WO2000002878A1 - Composes possedant une activite sur les recepteurs d'imidazoline - Google Patents

Composes possedant une activite sur les recepteurs d'imidazoline Download PDF

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Publication number
WO2000002878A1
WO2000002878A1 PCT/GB1999/002218 GB9902218W WO0002878A1 WO 2000002878 A1 WO2000002878 A1 WO 2000002878A1 GB 9902218 W GB9902218 W GB 9902218W WO 0002878 A1 WO0002878 A1 WO 0002878A1
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WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
alkenyl
compound
compounds
Prior art date
Application number
PCT/GB1999/002218
Other languages
English (en)
Inventor
Alan T. Hudson
Original Assignee
University Of Bristol
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9815010.5A external-priority patent/GB9815010D0/en
Priority claimed from GBGB9902586.8A external-priority patent/GB9902586D0/en
Application filed by University Of Bristol filed Critical University Of Bristol
Priority to AU49190/99A priority Critical patent/AU4919099A/en
Publication of WO2000002878A1 publication Critical patent/WO2000002878A1/fr

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Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

Definitions

  • This invention relates to the use of a class of compounds as selective ligands for imidazoline receptors.
  • the invention relates to the use of ⁇ -carbolines and their derivatives for treating diseases or disorders as a result of their activity at imidazoline receptors.
  • I imidazoline
  • l site ligands There are few selective l site ligands, most having a degree of affinity for ⁇ 2 -adrenoceptors; however, their I,- over l 2 -site selectivity is generally good.
  • the oxazoline compound rilmenidine which is chemically related to clonidine, is an antihypertensive agent which lacks the sedative effects of clonidine and shows selectivity for the I,- site.
  • l sites In addition to their brainstem location where they modulate blood pressure, l sites have also been identified in bovine frontal cortex and in rat locus coeruleus where their activation increases spontaneous neuronal firing.
  • l sites have also been reported in rat kidney, where they function to increase water and sodium excretion, in human platelets, where they are a marker of depression and dysphoric premenstrual syndrome and in rat pancreatic ⁇ cells where they mediate insulin secretion in response to efaroxan.
  • l 2A -amiloride sensitive and l 2B -amiloride insensitive sites.
  • l 2 -sites are widely distributed throughout mammalian brain and periphery. In rat brain l 2 -sites are localised to distinct brain nuclei such as interpeduncular nucleus, arcuate and pineal gland, whereas they are more widespread in rabbit and human brain. At the subcellular level they are associated with the mitochondrial fraction of membranes prepared from brain, liver, kidney, heart and striated muscle.
  • l 2 -sites The function of l 2 -sites is still not clear. This is due in part to the lack of selective ligands since most have affinity for ⁇ 2 - adrenoceptors or some other family of receptors. The following are a few examples of proposed functions.
  • l 2 -site activation inhibits Na + uptake into renal tubule cells.
  • l 2 -site activation leads to an increase in levels of mRNA for glial fibrillary acidic protein (GFAP) .
  • GFAP glial fibrillary acidic protein
  • l 2 -sites regulate levels of GFAP and that chronic treatment of rats with an l 2 -site selective compound, (2-(- benzofuranyD-imidazole) (2BFI), increased GFAP immunoreactivity in cerebral cortex.
  • This association with GFAP is of great interest since the brain density of l 2 -sites in man increases with age and idazoxan's neuroprotective effects following brain ischaemia are proposed to be mediated via l 2 -sites.
  • An l 2 -site selective compound has been noted to increase food consumption in rats, which may indicate a role for l 2 - sites in appetite.
  • the present invention is based on the discovery of a class of compounds which have high affinity for imidazoline receptors, even though they do not contain an imidazoline (or related) group.
  • the present invention provides the use of a compound of formula (1 ) in the manufacture of a medicament for the treatment or prevention of a disease or a disorder by selective action at an imidazoline receptor, wherein formula ( 1 ) is:
  • R is hydrogen, Z ⁇ to C 6 alkyl, C, to C 7 acyl, C, to C 6 alkyloxycarbonyl, C 2 to C 6 alkenyl, C 2 to C 6 alkenylcarbonyl or
  • C 2 to C 6 alkenyloxycarbonyl A is a ring forming a fused ring system with the ring containing X and is selected from
  • R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are independently selected from:
  • R' is hydrogen, C, to C 6 alkyl, C, to C 7 acyl, C, to C 6 alkyloxycarbonyl, C 2 to C 6 alkenyl, C 2 to C 6 alkenylcarbonyl or
  • the compounds of the invention have surprising affinity and/or selectivity for imidazoline I, and l 2 receptors relative to other receptor types and, therefore, are useful in the treatment or prevention of all diseases or disorders in which agonist or antagonist activity at these sites is pharmacologically useful.
  • Diseases or disorders which may benefit from treatment in this way include, for example: hypertension; Alzheimer's disease; Parkinson's disease; Huntington's chorea; other neurological disorders, such as depression, anxiety and eating disorders; opiate addiction; and diabetes.
  • the compounds may be used as neuroprotective agents, following brain ischaemia or in the treatment of other neuronal injuries, for increasing water and/or sodium excretion or as MAO inhibitors.
  • the compounds of the invention may have a greater affinity or selectivity for one imidazoline subtype over another (e.g., greater for I T than l 2 or for l 2 than I,) or may have substantially equal affinity and selectivity for both l and l 2 -sites.
  • X is NH and the compounds are based on a ⁇ - carboline ring system.
  • R 3 is preferably selected from the groups mentioned under (i) and (iii) above.
  • R 6 is preferably hydrogen.
  • R 1 , R 2 , R 4 , R 5 and R 6 are all hydrogen.
  • R 3 are either hydrogen or hydroxyl (OH), most preferably hydrogen.
  • R 7 is preferably hydrogen or C, to C 6 alkyl e.g., methyl.
  • R' when present, is preferably hydrogen.
  • compounds (A) and (B) are particularly preferred on account of their high affinity and selectivity for l 2 sites; and compound (C) for its selectivity for both I, and l 2 sites over other receptors.
  • the present invention also contemplates a method of treating or preventing a disease or disorder of an animal or human of the types mentioned above, comprising the administration to a patient of a pharmacologically effective amount of a compound of formula ( 1 ), as defined above.
  • alkyl as used herein is intended to cover groups having straight and branched chains and, for C 3 to C 6 groups, optionally substituted alicyclic rings, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, for example.
  • acyl alkenyl
  • alkynyl are defined similarly, the difference being that they comprise a terminal carbonyl group, one or more carbon-carbon double bonds and one or more carbon-carbon triple bonds, respectively.
  • Halo means fluoro, chloro, bromo or iodo.
  • aryl covers aromatic, carbocyclic and heterocyclic, monocyclic and polycyclic ring systems such as phenyl and naphthyl, for example.
  • Aralkyl means C, to C 6 alkyl substituted with aryl e.g., benzyl.
  • the compounds may be used as one enantiomer, a mixture enriched in one enantiomer or as a racemic mixture.
  • the compounds of the invention may be in the form of prodrugs, such as in vivo hydrolysable esters or amides, or pharmaceutically acceptable salts such as acid addition salts (e.g., hydrochlorides) and, where the compounds contain an acidic functional group, acid salts.
  • prodrugs such as in vivo hydrolysable esters or amides
  • pharmaceutically acceptable salts such as acid addition salts (e.g., hydrochlorides) and, where the compounds contain an acidic functional group, acid salts.
  • Certain of the compounds, and their salts, are known to form solvates and these solvates may also be used in the invention.
  • Preferred solvates are the hydrates.
  • the compounds may be formulated in conventional ways for use in the invention. While it is possible to administer the compounds of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical formulation comprising a pharmaceutically acceptable excipient and at least one compound of the invention. Such compositions contain from about 0.1 % by weight to about 90.0% by weight of the compound.
  • the compound is usually mixed with an excipient which can be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • an excipient which can be a carrier, or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the carrier serves as a diluent, it can be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the compound.
  • the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, emulsions, solutions, syrups, suspensions, aerosols (as a solid or in a liquid medium), and soft and hard gelatin capsules.
  • the compounds of the invention may be delivered transdermally, if desired.
  • Transdermal permeation enhancers and delivery systems including patches and the like, are well known to those skilled in the art.
  • Suitable carriers, excipients, and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, calcium silicate, microcrystalline cellulose, polyvinylp ⁇ rrolidone, cellulose, tragacanth, gelatin, syrup, methyl cellulose, methyl- and propylhydroxy- benzoates, talc, magnesium stearate, water, and mineral oil.
  • the formulations may also include wetting agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • a compound of this invention ideally can be admixed with carriers and diluents and moulded into tablets or enclosed in gelatin capsules.
  • the compounds of the invention exhibit selectivity for I, and l 2 receptors. Some of the compounds show further selectivity for l 2 receptors over ⁇ receptors.
  • selectivity means that the compounds show a higher affinity for the imidazoline receptors than for other receptors which are present in the human or animal body in the same region. For example, the compounds exhibit a higher affinity for I, and l 2 sites than benzodiazepine sites in the mammalian brain.
  • kidney P 2 membranes were prepared from male Wistar rats (250g) by homogenisation in ice-cold buffer (20 vol 50mM Tris-HCI, pH7.4), and washed twice by repeated centrification. For I, binding, aliquots of kidney membrane (0.5mg protein/ml) were incubated (45 min, 22 ° C) in triplicate with 3nM [ 3 H]clonidine (in the presence of 1 0 mM rauwolscine to preclude ⁇ 2 - adrenoceptor binding) alone or with increasing concentrations of the test compounds.
  • the ⁇ -carbolines were examined for their ability to compete with [ 3 HJ2BFI over the range of 0.01 nM-1 mM. Bound ligand was separated by rapid filtration and determined by liquid scintillation counting. Results were analysed by Prism (GraphPAD Software, 1 994) . Agmatine was of low affinity whereas the precursor of the ⁇ - carbolines, tryptamine, demonstrated reasonable affinity with a K, of 3 ⁇ M.
  • harmane (C) showed the highest affinity for l 2 sites with a K,H of 9.7 nM.
  • harmine (D) and harmaline (E) also demonstrated very high affinity for around 50% of labelled sites (Table 2) .
  • Ethyl ⁇ -carboline-3-carboxylate ( ⁇ -CCE) displaced from an apparent single site with very low affinity (Table 2).
  • Harmaline (E) 1 2.5 ⁇ 2.9 3 6650.7+1 104.7 3 ⁇ -CCE 7661 7 ⁇ 2978 3
  • Data are mean K, values + s.e.mean derived from three to four experiments performed in triplicate.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'un composé de la formule (1) dans la production d'un médicament destiné au traitement ou à la prévention d'une affection ou d'un trouble, par action sélective sur un récepteur d'imidazoline. Dans la formule selon l'invention, X représente NR, O ou S; R représente un hydrogène, un alkyle en C1 à C6, un acyle en C1 à C7, un alkyloxycarbonyle en C1 à C6, un alcényle en C2 à C6, un alcénylcarbonyle en C2 à C6 ou un alcényloxycarbonyle en C2 à C6 ; A représente un cycle formant un système de cycles accolés avec le cycle contenant X et est sélectionné dans le groupe formé par (a), (b) et (c).
PCT/GB1999/002218 1998-07-11 1999-07-12 Composes possedant une activite sur les recepteurs d'imidazoline WO2000002878A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU49190/99A AU4919099A (en) 1998-07-11 1999-07-12 Compounds having activity at imidazoline receptors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9815010.5 1998-07-11
GBGB9815010.5A GB9815010D0 (en) 1998-07-11 1998-07-11 Compounds having activity at imidazoline receptors
GB9902586.8 1999-02-06
GBGB9902586.8A GB9902586D0 (en) 1999-02-06 1999-02-06 Compounds having activity at imidazoline receptors

Publications (1)

Publication Number Publication Date
WO2000002878A1 true WO2000002878A1 (fr) 2000-01-20

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PCT/GB1999/002218 WO2000002878A1 (fr) 1998-07-11 1999-07-12 Composes possedant une activite sur les recepteurs d'imidazoline

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AU (1) AU4919099A (fr)
WO (1) WO2000002878A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004000312A2 (fr) * 2002-06-19 2003-12-31 Solvay Pharmaceuticals Gmbh Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph
US6864253B2 (en) 2000-05-17 2005-03-08 Orth-Mcneil Pharmaceutical, Inc. Benzo[4,5]thieno[2,3-c]pyridine and Benzo[4,5]furo[2,3-c]pyridine Derivatives Useful as Inhibitors of Phosphodiesterase
WO2005067969A2 (fr) * 2004-01-19 2005-07-28 Merck Patent Gmbh Association d'inhibiteurs de reprise de serotonine et d'agonistes d'imidazoline-i2
GB2422828A (en) * 2005-02-03 2006-08-09 Hunter Fleming Ltd Tricyclic cytoprotective compounds comprising an indole residue
EP1793817A2 (fr) * 2004-09-13 2007-06-13 Elixir Pharmaceuticals, Inc. Methodes de traitement d'une maladie
GB2447791A (en) * 2007-03-23 2008-09-24 Univ Dundee Pharmaceutical formulations and compounds for use in alleviating conditions related to Down's syndrome
EP2003129A1 (fr) 2007-06-11 2008-12-17 Nerviano Medical Sciences S.r.l. Dérivés de 1H-pyrido[3,4-B]indol-1-one et de 2,3,4,9-tétrahydro-1H-bêta-carbolin-1-one
WO2015021358A2 (fr) 2013-08-09 2015-02-12 Dominique Charmot Composés et procédés d'inhibition du transport de phosphate
US20150216848A1 (en) * 2010-08-17 2015-08-06 The Translational Genomics Research Institute Compounds that inhibit tau phosphorylation
US9540365B2 (en) 2013-03-14 2017-01-10 Osteoqc Inc. Compounds for bone growth
CN109893651A (zh) * 2017-12-11 2019-06-18 中国科学院大连化学物理研究所 β2-肾上腺素受体拮抗剂及应用
US10947236B2 (en) 2018-08-14 2021-03-16 Osteoqc Inc. Pyrrolo-dipyridine compounds
WO2021145785A1 (fr) 2020-01-17 2021-07-22 Борис Славинович ФАРБЕР Dérivés de benzimidazoles et leurs sels, ayant une action anti-gériatrique
US11903949B2 (en) 2018-08-14 2024-02-20 Ossifi Therapeutics Llc Fluoro beta-carboline compounds

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Title
"The Merck Index", AN ENCYCLOPEDIA OF CHEMICALS, DRUGS AND BIOLOGICALS; MERCK & CO., INC. 12TH. EDITION, PAGES 35, 787, 788, 1094, AND 1416, BUDAVARI S (ED ); WHITEHOUSE STATION, NJ, ISBN: 0-911910-12-3, XP002119175 *
B. SZABO ET AL.: "Role of I1 imidazoline receptors in the sympatho-inhibition produced by intracisternally administered Rilmenidine and Monoxnidine", ARZNEIMITTEL FORSCHUNG. DRUG RESEARCH., vol. 47, no. 9, 1997, EDITIO CANTOR. AULENDORF., DE, pages 1009 - 1015, XP002119174, ISSN: 0004-4172 *
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CHEMICAL ABSTRACTS, vol. 123, no. 7, 14 August 1995, Columbus, Ohio, US; abstract no. 74802t, MOLDERINGS, G. J. ET AL: "Inhibitory presynaptic imidazoline receptors on sympathetic nerves in the rabbit aorta differ from I1 - and I2 -imidazoline binding sites" page 104; XP002119176 *
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Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6864253B2 (en) 2000-05-17 2005-03-08 Orth-Mcneil Pharmaceutical, Inc. Benzo[4,5]thieno[2,3-c]pyridine and Benzo[4,5]furo[2,3-c]pyridine Derivatives Useful as Inhibitors of Phosphodiesterase
WO2004000312A3 (fr) * 2002-06-19 2004-02-19 Solvay Pharm Gmbh Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph
WO2004000312A2 (fr) * 2002-06-19 2003-12-31 Solvay Pharmaceuticals Gmbh Medicament pour traiter des affections impliquant une inhibition ou une baisse d'activite de proteines transporteuses de bicarbonate regulant le ph
US7309706B2 (en) 2002-06-19 2007-12-18 Solvay Pharmaceuticals Gmbh Method for the treatment of diseases requiring inhibition or a reduction in the activity of pH value-regulating bicarbonate transporter proteins
US8486990B2 (en) 2003-09-12 2013-07-16 Elixir Pharmaceuticals, Inc. SirT inhibitors that bind to NAD
AU2004313648B2 (en) * 2004-01-19 2010-09-30 Merck Patent Gmbh Combinations of serotonin reuptake inhibitors and imidazoline-I2-agonists
WO2005067969A2 (fr) * 2004-01-19 2005-07-28 Merck Patent Gmbh Association d'inhibiteurs de reprise de serotonine et d'agonistes d'imidazoline-i2
WO2005067969A3 (fr) * 2004-01-19 2007-04-05 Merck Patent Gmbh Association d'inhibiteurs de reprise de serotonine et d'agonistes d'imidazoline-i2
EP1793817A2 (fr) * 2004-09-13 2007-06-13 Elixir Pharmaceuticals, Inc. Methodes de traitement d'une maladie
EP1793817A4 (fr) * 2004-09-13 2008-04-02 Elixir Pharmaceuticals Inc Methodes de traitement d'une maladie
JP2008513370A (ja) * 2004-09-13 2008-05-01 エリクシアー ファーマシューティカルズ， インコーポレイテッド 障害を処置する方法
AU2006210727B2 (en) * 2005-02-03 2011-10-13 Hunter-Fleming Limited Tricyclic cytoprotective compounds
WO2006082409A3 (fr) * 2005-02-03 2006-12-14 Hunter Fleming Ltd Composes cytoprotecteurs tricycliques
GB2422828A (en) * 2005-02-03 2006-08-09 Hunter Fleming Ltd Tricyclic cytoprotective compounds comprising an indole residue
GB2447791A (en) * 2007-03-23 2008-09-24 Univ Dundee Pharmaceutical formulations and compounds for use in alleviating conditions related to Down's syndrome
EP2003129A1 (fr) 2007-06-11 2008-12-17 Nerviano Medical Sciences S.r.l. Dérivés de 1H-pyrido[3,4-B]indol-1-one et de 2,3,4,9-tétrahydro-1H-bêta-carbolin-1-one
US20150216848A1 (en) * 2010-08-17 2015-08-06 The Translational Genomics Research Institute Compounds that inhibit tau phosphorylation
US10501457B2 (en) 2013-03-14 2019-12-10 Osteoqc Inc. Compounds for bone growth
US11267814B2 (en) 2013-03-14 2022-03-08 OsteoQC, Inc. Compounds for bone growth
US9540365B2 (en) 2013-03-14 2017-01-10 Osteoqc Inc. Compounds for bone growth
EP3884935A1 (fr) 2013-08-09 2021-09-29 Ardelyx, Inc. Composés et procédés d'inhibition du transport de phosphate
EP3492106A1 (fr) 2013-08-09 2019-06-05 Ardelyx, Inc. Composés et procédés d'inhibition du transport de phosphate
WO2015021358A2 (fr) 2013-08-09 2015-02-12 Dominique Charmot Composés et procédés d'inhibition du transport de phosphate
CN109893651A (zh) * 2017-12-11 2019-06-18 中国科学院大连化学物理研究所 β2-肾上腺素受体拮抗剂及应用
US10947236B2 (en) 2018-08-14 2021-03-16 Osteoqc Inc. Pyrrolo-dipyridine compounds
US11655250B2 (en) 2018-08-14 2023-05-23 Osteoqc Inc. Pyrrolo-dipyridine compounds
US11903949B2 (en) 2018-08-14 2024-02-20 Ossifi Therapeutics Llc Fluoro beta-carboline compounds
WO2021145785A1 (fr) 2020-01-17 2021-07-22 Борис Славинович ФАРБЕР Dérivés de benzimidazoles et leurs sels, ayant une action anti-gériatrique

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