyrrolidine compounds |
EP09738535A EP2318367B1 (en) | 2008-04-30 | 2009-04-29 | Piperidine and pyrrolidine compounds |
JP2011506816A JP2011519849A (en) | 2008-04-30 | 2009-04-29 | Piperidine and pyrrolidine compounds |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IB2008051673 | 2008-04-30 | ||
IBPCT/IB2008/051673 | 2008-04-30 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2009133522A1 true WO2009133522A1 (en) | 2009-11-05 |
Family
ID=40792961
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2009/051735 WO2009133522A1 (en) | 2008-04-30 | 2009-04-29 | Piperidine and pyrrolidine compounds |
Country Status (7)
Country | Link |
---|---|
US (1) | US20110039857A1 (en) |
EP (1) | EP2318367B1 (en) |
JP (1) | JP2011519849A (en) |
KR (1) | KR20100135962A (en) |
CN (1) | CN102015645B (en) |
CA (1) | CA2722347A1 (en) |
WO (1) | WO2009133522A1 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2013059222A1 (en) * | 2011-10-19 | 2013-04-25 | Merck Sharp & Dohme Corp. | 2-pyridyloxy-4-nitrile orexin receptor antagonists |
CN103201261A (en) * | 2010-11-10 | 2013-07-10 | 埃科特莱茵药品有限公司 | Lactam derivatives useful as orexin receptor antagonists |
WO2014099696A1 (en) * | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | 2-pyridyloxy-4-ester orexin receptor antagonists |
WO2014165065A1 (en) * | 2013-03-13 | 2014-10-09 | Janssen Pharmaceutica Nv | Substituted piperidine compounds and their use as orexin receptor modulators |
WO2015095441A1 (en) * | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | 2-amino-3-ester-pyridyl orexin receptor antagonists |
WO2016040789A1 (en) * | 2014-09-11 | 2016-03-17 | Janssen Pharmaceutica Nv | Substituted 2-azabicycles and their use as orexin receptor modulators |
US9611277B2 (en) | 2013-03-13 | 2017-04-04 | Janssen Pharmaceutica Nv | Substituted 2-azabicycles and their use as orexin receptor modulators |
US9637496B2 (en) | 2013-03-13 | 2017-05-02 | Janssen Pharmaceutica Nv | Substituted 7-azabicycles and their use as orexin receptor modulators |
EP3215150A4 (en) * | 2014-11-07 | 2018-03-28 | The Regents of The University of Michigan | Inhibitors of myocardin-related transcription factor and serum response factor (mrtf/srf)-mediated gene transcription and methods for use of the same |
US10227336B2 (en) | 2014-10-30 | 2019-03-12 | Merck Sharp & Dohme Corp | Pyrazole orexin receptor antagonists |
Families Citing this family (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100016401A1 (en) * | 2006-09-29 | 2010-01-21 | Actelion Phamaceuticals Ltd. | 3-aza-bicyclo[3.1.0]hexane derivatives |
CN101568533A (en) | 2006-12-01 | 2009-10-28 | 埃科特莱茵药品有限公司 | 3-heteroaryl (amino or amido)-1- (biphenyl or phenylthiazolyl) carbonylpiperdine derivatives as orexin receptor inhibitors |
AR064561A1 (en) * | 2006-12-28 | 2009-04-08 | Actelion Pharmaceuticals Ltd | DERIVATIVES OF 2-AZA-BICYCLE [3.1.0] HEXANE AND ITS USE IN THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF DISEASES RELATED TO GENERAL DYSFUNCTIONS OF THE OREXINE SYSTEM. |
CL2008000836A1 (en) * | 2007-03-26 | 2008-11-07 | Actelion Pharmaceuticals Ltd | Thiazolidine derivative compounds, orexin receptor antagonists; pharmaceutical composition that includes them; and its use in the treatment of emotional neurosis, severe depression, psychotic disorders, Alzheimer's, parkinson's, pain, among others. |
BRPI0814593A2 (en) * | 2007-07-27 | 2015-01-20 | Actelion Pharmaceuticals Ltd | COMPOUND, PHARMACEUTICAL COMPOSITION CONTAINING AND USE OF THE COMPOUND. |
EP2207778A2 (en) * | 2007-09-24 | 2010-07-21 | Actelion Pharmaceuticals Ltd. | Pyrrolidines and piperidines as orexin receptor antagonists |
ATE555107T1 (en) * | 2008-02-21 | 2012-05-15 | Actelion Pharmaceuticals Ltd | 2-AZA-BICYCLO-Ä2,2,1-ÜHEPTAN DERIVATIVES |
WO2010044054A1 (en) * | 2008-10-14 | 2010-04-22 | Actelion Pharmaceuticals Ltd | Phenethylamide derivatives and their heterocyclic analogues |
AU2009307915A1 (en) * | 2008-10-21 | 2010-04-29 | Merck Sharp & Dohme Corp. | 2,5-disubstituted piperidine orexin receptor antagonists |
US9586934B2 (en) | 2013-12-09 | 2017-03-07 | Merck Sharp & Dohme Corp. | 2-pyridyloxy-4-methyl orexin receptor antagonists |
WO2015095108A1 (en) | 2013-12-18 | 2015-06-25 | Merck Sharp & Dohme Corp. | Thioether-piperidinyl orexin receptor antagonists |
US9556190B2 (en) | 2013-12-20 | 2017-01-31 | Merck Sharp & Dohme Corp. | Piperidinyloxy lactone orexin receptor antagonists |
AU2016360245B2 (en) | 2015-11-23 | 2020-07-09 | Sunshine Lake Pharma Co., Ltd. | Octahydropyrrolo [3, 4-c] pyrrole derivatives and uses thereof |
US11098029B2 (en) | 2019-02-13 | 2021-08-24 | Merck Sharp & Dohme Corp. | 5-alkyl pyrrolidine orexin receptor agonists |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001096302A1 (en) * | 2000-06-16 | 2001-12-20 | Smithkline Beecham P.L.C. | Piperidines for use as orexin receptor antagonists |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3282927A (en) * | 1964-05-21 | 1966-11-01 | Bristol Myers Co | 5-phenyl-4-thiazolylpenicillins |
CH621126A5 (en) * | 1974-02-07 | 1981-01-15 | Plantex Ltd | |
US6191124B1 (en) * | 1994-04-29 | 2001-02-20 | Pharmacia & Upjohn Company | Methanol derivatives for treatment of retroviral infections especially HIV infections |
AR016817A1 (en) * | 1997-08-14 | 2001-08-01 | Smithkline Beecham Plc | DERIVATIVES OF FENILUREA OR FENILTIOUREA, PROCEDURE FOR PREPARATION, COLLECTION OF COMPOUNDS, INTERMEDIARY COMPOUNDS, PHARMACEUTICAL COMPOSITION, METHOD OF TREATMENT AND USE OF SUCH COMPOUNDS FOR THE MANUFACTURE OF A MEDICINAL PRODUCT |
CA2331735A1 (en) * | 1998-05-08 | 1999-11-18 | Smithkline Beecham P.L.C. | Phenylurea and phenylthio urea derivatives |
ATE286897T1 (en) * | 2000-11-28 | 2005-01-15 | Smithkline Beecham Plc | MORPHOLINE DERIVATIVES AS ANTAGONISTS AT OREXIN RECEPTORS |
US20040192673A1 (en) * | 2001-05-05 | 2004-09-30 | Pascale Gaillard | N-aroyl cyclic amine derivatives as orexin receptor antagonists |
GB0115862D0 (en) * | 2001-06-28 | 2001-08-22 | Smithkline Beecham Plc | Compounds |
GB0124463D0 (en) * | 2001-10-11 | 2001-12-05 | Smithkline Beecham Plc | Compounds |
GB0127145D0 (en) * | 2001-11-10 | 2002-01-02 | Smithkline Beecham | Compounds |
US7119200B2 (en) * | 2002-09-04 | 2006-10-10 | Schering Corporation | Pyrazolopyrimidines as cyclin dependent kinase inhibitors |
ES2360376T3 (en) * | 2006-08-15 | 2011-06-03 | Actelion Pharmaceuticals Ltd. | AZETIDINE COMPOUNDS AS AN OREXINE RECEIVER ANTAGONISTS. |
US20100016401A1 (en) * | 2006-09-29 | 2010-01-21 | Actelion Phamaceuticals Ltd. | 3-aza-bicyclo[3.1.0]hexane derivatives |
CN101568533A (en) * | 2006-12-01 | 2009-10-28 | 埃科特莱茵药品有限公司 | 3-heteroaryl (amino or amido)-1- (biphenyl or phenylthiazolyl) carbonylpiperdine derivatives as orexin receptor inhibitors |
AR064561A1 (en) * | 2006-12-28 | 2009-04-08 | Actelion Pharmaceuticals Ltd | DERIVATIVES OF 2-AZA-BICYCLE [3.1.0] HEXANE AND ITS USE IN THE PREPARATION OF A MEDICINAL PRODUCT FOR THE TREATMENT OF DISEASES RELATED TO GENERAL DYSFUNCTIONS OF THE OREXINE SYSTEM. |
CL2008000836A1 (en) * | 2007-03-26 | 2008-11-07 | Actelion Pharmaceuticals Ltd | Thiazolidine derivative compounds, orexin receptor antagonists; pharmaceutical composition that includes them; and its use in the treatment of emotional neurosis, severe depression, psychotic disorders, Alzheimer's, parkinson's, pain, among others. |
CN101711247A (en) * | 2007-05-14 | 2010-05-19 | 埃科特莱茵药品有限公司 | 2-cyclopropyl-thiazole derivatives |
US8242121B2 (en) * | 2007-05-23 | 2012-08-14 | Merck Sharp & Dohme Corp. | Pyridyl piperidine orexin receptor antagonists |
WO2008150364A1 (en) * | 2007-05-23 | 2008-12-11 | Merck & Co., Inc. | Cyclopropyl pyrrolidine orexin receptor antagonists |
GB0712888D0 (en) * | 2007-07-03 | 2007-08-15 | Glaxo Group Ltd | Novel compounds |
CN101730696B (en) * | 2007-07-03 | 2013-01-09 | 埃科特莱茵药品有限公司 | 3-aza-bicyclo[3.3.0]octane compounds |
CL2008001951A1 (en) * | 2007-07-03 | 2009-01-09 | Glaxo Group Ltd | Substituted imidazo [1,2-a] pyrimidin-2-ylmethyl derived compounds; pharmaceutical composition comprising said compound; and use of the compound for sleep disorder, depression, anxiety, substance abuse-related disorder, among others. |
AR067665A1 (en) * | 2007-07-27 | 2009-10-21 | Actelion Pharmaceuticals Ltd | DERIVATIVES OF TRANS-3- AZA-BICYCLE (3.1.0) HEXANO |
BRPI0814593A2 (en) * | 2007-07-27 | 2015-01-20 | Actelion Pharmaceuticals Ltd | COMPOUND, PHARMACEUTICAL COMPOSITION CONTAINING AND USE OF THE COMPOUND. |
EP2207778A2 (en) * | 2007-09-24 | 2010-07-21 | Actelion Pharmaceuticals Ltd. | Pyrrolidines and piperidines as orexin receptor antagonists |
CA2705411A1 (en) * | 2007-12-21 | 2009-07-02 | F. Hoffmann-La Roche Ag | Heteroaryl derivatives as orexin receptor antagonists |
ATE555107T1 (en) * | 2008-02-21 | 2012-05-15 | Actelion Pharmaceuticals Ltd | 2-AZA-BICYCLO-Ä2,2,1-ÜHEPTAN DERIVATIVES |
-
2009
- 2009-04-29 WO PCT/IB2009/051735 patent/WO2009133522A1/en active Application Filing
- 2009-04-29 US US12/990,020 patent/US20110039857A1/en not_active Abandoned
- 2009-04-29 CA CA2722347A patent/CA2722347A1/en not_active Abandoned
- 2009-04-29 EP EP09738535A patent/EP2318367B1/en not_active Not-in-force
- 2009-04-29 JP JP2011506816A patent/JP2011519849A/en active Pending
- 2009-04-29 CN CN2009801165761A patent/CN102015645B/en not_active Expired - Fee Related
- 2009-04-29 KR KR1020107026700A patent/KR20100135962A/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001096302A1 (en) * | 2000-06-16 | 2001-12-20 | Smithkline Beecham P.L.C. | Piperidines for use as orexin receptor antagonists |
Cited By (25)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103201261A (en) * | 2010-11-10 | 2013-07-10 | 埃科特莱茵药品有限公司 | Lactam derivatives useful as orexin receptor antagonists |
US9156819B2 (en) | 2011-10-19 | 2015-10-13 | Merck Sharp & Dohme Corp. | 2-pyridyloxy-4-nitrile orexin receptor antagonists |
WO2013059222A1 (en) * | 2011-10-19 | 2013-04-25 | Merck Sharp & Dohme Corp. | 2-pyridyloxy-4-nitrile orexin receptor antagonists |
WO2014099696A1 (en) * | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | 2-pyridyloxy-4-ester orexin receptor antagonists |
US9556145B2 (en) | 2012-12-20 | 2017-01-31 | Merck Sharp & Dohme Corp. | 2-pyridyloxy-4-ester orexin receptor antagonists |
US9637496B2 (en) | 2013-03-13 | 2017-05-02 | Janssen Pharmaceutica Nv | Substituted 7-azabicycles and their use as orexin receptor modulators |
US9115117B2 (en) | 2013-03-13 | 2015-08-25 | Janssen Pharmaceutica Nv | Substituted piperidine compounds and their use as orexin receptor modulators |
US10183953B2 (en) | 2013-03-13 | 2019-01-22 | Janssen Pharmaceutica Nv | Substituted 2-azabicycles and their use as orexin receptor modulators |
AU2014248763B2 (en) * | 2013-03-13 | 2018-08-30 | Janssen Pharmaceutica Nv | Substituted piperidine compounds and their use as orexin receptor modulators |
US9845333B2 (en) | 2013-03-13 | 2017-12-19 | Janssen Pharmaceutica Nv | Substituted 2-azabicycles and their use as orexin receptor modulators |
US9611251B2 (en) | 2013-03-13 | 2017-04-04 | Janssen Pharmaceutica Nv | Substituted piperidine compounds and their use as orexin receptor modulators |
US9611277B2 (en) | 2013-03-13 | 2017-04-04 | Janssen Pharmaceutica Nv | Substituted 2-azabicycles and their use as orexin receptor modulators |
WO2014165065A1 (en) * | 2013-03-13 | 2014-10-09 | Janssen Pharmaceutica Nv | Substituted piperidine compounds and their use as orexin receptor modulators |
US9695183B2 (en) | 2013-03-13 | 2017-07-04 | Janssen Pharmaceutica Nv | Substituted 7-azabicycles and their use as orexin receptor modulators |
US9676751B2 (en) | 2013-12-20 | 2017-06-13 | Merck Sharp & Dohme Corp. | 2-amino-3-ester-pyridl orexin receptor antagonists |
WO2015095441A1 (en) * | 2013-12-20 | 2015-06-25 | Merck Sharp & Dohme Corp. | 2-amino-3-ester-pyridyl orexin receptor antagonists |
KR20170048563A (en) * | 2014-09-11 | 2017-05-08 | 얀센 파마슈티카 엔.브이. | Substituted 2-azabicycles and their use as orexin receptor modulators |
CN107108566A (en) * | 2014-09-11 | 2017-08-29 | 詹森药业有限公司 | Substitution 2 Azabicyclic compounds and they as orexin receptor conditioning agent purposes |
US9611262B2 (en) | 2014-09-11 | 2017-04-04 | Janssen Pharmaceutica Nv | Substituted 2-azabicycles and their use as orexin receptor modulators |
WO2016040789A1 (en) * | 2014-09-11 | 2016-03-17 | Janssen Pharmaceutica Nv | Substituted 2-azabicycles and their use as orexin receptor modulators |
CN107108566B (en) * | 2014-09-11 | 2020-11-24 | 詹森药业有限公司 | Substituted 2-azabicyclic compounds and their use as orexin receptor modulators |
KR102455043B1 (en) | 2014-09-11 | 2022-10-13 | 얀센 파마슈티카 엔.브이. | Substituted 2-azabicycles and their use as orexin receptor modulators |
US10227336B2 (en) | 2014-10-30 | 2019-03-12 | Merck Sharp & Dohme Corp | Pyrazole orexin receptor antagonists |
EP3215150A4 (en) * | 2014-11-07 | 2018-03-28 | The Regents of The University of Michigan | Inhibitors of myocardin-related transcription factor and serum response factor (mrtf/srf)-mediated gene transcription and methods for use of the same |
US10662183B2 (en) | 2014-11-07 | 2020-05-26 | The Regents Of The University Of Michigan | Inhibitors of myocardin-related transcription factor and serum response factor (MRTF/SRF)-mediated gene transcription and methods for use of the same |
Also Published As
Publication number | Publication date |
---|---|
KR20100135962A (en) | 2010-12-27 |
CN102015645A (en) | 2011-04-13 |
US20110039857A1 (en) | 2011-02-17 |
EP2318367B1 (en) | 2013-03-20 |
CA2722347A1 (en) | 2009-11-05 |
JP2011519849A (en) | 2011-07-14 |
EP2318367A1 (en) | 2011-05-11 |
CN102015645B (en) | 2012-11-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP2318367B1 (en) | Piperidine and pyrrolidine compounds | |
EP2155739B1 (en) | 2-cyclopropyl-thiazole derivatives | |
EP2247586B1 (en) | 2-aza-bicyclo[2.2.1]heptane derivatives | |
US8133901B2 (en) | 3-heteroaryl (amino or amido)-1-(biphenyl or phenylthiazolyl) carbonylpiperidine derivatives as orexin receptor inhibitors | |
US7994336B2 (en) | Azetidine compounds as orexin receptor antagonists | |
EP2185512B1 (en) | Trans-3-aza-bicyclo[3.1.0]hexane derivatives | |
WO2009040730A2 (en) | Pyrrolidines and piperidines as orexin receptor antagonists | |
WO2008087611A2 (en) | Pyrrolidine- and piperidine- bis-amide derivatives | |
NZ583487A (en) | 2-aza-bicyclo[3.3.0]octane derivatives | |
KR20090125195A (en) | Thiazolidine derivatives as orexin receptor antagonists | |
EP2079690A2 (en) | 3-aza-bicyclo[3.1.0]hexane derivatives | |
EP2164847A1 (en) | 3-aza-bicyclo[3.3.0]octane compounds | |
KR20100055464A (en) | 1,2-diamido-ethylene derivatives as orexin antagonists | |
WO2010038200A1 (en) | Oxazolidine compounds as orexin receptor antagonists |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 200980116576.1 Country of ref document: CN |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 09738535 Country of ref document: EP Kind code of ref document: A1 |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2009738535 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2722347 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 12990020 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2011506816 Country of ref document: JP |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
ENP | Entry into the national phase |
Ref document number: 20107026700 Country of ref document: KR Kind code of ref document: A |