WO2008115141A1 - Dérivés de 4,5-dihydro-1,3-thiazol-2-amine et leur utilisation pour le traitement de troubles respiratoires, cardiovasculaires, neurologiques ou gastrointestinaux - Google Patents

Dérivés de 4,5-dihydro-1,3-thiazol-2-amine et leur utilisation pour le traitement de troubles respiratoires, cardiovasculaires, neurologiques ou gastrointestinaux Download PDF

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WO2008115141A1
WO2008115141A1 PCT/SE2008/050300 SE2008050300W WO2008115141A1 WO 2008115141 A1 WO2008115141 A1 WO 2008115141A1 SE 2008050300 W SE2008050300 W SE 2008050300W WO 2008115141 A1 WO2008115141 A1 WO 2008115141A1
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compound
formula
dihydro
amine
phenyl
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PCT/SE2008/050300
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English (en)
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Rolf Bergman
Isabel Calaza-Cabanas
Anders M. Johansson
Anette Marie Svensson-Henriksson
Fredrik Thorstensson
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Albireo Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • 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
    • A—HUMAN NECESSITIES
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/39—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton
    • C07C211/41—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems
    • C07C211/42—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of an unsaturated carbon skeleton containing condensed ring systems with six-membered aromatic rings being part of the condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/08—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D277/12—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole 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
    • C07D277/18—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • the present invention relates to compounds of formula (I), (XI) or (CI), 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), (XI) or (CI) 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 life-threatening 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 which 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 ⁇ i-, ⁇ 2 - and ⁇ -receptors. The groups are further subdivided into six ⁇ -adrenoceptors, ⁇ iA, am, am, a 2 A, (X 2 B, a2C anc ⁇ three ⁇ -adrenoceptors ⁇ i, ⁇ 2 , ⁇ 3 (see e.g., Buddyerty J.
  • ⁇ -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.
  • ⁇ i -adrenoceptors are implicated in processes such as vasoconstriction, glycogeno lysis, cardiac inotrophy and chronotrophy.
  • ⁇ 2 -adrenoceptors are associated with platelet aggregation, neurotransmitter 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 ⁇ agonists.
  • WO 2005/063724 describes certain l-(azolin-2-yl)amino-l,2-diphenylethane compounds.
  • Brown D. G. et al. "Design and synthesis of amino imidazoline derived analogs as selective ⁇ 2 c-adrenoceptor agonists" describes 2-amino-indan analogues, poster presented at 219th American Chemical Society National Meeting, San Francisco, CA, March 26-30, 2000.
  • US 3636219 describes anticholinergic compositions containing certain thiazo lines or imidazolines.
  • 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, C1-C5 alkoxy, C1-C3 alkyl, C1-C3 alkylsulfonate or C1-C3 alkoxy substituted by C1-C3 alkoxy; wherein the alkyl group, alkoxy group or alkylsulfonate group may be substituted by one or more fiuoro atom(s); m is O, 1, 2, 3, 4 or 5; Ar 2 is
  • R 2 is independently selected from halogen, hydroxy or C1-C3 alkyl; wherein the alkyl group may be substituted by one or more fiuoro atom(s); n is 0, 1, 2, 3, 4 or 5; or Ar 1 and Ar 2 may be attached to each other and thus form an optionally substituted biphenyl group; or
  • 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;
  • R 2 is halogen, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy or CF 3 ; and n is 0 or 1 or 2 or 3; with the further exception of compounds wherein
  • X and Y and Z are carbon; R 1 is methoxy or CF 3 ; and m is 1 or 2; and n is 0; with the further exception of compounds wherein
  • X and Y and Z are carbon; R 1 is halogen; and m is 1 or 2 or 3 or 4 or 5; and n is 0; with the further exception of compounds wherein
  • X and Y and Z are carbon; R 1 is halogen or methoxy; and m is 1; and
  • R is halogen or methoxy; and n is 1.
  • R 1 of formula (I) is chloro, fluoro, bromo, hydroxy, trifiuoromethyl, methoxy, butoxy, methylsulfonate or cyano.
  • R 2 of formula (I) is chloro, hydroxy or trifiuoromethyl.
  • R 1 of formula (I) is hydroxy. In one embodiment of the present invention R 2 of formula (I) is hydroxy. In one embodiment of the present invention, m of formula (I) is 0, 1 or 2. In one embodiment of the present invention, n of formula (I) is 0, 1 or 2.
  • X or Y or Z of formula (I) is nitrogen. In one embodiment Y of formula (I) is nitrogen.
  • the present invention also provides a compound of the general formula (XI)
  • R 1 is hydrogen, phenyl or allyl; wherein the phenyl may be substituted by carbamoyl, methylcarbamoyl or dimethylcarbamoyl in the para position or by one or two halogen atom(s) in any position;
  • R 2 is hydrogen, Ci -C 3 alkyl or hydroxy; n is 1 or 2; wherein the alkyl group or allyl group may be substituted by one or more fluoro atom(s); as well as pharmaceutically and pharmacologically acceptable salts thereof and stereoisomers of the compound of formula (XI) and salts thereof; with the exception of compounds wherein both R 1 and R 2 are H.
  • R 1 of Formula (XI) is phenyl.
  • R 2 of Formula (XI) is methyl or hydroxy.
  • n of Formula (XI) is 1.
  • the present invention further provides a compound of the general formula (CI)
  • R 1 is hydrogen or Ci -C 5 alkyl
  • R is selected from hydrogen, halogen, Ci-C 3 alkyl, Ci-C 3 alkoxy, hydroxy, 4- carbamoyl, 4-methylcarbamoyl or 4-dimethylcarbamoyl;
  • R 3 is selected from hydrogen, halogen, Ci-C 3 alkyl, Ci-C 3 alkoxy or hydroxy;
  • X is O, S or NH; wherein the alkyl or alkoxy group may be substituted by one or more fluoro atom(s); as well as pharmaceutically and pharmacologically acceptable salts thereof, and stereoisomers of the compound of formula (CI).
  • R 1 of Formula (CI) is hydrogen or C 1 -C 3 alkyl.
  • X of Formula (CI) is NH.
  • X of Formula (CI) is S.
  • the present invention relates to compounds of formula (I), (XI) and (CI) 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), (XI) and (CI).
  • 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, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate,
  • 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), (XI) and (CI) 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), (XI) and (CI) 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), (XI) and (CI) can also be in the form of a racemic mixture, i.e. an equimolar mixture of enantiomers.
  • the present invention also relates to any and all tautomeric forms of the compounds of formula (I), (XI) and (CI).
  • Some compounds can exist as a mixture of conformational isomers.
  • the compounds of this invention comprise both mixtures of, and individual, conformational isomers.
  • Ci -C 3 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.
  • C 1 -C 5 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-propoxy, 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 difiuoromethoxy or trifiuoromethoxy.
  • C1-C5 alkyl includes straight as well as branched alkyl groups having 1 to 5 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, 1-methyl-propyl, 2-methyl-propyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 1,1- dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethyl-propyl and 1-ethylpropyl.
  • Ci-C 3 alkoxy includes straight as well as branched alkyl groups having 1 to 3 carbon atoms attached via an oxygen atom, for example methoxy, ethoxy, propoxy and iso-propoxy.
  • the alkyl group may be substituted by one or more fluoro atoms, such as in difiuoromethoxy or trifiuoromethoxy.
  • halogen includes fluorine, chlorine, bromine or iodine.
  • Ci-C 3 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.
  • the compounds of formula (XI) are selective ⁇ 2 B agonists.
  • a selective ⁇ 2 ⁇ agonist is defined herein as a compound having a ratio of EC50 for ot2A/ot2B >1 and ( X 1 AAx 2 B > ⁇ -
  • a pharmaceutical formulation comprising a compound of formula (I), (XI) or (CI), 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, inflammatory 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.
  • 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.
  • 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), (XI) or (CI) or a pharmaceutically acceptable salt thereof.
  • a compound of the formula (I), (XI) or (CI) 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), (XI) or (CI) 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 ⁇ adrenergic receptors is beneficial which comprises administering to a subject an effective amount of a compound of the formula (I), (XI) or (CI) or a pharmaceutically- acceptable salt thereof.
  • the present invention also provides the use of a compound of formula (I), (XI) or (CI) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in a disease condition wherein agonism of ⁇ adrenergic receptors is beneficial.
  • the compounds of formula (I), (XI) or (CI) 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 examples include 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), (XI) or (CI) for the manufacture of a medicament for the treatment of any of the disorders defined herein
  • 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 thereof, a therapeutically effective amount of a compound of formula (I), (XI) or (CI) or a pharmaceutically acceptable salt thereof.
  • ⁇ 2 adrenoceptor subtypes Three functional ⁇ 2 adrenoceptor subtypes are described, ⁇ 2 A, CX 2B and ⁇ 2 c and they all belonging to the GPCR superfamily. All three ⁇ 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 OI 2AB receptors were used for functional screening of compounds. Expression of engineered G qi 5 (the last 5 amino acids of G ⁇ q are replaced with the last 5 amino acids of Ga 1 ) allows to diverge signal from Ga 1 coupled receptor to Ga q signaling.
  • the degree of receptor activation correlates to the release of intracellular Ca 2+ measured with a Fluorescence Imaging Plate Reader (FLIPR).
  • FLIPR Fluorescence Imaging Plate Reader
  • Human embryonic kidney (HEK) 293SGqis cells were stably transfected with human CC 2A or human CC 2B receptors cDNA cloned into pIRESneo2 expression vector. Transfection was performed using cationic lipid reagent Lipofectamine plus and selection with 1 mg/ml
  • the potency of a compound of the invention to activate CC 2 A and CC 2 B receptors was assessed by the following procedure: HEK293Gqi5 cells stably transfected with human CC 2 A and CC 2B 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 2+ 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.
  • Apredilution 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.
  • results In general, the compounds of the invention, which were tested, demonstrated statistically significant agonistic activity at the CC 2 A and/or CC 2 B receptors at low levels.
  • the EC50 (0C 2B ) value was generally less than 260 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, is applied to the balloon until base line values are obtained. This is followed by a Ramp 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.
  • 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 isofiurane 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: a) reacting a compound of the formula (II) with a compound of the formula (III):
  • the coupling reaction is typically performed at a non-extreme temperature, for example at room temperature (RT), preferably in a non-polar solvent as for instance THF (tetr ahydr o fur an) .
  • a non-polar solvent as for instance THF (tetr ahydr o fur an) .
  • 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 formulae (IV) with hydroxylamine followed by a reduction of the formed oxime using as for instance reductive hydrogenation conditions.
  • the compounds of formulae (III) are commercially available or may be prepared by standard techniques.
  • the compounds of formulae (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].
  • the present invention provides a process for preparing a compound of the formula (XI) or salts thereof which process comprises: a) reacting a compound of the formula (XII) with a compound of the formula
  • n, R 1 and R 2 are as hereinbefore defined for formula (XI); L is a suitable leaving group such as methylthio or sulfo and R 3 is a hydrogen atom or a protective group such as t ⁇ t-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 (XII) and the 2-carbon atom of the imidazoline ring of the compounds of formula (XIII), and thereafter any optionally protective group is being removed by as for instance utilizing an acid or base catalysed hydro lytic 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 - 130 0 C, optionally by using microwave single node heating, preferably in a polar solvent for example 2-propanol.
  • the compounds of the formulae (XII) are known or may be prepared, for example, by a reductive amination reaction utilizing ammonia, a reducing agent and a compound of formulae (XIV):
  • Typical reducing agents include borohydrides such as sodium cyanoborohydride.
  • the compounds of formula (XII) may also be prepared by reacting a compound of formulae (XIV) with hydroxy lamine followed by a reduction of the formed oxime using as for instance reductive hydrogenation conditions.
  • the compounds of formulae (XIII) are known or may be prepared as for instance by the procedures described in Tetrahedron Lett.; 41 (2000) 6563-6566.
  • the compounds of formulae (XIV) are known or may be prepared by standard techniques for obtaining indan-1-ones and 1-tetralones as for instance by the procedures described in Chemistry Lett.; 5 (1988) 901-904.
  • the present invention provides a process for preparing a compound of the formula (CI) or salts thereof which process comprises: When X is NH; a) reacting a compound of the formula (CII) with a compound of the formula
  • R 1 , R 2 and R 3 are as hereinbefore defined for formula (CI);
  • X is NH;
  • L 1 is a suitable leaving group such as methylthio or sulfo and
  • R 4 is a hydrogen atom or a protective group such as t ⁇ t-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 (CII) and the 2-carbon atom of the imidazoline ring of the compounds of formula (CIII), and thereafter any optionally protective group is being removed by as for instance utilizing an acid or base catalysed hydro lytic 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 - 130 0 C, optionally by using microwave single node heating, preferably in a polar solvent for example methanol.
  • R 1 , R 2 and R 3 are as hereinbefore defined for formula (CI);
  • X is O or S;
  • L 2 is a suitable leaving group such as bromo or chloro and; 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 (CII) and the carbon atom of the isothiocyanate or isocyanate group of the compounds of formula (CIV) and an S-C or O-C bond is formed between the sulfur or oxygen atom of the compounds of formula (CIV) and the carbon atom adjacent to the leaving group L , and thereafter any optionally protective group is being removed by as for instance utilizing an acid or base catalysed hydro lytic reaction, and then by way of conclusion optionally forming a pharmaceutically acceptable salt.
  • the coupling reaction is typically performed at a non-extreme temperature, for example at room temperature (RT), preferably in a non-polar solvent as for instance THF (tetr ahydr o fur an) .
  • a non-polar solvent as for instance THF (tetr ahydr o fur an) .
  • the compounds of the formula (CII) are known or may be prepared, for example, by the procedures described in Bulletin de Ia Societe Chim. De France (1969), 1227-1233.
  • Example 1 ⁇ /-(l,2-Diphenylethyl)-4,5-dihydro-l,3-thiazol-2-amine acetate
  • the product was purified by crystallisation from a mixture of ethyl acetate and then further purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.2 M ammonium acetate as eluent. The proper fractions were combined and the solvent was removed by freeze-drying. There was obtained 42 mg (11%) of the title compound.
  • the product was purified by means of reversed phase chromatography using a mixture of acetonitrile and aqueous 0.2 M ammonium acetate as eluent (gradient, 0-40% acetonitrile during 30 minutes).
  • the two stereoisomers separated as the cis isomer came out first from the column. These fractions were combined and the solvent was removed by freeze-drying. There was obtained 51 mg (26%) of the title compound as a white powder.
  • the product was contaminated with approximately 20% of the trans isomer.
  • Example 12 ⁇ /-(4,5-dihydro- lH-imidazol-2-yl)- 1 -methyl-2-phenyl- lH-indol-3-amine acetate l-Methyl-2-phenyl-lH-indol-3-amine (see Journal fuer Praktician Chemie 28 (1965), 169-77; 0.18 g, 0.86 mmol) and 4,5-dihydro-lH-imidazole-2-sulfonic acid (0.15 g, 1.0 mmol) were mixed together with acetic acid (0.60 g, 10 mmol) and isopropanol (5 mL). The reaction mixture was heated at 140°C for 5 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 proper fractions were concentrated on a rotavapor and the remaining solvent was removed by freeze-drying. There was obtained 0.11 g (27%) of the title compound.
  • 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.

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Abstract

La présente invention concerne des composés de formule (I), (XI) ou (CI), des compositions pharmaceutiques qui contiennent lesdits composés et l'utilisation desdits composés en thérapie. La présente invention concerne également des procédés de préparation de composés de formule (I), (XI) ou (CI) et de nouveaux intermédiaires utilisés dans la préparation de ces composés.
PCT/SE2008/050300 2007-03-19 2008-03-18 Dérivés de 4,5-dihydro-1,3-thiazol-2-amine et leur utilisation pour le traitement de troubles respiratoires, cardiovasculaires, neurologiques ou gastrointestinaux WO2008115141A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009023758A1 (fr) * 2007-08-15 2009-02-19 Allergan, Inc. Carbocycles fusionnés substitués par hétérocyclyle utiles dans le traitement d'affections telles que le glaucome et la douleur
WO2009023757A1 (fr) * 2007-08-15 2009-02-19 Allergan, Inc. Composés thérapeutiques
WO2009091874A1 (fr) * 2008-01-18 2009-07-23 Allergan, Inc. Agents alpha 2 adrénergiques de sous-type sélectif et procédés d'utilisation de ceux-ci
WO2010077586A1 (fr) * 2008-12-08 2010-07-08 Allergan, Inc. Composés de n-(1-phényl-2-aryléthyl)-4,5-dihydro-3h-pyrrol-2-amine comme modulateurs sélectifs vis-à-vis du sous-type de récepteurs adrénergiques alpha-2b ou alpha-2b et alpha-2c
EP2265269A1 (fr) * 2008-03-24 2010-12-29 Allergan, Inc. Agents alpha-2 adrénergiques sélectifs et leurs procédés d utilisation
CN108586294A (zh) * 2018-05-29 2018-09-28 王若锴 一种脲类衍生物及其在防治炎症中的应用

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Publication number Priority date Publication date Assignee Title
WO2005063724A1 (fr) * 2003-12-23 2005-07-14 Basf Aktiengesellschaft Composes 1-(azolin-2-yl) amino-1,2-diphenylethane destines a la lutte contre les insectes, les arachnides et les nematodes
WO2006125748A1 (fr) * 2005-05-24 2006-11-30 Basf Aktiengesellschaft Composes 1-(imidazoline-2-yl)amino-1,2-diphenylethane pour lutter contre des parasites des animaux
WO2008000834A1 (fr) * 2006-06-30 2008-01-03 Basf Se Composés de 1-(azolin-2-yl)-amino-2-aryl-1-hétaryl-éthane substitués

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2005063724A1 (fr) * 2003-12-23 2005-07-14 Basf Aktiengesellschaft Composes 1-(azolin-2-yl) amino-1,2-diphenylethane destines a la lutte contre les insectes, les arachnides et les nematodes
WO2006125748A1 (fr) * 2005-05-24 2006-11-30 Basf Aktiengesellschaft Composes 1-(imidazoline-2-yl)amino-1,2-diphenylethane pour lutter contre des parasites des animaux
WO2008000834A1 (fr) * 2006-06-30 2008-01-03 Basf Se Composés de 1-(azolin-2-yl)-amino-2-aryl-1-hétaryl-éthane substitués

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009023758A1 (fr) * 2007-08-15 2009-02-19 Allergan, Inc. Carbocycles fusionnés substitués par hétérocyclyle utiles dans le traitement d'affections telles que le glaucome et la douleur
WO2009023757A1 (fr) * 2007-08-15 2009-02-19 Allergan, Inc. Composés thérapeutiques
US8815923B2 (en) 2007-08-15 2014-08-26 Allergan, Inc. Therapeutic compounds
WO2009091874A1 (fr) * 2008-01-18 2009-07-23 Allergan, Inc. Agents alpha 2 adrénergiques de sous-type sélectif et procédés d'utilisation de ceux-ci
US8809379B2 (en) 2008-01-18 2014-08-19 Allergan, Inc. Selective subtype alpha 2 adrenergic agents and methods for use thereof
EP2265269A1 (fr) * 2008-03-24 2010-12-29 Allergan, Inc. Agents alpha-2 adrénergiques sélectifs et leurs procédés d utilisation
WO2010077586A1 (fr) * 2008-12-08 2010-07-08 Allergan, Inc. Composés de n-(1-phényl-2-aryléthyl)-4,5-dihydro-3h-pyrrol-2-amine comme modulateurs sélectifs vis-à-vis du sous-type de récepteurs adrénergiques alpha-2b ou alpha-2b et alpha-2c
JP2012511044A (ja) * 2008-12-08 2012-05-17 アラーガン インコーポレイテッド アルファ２ｂまたはアルファ２ｂおよびアルファ２ｃアドレノセプターのサブタイプ選択性モジュレーターとしてのｎ‐（１‐フェニル‐２‐アリールエチル）‐４，５‐ジヒドロ‐３ｈ‐ピロール‐２‐アミン化合物
US8183414B2 (en) 2008-12-08 2012-05-22 Allergan, Inc. N-(1-phenyl-2-arylethyl)-4,5-dihydro-2H-pyrrol-5-amine compounds as subtype selective modulators of ALPHA2B or ALPHA2B and ALPHA2C adrenoceptors
CN108586294A (zh) * 2018-05-29 2018-09-28 王若锴 一种脲类衍生物及其在防治炎症中的应用

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