WO2011083316A1 - Dérivés de la benzazépine destinés à traiter des troubles du système nerveux central - Google Patents

Dérivés de la benzazépine destinés à traiter des troubles du système nerveux central Download PDF

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Publication number
WO2011083316A1
WO2011083316A1 PCT/GB2011/000016 GB2011000016W WO2011083316A1 WO 2011083316 A1 WO2011083316 A1 WO 2011083316A1 GB 2011000016 W GB2011000016 W GB 2011000016W WO 2011083316 A1 WO2011083316 A1 WO 2011083316A1
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Prior art keywords
benzazepin
tetrahydro
pyrrolo
methyl
cyclobutyl
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PCT/GB2011/000016
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English (en)
Inventor
Parminder Kaur Pooni
Kevin John Merchant
Catrina Morvern KERR
David Harrison
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Takeda Pharmaceutical Company Limited
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Publication date
Priority claimed from GBGB1000309.3A external-priority patent/GB201000309D0/en
Priority claimed from GBGB1017822.6A external-priority patent/GB201017822D0/en
Application filed by Takeda Pharmaceutical Company Limited filed Critical Takeda Pharmaceutical Company Limited
Publication of WO2011083316A1 publication Critical patent/WO2011083316A1/fr

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    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds and their uses, and in particular to compounds having a benzazepine scaffold and their therapeutic use in the treatment or prevention of conditions having an association with the histamine H3 receptor.
  • the H3 receptor was first identified pharmacologically in 1983 as an autoreceptor that regulates the production of histamine (1).
  • the receptor was later cloned in 1999 (2).
  • It is a constitutively active G protein-coupled receptor that is expressed predominantly in the central nervous system (CNS) and modulates a variety of CNS functions both centrally and peripherally. It is expressed on the presynaptic terminals of CNS neurones and acts as a negative modulator of release of neurotransmitters such as histamine, acetylcholine, norepinephrine, serotonin and dopamine (3).
  • the ability of the H3 receptor to regulate the release of a wide range of neurotransmitters has fuelled research into the development of antagonists / inverse agonists which have potential in behavioural and physiological conditions, for example CNS disorders such as narcolepsy, disorders of wakefulness, cognition or attention, pain and in suppression of food intake.
  • CNS disorders such as narcolepsy, disorders of wakefulness, cognition or attention, pain and in suppression of food intake.
  • Histaminergic neurones are located in the tuberomammillary nucleus of the posterior hypothalamus and project their axons into brain regions including the hypothalamus, thalamus, cerebral cortex, amygdala, and septum. Activity of histaminergic neurons is closely linked with the sleep / wake cycle and numerous reports in the literature have established that the H3 receptor plays a role in cognition and sleep / wake related processes, based on studies with known H3 receptor antagonists and their effects in animal models (4, 5, 6). H3 antagonist compound A-349821 is currently in preclinical development and has been shown to demonstrate cognition-enhancing effects in the rat (7).
  • the histaminergic system is one of the targets of leptin signalling in the hypothalamus.
  • Known H3 antagonist clobenpropit increases histamine release in the hypothalamus of mice and has the effect of reducing energy intake in both lean and obese mice (8).
  • the role of the H3 receptor in obesity has been further substantiated through studies with antagonists thioperamide and ciproxifan and more recently with non-imidazole compounds (10).
  • the non-selective antagonist thioperamide has an antinociceptive effect in a number of acute pain models (11).
  • H3 antagonists have been suggested for the treatment of neuropathic pain
  • GSK207040 and GSK334429 are selective non-imidazole H3 antagonist compounds that display high affinity for both rat and human H3 receptors. Both compounds reduced tactile allodynia in the rat, suggesting H3 antagonists have therapeutic potential in the treatment of neuropathic pain (13).
  • non-imidazole compounds have been at the forefront of research, for example A-349821 (7) and GSK207040 / GSK334429 (13).
  • ABT-239 is currently being investigated for use in attention deficit hyperactivity disorder, Alzheimer's Disease and schizophrenia (14).
  • WO05/123723, WO06/018260 and WO05/058837 disclose H3 antagonist benzazepine derivatives claimed to be useful in the treatment of neurological and psychiatric disorders.
  • WO05/058328 discloses dopamine D3 receptor benzazepine derivatives claimed to be useful in the treatment of CNS disorders such as schizophrenia and depression.
  • WO02/40471 also discloses benzazepine derivatives useful as modulators of the dopamine D3 receptor.
  • US2003/0158177 discloses melanin-concentrating hormone antagonists claimed to be useful in the treatment of obesity.
  • R a represents Ci. 6 alkyl, cyclobutyl or cyclopentyl
  • Ri represents H or Ci. 6 alkyl
  • Xi represents CR 3 or N
  • X 2 represents CR4 or N
  • X 3 represents CR5 or N
  • X4 represents CR 6 or N
  • R 3 , R4, R 5 and R6 each independently represent H, Ci. 6 alkoxy or -NR 7 R 8 ;
  • R 7 and R 8 independently represent H or Ci -6 alkyl, or R and R 8 and the N atom to which they are attached are joined to form a N-containing heterocyclyl ring, optionally substituted with one or more substituents independently selected from halogen, Ci-6 alkyl and Ci- alkoxy;
  • the compounds of the invention have been found to modulate the histamine H3 receptor.
  • the compounds possess antagonist or inverse agonist properties at this receptor. Based on the high affinity for the receptor, the compounds may have the potential to display useful selectivity for the H3 receptor.
  • Compounds of the invention have been found to display properties suggestive of blood brain barrier permeability, rendering them potentially suitable for the treatment of CNS disorders.
  • any group in the compound of formula (1) above is referred to as being optionally substituted, this group may be unsubstituted or substituted by one or more substituents. Typically any such group will be unsubstituted, or substituted by one or two substituents, generally one substituent.
  • Ci -6 alkyl refers to a linear or branched saturated hydrocarbon group containing from 1 to 6 carbon atoms.
  • Examples of Ci -6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert butyl, n- pentyl, isopentyl, neopentyl and hexyl.
  • 'C x . y alkoxy' refers to an -0-C x-y alkyl group wherein C x . y alkyl is as defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • the term 'N-containing-heterocyclyl' refers to a 4-7 membered saturated monocyclic ring containing at least one, typically one or two, nitrogen atoms and optionally 1 to 4 other heteroatoms selected from oxygen, silicon or sulphur. Examples of such rings include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.
  • 'halogen' refers to a fluorine, chlorine, bromine or iodine atom, unless otherwise specified. Typically, a fluorine is employed.
  • salts with inorganic bases include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic or acidic amino acids. Salts with acids may, in particular, be employed in some instances.
  • salts' of compounds of Formula (1) of the present invention include but are not limited to acid addition salts (for example, phosphates, nitrates, sulphates, borates acetates, maleates, citrates, fumarates, succinates, methanesulfonates, benzoates, salicylates and hydrohalides), and salts of amino acids (such as glycine, alanine, valine, leucine, isoleucine, cysteine, methionine, proline).
  • Further pharmaceutically acceptable salts include quaternary ammonium salts of the compounds of formula 1.
  • solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
  • the compound of Formula (1) of the present invention may be in either hydrate or non-hydrate form.
  • compounds of the invention may be prepared as isomeric mixtures or racemates, although the invention relates to all such enantiomers or isomers, whether present in an optically pure form or as mixtures with other isomers.
  • Individual enantiomers or isomers may be obtained by methods known in the art, such as optical resolution of products or intermediates (for example chiral chromatographic separation (e.g. chiral HPLC)), or an enantiomeric synthesis approach.
  • compounds of the invention may exist as alternative tautomeric forms (e.g. keto/enol, amide/imidic acid)
  • the invention relates to the individual tautomers in isolation, and to mixtures of the tautomers in all proportions.
  • the compounds of the invention bear one or more radiolabels.
  • radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of formula 1 , or may be introduced by coupling the compounds of formula 1 to chelating moieties capable of binding to a radioactive metal atom.
  • Such radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
  • R a represents cyclobutyl or cyclopentyl.
  • R a represents cyclopentyl. In certain other embodiments, R a represents cyclobutyl.
  • Ra represents Ci-6 alkyl, typically C 1 .3 a.kyl.
  • R a represents ethyl. In certain other embodiments, R a represents isopropyl.
  • Ri represents H or C
  • R 2 may in particular represent H.
  • Ri preferably represents H.
  • Ri and R 2 each represent H.
  • one of the groups X ); X 2, X3 or X 4 represents N. In certain other embodiments, two of the groups Xi, X 2 , X3 or X4 represent N.
  • Xi represents N. In other particular embodiments, Xi represents CR 3 .
  • Xj represents N
  • X 2 represents CR 4
  • X3 represents CR 5
  • X4 represents CR
  • X 2 represents N. In other particular embodiments, X 2 represents CR 4 .
  • X 2 represents N
  • Xi represents CR3
  • X3 represents CR5
  • 4 represents CR 6 or N.
  • X 2 represents N
  • Xi represents CR 3
  • X3 represents CR5
  • X4 represents CRe
  • X 2 represents N
  • Xi represents CR 3
  • X 3 represents CR 5
  • X represents N.
  • X 3 represents N. In other particular embodiments, X 3 represents CR 5 .
  • X 3 represents N
  • Xi represents CR 3
  • X 2 represents CR4
  • X 4 represents CR 6
  • X 4 represents N. In other particular embodiments, X 4 represents CRe.
  • X 4 represents N
  • Xi represents CR 3>
  • X 2 represents CR4 and X 3 represents CR 5
  • Xi represents CR 3 and X4 represents CR 6 .
  • Xi represents CR 3
  • X 2 represents CR» or N
  • X 3 represents CR 5 or N
  • X represents CR ⁇ , in which one of the groups selected from X 2 or X 3 represents N and the other represents CRj or CR 5 , respectively.
  • R 3 , R4, R 5 and R6 each independently represent H, C
  • R 3 , R4, R 5 and R6 each independently represent H, C
  • R 3 typically represents H.
  • R4 represents H or -NR 7 R «.
  • R4 may represent H, or methylamino or 3-methoxypyrrolidin-l-yl.
  • R4 represents H.
  • R 5 represents H, Ci -6 alkoxy or -NR 7 R 8 .
  • R 5 typically represents H, methoxy, methylamino, pyrrolidin-1 -yl, 3- fluoropyrrolidin-l-yl or 3-methoxypyrrolidin-l -yl.
  • R5 may also represent 3-methoxyazetidin-l - yl or 3-methoxy-3-methylazetidin-l-yl.
  • R 5 represents -NR 7 R 8 .
  • R 5 represents 3- methoxypyrrolidin-l-yl.
  • R 5 represents 3-methoxyazetidin-l -
  • 3 ⁇ 4 represents H or -NR 7 R 8 .
  • 3 ⁇ 4 typically represents H or methylamino.
  • R$ represents H. i
  • R 7 and R 8 independently represent H or Ci -6 alkyl, or R 7 and R 8 and the N atom to which they are attached are joined to form a N-containing heterocyclyl ring, optionally substituted with one or more substituents independently selected from halogen and Ci-6 alkoxy.
  • R 7 represents C
  • R 8 represents H.
  • R 7 and R 8 and the N atom to which they are attached are joined to form a pyrrolidinyl ring, optionally substituted with one or more substituents independently selected from halogen, such as fluorine, or Ci -6 alkoxy, such as methoxy.
  • R and R 8 and the N atom to which they are attached are joined to form a pyrrolidinyl ring, wherein the pyrrolidinyl ring is unsubstituted, or substituted at the 3 position as represented in formula (2):
  • R 9 represents H, halogen or Ci -6 alkoxy and when R 9 is other than H, * represents a chiral centre.
  • R 9 represents H, fluorine or methoxy.
  • R 9 when R 9 is other than H, * represents ,the (R) enantiomer. In another embodiment when R is other than H, * represents the (S) enantiomer. In a further embodiment when R 9 is other than H, * represents a racemic mixture.
  • compounds of the invention may have the form of the (S) enantiomer at these other chiral centre(s).
  • compounds of the invention are in the form of the (R) enantiomers at these other chiral centre(s), or are present as racemic mixtures with respect to these chiral centre(s).
  • the compounds of the invention may be present in each chiral combination (e.g. (S,S), (R,S), (S,R) or (R,R).
  • R 9 represents H, fluorine or methoxy. In such instances, R 9 may in particular represent H. In alternative such instances, R 9 may represent F. In yet further such instances, R 9 may represent methoxy.
  • R 7 and R 8 and the N atom to which they are attached are joined to form an azetidinyl ring, optionally substituted with one or more substituents independently selected from halogen, Ci -6 alkyl and Ci alkoxy.
  • substituents independently selected from halogen, Ci -6 alkyl and Ci alkoxy.
  • the optional substituents are selected from Ci -6 alkyl, such as methyl, and Ci- alkoxy, such as methoxy.
  • R 7 and Rg and the N atom to which they are attached are joined to form an azetidinyl ring, wherein the azetidinyl ring is substituted at the 3 position as represented in formula (3):
  • R ⁇ represents methoxy
  • Rn represents H. In other certain embodiments, Rn represents methyl.
  • X 2a represents CR4 a or N
  • X 3a represents CR 5a or N
  • X 2a represents N
  • X 3a represents CR 5a
  • X 2a represents CRs a
  • X 3a represents N
  • R 4a and R 5a each independently represent H, C i -6 alkoxy, typically methoxy, or -NR 7 R 8 .
  • R4 a represents H or -NR 7 R 8 .
  • R 4a may represent H, methylamino, pyrrolidin-l-yl, 3-fluoropyrrolidin-l-yl or 3-methoxypyrrolidin-l-yl.
  • R_ia represents H.
  • R 5a represents H, C ) . alkoxy, typically methoxy, or -NR7R8 In particular, R 5a typically represents H, methoxy, methylamino, pyrrolidin-l-yl, 3- fluoropyrrolidin-l-yl or 3-methoxypyrrolidin-l-yl. R 5a may also represent 3-methoxyazetidin- 1-yl or 3-methoxy-3-rnethylazetidin-] -yl.
  • R 5a represents -NR 7 R 8 .
  • R 5a may in particular represent 3-methoxypyrrolidin-l-yl.
  • R 5a represents 3- methoxyazetidin- 1 -yl.
  • R3 ⁇ 4b and R 6b are as herein defined for R 5 and R6 respectively;
  • X4b represents CR ⁇ . In some other embodiments, 3 ⁇ 4b represents N. R 6b typically represents H.
  • R 5b represents H, C )-6 alkoxy, typically methoxy, or -NR 7 R 8 .
  • R 5b typically represents H, methoxy, methylamino, pyrrolidin-l-yl, 3- fluoropyrrolidin-l-yl or 3-methoxypyrrolidin-l-yl.
  • R 5 b may also represent 3-methoxyazetidin-l - yl or 3-methoxy-3-methylazetidin-l-yl.
  • R 5 b represents -NR7R8.
  • R 5b may in particular represent 3-methoxypyrrolidin-l-yl.
  • Rs b represents 3- methoxyazetidin- 1 -yl.
  • Particularly useful compounds in accordance with the invention include each of the compounds described in the accompanying examples, and pharmaceutically acceptable salts thereof.
  • the compound of formula (1) is selected from the group consisting of:
  • the compound of formula (1) is selected from the group consisting of:
  • a pharmaceutical composition comprising a compound according to the first aspect of the invention, together with one or more pharmaceutically acceptable excipients.
  • compositions of this invention comprise any of the compounds of the first aspect of the present invention, or pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle.
  • Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates,
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as that described in Ph. Helv, or a similar alcohol.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.
  • compositions of this invention may also be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
  • the compounds of the present invention may be administered in a dose of around 1 to around 20,000 ⁇ g/kg per dose, depending on the condition to be treated or prevented, and the characteristics of the subject being administered with the compound. In many instances, the dose may be around 1 to around 1500 ⁇ g/kg per dose.
  • the dosing regimen for a given compound could readily be determined by the skilled person having access to this disclosure.
  • the pharmaceutical composition of the invention additionally comprises one or more additional active pharmaceutical ingredients.
  • additional active ingredients may be agents known to the skilled person to be useful in the treatment or prevention of the diseases mentioned in the present disclosure.
  • the present invention provides a compound according to the first aspect of the invention, or a composition according to the second aspect, for use in therapy.
  • the invention provides a compound according to the first aspect of the invention, or a composition according to the second aspect, for use in the treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity.
  • the invention also provides a method of treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity, the method comprising the administration, to a subject in need of such treatment or prevention, of a therapeutically effective amount of a compound according to the first aspect of the invention, or a composition according to the second aspect.
  • the condition to be treated may be selected from sleep disorders (such as narcolepsy and hypersomnia), cognitive disorders (such as dementia and schizophrenia), attentional disorders (such as attention deficit hyperactivity disorder), neurodegenerative disorders (such as AD), schizophrenia, epilepsy, pain (such as neuropathic pain) and obesity.
  • sleep disorders such as narcolepsy and hypersomnia
  • cognitive disorders such as dementia and schizophrenia
  • attentional disorders such as attention deficit hyperactivity disorder
  • neurodegenerative disorders such as AD
  • schizophrenia epilepsy
  • pain such as neuropathic pain
  • obesity such as narcolepsy and obesity.
  • the condition may be selected from narcolepsy, neuropathic pain and obesity.
  • the present invention provides the use of a compound according to the first aspect of the invention in the preparation of a medicament for the treatment or prevention of a condition whose development or symptoms are linked to histamine H3 receptor activity.
  • a condition whose development or symptoms are linked to histamine H3 receptor activity.
  • Such conditions may be selected from those described above.
  • Novel intermediates form a further aspect of the invention.
  • Nuclear magnetic resonance (NMR) spectra were recorded at 400MHz; the chemical shifts ( ⁇ ) are reported in parts per million. Spectra were recorded using a Bruker 400 Avance instrument fitted with a 5mm BBFO probe or DUL probe. Instrument control was by Bruker TopSpin 2.1 software.
  • Preparative HPLC was performed using an Agilent Technologies 1 100 Series system typically using Waters 19mm id x 100mm long C18 columns such as XBridge or SunFire 5 ⁇ materials at room temperature.
  • Mobile phases typically consisted of acetonitrile or methanol mixed with water containing either 0.1% formic acid or 0.1% ammonia.
  • Room temperature in the following schemes means the temperature ranging from 20°C to 25°C.
  • Schemes 1.1 - 1.12 serve to illustrate the methodologies that may be used to synthesize the exemplified compounds of formula (1) and the intermediates. 1. Schemes:
  • Reagents a) CI 2 CHOCH 3 , AICI 3 / PhN0 2 ; b) eONH 2 HCI
  • Benzazepine intermediate (1) can be prepared by methods outlined in WO 2005/058328 and WO 2005/094834.
  • the reaction mixture was diluted with EtOAc (280 ml) and undissolved material was filtered The layers of the biphasic filtrate were separated and the aqueous layer extracted with EtOAc (140 ml). The combined organic layers were washed with brine (140 ml), and then dried over MgS0 . The solvent was evaporated under reduced pressure to afford yellow oil (31 g). This was dissolved in IPE (62 ml) and then hexane (124 ml) was added dropwise with stirring.
  • reaction mixture was extracted with EtOAc (90 ml x 2) and combined organic layers were washed with brine (90 ⁇ ), and then dried over MgS0 4 .
  • the solvent was evaporated under reduced pressure to give light brown syrup, which was treated with hexane (70 ml) to afford white precipitate.
  • the obtained precipitate was collected by filtration and washed with hexane (20 ml), and then was dried under reduced pressure to give /er/-butyl ⁇ [3-(trifluoroacetyl)-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl]methyl ⁇ carbamate as white powder (21.0 g, 94 %).
  • Reagents and conditions a) NBS, (PhCOOfe. eOAc, MW. 130 °C; b) 1-(7-(aminomethyl)-4,5-dihydro-1H-3-benzazepin-3(2H)-yl)-2,2,2- trifluoroethanone HCI (Int 4), DIPEA, DMF, 100 °C; c) Sodium carbonate, methanol and then cyclobutanone, sodium triacetoxyborohydride, acetic acid
  • Reagents and conditions a) i) nBuLi, 2,2,6,6-tetramethylpiperidine, THF, -55 °C-25 °C ii) DMF;
  • Reagents and conditions a) nBuLi, TMP, N-methoxy-N-methylacetamide, THF, -78 °C - 0 °C, 6 h;
  • Reagents and conditions a) triethylorthoformate, Ac 2 0, 130 °C, 5 h; b) 2-Methyl-2-thiopseudourea hemisulfate salt, sodium acetate, DMF, 80 °C, 3.5 h; c) Br 2 , AcOH, 60 °C, 1.5 h; d) DIPEA, DMF, r.t., 67 h; e) mCPBA, 3-methoxyazetidine hydrochloride, DIPEA, DCM, 0 °C-r.t, 5 h; f) 2.0 M NaOH, MeOH, r.t., 16 h; g) cyclobutanone, AcOH, NaBH(OAc) 3 , DCM, r.t., 90 min; h) (S)-3-methoxypyrrolidine hydrochloride, NaH, DIPEA, 2-feri-butyl-1 ,1,3,3-te
  • the reaction was then treated with AcOH (200 ⁇ , 3.49 mmol) and cyclobutanone (100 ⁇ , 1.34 mmol) and stirred under nitrogen for 1 h before portionwise addition of sodium triacetoxyborohydride (0.25 g, 1.18 mmol) and subsequent stirring for 4 h. Further cyclobutanone (100 ⁇ , 1.34 mmol) and sodium triacetoxyborohydride (150 mg) were added and the reaction stirred under nitrogen for 20 h. The reaction was evaporated to dryness, sodium bicarbonate solution (30 ml) was added and the organics extracted with DCM (x 3), dried using an hydrophobic frit and evaporated to dryness.
  • the crude product was purified by column chromatography (Si0 2 ; 0-10 % MeOH containing 3 % NH4OH/DCM) and then by reverse phase chromatography (C 18; 5 - 100 % (MeOH + 2% 2M ammonia) in water) to yield 6-((3-cyclobutyl-2,3,4,5-tetrahydro-l H-3-benzazepin-7- yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (58 mg, 27 %).
  • Example 4 The compound according to Example 4 was prepared in a similar manner to the methodology described for Example 3, starting from commercially available methyl 3-methylpicolinate.
  • Example 5 The compound according to Example 5 was prepared in a similar manner to the methodology described for Example 3 starting from ethyl 3-methylisonicotinate.
  • Example 9 The compound according to Example 9 was prepared in a similar manner to the methodology described for Example 7 using pyrrolidine instead of methanamine.
  • ⁇ NMR (400 MHz, MeOD-d4) ⁇ 8.44 - 8.57 (s, 1H), 7.02 - 7.16 (m, 3H), 6.51 - 6.59 (s, 1H), 4.62 - 4.71 (s, 2H), 4.26 - 4.38 (s, 2H), 3.46 - 3.59 (m, 4H), 2.79 - 2.98 (m, 5H), 2.37 - 2.58 (m, 4H), 2.02 - 2.18 (m, 6H), 1.85 - 2.00 (m, 2H), 1.62 - 1.80 (m, 2H).
  • Example 1 1 The compound according to Example 1 1 was prepared in a similar manner to the methodology described for Example 10 starting from (S)-3-fluoropyrrolidine hydrochloride.
  • Example 13 The compound according to Example 13 was prepared in a similar manner to the methodology described for Example 12 starting from (R)-3-methoxypyrrolidine hydrochloride.
  • the crude product was purified by KP-C18-HS Biotage SNAP cartridge eluting with 5-100 % acetonitrile + 0.05 % formic acid / water + 0.1 % formic acid.
  • the crude product was further purified by column chromatography using basic silica eluting with 0-15 % MeOH in DCM to yield 4-formyl-2-(methylsulfanyl)pyrimidine-5-carboxylic acid (0.93 g, 37 %).
  • the reaction was stirred for 3.5 h at -20 °C to -30 °C.
  • the reaction mixture was poured onto ice and acidified with 10 % aq. citric acid and extracted with ethyl acetate.
  • the organic layer was washed with brine, dried over MgS0 4 and evaporated to dryness to yield crude 4-acetyl-6-chloronicotinic acid as an orange gum which was used directly in the next step (12.67 g, quantitative).
  • reaction was then heated to 60 °C for 3 h.
  • the reaction mixture was cooled and concentrated under reduced pressure.
  • DCM and saturated sodium bicarbonate solution were added and the titanium salts were filtered, washing with copious volumes of DCM.
  • the layers were separated and the aqueous further extracted with DCM and the combined organics were washed with 10% aq. citric acid, dried over MgSC ⁇ and concentrated under reduced pressure.
  • Example 18 2-[(3-Cyclobutyl-2,3,4,5-tetrahydro-lH-3-benzazepin-7-yl)methyl]-6-(3-methoxyazetidin-l - yl)-l,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one
  • the compound according to Example 18 was prepared in a similar manner to the methodology described for Example 12 starting from 3-methoxyazetidine hydrochloride.
  • Example 19 The compound according to Example 19 was prepared in a similar manner to the methodology described for Example 12 starting from 3-methoxy-3-methylazetidine hydrochloride.
  • 6-(3-methoxyazetidin-l -yI)-2-((3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-l H- 3-benzazepin-7-yl)methyl)-l H-pyrrolo[3,4-c]pyridin-3(2H)-one (Int 23) (3.21 g, 6.77 mmol) in MeOH (22.5 ml) was added 2 M NaOH (10 ml, 20 mmol).
  • reaction mixture was diluted with DCM (20 ml) then 3-methoxyazetidine hydrochloride (2.1 1 g, 17.1 mmol) and DIPEA (7 ml, 39.9 mmol) were added and the reaction stirred for 90 min.
  • the reaction mixture was washed with 10 % aq. citric acid and extracted with DCM (x 3).
  • Example 23 A solution of (S)-2-(3-Methoxypyrrolidin-l-yl)-6-((3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro- lH-3-benzazepin-7-yl)methyl)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-5-one (Int 31) (576 mg, 1.18 mmol) in EtOH (10 ml) was treated with 8 M NaOH (0.29 ml, 2.35 mmol) and stirred at r.t. for 1 h.
  • Example 24 The compound according to Example 24 was prepared in a similar manner to the methodology described for Example 23 in Scheme 12 starting from Intermediate 28 and (R)-3- methoxypyrrolidine hydrochloride.
  • Example 25 The compound according to Example 25 was prepared in a similar manner to the methodology described in Scheme 1 1 starting from Intermediate 30 and iodoethane.
  • the ability of compounds to bind to the H3 receptor was determined by measuring the reduction in tritiated N-a-methyl-histamine ( 3 H-No MH) binding in a competition binding assay. Changes in the levels of bound radio-label were monitored by scintillation counting with a Trilux Microbeta (Perkin Elmer).
  • Membranes were prepared from CHO-KI cells stably expressing human H3 receptor; routinely grown as monolayers in Ham's F12 medium (Invitrogen) supplemented with 10% Foetal Clone III (Hyclone), 500 ⁇ g/ml G418 (Invitrogen), 5 ⁇ g/ml blasticidine S (Invivogen) and 50 ⁇ g/ml Gentamicin (Sigma) in 5% C0 2 at 37°C. Cells were grown to 80-95% confluency, rinsed once with lx PBS (Invitrogen) and detached by incubating with lx .PBS containing 0.02% EDTA (Sigma) for 10 m at room temperature.
  • Cells were collected by centrifugation at 900 xg, 4°C for 10 min. Cells were rinsed once with lx PBS and re-suspended in ice cold homogenisation buffer (50mM Tris-HCl (pH 7.4), 2.5mM EDTA, 5mM MgCl 2) 200mM Sucrose) at lxlO 7 cells/ml and kept on ice. Cells were homogenised on ice and debris removed by centrifugation at 500 x g, 4°C for 5 min. The resulting supernatant was centrifuged at 75,600 xg, 4°C for 60 min. Membranes were suspended in homogenisation buffer, protein concentration was determined (BCA Protein Assay kit (Pierce)), diluted to 2.2 mg/ml, dispensed into 1ml aliquots and stored at -80 °C.
  • BCA Protein Assay kit Pieris
  • Membranes were thawed on ice, sonicated with 4 cycles of 20 pulses (50% amplitude, 0.5 pulse) (UP200S Hielscher) on ice, diluted in assay buffer (50mM Tris-HCl (pH7.4), 5mM MgCl 2 ) to 62.5 ⁇ g/ml. Compound was serially diluted in DMSO before being diluted 1 : 10 with assay buffer. 5 ⁇ g of membrane in 80 ⁇ of assay buffer was added per well of a 96 well polystyrene plate (Corning). 10 ⁇ of compound was added per well.
  • the assay was initiated by the addition of 10 ⁇ of 20nM 3 H-NaMH per well and incubated for one h at room temperature with shaking. Total binding was determined in the presence of 1% DMSO and non-specific binding was determined by the inclusion of 1 ⁇ R-a-methyl-histamine (RaMH). Incubations were then filtered through filtermat A (Perkin Elmer) and washed three times with assay buffer. Filtermats were dried at 42°C for two h, scintillant added and the level of bound radioactivity determined.
  • IC50 values for compounds were determined from seven point log scale dose-response studies and represent the concentration of compound required to inhibit 50% of the specific binding of 2nM 3 H-NaMH (difference between total and non-specific binding). Curves were generated using the average of duplicate wells for each data point and analyzed using nonlinear regression of sigmoidal dose response (variable slope).
  • the functional activity of compounds at the H3 receptor was determined by measuring changes in the level of intracellular cAMP using a cAMP response element driven luciferase reporter assay. The changes in luciferase expression were monitored by a luminescence plate reader, Analyst HT (MDS Analytical). Increases in intracellular cAMP were readily detected upon activation of protein kinase A by forskolin (Sigma) and suppression of this response observed with the application of the H3 receptor agonist RaMH (Sigma).
  • CHO(dhfr + )-cre-luc cells stably expressing human H3 receptor were routinely grown as monolayers in Minimal Essential Medium a (MEMa) (Invitrogen) supplemented with 10% dialysed FBS (Hyclone), in 5% C0 2 at 37°C. 48 h prior to assay, cells were seeded in clear- base white walled 384-well plates (Corning) at a density of 5000 cells/well. On the day of assay, growth media was removed and replaced with 15 ⁇ of assay buffer (MEMa, 5 mg/ml fatty acid free BSA (Sigma)) per well. Cells were then incubated for 30 m at 37°C, 5% C0 2 .
  • MEMa Minimal Essential Medium a
  • FBS dialysed FBS
  • Compound was serially diluted in DMSO before being diluted 1 :10 with assay buffer.
  • 2.5 ⁇ of compound diluted in assay buffer was added and cells incubated for 5 m at 37°C, 5% C0 2 .
  • 2.5 ⁇ of each reagent was then added in the following order: RaMH (10 nM), isobutylmethylxanthine (l -methyl-3-(2-methylpropyl)-7H-purine-2,6-dione; IBMX) (500 ⁇ ) (Sigma) and forskolin (1 ⁇ ).
  • Cells were then incubated for 90 m at 37°C, 5% C0 2 , followed by 30 m at room temperature.
  • IC J O values for compounds were determined from ten point half log scale dose-response studies and represent the concentration of compound required to prevent 50% inhibition of forskolin stimulated cells in the presence of RaMH alone. Curves were generated using the average of duplicate wells for each data point and analyzed using nonlinear regression of four parameter dose response.
  • the compounds of the invention have potent antagonist or inverse agonist activity at the H3 receptor, both in terms of binding and in terms of inhibition of the functional response caused by receptor activation.
  • the compounds tested above exhibit IC 50 values significantly less than 1 ⁇ , with the compounds showing low nanomolar affinity at the H3 receptor. Accordingly, the compounds of the invention are expected to have usefulness in the prevention or treatment of conditions, such as those discussed above, in which H3 receptor activity is implicated.
  • the compounds of the present invention may possess variously advantageous pharmacological and/or toxicological profiles, when tested in a variety of standard tests for such parameters.
  • the compounds of the invention may exhibit one or more potentially useful properties for in vivo use, when characterised by pharmacological and/or toxicological tests including: HERG interaction (which is an indication of potential cardiotoxicity, and measures the effects of the compounds on the human ether-a-go-go-related gene, using for example the PatchXpress 7000A platform); CypP 50 interactions (which may be measured in accordance with the FDA draft guidelines for drug interaction studies (study design, data analysis and implications for dosing and labeling) (Sep.
  • HERG interaction which is an indication of potential cardiotoxicity, and measures the effects of the compounds on the human ether-a-go-go-related gene, using for example the PatchXpress 7000A platform
  • CypP 50 interactions which may be measured in accordance with the FDA draft guidelines for drug interaction studies (study design, data analysis and implications for dosing and labeling) (Sep.
  • phototoxicity for example using a protocol in accordance with assay details outlined in the OECD guidelines for testing of chemicals: 432 In Vitro 3T3 Neutral Red Uptake phototoxicity test, April 2004); determination of pharmacokinetic parameters (for example following in vivo dosing via multiple routes, with plasma concentrations of compounds being determined from venous blood samples using an LC-MS/MS protocol); and in vivo receptor occupancy (determined, for example, using protocols based on Medhurst et al., Journal of Pharmacology and Experimental Therapeutics, 2007, 321, 1032). These standard tests for the characterisation of drug molecules are well known to the skilled person.
  • Witkin JM Nelson DL. Selective histamine H3 receptor antagonists for treatment of cognitive deficiencies and other disorders of the central nervous system. Pharmacol. Ther. 2004;103: 1-20 6. Monti J.M et al. Effect of Selective activation or blockade of the hitamine H3 receptor on sleep and wakefulness. 1991 Eur. J. Pharmacol.205, 283-287.

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Abstract

La présente invention concerne un composé de formule (1) dans laquelle : Ra représente un alkyle en C1 à C6, un cyclobutyle ou un cyclopentyle ; R1 représente H ou un alkyle en C1 à C6 ; R2 représente H ou R1 et R2 représentent conjointement =0 ; X1 représente CR3 ou N ; X2 représente CR4 ou N ; X3 représente CR5 ou N ; X4 représente CR6 ou N ; un ou deux parmi les X1, X2, X3 et X4 représentant N ; R3, R4, R5 et R6 représentant chacun indépendamment H, un alcoxy en C1 à C6 ou -NR7R8 ; R7 et R8 représentant indépendamment H ou un alkyle en C1 à C6 ; ou R7 et R8 et l'atome d'N auxquels ils sont liés sont reliés pour former un hétérocycle contenant N éventuellement substitué par un ou plusieurs substituants indépendamment choisis parmi un halogène, un alkyle en C1 à C6 ou un alcoxy en C1 à C6 ; ou un sel pharmaceutiquement acceptable de celui-ci. Les composés de l'invention se sont avéré moduler le récepteur H3 de l'histamine.
PCT/GB2011/000016 2010-01-08 2011-01-07 Dérivés de la benzazépine destinés à traiter des troubles du système nerveux central WO2011083316A1 (fr)

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US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
KR20150006001A (ko) * 2012-04-25 2015-01-15 라퀄리아 파마 인코포레이티드 Ttx-s 차단제로서의 피롤로피리디논 유도체
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
CN106866659A (zh) * 2017-01-05 2017-06-20 浙江宏冠生物药业有限公司 2‑取代‑4‑卤‑2,3‑二氢‑1H‑吡咯[3,4‑c]吡啶‑1‑酮的制备方法
WO2023101543A1 (fr) * 2021-12-03 2023-06-08 서울대학교 산학협력단 Nouveau phosphore synthétisé à partir d'une substance naturelle et son procédé de préparation

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8829041B2 (en) 2006-06-23 2014-09-09 Abbvie Inc. Cyclopropyl amine derivatives
US9108948B2 (en) 2006-06-23 2015-08-18 Abbvie Inc. Cyclopropyl amine derivatives
US9186353B2 (en) 2009-04-27 2015-11-17 Abbvie Inc. Treatment of osteoarthritis pain
US8853390B2 (en) 2010-09-16 2014-10-07 Abbvie Inc. Processes for preparing 1,2-substituted cyclopropyl derivatives
KR20150006001A (ko) * 2012-04-25 2015-01-15 라퀄리아 파마 인코포레이티드 Ttx-s 차단제로서의 피롤로피리디논 유도체
JP2015514679A (ja) * 2012-04-25 2015-05-21 ラクオリア創薬株式会社 Ｔｔｘ−ｓ遮断薬としてのピロロピリジノン誘導体
EP2841435A4 (fr) * 2012-04-25 2015-11-11 Raqualia Pharma Inc Dérivés de pyrrolopyridinone en tant que bloquants des ttx-s
US9187475B2 (en) * 2012-04-25 2015-11-17 Raqualia Pharma Inc. Pyrrolopyridinone derivatives as TTX-S blockers
RU2646754C2 (ru) * 2012-04-25 2018-03-07 Раквалиа Фарма Инк. Производные пирролопиридинона в качестве ttx-s блокаторов
KR102090944B1 (ko) 2012-04-25 2020-03-19 라퀄리아 파마 인코포레이티드 Ttx-s 차단제로서의 피롤로피리디논 유도체
CN106866659A (zh) * 2017-01-05 2017-06-20 浙江宏冠生物药业有限公司 2‑取代‑4‑卤‑2,3‑二氢‑1H‑吡咯[3,4‑c]吡啶‑1‑酮的制备方法
WO2023101543A1 (fr) * 2021-12-03 2023-06-08 서울대학교 산학협력단 Nouveau phosphore synthétisé à partir d'une substance naturelle et son procédé de préparation

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