WO2008123821A1 - 4, 5-dihydro-lh-imidazol-2-amine derivatives for use in the treatment of respiratory, cardiovascular, neurological or gastrointestinal disorders - Google Patents

4, 5-dihydro-lh-imidazol-2-amine derivatives for use in the treatment of respiratory, cardiovascular, neurological or gastrointestinal disorders Download PDF

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Publication number
WO2008123821A1
WO2008123821A1 PCT/SE2008/050226 SE2008050226W WO2008123821A1 WO 2008123821 A1 WO2008123821 A1 WO 2008123821A1 SE 2008050226 W SE2008050226 W SE 2008050226W WO 2008123821 A1 WO2008123821 A1 WO 2008123821A1
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imidazol
dihydro
phenylethyl
amine
compound
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PCT/SE2008/050226
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French (fr)
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Isabel Calaza-Cabanas
Anders M. Johansson
Joachim Persson
Anette Svensson Henriksson
Fredrik Thorstensson
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Albireo Ab
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/48—Nitrogen atoms not forming part of a nitro radical with acyclic hydrocarbon or substituted acyclic hydrocarbon radicals, attached to said nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory 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
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/52—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C07C217/60—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/59—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/64—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms
    • C07C309/65—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C07C309/66—Methanesulfonates
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D233/44—Nitrogen atoms not forming part of a nitro radical
    • C07D233/50—Nitrogen atoms not forming part of a nitro radical with carbocyclic radicals directly attached to said nitrogen atoms
    • 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
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    • C07—ORGANIC CHEMISTRY
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    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention relates to compounds of formula (I), to pharmaceutical compositions containing said compounds and to the use of said compounds in therapy.
  • the present invention further relates to processes for the preparation of compounds of formula (I) and to new intermediates used in the preparation thereof.
  • Adrenergics constitute a group of drugs with very varied clinical use.
  • the field of application is broad, from lifethreatening conditions as asthma and hypertension to use for minor ailments such as the common cold.
  • Adrenergic receptors or adrenoceptors are defined as the sites at wich the neurotransmitters adrenaline and noradrenaline produce their physiologic effect in the cell. They are cell membrane receptors belonging to the transmembrane G-protein-coupled family of receptors. These receptors are broadly classified into CCi-, OC 2 - and ⁇ -receptors. The groups are further subdivided into six ⁇ -adrenoceptors, GC 1 A, OC 1 B, OC 1 D, OC 2 A, OC 2 B, oc 2 c and three ⁇ -adrenoceptors ⁇ i, ⁇ 2, ⁇ 3 (see e.g., Buddyty J.
  • cc-receptors are widely studied because of the major physiological importance of these receptors in control of blood pressure and blood flow, neural modulation, digestion, micturition, airways, reproduction, pupil diameter, endocrine and metabolic processes and in behaviour.
  • CCi -adrenoceptors are implicated in processes such as vasoconstriction, glycogeno lysis, cardiac inotrophy and chronotrophy.
  • cc 2 -adrenoceptors are associated with platelet aggregation, neorotransmitter release, vasoconstriction, regulation of ion secretion and inhibition of insulin secretion, chronic pain, neuropathic pain, glaucoma and IBS, (see e.g. Abraham D. J., Burger's Medicinal Chemistry and Drug Discovery, 6 th edition, vol. 6, chapter one) and (Exp. Opin. Ther. Patents 10(11): 1741-1748).
  • Adrenergic agonists showing activity on both ⁇ and ⁇ receptor families have limited clinical application since the compounds would then stimulate the entire adrenergic system. There is therefore a further need for subtype-selective CC agonists.
  • WO 2006/125748 discloses the compounds N-[l-(3-chlorophenyl)-2-phenylethyl]-4,5- dihydro- lH-imidazol-2-amine, N-[I -(3-chlorophenyl)-2-phenylethyl]-4,5-dihydro- IH- imidazol-2-amine hydroiodide, N-[I -(4-chlorophenyl)-2-phenylethyl]-4,5-dihydro- IH- imidazol-2-amine hydroiodide, N-[I -(2-chloro-4-fluorophenyl)-2-phenylethyl]-4,5-dihydro- lH-imidazol-2-amine and N-[I -(3-fluorophenyl)-2-phenylethyl]-4,5-dihydro- lH-imidazol-2-amine.
  • the object of the present invention was to provide novel ⁇ -receptor agonists useful in therapy.
  • the present invention provides a compound of formula (I)
  • R 1 is independently selected from halogen, hydroxy, cyano, Q-C5 alkoxy, Q-C3 alkyl, Q-
  • R 2 is independently selected from halogen, hydroxy or Q-C3 alkyl; wherein the alkyl group may be substituted by one or more fluoro atom(s); n is O, 1, 2, 3 or 4;
  • Ar 1 and Ar 2 may be attached to each other and thus form an optionally substituted biphenyl group;
  • Ar 1 or Ar 2 may be fused with a six-membered aromatic ring wherein the ring atoms are selected from C or N and at least three ring atoms are C;
  • X is carbon or nitrogen
  • Y is carbon or nitrogen
  • Z is carbon or nitrogen
  • R 1 is chloro, hydroxy, fluoro, bromo, trifluoromethyl, methoxy, butoxy, methylsulfonate or cyano.
  • R 2 is chloro, hydroxy or trifluoromethyl.
  • m is 0, 1 or 2.
  • n 0, 1 or 2.
  • X is carbon
  • Y is carbon
  • Z is carbon.
  • the present invention relates to compounds of formula (I) as defined above as well as to salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I).
  • the compounds of the present invention are capable of forming salts with various inorganic and organic acids and such salts are also within the scope of this invention.
  • acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclohexyl sulfamate, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, palmoate, persulfate, phenylacetate, phosphate, picrate, pivalate, propionate,
  • Non-pharmaceutically-acceptable salts may be prepared from the corresponding acid in conventional manner.
  • Non-pharmaceutically-acceptable salts may be useful as intermediates and as such are another aspect of the present invention.
  • Acid addition salts may also be in the form of polymeric salts such as polymeric sulfonates.
  • the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalent of the appropriate acid in a solvent or a medium in which the salt is hardly soluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
  • Compounds of formula (I) have at least one chiral center, and it is to be understood that the invention encompasses all enantiomers and diastereomers.
  • the compounds according to formula (I) can be in the form of the single stereoisomers, i.e. the single enantiomer (the R- enantiomer or the S-enantiomer) and/or diastereomer.
  • the compounds according to formula (I) can also be in the form of a racemic mixture, i.e. an equimolar mixture of enantiomers. It is to be understood that the present invention also relates to any and all tautomeric forms of the compounds of formula (I).
  • Some compounds can exist as a mixture of conformational isomers.
  • the compounds of this invention comprise both mixtures of, and individual, conformational isomers.
  • C1-C3 alkyl includes straight as well as branched chain hydrocarbon groups having 1 to 3 carbon atoms, for example methyl, ethyl, n-propyl or i- propyl.
  • the alkyl group may be substituted by one or more fluoro atoms, such as in difluoromethyl or trifluoromethyl.
  • C1-C5 alkoxy includes straight as well as branched alkyl groups having 1 to 5 carbon atoms attached via an oxygen atom, for example methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, 1 -methyl-prop oxy, 2-methyl-propoxy, t-butoxy, n- pentoxy, 1-methylbutoxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1 ,2-dimethylpropoxy, 2,2- dimethyl-propoxy and 1-ethylpropoxy.
  • the alkyl group may be substituted by one or more fluoro atoms, such as in difluoromethoxy or trifluoromethoxy.
  • halogen includes fluorine, chlorine, bromine or iodine.
  • C1-C3 alkylsulfonate includes straight as well as branched alkyl groups having 1 to 3 carbon atoms attached via a sulfonate group, for example methanesulfonate, ethanesulfonate, propanesulfonate or iso-propanesulfonate.
  • a pharmaceutical formulation comprising a compound of formula (I), as a single enantiomer, a racemate or a mixture thereof as a free base or pharmaceutically acceptable salt thereof, for use in prevention and/or treatment of respiratory, cardiovascular, neurological, pain, oncology, imflammatory and/or gastrointestinal disorders.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation.
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, pellets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
  • composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
  • compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.01 to 25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) is received.
  • This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
  • unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention.
  • a tablet or capsule for oral administration may conveniently contain up to 250 mg (and typically 5 to 100 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof.
  • a compound of the formula (I) or a pharmaceutically acceptable salt thereof may be administered in a daily dosage range of 5 to 100 mg, in a single dose or divided into two to four daily doses.
  • a sterile solution or suspension containing up to 10% w/w (and typically 5% w/w) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof may be used.
  • the present invention provides a method of treating or preventing a disease condition wherein activation of CC adrenergic receptors is beneficial which comprises administering to a subject an effective amount of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof.
  • the present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a disease condition wherein agonism of CC adrenergic receptors is beneficial.
  • the compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof may be used in the manufacture of a medicament for use in the prevention or treatment of respiratory, cardiovascular, neurological, pain and/or gastrointestinal disorders.
  • disorders are asthma, pulmonary disease, cough, cold, inflammation, chronic obstructive pulmonary disease, airway reactivity, urticaria, hypertension, edema, angiogenesis, chronic pain, neuropathic pain, allodynia, migraine, tension headache, psychoses, depression, anxiety, Alzheimer's disease, schizophrenia, Huntington's disease, bladder hypermotility, urinary incontinence, eating disorder, manic depression, substance dependence, movement disorder, cognitive disorder, obesity, stress disorders, micturition disorders, mania, hypomania and aggression, bipolar disorder, carcinoma, fibromyalgia, non cardiac chest pain, gastrointestinal hypermotility, gastric asthma, Crohn's disease, gastric emptying disorders, ulcerative colitis, irritable bowel syndrome, inflammatory bowel disease, emesis, diabetes or functional dyspepsia.
  • One aspect of the present invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment of any of the disorders defined hereinbefore.
  • a further aspect of the present invention is a method for the treatment or prevention of a disorder defined hereinbefore, comprising administering to a person in need thererof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • CC 2 adrenoceptor subtypes Three functional CC 2 adrenoceptor subtypes are described, CC 2 A, OC 2 B and cc 2 c and they all belonging to the GPCR superfamily. All three CC 2 receptor subtypes are predominantly coupled to Ga 1 and as a consequence of their activation, the level of intracellular cAMP is decreased.
  • Clones of HEK293SG qi 5 cells expressing each of human CC 2AB receptors were used for functional screening of compounds. Expression of engineered G qi 5 (the last 5 amino acids of GcCq are replaced with the last 5 amino acids Of Ga 1 ) allows to diverge signal from Ga 1 coupled receptor to Ga q signaling.
  • FLIPR Fluorescence Imaging Plate Reader
  • Human embryonic kidney (HEK) 293SGqis cells were stably transfected with human ⁇ 2 A or human ⁇ 2 ⁇ receptors cDNA cloned into pIRESneo2 expression vector. Transfection was performed using cationic lipid reagent Lipofectamine plus and selection with 1 mg/ml Geneticin and 0.3 mg/ml hygromycin B. Individual clones were selected by flow cytometry for human ⁇ 2 A receptor and by manually adding drops containing one cell to 96 well plates for human ⁇ 2 ⁇ receptor.
  • the HEK293SGqis cells stably expressing human ⁇ 2 A and ⁇ 2 ⁇ receptors were cultured in a humified incubator at 37°C under 5% CO 2 , in DMEM, 10% FBS supplemented with withl mg/ml Geneticin and 0.3 mg/ml hygromycin B. Cells were grown in T- 175 flasks and routinely passaged 1:10 when they were 70-90% confluent.
  • HEK293Gqi5 cells stably transfected with human CC 2 A and CC 2 B receptors were detached from the flask by hitting it on the side and plated in Falcon Poly-D-Lysine coated black-walled, clear-bottomed 384-well plates at a density of 2 x 10 5 cells/ml and 25 ⁇ l (5000 cells) in each well using a Multidrop 384 and grown for approximately 24h in normal growth media in a 37°C, CO 2 incubator. The cells were then washed three times with wash buffer, Hanks balanced salt solution (HBSS) and 20 mM Hepes, using 100 ⁇ l /well in a BioTek EL x 405 washer leaving 20 ⁇ l in each well after the last wash.
  • HBSS Hanks balanced salt solution
  • the cells of each 384-well plate were loaded with fluorescent Ca + chelator. Fluo 4 at 2 ⁇ M in a loading buffer containing HBSS, 20 mM Hepes and 0.02% Pluronic F-127, 20 ⁇ l/well, using a Biomek NX P (Beckman coulter) and incubated at 37°C for 45-60 min.
  • Test compounds were diluted in serial dilutions with ten concentrations in steps of three in DMSO using a ROSYS with the highest concentration at 3.3 mM.
  • a predilution plate of the compounds was made using a Biomek NX P (Beckman coulter) where 1 ⁇ l compound was diluted with 40 ⁇ l assay buffer (wash buffer and 0.1% (w/v) BSA) in quadruplicates in a 384 well plate. The cells were washed once again as before and placed in the 384 FLIPR together with the compound predilution plate where 20 ⁇ l of compound in assay buffer was added to each well automatically pipetted by FLIPR (pipettor height 40 ⁇ l, pipettor speed 20 ⁇ l/s).
  • the fluorescence intensity was recorded (excitation 488 nm and emission 510-570 nm) by the FLIPR CCD camera for 3 min and results were calculated from RFU max-min values exported from FLIPR, samples 12-70 included.
  • the baseline was exported as a separate statistic file set as the average of samples 1-5 to allow calculation of Fluo-4 loading level.
  • the EC50 value was calculated from a ten-point concentration-response curve for each compound in an excel-based program. Intrinsic activity of compounds were expressed as a fraction of the maximum response relative to 0.1 ⁇ M of NA.
  • the compounds of the invention demonstrated statistically significant agonistic activity at CC 2B receptors at low levels.
  • the EC50 value was generally less than 200 nM.
  • An in vivo gastric distension model is used as a model for functional gastrointestinal disorders, in particular for functional dyspepsia (FD), (Bayati A, Astin M, Ekman C, Mattsson H, Gastroenterology 2003; 124 (4, suppl 1): W1471 (abstract)) and
  • the gastric distension model enables detailed analysis of the physico -mechanical properties of the stomach, e.g. basal gastric tone, threshold for accommodation, accommodation rate, accommodation volume, and maximal gastric volume.
  • basal gastric tone e.g. basal gastric tone
  • threshold for accommodation
  • accommodation rate accommodation rate
  • accommodation volume e.g. maximal gastric volume.
  • WKY Wistar Kyoto
  • SD Sprague Dawley
  • the advantage of the presently used barostat technique compared to other barostat techniques normally used in experimental clinical studies is that it is possible to discriminate between if a compound exerts its effect directly on gastric smooth muscles or if the effect involves the vagal reflex mechanism.
  • the rats are equipped with fistulas chronically implanted into the stomach.
  • a small inflatable plastic bag with a spherical shape is inserted through fistula into the glandular part of the stomach (middle to distal part in the rat).
  • the experiments are performed in conscious rats.
  • a combination of ramp and tonic distension paradigm is used for detailed analysis of the physico-mechanical properties of the stomach. Pressure and volume data collected during experiments are saved for and further analysis.
  • a balloon is inserted into the stomach of the animal and a four phase protocol which includes a start phase, a ramp phase, a tonic phase and an end phase is performed.
  • the pressure applied to the balloon and the corresponding changes to the volume of the balloon are monitored throughout, e.g., using any barostat system known in the art (e.g., see Toma et al, Neurogastroenterol Mot., 8, 19-28, 1996).
  • a minimum distension pressure e.g. 1 mm Hg
  • a Ramp Phase During this phase the pressure applied to the balloon is increased linearly with a constant increase in pressure.
  • the pressure delivered to the balloon can be between 2-20 mm Hg.
  • This phase is then followed by the Tonic Phase.
  • the pressure is kept constant at the maximum pressure.
  • the pressure is dropped to the starting minimum distension pressure and this period is known as the End Phase.
  • the maximum gastric accommodation capacity in the animal following administration of the compound is calculated.
  • a compound of interest will be a compound that alters the maximum gastric accommodation capacity in the animal and this is calculated by determining a difference in the maximum gastric accommodation capacity before and after administration of the compound.
  • the Wistar Kyoto rats (WKY; M&B Denmark) are starved about 8 or 18 hours before each experiment depending on if the experiments are performed in the morning or in the afternoon.
  • a small, inflatable balloon is inserted through the central hole of the fistula into the distal part of stomach under isoflurane anaesthesia (Forene ® , Abbott Scandinavia AB) and fixed in its position through the tightening of the fistula.
  • the balloon has a spherical shape with a wall thickness of about 15 ⁇ m, a non-distensible max diameter of 25 mm and a max volume of about 7 ml.
  • the balloon is connected to a double-lumen polyethylene catheter with an outer diameter of 1.40 mm and a length of about 20 cm.
  • the inner lumen diameter of the catheter was about 0.58 mm.
  • the animals are placed in a specially designed Bollmann cage, with an inner diameter of 60 mm for females and 70 mm for males.
  • the catheter is then, via a pressure transducer, connected to a barostat system.
  • a barostat system maintains the pressure by pumping air into and out of the balloon. After the experiment the balloon and the connecting cable are removed under isofiurane anaesthesia and the animals are returned to their normal cages.
  • a combination of ramp and tonic distension is used in all the experiments.
  • the protocol starts with a minimum distension pressure of 1 mm Hg and continues for 20 min in order to collect base line values.
  • the pressure is then increased by a velocity of 1-4 mm Hg/min for 10 min to a maximum pressure of 10-20 mm Hg (ramp phase).
  • the barostat then keeps the pressure at the maximum pressure for 10 more min (tonic phase).
  • the tonic phase the pressure drops to the minimum distension pressure of 1 mm Hg in about Is. The pressure is then kept at this level for another 20-minute period.
  • the present invention provides a process for preparing a compound of the formula (I) or salts thereof which process comprises:
  • the coupling reaction is typically performed at an elevated temperature, for example 30 - 130 0 C, optionally by using microwave single node heating, preferably in a polar solvent for example methanol.
  • the compounds of the formulae (II) may be prepared, for example, by reacting a compound of formulae (IV) with ammonia under conditions of reductive amination.
  • the reductive amination reaction is typically performed at a non-extreme temperature, for example 0-130 0 C, in a substantially inert solvent for example dichloromethane.
  • Typical reducing agents include borohydrides such as sodium cyanoborohydride.
  • the compounds of formula (II) may also be prepared by reacting a compound of formula (IV) with hydroxylamine followed by a reduction of the formed oxime using as for instance reductive hydrogenation conditions.
  • the compounds of formula (III) are known or may be prepared as for instance by the procedures described in Tetrahedron Lett; 41 (2000) 6563-6566.
  • the compounds of formula (IV) are known or may be prepared by standard techniques for obtaining aryl arylmethyl ketones. Examples of such methods are for instance Grignard reaction (see e.g. J. Am. Chem. Soc; 55 (1933) 703-704), Horner-Emmons condensation (see e.g. Tetrahedron Lett.; 39 (1998) 1717-1720), or Friedel-Craft acylation (see e.g. J. Med. Chem.; 46 (2003) 1870-1877).
  • DIPEA N, N- diisopropylethylamine
  • DMF 7V, ⁇ /-dimethylformamide
  • EDC l-ethyl-3-[3- dimethylaminopropyl]carbodiimide
  • HOBt N-hydroxybenzotriazole
  • THF tetrahydrofuran
  • RT room temperature
  • (+)-4-[l-Amino-2-phenylethyl]phenol see Intermediate 1 b; 0.21 g, 0.97 mmol
  • tert-butyl 2- (methylthio)-4,5-dihydro-lH-imidazole-l-carboxylate (0.30 g, 1.4 mmol)
  • acetic acid 0.5 mL
  • methanol 4.5 mL
  • the product was purified by means of reversed phase chromatography (Kromasil ®, C8) using a mixture of acetonitrile and aqueous 0.2% acetic acid as eluent. The proper fraction were combined and the solvent was removed by freeze- drying. There was obtained 0.24 g (71%) of the title compound.
  • (+)-4-[l -(4,5-Dihydro- lH-imidazol-2-ylamino)-2-phenylethyl]phenol acetate (0.17 g, 0.49 mmol) was dissolved in water (100 mL) and to the resultant solution was added hydrochloric acid (2M, 1 mL). The volatiles were removed by freeze-drying and there was obtained 0.14 g (90%) of the title compound.
  • Examples 6-36 The following compounds, which are tabulated below, were synthesised in an analogous way to one or other of the examples above (Method A, Method B, Method C or Method D) using an appropriate intermediate amino compound (see below): 7V- ⁇ 2-(4-bromophenyl)-l-[3- (trifluoromethyl)phenyl] ethyl ⁇ -4,5-dihydro- lH-imidazol-2-amine (Example 6), N-[2-(3- fluorophenyl)-l-phenylethyl]-4,5-dihydro-l//-imidazol-2-amine formate (Example 7), 3-[2- (4,5-dihydro- l//-imidazol-2-ylamino)-2-(4-hydroxyphenyl)ethyl]benzonitrile acetate (Example 8), 3-[2-(4,5-dihydro- l//-imidazol-2-ylamin
  • Ex 18 see EP 356035
  • Ex 19 see Intermediate 9
  • Ex 20 commercially available
  • Ex 21 see Intermediate 10
  • Ex 22 see Intermediate 11
  • Ex 23 see EP 659737
  • Ex 24 see Intermediate 12
  • Ex 25 see Angew. Chem.; 63 (1951) 421-430
  • Ex 26 see Intermediate 13
  • Ex 27 see J. of Med. Chem.; 21 (1978) 1265-1269
  • Ex 28 see Intermediate 14
  • Ex 29 see Intermediate 15
  • Ex 30 see Intermediate 16
  • Ex 31 see J. of Med. Chem.; 21 (1978) 1265-1269
  • Ex 32 see Intermediate 17
  • Ex 33 see Intermediate 18
  • Ex 34 see Intermediate 19
  • Ex 35 and Ex 36 see J. Med. Chem.; 38 (1995) 1600-1607
  • the starting materials for the examples above are either commercially available or, they are readily prepared by standard methods from known materials. For example, the following reactions are an illustration, but not a limitation, of some of the starting materials.
  • the catalyst was filtered off using Celite® and the solvent was removed by evaporation. The residue was dissolved in diethyl ether (15 mL) and the solution was then treated with a saturated solution of HCl in diethylether (15 mL) for 30 min. The product was isolated by filtration and there was obtained 2.8 g (60%) of the title compound as a white solid.
  • the combined aqueous solutions were neutralised with NaHCO 3 and extracted three times with ethyl acetate.
  • the organinc solutions were dried over MgSO 4 and the solvent was removed by evaporation.
  • the product was purified by reversed phase chromatography (Kromasil ®, C8) using a mixture of acetonitrile and aqueous 0.2% acetic acid as eluent. The proper fractions were combined and concentrated. The remaining concentrated aqueous solution was neutralised with NaHCO 3 and then extracted three times with ethyl acetate. The organic solution was dried over MgSO 4 and the solvent was removed by evaporation. There was obtained 0.32 g (45%) of the title compound as colorless oil.

Abstract

The present invention relates to new compounds of formula (I), as a free base or salts thereof, to pharmaceutical compositions containing said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of compounds of formula (I) and to new intermediates used in the preparation thereof.

Description

4,5-dihydro-lH-imidazol-2-amine derivatives for use in the treatment of respiratory, cardiovascular, neurological or gastrointestinal disorders
Field of the Invention
The present invention relates to compounds of formula (I), to pharmaceutical compositions containing said compounds and to the use of said compounds in therapy. The present invention further relates to processes for the preparation of compounds of formula (I) and to new intermediates used in the preparation thereof.
Background of the Invention
Adrenergics constitute a group of drugs with very varied clinical use. The field of application is broad, from lifethreatening conditions as asthma and hypertension to use for minor ailments such as the common cold.
Adrenergic receptors or adrenoceptors are defined as the sites at wich the neurotransmitters adrenaline and noradrenaline produce their physiologic effect in the cell. They are cell membrane receptors belonging to the transmembrane G-protein-coupled family of receptors. These receptors are broadly classified into CCi-, OC2- and β-receptors. The groups are further subdivided into six α-adrenoceptors, GC1A, OC1B, OC1D, OC2A, OC2B, oc2c and three β-adrenoceptors βi, β2, β3 (see e.g., Docherty J. R, European Journal of Pharmacology 361 (1998) 1-15). cc-receptors are widely studied because of the major physiological importance of these receptors in control of blood pressure and blood flow, neural modulation, digestion, micturition, airways, reproduction, pupil diameter, endocrine and metabolic processes and in behaviour.
CCi -adrenoceptors are implicated in processes such as vasoconstriction, glycogeno lysis, cardiac inotrophy and chronotrophy. cc2-adrenoceptors are associated with platelet aggregation, neorotransmitter release, vasoconstriction, regulation of ion secretion and inhibition of insulin secretion, chronic pain, neuropathic pain, glaucoma and IBS, (see e.g. Abraham D. J., Burger's Medicinal Chemistry and Drug Discovery, 6th edition, vol. 6, chapter one) and (Exp. Opin. Ther. Patents 10(11): 1741-1748). Adrenergic agonists showing activity on both α and β receptor families have limited clinical application since the compounds would then stimulate the entire adrenergic system. There is therefore a further need for subtype-selective CC agonists.
WO 2006/125748 discloses the compounds N-[l-(3-chlorophenyl)-2-phenylethyl]-4,5- dihydro- lH-imidazol-2-amine, N-[I -(3-chlorophenyl)-2-phenylethyl]-4,5-dihydro- IH- imidazol-2-amine hydroiodide, N-[I -(4-chlorophenyl)-2-phenylethyl]-4,5-dihydro- IH- imidazol-2-amine hydroiodide, N-[I -(2-chloro-4-fluorophenyl)-2-phenylethyl]-4,5-dihydro- lH-imidazol-2-amine and N-[I -(3-fluorophenyl)-2-phenylethyl]-4,5-dihydro- lH-imidazol-2- amine.
The object of the present invention was to provide novel α-receptor agonists useful in therapy.
Outline of the Invention
The present invention provides a compound of formula (I)
Figure imgf000004_0001
(I)
wherein
Ar1 is
Figure imgf000004_0002
R1 is independently selected from halogen, hydroxy, cyano, Q-C5 alkoxy, Q-C3 alkyl, Q-
C3 alkylsulfonate or Q-C3 alkoxy substituted by Q-C3 alkoxy; wherein the alkyl group, alkoxy group or alkylsulfonate group may be substituted by one or more fluoro atom(s); m is 0, 1, 2, 3, 4 or 5; Ar2 is
Figure imgf000004_0003
R2 is independently selected from halogen, hydroxy or Q-C3 alkyl; wherein the alkyl group may be substituted by one or more fluoro atom(s); n is O, 1, 2, 3 or 4;
or
Ar1 and Ar2 may be attached to each other and thus form an optionally substituted biphenyl group; or
Ar1 or Ar2 may be fused with a six-membered aromatic ring wherein the ring atoms are selected from C or N and at least three ring atoms are C;
X is carbon or nitrogen; Y is carbon or nitrogen; Z is carbon or nitrogen;
with the proviso that R is covalently attached to a carbon atom;
as well as pharmaceutically and pharmacologically acceptable salts thereof and enantiomers of the compound of formula (I) and salts thereof.
In one embodiment of the present invention R1 is chloro, hydroxy, fluoro, bromo, trifluoromethyl, methoxy, butoxy, methylsulfonate or cyano.
In one embodiment of the present invention R2 is chloro, hydroxy or trifluoromethyl.
In one embodiment of the present invention, m is 0, 1 or 2.
In one embodiment of the present invention, n is 0, 1 or 2.
In one embodiment X is carbon, Y is carbon and Z is carbon. The present invention relates to compounds of formula (I) as defined above as well as to salts thereof. Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (I).
The compounds of the present invention are capable of forming salts with various inorganic and organic acids and such salts are also within the scope of this invention. Examples of such acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, citrate, cyclohexyl sulfamate, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, 2-naphthalenesulfonate, nitrate, oxalate, palmoate, persulfate, phenylacetate, phosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), and undecanoate.
Pharmaceutically acceptable salts may be prepared from the corresponding acid in conventional manner. Non-pharmaceutically-acceptable salts may be useful as intermediates and as such are another aspect of the present invention.
Acid addition salts may also be in the form of polymeric salts such as polymeric sulfonates.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalent of the appropriate acid in a solvent or a medium in which the salt is hardly soluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
Compounds of formula (I) have at least one chiral center, and it is to be understood that the invention encompasses all enantiomers and diastereomers. The compounds according to formula (I) can be in the form of the single stereoisomers, i.e. the single enantiomer (the R- enantiomer or the S-enantiomer) and/or diastereomer. The compounds according to formula (I) can also be in the form of a racemic mixture, i.e. an equimolar mixture of enantiomers. It is to be understood that the present invention also relates to any and all tautomeric forms of the compounds of formula (I).
Some compounds can exist as a mixture of conformational isomers. The compounds of this invention comprise both mixtures of, and individual, conformational isomers.
Unless stated otherwise, the term "C1-C3 alkyl" includes straight as well as branched chain hydrocarbon groups having 1 to 3 carbon atoms, for example methyl, ethyl, n-propyl or i- propyl. The alkyl group may be substituted by one or more fluoro atoms, such as in difluoromethyl or trifluoromethyl.
Unless stated otherwise, the term "C1-C5 alkoxy" includes straight as well as branched alkyl groups having 1 to 5 carbon atoms attached via an oxygen atom, for example methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, 1 -methyl-prop oxy, 2-methyl-propoxy, t-butoxy, n- pentoxy, 1-methylbutoxy, 2-methylbutoxy, 1,1-dimethylpropoxy, 1 ,2-dimethylpropoxy, 2,2- dimethyl-propoxy and 1-ethylpropoxy. The alkyl group may be substituted by one or more fluoro atoms, such as in difluoromethoxy or trifluoromethoxy.
Unless stated otherwise, the term "halogen" includes fluorine, chlorine, bromine or iodine.
Unless stated otherwise, the term "C1-C3 alkylsulfonate" includes straight as well as branched alkyl groups having 1 to 3 carbon atoms attached via a sulfonate group, for example methanesulfonate, ethanesulfonate, propanesulfonate or iso-propanesulfonate.
Chemical names are generated by ACD/Labs® from Advanced Chemistry Development, Inc.
Pharmaceutical Formulations
According to one aspect of the present invention there is provided a pharmaceutical formulation comprising a compound of formula (I), as a single enantiomer, a racemate or a mixture thereof as a free base or pharmaceutically acceptable salt thereof, for use in prevention and/or treatment of respiratory, cardiovascular, neurological, pain, oncology, imflammatory and/or gastrointestinal disorders.
The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, topical, parenteral, buccal, nasal, vaginal or rectal administration or by inhalation or insufflation. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, pellets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
In addition to the compounds of the present invention the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
The pharmaceutical compositions of this invention will normally be administered to humans so that, for example, a daily dose of 0.01 to 25 mg/kg body weight (and preferably of 0.1 to 5 mg/kg body weight) is received. This daily dose may be given in divided doses as necessary, the precise amount of the compound received and the route of administration depending on the weight, age and sex of the patient being treated and on the particular disease condition being treated according to principles known in the art.
Typically unit dosage forms will contain about 1 mg to 500 mg of a compound of this invention. For example a tablet or capsule for oral administration may conveniently contain up to 250 mg (and typically 5 to 100 mg) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof. In another example, for administration by inhalation, a compound of the formula (I) or a pharmaceutically acceptable salt thereof may be administered in a daily dosage range of 5 to 100 mg, in a single dose or divided into two to four daily doses. In a further example, for administration by intravenous or intramuscular injection or infusion, a sterile solution or suspension containing up to 10% w/w (and typically 5% w/w) of a compound of the formula (I) or a pharmaceutically acceptable salt thereof may be used.
Medical and Pharmaceutical Use
The present invention provides a method of treating or preventing a disease condition wherein activation of CC adrenergic receptors is beneficial which comprises administering to a subject an effective amount of a compound of the formula (I) or a pharmaceutically-acceptable salt thereof. The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a disease condition wherein agonism of CC adrenergic receptors is beneficial.
The compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof may be used in the manufacture of a medicament for use in the prevention or treatment of respiratory, cardiovascular, neurological, pain and/or gastrointestinal disorders.
Examples of such disorders are asthma, pulmonary disease, cough, cold, inflammation, chronic obstructive pulmonary disease, airway reactivity, urticaria, hypertension, edema, angiogenesis, chronic pain, neuropathic pain, allodynia, migraine, tension headache, psychoses, depression, anxiety, Alzheimer's disease, schizophrenia, Huntington's disease, bladder hypermotility, urinary incontinence, eating disorder, manic depression, substance dependence, movement disorder, cognitive disorder, obesity, stress disorders, micturition disorders, mania, hypomania and aggression, bipolar disorder, carcinoma, fibromyalgia, non cardiac chest pain, gastrointestinal hypermotility, gastric asthma, Crohn's disease, gastric emptying disorders, ulcerative colitis, irritable bowel syndrome, inflammatory bowel disease, emesis, diabetes or functional dyspepsia.
One aspect of the present invention is the use of a compound of formula (I) for the manufacture of a medicament for the treatment of any of the disorders defined hereinbefore.
A further aspect of the present invention is a method for the treatment or prevention of a disorder defined hereinbefore, comprising administering to a person in need thererof, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
Pharmacology
Three functional CC2 adrenoceptor subtypes are described, CC2A, OC2B and cc2c and they all belonging to the GPCR superfamily. All three CC2 receptor subtypes are predominantly coupled to Ga1 and as a consequence of their activation, the level of intracellular cAMP is decreased. Clones of HEK293SGqi5 cells expressing each of human CC2AB receptors were used for functional screening of compounds. Expression of engineered Gqi5 (the last 5 amino acids of GcCq are replaced with the last 5 amino acids Of Ga1) allows to diverge signal from Ga1 coupled receptor to Gaq signaling. Therefore the degree of receptor activation correlates to the release of intracellular Ca2+ measured with a Fluorescence Imaging Plate Reader (FLIPR). This approach provided a robust and sensitive method to estimate both potency and efficacy of screened molecules. The potency and efficacy are expressed as EC50 (μM) and % of maximal response achieved by noradrenalin (NA) respectively. Transfection and culturing of cells used in FLIPR
Human embryonic kidney (HEK) 293SGqis cells were stably transfected with human α2A or human α2β receptors cDNA cloned into pIRESneo2 expression vector. Transfection was performed using cationic lipid reagent Lipofectamine plus and selection with 1 mg/ml Geneticin and 0.3 mg/ml hygromycin B. Individual clones were selected by flow cytometry for human α2A receptor and by manually adding drops containing one cell to 96 well plates for human α2β receptor. The HEK293SGqis cells stably expressing human α2A and α2β receptors were cultured in a humified incubator at 37°C under 5% CO2, in DMEM, 10% FBS supplemented with withl mg/ml Geneticin and 0.3 mg/ml hygromycin B. Cells were grown in T- 175 flasks and routinely passaged 1:10 when they were 70-90% confluent.
Assessing the Potency of Selected test Compounds to Activate Human α2A and α2β receptors The potency of a compound of the invention to activate CC2A and CC2B receptors was assessed by the following procedure:
HEK293Gqi5 cells stably transfected with human CC2A and CC2B receptors were detached from the flask by hitting it on the side and plated in Falcon Poly-D-Lysine coated black-walled, clear-bottomed 384-well plates at a density of 2 x 105 cells/ml and 25 μl (5000 cells) in each well using a Multidrop 384 and grown for approximately 24h in normal growth media in a 37°C, CO2 incubator. The cells were then washed three times with wash buffer, Hanks balanced salt solution (HBSS) and 20 mM Hepes, using 100 μl /well in a BioTek ELx 405 washer leaving 20 μl in each well after the last wash. Before the FLIPR assay the cells of each 384-well plate were loaded with fluorescent Ca + chelator. Fluo 4 at 2 μM in a loading buffer containing HBSS, 20 mM Hepes and 0.02% Pluronic F-127, 20 μl/well, using a Biomek NXP (Beckman coulter) and incubated at 37°C for 45-60 min.
Test compounds were diluted in serial dilutions with ten concentrations in steps of three in DMSO using a ROSYS with the highest concentration at 3.3 mM. A predilution plate of the compounds was made using a Biomek NXP (Beckman coulter) where 1 μl compound was diluted with 40 μl assay buffer (wash buffer and 0.1% (w/v) BSA) in quadruplicates in a 384 well plate. The cells were washed once again as before and placed in the 384 FLIPR together with the compound predilution plate where 20 μl of compound in assay buffer was added to each well automatically pipetted by FLIPR (pipettor height 40 μl, pipettor speed 20 μl/s). The fluorescence intensity was recorded (excitation 488 nm and emission 510-570 nm) by the FLIPR CCD camera for 3 min and results were calculated from RFU max-min values exported from FLIPR, samples 12-70 included. The baseline was exported as a separate statistic file set as the average of samples 1-5 to allow calculation of Fluo-4 loading level. The EC50 value was calculated from a ten-point concentration-response curve for each compound in an excel-based program. Intrinsic activity of compounds were expressed as a fraction of the maximum response relative to 0.1 μM of NA.
Results
In general, the compounds of the invention, which were tested, demonstrated statistically significant agonistic activity at CC2B receptors at low levels. The EC50 value was generally less than 200 nM. Also, a number of the compounds of the invention, which were tested, demonstrated statistically significant agonistic activity at CC2A receptors at low levels (NT=not tested).
Figure imgf000012_0001
Figure imgf000013_0001
Biological evaluation
An in vivo gastric distension model is used as a model for functional gastrointestinal disorders, in particular for functional dyspepsia (FD), (Bayati A, Astin M, Ekman C, Mattsson H, Gastroenterology 2003; 124 (4, suppl 1): W1471 (abstract)) and
(Astin Nielsen M, Bayati A, Mattson H, Scandinavian Journal of Gastroenterology, 2006; 41: 773-781).
The gastric distension model enables detailed analysis of the physico -mechanical properties of the stomach, e.g. basal gastric tone, threshold for accommodation, accommodation rate, accommodation volume, and maximal gastric volume. By using the same model in both rats and humans it has been found that the gastric volume responses is very similar in the rat glandular stomach to that in human proximal stomach. Furthermore, it has been shown that patients with Functional Dyspepsia as well as Wistar Kyoto (WKY) rats have an impaired gastric adaptive response and also a lower total gastric volume as compared to healthy subjects and Sprague Dawley (SD) rats, respectively. In addition, the method has shown to be reproducible and reliable. Moreover, the advantage of the presently used barostat technique compared to other barostat techniques normally used in experimental clinical studies is that it is possible to discriminate between if a compound exerts its effect directly on gastric smooth muscles or if the effect involves the vagal reflex mechanism.
The rats are equipped with fistulas chronically implanted into the stomach. During gastric experiments, a small inflatable plastic bag with a spherical shape is inserted through fistula into the glandular part of the stomach (middle to distal part in the rat). The experiments are performed in conscious rats. For detailed analysis of the physico-mechanical properties of the stomach, a combination of ramp and tonic distension paradigm is used. Pressure and volume data collected during experiments are saved for and further analysis.
In order to determine an animal's maximum gastric accommodation capacity, a balloon is inserted into the stomach of the animal and a four phase protocol which includes a start phase, a ramp phase, a tonic phase and an end phase is performed. The pressure applied to the balloon and the corresponding changes to the volume of the balloon are monitored throughout, e.g., using any barostat system known in the art (e.g., see Toma et al, Neurogastroenterol Mot., 8, 19-28, 1996).
During the start phase a minimum distension pressure, e.g., 1 mm Hg, is applied to the balloon until base line values are obtained. This is followed by a Ramp Phase. During this phase the pressure applied to the balloon is increased linearly with a constant increase in pressure. The pressure delivered to the balloon can be between 2-20 mm Hg. This phase is then followed by the Tonic Phase. During the tonic phase the pressure is kept constant at the maximum pressure. Finally the pressure is dropped to the starting minimum distension pressure and this period is known as the End Phase.
To determine if an agent, e.g., a compound is useful in the treatment of FD, the maximum gastric accommodation capacity in the animal following administration of the compound is calculated. A compound of interest will be a compound that alters the maximum gastric accommodation capacity in the animal and this is calculated by determining a difference in the maximum gastric accommodation capacity before and after administration of the compound.
The Wistar Kyoto rats (WKY; M&B Denmark) are starved about 8 or 18 hours before each experiment depending on if the experiments are performed in the morning or in the afternoon. A small, inflatable balloon is inserted through the central hole of the fistula into the distal part of stomach under isoflurane anaesthesia (Forene®, Abbott Scandinavia AB) and fixed in its position through the tightening of the fistula. The balloon has a spherical shape with a wall thickness of about 15 μm, a non-distensible max diameter of 25 mm and a max volume of about 7 ml. The balloon is connected to a double-lumen polyethylene catheter with an outer diameter of 1.40 mm and a length of about 20 cm. The inner lumen diameter of the catheter was about 0.58 mm. The animals are placed in a specially designed Bollmann cage, with an inner diameter of 60 mm for females and 70 mm for males. The catheter is then, via a pressure transducer, connected to a barostat system.
A barostat system maintains the pressure by pumping air into and out of the balloon. After the experiment the balloon and the connecting cable are removed under isofiurane anaesthesia and the animals are returned to their normal cages.
A combination of ramp and tonic distension is used in all the experiments. The protocol starts with a minimum distension pressure of 1 mm Hg and continues for 20 min in order to collect base line values. The pressure is then increased by a velocity of 1-4 mm Hg/min for 10 min to a maximum pressure of 10-20 mm Hg (ramp phase). The barostat then keeps the pressure at the maximum pressure for 10 more min (tonic phase). After the tonic phase the pressure drops to the minimum distension pressure of 1 mm Hg in about Is. The pressure is then kept at this level for another 20-minute period.
Methods of Preparation
In another aspect the present invention provides a process for preparing a compound of the formula (I) or salts thereof which process comprises:
a) reacting a compound of the formula (II) with a compound of the formula (III):
Figure imgf000015_0001
(H)
Figure imgf000015_0002
(HI) wherein Ar1 and Ar2 are as hereinbefore defined; L is a suitable leaving group such as methylthio or sulfo and R is a hydrogen atom or a protective group such as tert- butyloxycarbonyl; and wherein any other functional group before then has been protected, if necessary; and the conditions are such that an N-C bond is formed between the nitrogen atom of the amino group of the compounds of formula (II) and the 2-carbon atom of the imidazoline ring of the compounds of formula (III), and thereafter any optionally protective group is being removed by as for instance utilizing an acid or base catalysed hydrolytic reaction, and then by way of conclusion optionally forming a pharmaceutically acceptable salt.
The coupling reaction is typically performed at an elevated temperature, for example 30 - 1300C, optionally by using microwave single node heating, preferably in a polar solvent for example methanol.
The compounds of the formulae (II) may be prepared, for example, by reacting a compound of formulae (IV) with ammonia under conditions of reductive amination.
Figure imgf000016_0001
(IV)
The reductive amination reaction is typically performed at a non-extreme temperature, for example 0-1300C, in a substantially inert solvent for example dichloromethane. Typical reducing agents include borohydrides such as sodium cyanoborohydride.
The compounds of formula (II) may also be prepared by reacting a compound of formula (IV) with hydroxylamine followed by a reduction of the formed oxime using as for instance reductive hydrogenation conditions.
The compounds of formula (III) are known or may be prepared as for instance by the procedures described in Tetrahedron Lett; 41 (2000) 6563-6566. The compounds of formula (IV) are known or may be prepared by standard techniques for obtaining aryl arylmethyl ketones. Examples of such methods are for instance Grignard reaction (see e.g. J. Am. Chem. Soc; 55 (1933) 703-704), Horner-Emmons condensation (see e.g. Tetrahedron Lett.; 39 (1998) 1717-1720), or Friedel-Craft acylation (see e.g. J. Med. Chem.; 46 (2003) 1870-1877).
Examples
The following abbreviations are used in the experimental description: DIPEA (N, N- diisopropylethylamine), DMF (7V,Λ/-dimethylformamide), EDC (l-ethyl-3-[3- dimethylaminopropyl]carbodiimide), HOBt (N-hydroxybenzotriazole), THF (tetrahydrofuran) and RT (room temperature).
The following abbreviations are used in the chemical structures: Ms (methanesulfonyl) and Bu (n-butyl).
The following abbreviations are used in the presentation of the NMR data of the compounds: s-singlet; d-doublet; t-triplet; qt-quartet; qn-quintet; m-multiplet; b-broad.
The following examples will describe, but not limit, the invention.
Example 1 (Method A)
(+)-4-[ 1 -(4,5-dihvdro- lH-imidazol-2-ylamino)-2-phenylethvHphenol acetate
Figure imgf000017_0001
(+)-4-[l-Amino-2-phenylethyl]phenol (see Intermediate 1 b; 0.21 g, 0.97 mmol), tert-butyl 2- (methylthio)-4,5-dihydro-lH-imidazole-l-carboxylate (0.30 g, 1.4 mmol), acetic acid (0.5 mL) and methanol (4.5 mL) were mixed. The reaction mixture was heated at 100°C for one hour and then at 140°C for 10 min, each time using microwave single node heating. The solvent was removed by evaporation. The product was purified by means of reversed phase chromatography (Kromasil ®, C8) using a mixture of acetonitrile and aqueous 0.2% acetic acid as eluent. The proper fraction were combined and the solvent was removed by freeze- drying. There was obtained 0.24 g (71%) of the title compound. 1H NMR (500 MHz, CD3OD): 1.9 (s, 3H), 3.0-3.1 (m, 2H), 3.5-3.6 (s, 4H), 4.6 (t, IH), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (m, 3H), 7.3 (t, 2H); LC MS: m/z 282 (M+l) +; [α] = +6.75 (c. 0.4 g/mL in chloroform, RT and 589 nm).
Example 2 (Method B)
(+)-4-[ 1 -(4,5-Dihvdro- lH-imidazol-2-ylamino)-2-phenylethvHphenol hydrochloride
Figure imgf000018_0001
(+)-4-[l -(4,5-Dihydro- lH-imidazol-2-ylamino)-2-phenylethyl]phenol acetate (0.17 g, 0.49 mmol) was dissolved in water (100 mL) and to the resultant solution was added hydrochloric acid (2M, 1 mL). The volatiles were removed by freeze-drying and there was obtained 0.14 g (90%) of the title compound. 1U NMR (500 MHz, CD3OD): 3.0-3.1 (m, 2H), 3.5-3.6 (m, 4H), 4.6 (dd, IH), 6.8 (d, 2H), 7.1 (d, 2H), 7.2 (m, 3H), 7.3 (t, 2H); LC MS m/z 282 (M+l) +.
Example 3 (Method C)
N-(9, 10-Dihvdrophenanthren-9-yl)-4,5-dihydro- lH-imidazol-2-amine acetate
Figure imgf000018_0002
9,10-Dihydrophenanthren-9-amine (see J. Org. Chem.; 52; (1987) 753-759; 0.31 g, 1.6 mmol) and 4,5-dihydro-lH-imidazole-2-sulfonic acid (0.24 g, 1.6 mmol were mixed together with isobutanol (5 mL). The reaction mixture was heated at 140°C for 10 min using microwave single node heating. The solvent was removed by evaporation. The product was purified by means of reversed phase chromatography (Kromasil ®, C8) using a mixture of acetonitrile and aqueous 0.2 M ammonium acetate as eluent. The solvent was removed by freeze-drying. There was obtained 0.26 g (52%) of the title compound. 1H NMR (500 MHz, CDCl3): 1.7 (s, 3H), 2.8-3.0 (m, 2H), 3.4 (b, 4H), 3.7 (s, IH), 4.6 (dd, IH), 7.1 (d, IH), 7.2-7.4 (m, 5H), 7.6- 7.8 (m, 2H); LC MS: m/z 264 (M+l) +.
Example 4 (Method D) Λ/-r2-(3,5-Difluorophenyl)-l-phenylethyll-4,5-dihvdro-lH-imidazol-2-amine formate
Figure imgf000019_0001
2-(3,5-Difluorophenyl)-l-phenylethanamine hydrochloride (see Intermediate 2; 0.27 g, 1.0 mmol) and 4,5-dihydro-lH-imidazole-2-sulfonic acid (0.18 g, 1.1 mmol) were mixed together with triethylamine (0.11 g, 1.1 mmol) and isopropanol (5 mL). The reaction mixture was heated at 140°C for 10 min. The solvent was removed by evaporation. The product was purified by means of reversed phase chromatography (SunFire™ Prep C 18) using a mixture of acetonitrile and aqueous formic acid (0.1 M) as eluent. The solvent was removed by vacuum-centrifugation. There was obtained 43 mg (14%) of the title compound. 1H NMR (600 MHz, DMSOd6): 3.0 (d, 2H), 3.4-3.5 (s, 4H), 4.7-4.8 (t, IH), 7.0 (d, 2H), 7.0-7.1 (t, IH), 7.2-7.3 (t, IH), 7.3-7.4 (m, 4H), 8.4-8.5 (s, IH); LC MS: m/z 302 (M+ 1) +.
Example 5
N- (2-phenyl- 1 -r3-(trifluoromethyl)phenvHethvU -4,5-dihydro- lH-imidazol-2-amine hydrobromide
Figure imgf000020_0001
N- (2-(4-Bromophenyl)- 1 -[3-(trifluoromethyl)phenyl]ethyl} -4,5-dihydro- lH-imidazol-2- amine (see Example 6; 48 mg, 0.12 mmol) and Pd/C (5%, 17 mg) were mixed together with a small amount of ethanol. The mixture was hydrogenated at RT for 2 h. The catalyst was filtered off and the solvent was removed by evaporation. The product was dissolved in water and the volatiles were removed by freeze-drying. There was obtained 43 mg (88%) of the title compound. 1R NMR (500 MHz, CD3OD): 3.0-3.2 (m, 2H), 3.6 (s, 4H), 4.9 (dd, IH), 7.2-7.3 (m, 5H), 7.5-7.7 (m, 4H); LC MS: m/z 334 (M+l) +.
Examples 6-36 The following compounds, which are tabulated below, were synthesised in an analogous way to one or other of the examples above (Method A, Method B, Method C or Method D) using an appropriate intermediate amino compound (see below): 7V-{2-(4-bromophenyl)-l-[3- (trifluoromethyl)phenyl] ethyl} -4,5-dihydro- lH-imidazol-2-amine (Example 6), N-[2-(3- fluorophenyl)-l-phenylethyl]-4,5-dihydro-l//-imidazol-2-amine formate (Example 7), 3-[2- (4,5-dihydro- l//-imidazol-2-ylamino)-2-(4-hydroxyphenyl)ethyl]benzonitrile acetate (Example 8), 3-[2-(4,5-dihydro- l//-imidazol-2-ylamino)-2-phenylethyl]phenyl methanesulfonate formate (Example 9), 4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2-(3- hydroxyphenyl)ethyl]benzonitrile (Example 10), 7V-[l-(3-chlorophenyl)-2-phenylethyl]-4,5- dihydro-lH-imidazol-2-amine acetate (Example 11), 7V-[2-(3-chlorophenyl)-l-phenylethyl]- 4,5-dihydro- lH-imidazol-2-amine hydrochloride (Example 12), 4-[2-(4,5-dihydro-lH- imidazol-2-ylamino)-2-phenylethyl]phenol acetate (Example 13), 4-[2-(4,5-dihydro-lH- imidazol-2-ylamino)-2-(4-hydroxyphenyl)ethyl]benzonitrile (Example 14), N-[2-(4- chlorophenyl)-l-phenylethyl]-4,5-dihydro-l//-imidazol-2-amine acetate (Example 15), 4,4'- [ 1 -(4,5-dihydro- l//-imidazol-2-ylamino)ethane- 1 ,2-diyl]diphenol hydrochloride (Example 16), 3-[l -(4,5-dihydro- l//-imidazol-2-ylamino)-2-phenylethyl]phenol acetate (Example 17), 4-[l-(4,5-dihydro-lH-imidazol-2-ylamino)-2-phenylethyl]phenol acetate (Example 18), (+)-3- [l-(4,5-dihydro-lH-imidazol-2-ylamino)-2-phenylethyl]phenol (Example 19), 7V-(1,2- diphenylethyl)-4,5-dihydro-lH-imidazol-2-amine acetate (Example 20), 7V-[2-(2,3- dimethoxyphenyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine formate (Example 21), Λ/-[2-(2-fiuorophenyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine acetate (Example 22), Λ/-[2-(l-naphthyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine formate (Example 23), 7V-[2-(2-chlorophenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine hydrochloride (Example 24), 7V-[2-(4-butoxyphenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine acetate (Example 25), 4-[2-(2,3-dichlorophenyl)-2-(4,5-dihydro-lH-imidazol-2- ylamino)ethyl]phenol acetate (Example 26), 3-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2- phenylethyljphenol formate (Example 27), Λ/-{l-phenyl-2-[2-(trifluoromethyl)phenyl]ethyl}- 4,5-dihydro-lH-imidazol-2-amine formate (Example 28), 7V-[2-(3-butoxyphenyl)-l- phenylethyl]-4,5-dihydro-lH-imidazol-2-amine formate (Example 29), 7V-[2-(2,5- dimethoxyphenyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine formate (Example 30), Λ/-[2-(2-methoxyphenyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine formate (Example 31), 7V-[2-(2,3-difluorophenyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine formate (Example 32), 7V-[2-(2-chloro-6-fluorophenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2- amine acetate (Example 33), 4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2- phenylethyljphenyl methanesulfonate acetate (Example 34), 7V-(2-phenyl-l-pyridin-3- ylethyl)-4,5-dihydro-lH-imidazol-2-amine (Example 35) and N-(2 -phenyl- 1 -pyridin-4- ylethyl)-4,5-dihydro-lH-imidazol-2-amine (Example 36).
The amino compounds, used as key intermediates in the syntheses of Examples 6-36, are either known compounds or the preparation thereof being described in the literature cited below, or the preparation thereof being described in the Intermediate examples below: Ex 6 (see Intermediate 3), Ex 7 (see Intermediate 4), Ex 8 (see Intermediate 5), Ex 9 (see Intermediate 6), Ex 10 (see Intermediate 7), Ex 11 (see US 4536599), Ex 12 (see Arzneimittel-Forschung; 28 (1978) 1561-1564), Ex 13 (see Arch. Pharm.; 274 (1936) 153- 173), Ex 14 (see Intermediate 8), Ex 15 (see Bull. Chem. Soc. Jap.; 59 (1986) 3581-3587), Ex 16 (see J. Am. Chem. Soc; 71 (1986) 3219-3221), Ex 17 (see Tetrahedron; 33 (1977) 489-
495), Ex 18 (see EP 356035), Ex 19 (see Intermediate 9), Ex 20 (commercially available), Ex 21 (see Intermediate 10), Ex 22 (see Intermediate 11), Ex 23 (see EP 659737), Ex 24 (see Intermediate 12), Ex 25 (see Angew. Chem.; 63 (1951) 421-430), Ex 26 (see Intermediate 13), Ex 27 (see J. of Med. Chem.; 21 (1978) 1265-1269), Ex 28 (see Intermediate 14), Ex 29 (see Intermediate 15), Ex 30 (see Intermediate 16), Ex 31 (see J. of Med. Chem.; 21 (1978) 1265-1269), Ex 32 (see Intermediate 17), Ex 33 (see Intermediate 18), Ex 34 (see Intermediate 19), Ex 35 and Ex 36 (see J. Med. Chem.; 38 (1995) 1600-1607).
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0002
Preparation of Starting Materials
The starting materials for the examples above are either commercially available or, they are readily prepared by standard methods from known materials. For example, the following reactions are an illustration, but not a limitation, of some of the starting materials.
Intermediate 1
(+) and (-)-enantiomers of 4-ri-amino-2-phenylethvHphenol
Figure imgf000027_0001
The enantiomers of 4-[l-amino-2-phenylethyl]phenol (for racemate, see Obshch. Khim.; 21 (1951) 867-875; 0.35 g, 1.6 mmol) were separated by means of chiral HPLC using a Chiralcel® OJ column (250x20 mm). Approximately 45 mg were loaded on the column and then successively eluted with a mixture of heptane, ethanol and triethylamine (90/10/0.1). In total, there was obtained 0.14 g (99.9 % ee.) of the (-)-enantiomer and 0.12 g (98.9% ee.) of the (+)-enantiomer. The (-)-isomer eluted first from the column. (a) (-)-4-[ 1 -Amino-2-phenylethyl]phenol
1R NMR (500 MHz, CD3OD): 2.9 (d, 2H), 4.0 (t, IH), 6.7 (d, 2H), 7.1 (m, 4H), 7.1-7.2 (t, IH), 7.2 (t, 2H); LC MS: m/z 214 (M+l) +; [α] = -56.2° (0.5 g/100 mL in acetonitrile, RT and 589 mn)
(b) (+)-4-[ 1 -Amino-2-phenylethyl]phenol
1U NMR (500 MHz, CD3OD): 2.9 (d, 2H), 4.0 (t, IH), 6.7 (d, 2H), 7.1 (m, 4H), 7.1-7.2 (t, IH), 7.2 (t, 2H); LC MS: m/z 214 (M+l) +; [α] = +56.6° (0.5 g/100 mL in acetonitrile, RT and 589 nm).
Intermediate 2
2-(3 ,5-DifluorophenvD- 1 -phenylethanamine hydrochloride
Figure imgf000028_0001
(a) 2-(S, 5-Difluorophenyl)-l-phenylethanone
To a solution of 3,5-difluorophenylacetic acid (10.0 g, 0.058 mol) in dichloromethane (100 mL) was added thionyl chloride (8 mL, 0.11 mol) followed by a drop of DMF. The reaction mixture was stirred at RT for 2 h. The solvent was removed by evaporation and then the residue was dissolved in benzene (150 mL). The solution was cooled and aluminium chloride (16.7 g, 0.13 mol) was added portionwise. The reaction mixture was stirred at RT for 10 h and then quenched with ice water. The mixture was extracted with diethyl ether. The organic layer was washed with aqueous 15% NaHCO3 and then with brine. The solution was dried over Na2SO4 and the solvent was removed by evaporation. The product was purified by chromatography on silica gel using a mixture of ethyl acetate and petroleum ether. There was obtained 8.0 g (60%) of 2-(3,5-difluorophenyl)-l-phenylethanone as a yellow oil.
(b) 2-(3,5-Difluorophenyl)-l -phenylethanamine hydrochloride
A mixture of 2-(3,5-difluorophenyl)-l-phenylethanone (4.0 g, 17 mmol), sodium acetate (3.5 g, 43 mmol), hydroxylamine hydrochloride (2.6 g, 34 mmol) and methanol (50 mL) was heated to reflux for one hour. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and water. The organic solution was washed with brine and dried over Na2SO4. The solvent was removed by evaporation and the residue (3.4 g) was dissolved in ethanol (50 mL). To the solution was added Pd/C (10%, 0.5 g) and the mixture was hydrogenated at RT overnight. The catalyst was filtered off using Celite® and the solvent was removed by evaporation. The residue was dissolved in diethyl ether (15 mL) and the solution was then treated with a saturated solution of HCl in diethylether (15 mL) for 30 min. The product was isolated by filtration and there was obtained 2.8 g (60%) of the title compound as a white solid. 1U NMR (400 MHz, DMSOd6): 3.1-3.2 (m, IH), 3.4 (m, IH), 4.6 (m, IH), 6.9 (d, 2H), 7.0 (m, IH), 7.3-7.4 (m, 3H), 7.5 (d, 2H), 8.7 (b, 3H); LCMS: m/z 234 (M+ 1) +.
Intermediate 3
2-(4-BromophenvD- 1 -r3-(trifluoromethyl)phenyllethanamine
Figure imgf000029_0001
To a solution of 2-(4-bromophenyl)-l-[3-(trifluoromethyl)phenyl]ethanone (0.71 g, 2.1 mmol) and ammonium acetate (1.5 g, 19 mmol) in methanol (50 mL) was added sodium cyano borohydride (1.5 g, 23.4 mmol). The reaction mixture was stirred at 60°C overnight. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with water and then extracted several times with HCl (aq, 2M). The combined aqueous solutions were neutralised with NaHCO3 and extracted three times with ethyl acetate. The organinc solutions were dried over MgSO4 and the solvent was removed by evaporation. The product was purified by reversed phase chromatography (Kromasil ®, C8) using a mixture of acetonitrile and aqueous 0.2% acetic acid as eluent. The proper fractions were combined and concentrated. The remaining concentrated aqueous solution was neutralised with NaHCO3 and then extracted three times with ethyl acetate. The organic solution was dried over MgSO4 and the solvent was removed by evaporation. There was obtained 0.32 g (45%) of the title compound as colorless oil. 1U NMR (500 MHz, CDCl3): 2.8 (dd, IH), 2.9-3.0 (dd, IH), 4.2 (dd, IH), 7.0 (d, 2H), 7.4 (m, 3H), 7.5 (m, 2H), 7.6 (s, IH); LC MS: m/z 345 (M+ 1) +. Intermediate 4
2-(3 -Fluorophenyl)- 1 -phenylethanamine hydrochloride
Figure imgf000030_0001
The title compound was prepared according to the protocol described in Intermediate 2 b using 2-(3-fluorophenyl)-l-phenylethanone as the ketone starting material (yield 49%). 1H NMR (400 MHz, DMSOd6): 3.1-3.2 (m, IH), 3.4 (m, IH), 4.5-4.6 (m, IH), 6.9-7.0 (m, 2H), 7.2-7.3 (m, IH), 7.3-7.4 (m, 3H), 7.4-7.5 (m, 2H), 8.6-8.7 (b, 3H); LCMS: m/z 216 (M+l) +.
Intermediate 5
3-r2-Amino-2-(4-hvdroxyphenyl)ethvHbenzonitrile
Figure imgf000030_0002
The title compound was prepared according to the protocol described in Intermediate 2 a but using (3-cyanophenyl)acetyl chloride (see Pharmazie 31 (1976), 432-436) and phenol as starting materials, followed by an reductive amination procedure as described in inter-mediate 3 (yield 8%). 1U NMR (500 MHz, CD3OD): 2.9 (dd, IH), 3.0 (dd, IH), 4.0 (t, IH), 6.7 (d, 2H), 7.0-7.1 (d, IH), 7.3-7.4 (m, 3H), 7.4-7.5 (m, IH); LCMS: m/z 239 (M+l) +.
Intermediate 6 3-(2-Amino-2-phenylethyl)phenyl methanesulfonate hydrochloride
Figure imgf000030_0003
(a) tert-Butyl [2-(3-hydroxyphenyl)-l-phenylethyl] carbamate
To a cooled mixture of 3-(2-amino-2-phenylethyl)phenol (see J. Med. Chem. 21 (1978),
1265; 4.0 g, 19 mmol) in THF (50 mL) and an aqueous solution of saturated NaHCO3 (50 mL) was added BOC-anhydride (4.5 g, 21 mmol) drop wise. The reaction mixture was stirred at RT for 2 h. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic layer was washed with water and with brine and then dried over Na2SO4. The solvent was removed by evaporation and there was obtained 6 g ( 100%) of tert-butyl [2-(3 -hydroxyphenyl)- 1 -phenylethyl] carbamate .
(b) 3-{2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}phenyl methanesulfonate
To an ice-cooled solution of tert-butyl [2-(3 -hydroxyphenyl)- 1 -phenylethyl] carbamate (3.0 g, 10 mmol) and triethylamine (2 mL, 14 mmol) in dichloromethane (30 mL) was added mesyl chloride (1.2 g, 10.5 mmol) dropwise. The reaction mixture was stirred at RT for one hour and then cooled water was added. The phases were separated and the aqueous solution was extracted with dichloromethane. The combined organic layers were washed with water and with brine and then dried over Na2SO4. The solvent was removed by evaporation and there was obtained 2.8 g (74%) of 3-{2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}phenyl methanesulfonate as a yellow gum.
(c) 3-(2-Amino-2-phenylethyl)phenyl methanesulfonate hydrochloride
To a solution of 3-{2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}phenyl methanesulfonate (2.8 g, 7.1 mmol) in ethanol (30 mL) was added concentrated hydrochloric acid (10 mL). The reaction mixture was stirred at RT for 2 h and then cooled water was added. The solvent was removed by evaporation and to the residue was added diethyl ether. The hydrochloride was isolated by filtration. There was obtained 1.5 g (64%) of the title compound as a white solid. 1U NMR (400 MHz, DMSO-de): 3.2 (dd, IH), 3.2-3.3 (s, 3H), 3.4 (m, IH), 4.5 (m, IH), 7.1- 7.2 (m, 3H), 7.4 (m, 4H), 7.4-7.5 (m, 2H), 8.7 (b, 3H); LC MS: m/z 292 (M+l) +.
Intermediate 7
4-r2-Amino-2-(3-hvdroxyphenyl)ethvHbenzonitrile
Figure imgf000032_0001
(a) 4- [2-Amino-2-(3-methoxyphenyl)ethyl] benzonitrile The compound was synthesised according to the reductive animation procedure described in Intermediate 3 but using 4-[2-(3-methoxyphenyl)-2-oxoethyl]benzonitrile as the ketone starting material (yield 47%).
(b) 4-[2-Am.ino-2-(3-hydroxyphenyl)ethyl]benzonitrile A solution of 4-[2-amino-2-(3-methoxyphenyl)ethyl]benzonitrile (0.16 g, 0.63 mmol) in dichloromethane (7 mL) under nitrogen was cooled to -78°C and then boron tribromide (2 mL, IM in dichloromethane, 2 mmol) was added dropwise. The reaction mixture was stirred at -78°C for one hour and then at RT for 30 min. Methanol (10 mL) was added with caution and the formed precipitation was dissolved gradually. The solvent was removed by evaporation and the residue was purified by reversed phase chromatography (Kromasil ®, C8) using a mixture of acetonitrile and aqueous 0.1 M ammonium acetate as eluent. The volatiles were removed by freeze-drying and there was obtained 0.12 g (40%) of the title compound as a white powder. 1R NMR (500 MHz, CD3OD): 3.3 (m, IH), 3.4-3.5 (dd, IH), 4.5 (m, IH), 6.8-6.9 (m, 3H), 7.2-7.3 (t, IH), 7.3-7.4 (d, 2H), 7.6 (d, 2H); LC MS: m/z 239 (M+l) +.
Intermediate 8 4-r2-Amino-2-(4-hvdroxyphenyl)ethvHbenzonitrile acetate
Figure imgf000032_0002
The compound was synthesised according to the reductive amination procedure described in Intermediate 3 with the exception that the last neutralisation step was excluded and buy way of using 4-[2-(4-hydroxyphenyl)-2-oxoethyl]benzonitrile (see Pharmazie; 31 (1976) 432-436) as the ketone starting material (yield 5%). 1R NMR (500 MHz, CD3OD): 1.9 (s, 3H), 3.2 (dd, IH), 3.3-3.4 (dd, IH), 4.4 (dd, IH), 6.8 (d, 2H), 7.1-7.2 (d, 2H), 7.2-7.3 (d, 2H), 7.6 (d, 2H); LC MS: m/z 239 (M+l) +.
Intermediate 9 (+)-3-(l-amino-2-phenylethyl)phenol
Figure imgf000033_0001
The (+)-isomer was isolated by analogy with the procedure described in Intermediate 1 using racemic 3-(l-amino-2-phenylethyl)phenol (see Tetrahedron; 33 (1977) 489-495) as the ketone starting material (99.8% ee). 1R NMR (500 MHz, CD3OD): 2.8-3.0 (m, 2H), 4.0 (t, IH), 6.6 (d, IH), 6.7 (s, IH), 6.7-6.8 (d, IH), 7.0-7.3 (m, 6H); LC MS: m/z 214 (M+l) +.
Intermediate 10
2-(2,3-DimethoxyphenvD- 1 -phenylethanamine hydrochloride
Figure imgf000033_0002
(a) 2-(2,3Diimethoxyphenyl)-N-methoxy-N-methylacetamide
To an ice-cooled solution of 2,3-dimethoxyphenyl acetic acid (5.0 g, 25 mmol), N, O-dimethyl hydroxylamine hydrochloride (2.7 g, 28 mmol), EDC hydrochloride (5.4 g, 28 mmol) and HOBt (0.58 g, 3 mmol) in dichloromethane (50 mL) triethylamine (11 mL, 76 mmol) was added under nitrogen. The mixture was stirred at RT over night and then diluted with water. The organic layer was washed with water and brine and then dried over Na2SO4. The solvent was removed by evaporation and there was obtained 5.8 g (96%) of 2-(2,3-dimethoxyphenyl)- 7V-methoxy-7V-methylacetamide as a brown oil.
(b) 2-(2, S -Dimethoxy phenyl) -1-phenylethanone Butyllithium (18.8 mL, 1.6 M in hexane, 30 mmol) was added to a solution of bromobenzene (3.0 mL, 27 mmol) in THF (50 mL) at -78°C under nitrogen. The mixture was stirred at -78°C for 4 h and then 2-(2,3-dimethoxyphenyl)-Λ/-methoxy-Λ/-methylacetamide (5.8 g, 24 mmol) in THF (50 mL) was added dropwise. The mixture was stirred at -78°C for 5 h and then saturated aqueous ammonium chloride was added with caution and the mixture was concentrated. The residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over Na2SO4 and then the solvent was removed by evaporation. The product was purified by chromatography on silica gel using a mixture of ethyl acetate and heptane. There was obtained 2.3 g (36%) of 2-(2,3-dimethoxyphenyl)-l- phenylethanone as an oil.
(c) 2-(2,3-Dimethoxyphenyl)-l-phenylethanamine hydrochloride
The compound was synthesised according to the procedure described in Intermediate 2b using 2-(2,3-dimethoxyphenyl)-l-phenylethanone (yield 61%). 1R NMR (400 MHz, DMSOd6): 3.1-3.2 (dd, IH), 3.3 (dd, IH), 3.6 (s, 3H), 3.7-3.8 (s, 3H), 4.5 (m, IH), 6.6 (t, IH), 6.8-6.9 (d, 2H), 7.3 (m, 3H), 7.4 (d, 2H), 8.7 (b, 3H); LC MS: m/z 358 (M+l) +.
Intermediate 11
2-(2-Fluorophenyl)- 1 -phenylethanamine
Figure imgf000034_0001
The compound was synthesised according to the reductive amination procedure described in Intermediate 3 but using 2-(2-fluorophenyl)-l-phenylethanone as the ketone starting material (yield 69%). 1U NMR (500 MHz, CDCl3): 2.9 (dd, IH), 3.1 (dd, IH), 4.3 (dd, IH), 7.0-7.4 (m, 9H); LC MS: m/z 216 (M+l) +. Intermediate 12 2-(2-Chlorophenyl)- 1 -phenylethanamine
Figure imgf000034_0002
The compound was synthesised according to the reductive amination procedure described in
Intermediate 3 but using 2-(2-chlorophenyl)-l-phenylethanone as the ketone starting material (yield 73%). 1R NMR (500 MHz, CDCl3): 3.0 (dd, IH), 3.2 (dd, IH), 4.3 (dd, IH), 7.1-7.4 (m, 9H); LC MS: m/z 232 (M+l) +.
Intermediate 13 4-r2-Amino-2-(2,3-dichlorophenyl)ethvHphenol
Figure imgf000035_0001
(a) l-(2, 3-Dichlorophenyl)-2-(4-methoxyphenyl)ethanone
Bis(dibenzylideneacetone)palladium (0.24 g, 0.42 mmol), l,l '-bis(diphenylphosphmo)- ferrocene (0.25 g, 0.45 mmol) and potassium hexamethyldisilazide (2.3 g, 11.5 mmol) were mixed in a two necked flask under nitrogen. THF (10 mL) was added followed by 4- bromoanisole (0.99 g, 5.3 mmol). The mixture was stirred at RT for 30 min and then 2',3'- dichloroacetophenone was added. The reaction mixture was refluxed for 3 h, cooled to RT and then partitioned between ether and water. The organic layer was washed twice with water, dried over MgSO4 and then the solvent was removed by evaporation. The product was purified by chromatography on silica gel using a mixture of ethyl acetate and heptane. There was obtained 0.28 g (18%) of l-(2,3-dichlorophenyl)-2-(4-methoxyphenyl)ethanone as a solid.
(b) l-(2, 3-Dichlorophenyl)-2-(4-methoxyphenyl)ethanamine
The compound was synthesised according to the reductive amination procedure described in Intermediate 3 but using l-(2,3-dichlorophenyl)-2-(4-methoxyphenyl)ethanone as the ketone (yield 4%). 1R NMR (500 MHz, CD3OD): 2.9 (dd, IH), 3.0-3.1 (dd, IH), 3.8-3.9 (s, 3H), 4.7 (t, IH), 6.8 (d, 2H), 7.0 (d, 2H), 7.3 (t, IH), 7.4-7.5 (m, 2H); LC MS: m/z 296 (M+l) +.
(c) 4-[2-Amino-2-(2, 3-dichlorophenyl)ethyl] phenol An aqueous solution of HBr (48%) was added to l-(2,3-dichlorophenyl)-2-(4- methoxyphenyl)ethanamine and the mixture was heated to reflux for 5 h and then left at RT over night. The mixture was extracted three times with ethyl acetate and the combined organic solutions were dried over MgSO4 and then the solvent was removed by evaporation. The residue was partitionated between dichloro methane and an aqueous solution OfNaHCO3. The organic solution was dried using a phase separator and then the solvent was removed by evaporation. There was obtained 7 mg (73%) of the title product.1H NMR (500 MHz, CD3OD): 2.7 (dd, IH), 2.9-3.0 (dd, IH), 4.6 (t, IH), 6.7 (d, 2H), 6.9 (d, 2H), 7.3 (m, IH), 7.4- 7.5 (m, 2H); LC MS: m/z 283 (M+l) +.
Intermediate 14
2-(2-TrifluoromethylphenvD- 1 -phenylethanamine
Figure imgf000036_0001
The compound was synthesised according to the procedures described in Intermediate 10 using 2-trifluoromethylphenyl acetic acid as the starting material (yield 6%). 1H NMR (400 MHz, DMSOd6): 3.3 (dd, IH), 3.4-3.5 (dd, IH), 4.5-4.6 (dd, IH), 7.2 (d, IH), 7.3-7.6 (m, 7H), 7.6-7.7 (d, IH); LC MS: m/z 266 (M+l) +.
Intermediate 15
2-(3-ButoxyphenvD- 1 -phenylethanamine hydrochloride
Figure imgf000037_0001
(a) tert-Butyl [2-(3-butoxyphenyl)-l-phenylethyl] carbamate To an ice-cooled mixture of tøt-butyl [2-(3-hydroxyphenyl)-l-phenylethyl] carbamate (see Intermediate 6a; 3.0 g, 10 mmol) and cesium carbonate (3.4 g, 10.5 mmol) in dichloromethane (30 mL) was added n-butyl iodide (1.9 g, 10.5 mmol) dropwise. The reaction mixture was stirred at RT for one hour and then cooled water was added. The phases were separated and the aqueous solution was extracted with dichloromethane. The combined organic layers were washed with water and with brine and then dried over Na2SO4. The solvent was removed by evaporation and the residue was purified by chromatography on silica gel using a mixture of ethyl acetate and heptane. There was obtained 3.2 g (90%) of tert-hvXy\ [2-(3-butoxyphenyl)-l-phenylethyl] carbamate as a yellow gum.
(b) 2-(3-Butoxyphenyl)-l -phenylethanamine hydrochloride
Concentrated aqueous HCl (10 mL) was added dropwise to a solution of tert-bvXy\ [2-(3- butoxyphenyl)-l-phenylethyl] carbamate in ethanol (30 mL). The reaction mixture was stirred at RT for 2 h. The solvent was removed by evaporation and to the residue was added diethyl ether. The formed precipitate was isolated by filtration and there was obtained 1.5 g (57%) of 2-(3-butoxyphenyl)-l -phenylethanamine hydrochloride as a white solid. 1H NMR (400 MHz, DMSOd6): 0.9 (t, 3H), 1.4 (m, 2H), 1.6 (m, 2H), 3.1 (dd, IH), 3.2 (dd, IH), 3.8 (m, 2H), 4.5- 4.6 (dd, IH), 6.6 (m, 2H), 6.7 (d, IH), 7.1 (t, IH), 7.3-7.4 (m, 5H); LC MS: m/z 270 (M+l) +.
Intermediate 16
2-(2,5-Dimethoxyphenyl)- 1 -phenylethanamine
Figure imgf000038_0001
The compound was synthesised according to the procedures described in Intermediate 10 using 2,5-dimethoxyphenyl acetic acid as the starting material (yield 13%). 1H NMR (400 MHz, DMSOd6): 3.1-3.2 (dd, IH), 3.3 (dd, IH), 3.6 (s, 3H), 3.7 (s, 3H), 4.5 (m, IH), 6.6 (d, IH), 6.7 (dd, 2H), 6.8 (d, IH), 7.3 (m, 3H), 7.4 (d, 2H), 8.6-8.7 (b, 3H); LC MS: m/z 358 (M+ 1) +.
Intermediate 17
2-(2,3-DifluorophenvD- 1 -phenylethanamine
Figure imgf000038_0002
The compound was synthesised according to the procedures described in Intermediate 2 using 2,3-difluorophenyl acetic acid as the starting material (yield 35%). 1H NMR (400 MHz, DMSOd6): 3.2-3.3 (dd, IH), 3.3-3.4 (dd, IH), 3.6 (s, 3H), 4.5 (dd, IH), 6.9 (t, IH), 7.0 (m, IH), 7.2-7.3 (m, IH), 7.3-7.5 (m, 5H), 8.7 (b, 3H); LC MS: m/z 234 (M+l) +.
Intermediate 18
2-(2-Chloro-6-fluorophenyl)- 1 -phenylethanamine
Figure imgf000038_0003
The compound was synthesised according to the procedures described in Intermediate 2 using
2-chloro-6-fluorophenyl acetic acid as the starting material (yield 8%). 1H NMR (400 MHz, DMSOd6): 3.4-3.5 (d, 2H), 4.7 (m, IH), 7.0-7.1 (m, IH), 7.2-7.4 (m, 7H), 9.0 (b, 3H); LC MS: m/z 234 (M+ 1) +.
Intermediate 19 4-(2-amino-2-phenylethyl)phenyl methanesulfonate
Figure imgf000039_0001
The compound was synthesised according to the procedures described in Intermediate 6 using 4-(2-amino-2-phenylethyl)phenol (see J. of Med. Chem.; 21 (1978) 1265-1269) as the starting material (yield 60%). 1U NMR (400 MHz, DMSOd6): 3.3 (s, 3H), 3.3-3.4 (m, 2H), 4.6-4.7 (m, IH), 7.2 (s, 4H), 7.4 (m, 2H), 7.4 (m, 3H); LC MS: m/z 292 (M+ 1) +.

Claims

Claims
1. A compound of formula (I)
Figure imgf000040_0001
(I)
wherein
Ar1 is
Figure imgf000040_0002
R1 is independently selected from halogen, hydroxy, cyano, Q-C5 alkoxy, Q-C3 alkyl, Q-
C3 alkylsulfonate or Q-C3 alkoxy substituted by Q-C3 alkoxy; wherein the alkyl group, alkoxy group or alkylsulfonate group may be substituted by one or more fluoro atom(s); m is 0, 1, 2, 3, 4 or 5;
Ar2 is
Figure imgf000040_0003
R2 is independently selected from halogen, hydroxy or Q-C3 alkyl; wherein the alkyl group may be substituted by one or more fluoro atom(s); n is 0, 1, 2, 3 or 4; or Ar1 and Ar2 may be attached to each other and thus form an optionally substituted biphenyl group; or
Ar1 or Ar2 may be fused with a six-membered aromatic ring wherein the ring atoms are selected from C or N and at least three ring atoms are C;
X is carbon or nitrogen; Y is carbon or nitrogen; Z is carbon or nitrogen;
with the proviso that R2 is covalently attached to a carbon atom;
as well as pharmaceutically and pharmacologically acceptable salts thereof and enantiomers of the compound of formula (I) and salts thereof;
with the exception of:
N-[I -(3-chlorophenyl)-2-phenylethyl]-4,5-dihydro- lH-imidazol-2-amine;
N-[I -(3-chlorophenyl)-2-phenylethyl]-4,5-dihydro- lH-imidazol-2-amine hydro iodide;
N-[I -(4-chlorophenyl)-2-phenylethyl]-4,5-dihydro- lH-imidazol-2-amine hydro iodide; Λ/-[l-(2-chloro-4-fluorophenyl)-2-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine; and
Λ/-[l-(3-fluorophenyl)-2-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine.
2. A compouoond according to claim 1 wherein X is carbon, Y is carbon and Z is carbon.
3. A compound according to claim 1 or 2 wherein R1 is bromo, chloro, fiuoro, hydroxy, trifluoromethyl, methoxy, butoxy, methylsulfonate or cyano.
4. A compound according to claims 1 - 3 wherein R is chloro, hydroxy or trifluoromethyl.
5. A compound according to any one of claims 1-4, wherein m is 0, 1 or 2.
6. A compound according to any one of claims 1-5, wherein n is 0, 1 or 2.
7. A compound according to claim 1 selected from:
(+)-4-[ 1 -(4,5-dihydro- lH-imidazol-2-ylamino)-2-phenylethyl]phenol; N-(9, 10-dihydrophenanthren-9-yl)-4,5-dihydro- lH-imidazol-2-amine;
Λ/-[2-(3,5-difluorophenyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine;
N- {2-phenyl- 1 -[3-(trifluoromethyl)phenyl]ethyl} -4,5-dihydro- lH-imidazol-2-amine;
N- (2-(4-bromophenyl)- 1 -[3-(trifluoromethyl)phenyl]ethyl} -4,5-dihydro- lH-imidazol-2- amine; N- [2-(3 -fluorophenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine;
3-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2-(4-hydroxyphenyl)ethyl]benzonitrile;
3-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2-phenylethyl]phenyl methanesulfonate;
4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2-(3-hydroxyphenyl)ethyl]benzonitrile;
N-[I -(3-chlorophenyl)-2-phenylethyl]-4,5-dihydro- lH-imidazol-2-amine; 7V-[2-(3-chlorophenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine;
4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2-phenylethyl]phenol;
4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2-(4-hydroxyphenyl)ethyl]benzonitrile;
N-[2-(4-chlorophenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine;
4,4'-[ 1 -(4,5-dihydro- l//-imidazol-2-ylamino)ethane- 1 ,2-diyl]diphenol; 3-[l-(4,5-dihydro-lH-imidazol-2-ylamino)-2-phenylethyl]phenol;
4-[l-(4,5-dihydro-lH-imidazol-2-ylamino)-2-phenylethyl]phenol;
(+)-3-[ 1 -(4,5-dihydro- l//-imidazol-2-ylamino)-2-phenylethyl]phenol;
Λ/-(l,2-diphenylethyl)-4,5-dihydro-lH-imidazol-2-amine;
N-[2-(2,3-dimethoxyphenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine; Λ/-[2-(2-fluorophenyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine;
N-[2-(\ -naphthyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine;
7V-[2-(2-chlorophenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine;
N-[2-(4-butoxyphenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine;
4-[2-(2,3-dichlorophenyl)-2-(4,5-dihydro-lH-imidazol-2-ylamino)ethyl]phenol; 3-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2-phenylethyl]phenol;
N- {1 -phenyl-2-[2-(trifluoromethyl)phenyl]ethyl} -4,5-dihydro- lH-imidazol-2-amine; 7V-[2-(3-butoxyphenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine; 7V-[2-(2,5-dimethoxyphenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine; 7V-[2-(2-methoxyphenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine; 7V-[2-(2,3-difluorophenyl)- 1 -phenylethyl]-4,5-dihydro- lH-imidazol-2-amine; Λ/-[2-(2-chloro-6-fluorophenyl)-l-phenylethyl]-4,5-dihydro-lH-imidazol-2-amine; 4-[2-(4,5-dihydro-lH-imidazol-2-ylamino)-2-phenylethyl]phenyl methanesulfonate; N-(2 -phenyl- 1 -pyridin-3-ylethyl)-4,5-dihydro- lH-imidazol-2-amine and N-(2 -phenyl- 1 -pyridin-4-ylethyl)-4,5-dihydro- lH-imidazol-2-amine; or pharmaceutically and pharmacologically acceptable salts thereof and enantiomers of said compounds and salts thereof.
8. A compound of formula (I);
Figure imgf000043_0001
(I)
wherein
Ar is
Figure imgf000043_0002
R1 is independently selected from halogen, hydroxy, cyano, Q-C5 alkoxy, Q-C3 alkyl, Q-
C3 alkylsulfonate or Q-C3 alkoxy substituted by Q-C3 alkoxy; wherein the alkyl group, alkoxy group or alkylsulfonate group may be substituted by one or more fluoro atom(s); m is O, 1, 2, 3, 4 or 5;
Ar2 is
Figure imgf000044_0001
R2 is independently selected from halogen, hydroxy or Q-C3 alkyl; wherein the alkyl group may be substituted by one or more fluoro atom(s); n is 0, 1, 2, 3 or 4;
or
Ar1 and Ar2 may be attached to each other and thus form an optionally substituted biphenyl group; or
Ar1 or Ar2 may be fused with a six-membered aromatic ring wherein the ring atoms are selected from C or N and at least three ring atoms are C;
X is carbon or nitrogen; Y is carbon or nitrogen;
Z is carbon or nitrogen;
with the proviso that R is covalently attached to a carbon atom; as well as pharmaceutically and pharmacologically acceptable salts thereof and enantiomers of the compound of formula (I) and salts thereof; for use in therapy.
9. Use of a compound of formula (I) as defined in claim 8 or a pharmaceutically and pharmacologically acceptable salt thereof or enantiomer of the compound of formula (I) or a salt thereof in the manufacture of a medicament for the treatment or prophylaxis of respiratory, cardiovascular, neuro, pain and gastrointestinal disorders.
10. Use of a compound of formula (I) as defined in claim 8 or a pharmaceutically and pharmacologically acceptable salts thereof and enantiomers of the compound of formula (I) and salts thereof in the manufacture of a medicament for the treatment or prophylaxis of functional dyspepsia.
11. Use of a compound of formula (I) as defined in claim 8 or a pharmaceutically and pharmacologically acceptable salts thereof and enantiomers of the compound of formula (I) and salts thereof in the manufacture of a medicament for the treatment or prophylaxis of diabetes.
12. A pharmaceutical formulation comprising a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, or an enantiomer of the compound of formula
(I) or salt thereof, optionally in admixture with a pharmaceutically acceptable diluent or carrier.
13. A method for the treatment or prevention of respiratory, cardiovascular, neurological, pain and/or gastrointestinal disorders which comprises administering to a person in need thereof a therapeutically effective amount of a compound of formula (I), as defined in claim 8, or a pharmaceutically acceptable salt thereof, or an enantiomer of the compound of formula (I) or salt thereof.
14. A compound selected from:(+)-4-[l-amino-2-phenylethyl]phenol;
(-)-4-[ 1 -amino-2-phenylethyl]phenol;
2-(3 ,5-difiuorophenyl)- 1 -phenylethanamine;
2-(4-bromophenyl)- 1 -[3-(trifluoromethyl)phenyl]ethanamine;
2-(3 -fluorophenyl)- 1 -phenylethanamine; 3-[2-amino-2-(4-hydroxyphenyl)ethyl]benzonitrile;
3-(2-amino-2-phenylethyl)phenyl methanesulfonate; 4-[2-amino-2-(3-hydroxyphenyl)ethyl]benzonitrile; 4-[2-amino-2-(4-hydroxyphenyl)ethyl]benzonitrile; (+)-3-(l-amino-2-phenylethyl)phenol; 2-(2,3-dimethoxyphenyl)- 1 -phenylethanamine; 2-(2-fluorophenyl)- 1 -phenylethanamine; 2-(2-chlorophenyl)- 1 -phenylethanamine; 4-[2-amino-2-(2,3-dichlorophenyl)ethyl]phenol; 2-(2-trifluoromethylphenyl)- 1 -phenylethanamine; 2-(3 -butoxyphenyl)- 1 -phenylethanamine; 2-(2,5-dimethoxyphenyl)- 1 -phenylethanamine; 2-(2,3-difluorophenyl)- 1 -phenylethanamine; 2-(2-chloro-6-fluorophenyl)- 1 -phenylethanamine and 4-(2-amino-2-phenylethyl)phenyl methanesulfonate.
PCT/SE2008/050226 2007-03-01 2008-02-29 4, 5-dihydro-lh-imidazol-2-amine derivatives for use in the treatment of respiratory, cardiovascular, neurological or gastrointestinal disorders WO2008123821A1 (en)

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