WO2009080682A1 - Dérivés de pyrrolo[2,3-d]pyrimidine convenant comme antagonistes du récepteur gcrp - Google Patents

Dérivés de pyrrolo[2,3-d]pyrimidine convenant comme antagonistes du récepteur gcrp Download PDF

Info

Publication number
WO2009080682A1
WO2009080682A1 PCT/EP2008/067823 EP2008067823W WO2009080682A1 WO 2009080682 A1 WO2009080682 A1 WO 2009080682A1 EP 2008067823 W EP2008067823 W EP 2008067823W WO 2009080682 A1 WO2009080682 A1 WO 2009080682A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
pyrrolo
pyrimidin
reduced pressure
ethyl
Prior art date
Application number
PCT/EP2008/067823
Other languages
English (en)
Inventor
Paula Louise Nichols
Sanjeet Singh Sehmi
Robert William Ward
David Matthew Wilson
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Publication of WO2009080682A1 publication Critical patent/WO2009080682A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds, and to the use thereof in treating diseases and conditions mediated by Calcitonin-Gene-Related Peptide (CGRP).
  • CGRP Calcitonin-Gene-Related Peptide
  • the invention relates to compositions containing compounds of the invention and processes for their preparation.
  • Calcitonin Gene Related Peptide is a 37 amino acid neurotransmitter, which is widely distributed throughout the central and peripheral nervous system. It is a potent dilator of arteries and veins, particularly in the cerebral vasculature and is released into the venous circulation in migraineurs. These actions together with its localisation in the trigeminovascular system, suggests a role for CGRP in the pathogenesis of migraine. This includes a vasodilator role as well as a possible involvement in the central sensitisation of nociceptive pathways, which are also thought to be a component of migraine.
  • CGRP1 receptors which have a molecular correlate in the calcitonin receptor like receptor (CL) and the accessory protein, RAMP1 , the association between which is essential for function.
  • CGRP receptor antagonists would therefore be expected to be effective in the treatment of migraine and other headache syndromes.
  • the novel non-peptide CGRP receptor antagonist, BIBN 4096 antagonised the vasodilator effects of CGRP on human cerebral vessels and, when given intravenously, was effective in treating headache in migraineurs, thereby providing proof of concept for the use of CGRP receptor antagonists to treat migraine. It would therefore be desirable to identify a CGRP receptor antagonist that is selective for the human CGRP receptor and which could be given by a convenient route of administration, e.g. orally from a convenient pharmaceutical dosage form.
  • US Patent No 6,344,449 describes the compound N-[(1 R)-2-[[(1 S)-5-amino-1 -[[4-(4- pyridinyl)-1-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4- hydroxyphenyl)methyl]-2-oxoethyl]-4-(1 ,4-dihydro-2-oxo-3(2H)-quinazolinyl)-1- piperidinecarboxamide (olcegepant; BIBN 4096) as an antagonist of CGRP for the treatment of migraine: In trials, the compound was administered by intravenous infusion.
  • MK-0974 is described and claimed in WO04/092168.
  • WO04/092166, WO06/044504, and WO06/099268 inter alia describe as CGRP antagonists for the treatment of headache, migraine, and cluster headache certain compounds of formula
  • R' is a carbon-linked nitrogen-containing cyclic group, n is 0, 1 or 2, and R" and R'" together form a fused six-membered aromatic ring which is optionally substituted and contains 0, 1 or 2 nitrogen atoms.
  • the object of the present invention is to identify a CGRP antagonist which is selective for the hCGRP receptor and, preferably, readily bioavailable from a convenient pharmaceutical dosage form.
  • the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:
  • R1 is selected from the group consisting of hydrogen, aryl, heterocyclyl, alkyl, alkyloxy, alkylamino, dialkylamino, and arylamino;
  • R2 is an aryl group; n is 0, 1 or 2; and R3 and R4 together form a fused six-membered aromatic ring which is optionally substituted and contains 0, 1 or 2 nitrogen atoms.
  • the invention provides a compound of formula (IA) or a pharmaceutically acceptable salt thereof:
  • R1 and R2 have the values set out hereinabove.
  • the invention provides a compound of formula (I) or (IA) as defined hereinabove or a pharmaceutically acceptable salt thereof, wherein R1 is instead selected from the group consisting of acetyl, amino, cyano, ethoxycarbonyl, and acetamido.
  • R1 is instead selected from the group consisting of acetyl, amino, cyano, ethoxycarbonyl, and acetamido.
  • aryl includes optionally substituted phenyl.
  • a phenyl group can be substituted by up to three substituents independently selected from the group consisting of halogen, trifluoromethyl, methyl and methoxy.
  • aryl includes phenyl, naphthyl, benzodioxolyl, benzofuranyl, and benzothienyl, any of which can be substituted by up to three substituents independently selected from the group consisting of halogen, trifluoromethyl, methyl, hydroxy, cyano, isopropyl, and methoxy.
  • halogen means fluorine, chlorine, bromine or iodine.
  • heterocyclyl means a saturated, partially saturated or unsaturated four to seven membered ring, containing one or two heteroatoms selected from nitrogen, oxygen and sulphur, and optionally substituted by up to three substituents independently selected from the group consisting of heterocyclyl, halogen, alkyl, and alkyloxycarbonyl.
  • Heterocyclyl groups include 1-piperazinyl, 1-azetidinyl, 1- piperidinyl, 4-morpholinyl, 3-pyridinyl, and 1-pyrrolidinyl.
  • a heterocyclyl group can be substituted by up to three substituents independently selected from the group consisting of heterocyclyl, halogen, alkyl, alkylamino, dialkylamino, hydroxy, methoxy, cyano, and alkyloxycarbonyl.
  • alkyl' refers to a linear or branched saturated hydrocarbon group typically containing up to six, for example one, two or three, carbon atoms.
  • alkyl groups include n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert butyl, n-pentyl, isopentyl (3-methylbutyl), neopentyl (2,2-dimethylpropyl), hexyl, 4- methylpentyl, 3,3-dimethylbutyl or heptyl and the like.
  • Any alkyl group referred to herein is optionally further substituted by a group selected from the group consisting of alkyloxy, alkylamino, dialkylamino, and heterocyclyl.
  • an alkyl group can be substituted by up to three substituents independently selected from the group consisting of alkyloxy, alkylamino, dialkylamino, hydroxy, halogen, and heterocyclyl.
  • R1 is selected from the group consisting of hydrogen; optionally substituted 1- piperazinyl, 1-azetidinyl, 1-piperidinyl, 4-morpholinyl, 3-pyridinyl, or 1-pyrrolidinyl; optionally substituted phenyl; optionally substituted phenylamino; methyl; ethyl; methoxy; methylamino; dimethylamino; dimethylaminoethyloxy; 2-(1- pyrrolidinyl)ethyloxy; and methyloxyethylamino; and/or
  • R2 is phenyl optionally substituted by up to three substituents independently selected from the group consisting of chloro, fluoro and methyl; and/or n is 0 and R3 and R4 together form a fused pyridyl, or n is 1 or 2 and R3 and R4 together form a fused phenyl; or
  • Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable acids including inorganic and organic acids.
  • Such acids include acetic, L-ascorbic acid (vitamin C), L-aspartic acid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanedisulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, nicotinic, phosphoric, succinic, sulphuric, tartaric, p-toluenesulfonic, perchloric, fluoboric, and the like.
  • the compound of formula (I) may exist in stereoisomeric forms (e.g. diastereoisomers and enantiomers) and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemates.
  • the different stereoisomeric forms of the compound of formula (I) may be obtained according to methods well known in the literature, for example by separation one from the other by the usual methods such as preparative HPLC or by chromatographic purifications.
  • a racemic mixture may either be separated using preparative HPLC and a column with a chiral stationary phase or resolved to yield individual enantiomers utilising methods known to those skilled in the art. Any given isomer may also be obtained by stereospecific or asymmetric synthesis.
  • racemic intermediate compounds may be resolved and used to prepare individual stereoisomeric forms of chiral compounds of the invention.
  • the invention also extends to any tautomeric forms and mixtures thereof.
  • the compounds of the invention may exist as pharmaceutically acceptable solvates such as hydrates and may form polymorphs and pseudopolymorphs.
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 O, 18 0, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of the invention for example, those in which a radioactive isotope such as 3 H or 14 C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances.
  • Isotopic variations of the compounds of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples and Descriptions hereafter using appropriate isotopic variations of suitable reagents.
  • the compounds of the present invention have potential utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or diseases: headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; visceral pain; eye pain; tooth pain; cancer pain; diabetes; non- insulin dependant diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity; asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; encephalitis, brain trauma; epilepsy; neurodegenerative diseases; skin diseases; psoriasis; prevention of tumour growth; neurogenic cutaneous redness, skin rosaceousness and erythema;
  • compounds of the invention are particularly useful for the treatment of migraine, headache, and cluster headache.
  • the invention provides compounds of the invention for use as a medicament, such as a human medicament.
  • the invention further provides a method of treating migraine, headache, or cluster headache, which method comprises administering to a patient in need thereof an effective amount of a compound of the the invention.
  • the invention provides the use of compounds of the invention in the manufacture of a medicament for treating or preventing migraine, headache or cluster headache.
  • references herein to "treatment” extend to prophylaxis, prevention of recurrence and suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
  • the compound of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • the carrier, diluent and/or excipient must be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • the compounds of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with standard pharmaceutical carriers or diluents according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
  • compositions may be formulated for administration by any route.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulfate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • the dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient.
  • the dosage as employed for adult human treatment will preferably range from 10 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 0.1 to 50 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular mammal being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • the compounds of the present invention may be used in combination with one or more other drugs, which other drug(s) may be administered contemporaneously or sequentially with a compound of the invention.
  • a pharmaceutical composition in unit dosage form containing the other drug(s) and the compound of of the invention is preferred.
  • the compound of the invention and one or more other drugs may alternatively be administered on different overlapping schedules.
  • the pharmaceutical compositions of the present invention include those that contain one or more other active ingredients, in addition to a compound of the invention.
  • the present compounds may be used in conjunction with an antiinflammatory or analgesic agent or an anti-migraine agent, such as an ergotamine and dihydroergotamine, or other serotonin agonists (e.g. 5-HT 1 agonists), especially a 5-HTi B /i D agonist, for example sumatriptan, naratriptan, zolmitriptam, eletriptan, almotriptan, frovatriptan, doniitriptan, and rizatriptan; a 5-HT 10 agonist such as PNU- 142633 and a 5-HT 1F agonist such as LY334370; a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti-inflammatory agent, such
  • anti-inflammatory agents examples include prostanoid receptor agonists or antagonists (e.g. EP1 , EP2, EP3 or EP4) and VR1 receptor antagonists.
  • the compounds of the invention may be administered with an analgesic such as aspirin, choline magnesium trisalicylate, diflunisal, acetaminophen, phenacetin, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine, hydromorphone, levorphanol, meperidine, oxycodone, oxymorphone, propoxyphene, butorpanol, dezocine, nalbuphine, pentazocine or morphine.
  • the compounds of the invention may also be used in combination with COX-2 inhibitors.
  • an interleukin inhibitor such as an interleukin-1 inhibitor; an NK-I receptor antagonist, for example aprepitant; an NMDA antagonist; an NR2B antagonist; a bradykinin-1 receptor antagonist; an adenosine A1 receptor agonist; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; a renin inhibitor; a granzyme B inhibitor; a substance P antagonist; an endothelin antagonist; a norepinephrin precursor; anti-anxiety agents such as diazepam, alprazolam, chlordiazepoxide and chlorazepate; serotonin 5-HT 2 receptor antagonists; opiod agonists such as
  • the compounds of the invention may also be used in conjunction with ergot alkaloids other than ergotamine and dihydroergotamine, for example ergonovine, ergonovine, methylergonovine, metergoline, ergoloid mesylates, dihydroergocornine dihydroergocristine, dihydroergocryptine, dihydro- ⁇ -ergocryptine, dihydro- ⁇ - ergocryptine, ergotoxine, ergocornine, ergocristine, ergocryptine, ⁇ -ergocryptine, ⁇ -ergocryptine,ergosine, ergostane, bromocriptine, or methysergide.
  • ergonovine ergonovine, methylergonovine, metergoline, ergoloid mesylates
  • dihydroergocornine dihydroergocristine dihydroergocryptine, dihydro- ⁇ -ergocryptine, di
  • the compounds of the present invention may be used in conjunction with a beta- adrenergic antagonist such as timolol, propanolol, atenolol, metoprolol or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example, diltiazem, amlodipine, felodipine, nisolipine, isradipine, nimodipine, lomerizine, nifedipine, or prochlorperazine; neuroleptics such as olanzapine, droperidol, prochlorperazine, chlorpromazine and quetiapine; an anticonvulsant such as topiramate, tonabersat, carabersat, levetiracetam, or tiagabine; an anti-hypertensive such as an angiotensin Il antagonist, for example losartan, ir
  • the compounds of the present invention may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo- desoxy-ephedrine; an antitussive such as caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone; a sedating or non- sedating antihistamine such as acrivastine, azatadine, bromodiphenhydramine, brompheniramine, carbinoxamine, chlorpheniramine, clemastine, dexbrompheniramine, dexchlorpheniramine, diphenhydramine, doxylamine, loratadine, phenindamine,
  • nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds ofthe invention.
  • anesthesiology intraspinal infusion, neural blockade
  • neurosurgical neurolysis of CNS pathways
  • neurostimulatory transcutaneous electrical nerve stimulation, dorsal column stimulation
  • physiatric physical therapy, orthotic devices, diathermy
  • psychologic psychologic
  • the present invention also provides a process for the preparation of a compound of formula (I) or (IA), which process comprises:
  • the sodium alkoxide is preformed from the parent alcohol using sodium hydride.
  • the displacement reaction is performed at elevated temperature, e.g. in a microwave at 10O 0 C.
  • RI OMe
  • commercially available 25% sodium methoxide in methanol is used directly.
  • PG protecting group such as lower alkyl
  • the compound of formula (II) can be isolated as the free acid (as shown) or, where a protecting group is removed by base hydrolysis, as the salt of the base used.
  • a 2 minute generic LC/MS method may be employed using a Waters Acquity system coupled with a Waters ZQ Mass Spectrometer.
  • NMR Nuclear Magnetic Resonance
  • Mass Directed Automated Preparative (MDAP) HPLC instruments consist of the following: Waters 2525 Binary Gradient Module, Waters 515 Makeup Pump, Waters Pump Control Module, Waters 2767 Inject Collect, Waters Column Fluidics
  • 5-Bromo-4-(1-pyrrolidinyl)-7H-pyrrolo[2,3-d]pyrimidine may also be prepared by heating 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (D5) and pyrrolidine in dioxane at 90 0 C for 4.5 hours, from 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (D5) and pyrrolidine in iso-propylalcohol at reflux for 20 minutes and from 5-bromo-4-chloro- 7H-pyrrolo[2,3-d]pyrimidine (D5), pyrrolidine and N,N'-diisopropylethylamine in iso- propylalcohol at reflux for 1 hour.
  • the displacement reaction is analogous to a literature method: see Tetrahedron Lett, 2006, 47(25), 4149-4151 for the displacement of 4-CI from 5-bromo-4-chloro-7H- pyrrolo[2,3-d]pyrimidine (D5) with a nitrogen nucleophile.
  • reaction mixture was diluted with water and extracted with ethyl acetate (x 3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography eluting with 1 :1 ethyl acetate/iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a solid.
  • Ethyl (5-bromo-4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (D12, 365 mg, 1.013 mmol), (2-chlorophenyl)boronic acid (317 mg, 2.027 mmol), bis(triphenylphosphene)palladium(ll) chloride (35.6 mg, 0.051 mmol) and sodium carbonate (215 mg, 2.027 mmol) were added together in 1 ,2-dimethoxyethane (4 ml.) and water (1 ml_). The resulting mixture was heated at 100°C in the microwave for 20 minutes at normal absorption.
  • the reaction mixture was diluted with water and extracted with ethyl acetate (x 3). The ethyl acetate layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography eluting with a gradient of 0-40 % ethyl acetate/iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a yellow oil.
  • Ethyl (5-bromo-4-ethyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (D25, 122 mg, 0.391 mmol), (2-chlorophenyl)boronic acid (D25, 122 mg, 0.782 mmol), bis(triphenylphosphine)palladium(ll) chloride (13.72 mg, 0.020 mmol) and sodium carbonate (83 mg, 0.782 mmol) were added together in 1 ,2-dimethoxyethane (2 ml.) and water (0.5 ml.) and the resulting mixture was heated at 100°C in the microwave for 20 minutes.
  • reaction mixture was diluted with water and extracted with ethyl acetate (x 2).
  • ethyl acetate layers were combined, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by column chromatography eluting with 0-50% ethyl acetate/iso-hexane to give the title compound as a yellow oil which crystallised.
  • Ethyl (5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimicliri-7-yl)acetate (D30, 400 mg, 1.256 mmol) was dissolved in 1 ,4-dioxane (10 mL) and treated with N,N-dimethyl-3- azetidinamine (172 mg, 1.256 mmol) and N,N-diisopropylethylamine (0.439 mL, 2.51 mmol). The resulting mixture was stirred at room temperature for 20 hours.
  • Ethyl (5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)acetate (D30, 500 mg, 1.570 mmol) was dissolved in 1 ,4-dioxane (15 ml_), treated with isopropylamine (0.134 ml_, 1.570 mmol) and N,N-diisopropylethylamine (0.548 ml_, 3.14 mmol) and the resulting mixture was stirred at room temperature under argon for 18 hours. The reaction mixture was then heated under reflux for 5 hours. A further quantity of isopropylamine (0.067 ml_, 0.785 mmol) was added and the mixture was heated under reflux for 8 hours.
  • reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure.
  • the residue was purified by column chromatography eluting with a gradient of 0-50 % ethyl acetate in iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a white solid.
  • Ethyl [4-chloro-5-(2-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetate (D37, 350 mg, 1 mmol), tributyl[1-(ethyloxy)ethenyl]stannane (0.507 ml_, 1.500 mmol) and bis(triphenylphosphine)palladium(ll) chloride (35.1 mg, 0.050 mmol) were disolved in N,N-dimethylformamide (5 mL) under argon and the mixture heated at 100 0 C in the microwave for 30 minutes, then at 120 0 C for a further 60 minutes.
  • the reaction mixture was allowed to cool to room temperature and then further cooled to 0 0 C and 6N hydrochloric acid (150 ml.) added. The resulting solution was heated at reflux for 3 hours.
  • the crude mixture was concentrated under reduced pressure, diluted with ice-cold water and basified with 5N sodium hydroxide solution, extracted with ethyl acetate (200 ml_), washed with brine (50 ml.) and dried over sodium sulphate, then concentrated under reduced pressure. Purification by column chromatography (60-120 mesh silica gel) using 70% ethyl acetate / petroleum ether as solvent afforded the title compound.
  • Triethylamine (7.8 ml_, 56.15 mmol) was added to a solution of 1 ,1-dimethylethyl 4- ⁇ [1-(2-aminophenyl)-1-methylethyl]amino ⁇ -1-piperidinecarboxylate (D48, 8.5 g, 25.52 mmol) in acetonitrile (85 ml_), followed by 1 ,1 '-carbonyldiimidazole (12.4 g, 78.46 mmol) at room temperature under nitrogen and the mixture stirred for 2 hours. The resulting mixture was heated at reflux for 30 minutes. The reaction mixture was then concentrated under reduced pressure, and diluted with ethyl acetate and water.
  • Ethyl [4-chloro-5-(2-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]acetate (D37, 178 mg, 0.508 mmol), bis(triphenylphosphine)palladium(ll) chloride (17.84 mg, 0.025 mmol), copper (I) iodide (9.68 mg, 0.051 mmol) and N,N-dimethylpropargylamine (0.109 ml_, 1.017 mmol) were suspended in N,N-dimethylformamide (2 ml.) and triethylamine (1 ml.) and mixture heated at 12O 0 C for 90 minutes.
  • the mixture was dissolved in methanol and passed through a 10 g SCX cartridge, eluting with methanol then 2M ammonia in methanol.
  • the basic fractions were combined and evaporated to leave the title compound (containing a small amount of the corresponding methyl ester) as a clear gum.
  • Inorganic material was filtered off and washed with ethyl acetate.
  • the resultant solution was treated with ethyl acetate (100 ml.) and washed with a mixture of water (100 ml.) and brine (20 ml_). After a final wash with brine (50 ml.) the solution was dried over magesium sulfate. Solvent was evaporated and the residue purified by column chromatography (Biotage, ethyl acetate/hexane 1 :3) to obtain the title compound as a colourless oil.
  • Example 5 1 -(1 - ⁇ [S ⁇ -ChlorophenylJ ⁇ -phenyl-ZH-pyrrolo ⁇ .S-rflpyrimidin-y-yllacetyl ⁇ - piperidinyl)-1,3-dihydro-2H-imidazo[4,5-fe]pyridin-2-one dihydrochloride (E5)
  • the reaction mixture was stirred for 3 hours at room temperature under an atmosphere of argon. It was then concentrated under reduced pressure to form a brown oil.
  • the product was partitioned between dichloromethane (15 ml.) and water (7 ml_). The aqueous layer was washed with dichloromethane (10 ml_). The combined organic extracts were washed with 5 % citric acid (7 ml_), sodium bicarbonate solution (7 ml.) and brine (7 ml_). The combined organic extracts were dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried under vacuum overnight at 5O 0 C.
  • a further quantity of 4M hydrochloric acid in dioxane (0.229 ml_, 0.915 mmol) was added and the resulting mixture heated at 7O 0 C under argon for 1 hour. The reaction mixture was allowed to cool to room temperature and stirred for 18 hours. The reaction mixture was heated under reflux for 1 hour allowed to cool to room temperature and treated with methanol (5 ml.) to aid solubility. A further quantity of 4M hydrochloric acid in dioxane (0.229 ml_, 0.915 mmol) was added and the resulting mixture was stirred at room temperature for 4 hours. The solvent was removed under reduced pressure and the residue dried at 50 0 C under high vacuum overnight.
  • the solid was dissolved in methanol and passed down an SCX cartridge (2 g) eluting with methanol, followed by 2M ammonia/methanol.
  • Product containing fractions were combined and evaporated under reduced pressure.
  • the residue was purified by MDAP.
  • Product containing fractions were combined and evaporated under reduced pressure.
  • the residue was taken up in methanol and passed down an SCX cartridge (2 g) eluting with methanol, followed by 2M ammonia/methanol.
  • the reaction mixture was stirred at room temperature for 3 hours under an atmosphere of argon.
  • the reaction mixture was concentrated under reduced pressure to form a pale yellow oil.
  • the product was partitioned between dichloromethane (15 ml.) and water (15 ml_).
  • the aqueous layer was washed with dichloromethane (10 ml_).
  • the combined organic extracts were washed with 5% citric acid (10 ml_), sodium bicarbonate solution (10 ml.) and brine (10 ml_).
  • the combined organic extracts were dried over magnesium sulfate, filtered, concentrated under reduced pressure and dried under vacuum at 5O 0 C overnight.
  • the starting material used in Method I can be a free acid or a salt.
  • E74 and E104 describe the use of a lithium salt.
  • HEK293 Human embryonic kidney 293cells (HEK293) were maintained in DMEM containing 2mM glutamine (Gibco 41966-029) with 10% Heat inactivated FCS (Gibco 10100- 147)
  • the cells were dilution cloned into 96-well plates using selection media containing DMEM containing 2mM glutamine (Gibco 41966- 029), 10% Heat inactivated FCS (Gibco 10100-147), 500 ⁇ g/ml Geneticin (Gibco 10131-027) and 200 ⁇ g/ml of hygromycin B (Gibco 10687-010). 10 to 14 days post dilution cloning, antibiotic resistant clones were grown on and expanded.
  • selection media containing DMEM containing 2mM glutamine (Gibco 41966- 029), 10% Heat inactivated FCS (Gibco 10100-147), 500 ⁇ g/ml Geneticin (Gibco 10131-027) and 200 ⁇ g/ml of hygromycin B (Gibco 10687-010). 10 to 14 days post dilution cloning, antibiotic resistant clones were grown on and expanded.
  • the clones were screened for increases in cAMP production on addition of human ⁇ - CGRP using cAMP SPA screening Biotrack assay (GE healthcare RPA556) according to the manufacturers instructions. A positive clone from this screening was then chosen and used for all subsequent assay work.
  • Calcitonin Receptor Like Receptor CRLR
  • RAMP1 Receptor Activity Modifying Protein
  • CRLR-RAMP1 CRLR-RAMP1 Receptor Activity Modifying Protein
  • CGRP Calcitonin Gene Related Peptide
  • Receptor activity can therefore be measured using a cAMP accumulation immunoassay. This assay is based on competition between a europium labelled cAMP complex and cellular cAMP for binding sites on anti-cAMP antibodies labelled with Alexa Fluor 647(Trade Mark).
  • TR-FRET Time Resolved Fluorescence Resonance Energy Transfer

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés antagonistes du récepteur GCRP, des procédés d'élaboration correspondants, des compositions les contenant, et leur utilisation pour le traitement de la migraine, du mal de tête et de l'algie vasculaire de la face.
PCT/EP2008/067823 2007-12-21 2008-12-18 Dérivés de pyrrolo[2,3-d]pyrimidine convenant comme antagonistes du récepteur gcrp WO2009080682A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB0725103.6A GB0725103D0 (en) 2007-12-21 2007-12-21 Novel compounds
GB0725103.6 2007-12-21

Publications (1)

Publication Number Publication Date
WO2009080682A1 true WO2009080682A1 (fr) 2009-07-02

Family

ID=39048653

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2008/067823 WO2009080682A1 (fr) 2007-12-21 2008-12-18 Dérivés de pyrrolo[2,3-d]pyrimidine convenant comme antagonistes du récepteur gcrp

Country Status (2)

Country Link
GB (1) GB0725103D0 (fr)
WO (1) WO2009080682A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011113798A2 (fr) 2010-03-15 2011-09-22 Proximagen Limited Nouveaux composés d'inhibiteurs enzymatiques
DE102011008352A1 (de) 2011-01-12 2012-07-12 Merck Patent Gmbh 5-([1,2,3]Triazol-4-yl)-7H-pyrrolo-[2,3-d]pyrimidinderivate
WO2013038189A1 (fr) 2011-09-14 2013-03-21 Proximagen Ltd. Nouveaux composés inhibiteurs d'enzymes
WO2014064131A2 (fr) * 2012-10-26 2014-05-01 F. Hoffmann-La Roche Ag Inhibiteurs de la tyrosine kinase de bruton
WO2014039714A3 (fr) * 2012-09-06 2014-10-02 Plexxikon Inc. Composés et procédés pour la modulation des kinases, et leurs indications
US9150574B2 (en) 2011-09-14 2015-10-06 Proximagen Limited Enzyme inhibitor compounds
WO2015164308A1 (fr) * 2014-04-22 2015-10-29 Merck Sharp & Dohme Corp. Inhibiteurs du facteur xia
WO2016075224A1 (fr) 2014-11-14 2016-05-19 Nerviano Medical Sciences S.R.L. Dérivés 6-amino -7-bicyclo -7-déazapurine utiles en tant qu'inhibiteurs de protéine kinase
JP2018500349A (ja) * 2014-12-23 2018-01-11 ガルデルマ・リサーチ・アンド・デヴェロップメント 新規な複素環式化合物並びに医薬及び化粧品におけるその使用
CN107586338A (zh) * 2011-05-20 2018-01-16 奥尔德生物控股有限责任公司 抗cgrp组合物及其用途
WO2020249969A1 (fr) * 2019-06-12 2020-12-17 Heptares Therapeutics Limited Composés antagonistes de cgrp
WO2021005497A1 (fr) * 2019-07-05 2021-01-14 Allergan Pharmaceuticals International Limited Antagonistes du cgrp et dérivés de clostridium pour le traitement de troubles associés à la dépression corticale envahissante
CN113527308A (zh) * 2021-06-28 2021-10-22 上海应用技术大学 一种利用铁配合物催化合成7-脱氮嘌呤类化合物的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006044504A1 (fr) * 2004-10-13 2006-04-27 Merck & Co., Inc. Antagonistes aux récepteurs de cgrp

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006044504A1 (fr) * 2004-10-13 2006-04-27 Merck & Co., Inc. Antagonistes aux récepteurs de cgrp

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2927233A1 (fr) 2010-03-15 2015-10-07 Proximagen Limited Inhibiteurs de amine oxydase sensible à semicarbazide
JP2013529179A (ja) * 2010-03-15 2013-07-18 プロクシマゲン リミテッド 新規酵素阻害化合物
US9227967B2 (en) 2010-03-15 2016-01-05 Proximagen Limited Inhibitor compounds of semicarbazide-sensitive amine oxidases
WO2011113798A2 (fr) 2010-03-15 2011-09-22 Proximagen Limited Nouveaux composés d'inhibiteurs enzymatiques
DE102011008352A1 (de) 2011-01-12 2012-07-12 Merck Patent Gmbh 5-([1,2,3]Triazol-4-yl)-7H-pyrrolo-[2,3-d]pyrimidinderivate
WO2012095142A1 (fr) 2011-01-12 2012-07-19 Merck Patent Gmbh Dérivés de 5-([1,2,3]triazol-4-yl)-7h-pyrrolo[2,3-d]pyrimidine
CN107586338B (zh) * 2011-05-20 2021-09-17 H.伦德贝克公司 抗cgrp组合物及其用途
CN107586338A (zh) * 2011-05-20 2018-01-16 奥尔德生物控股有限责任公司 抗cgrp组合物及其用途
WO2013038189A1 (fr) 2011-09-14 2013-03-21 Proximagen Ltd. Nouveaux composés inhibiteurs d'enzymes
JP2014526495A (ja) * 2011-09-14 2014-10-06 プロクシマゲン リミテッド 新規な酵素阻害化合物
US9150574B2 (en) 2011-09-14 2015-10-06 Proximagen Limited Enzyme inhibitor compounds
CN104981247A (zh) * 2012-09-06 2015-10-14 普莱希科公司 用于激酶调节的化合物和方法及其适应症
WO2014039714A3 (fr) * 2012-09-06 2014-10-02 Plexxikon Inc. Composés et procédés pour la modulation des kinases, et leurs indications
US10227357B2 (en) 2012-09-06 2019-03-12 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2014064131A3 (fr) * 2012-10-26 2014-10-16 F. Hoffmann-La Roche Ag Inhibiteurs de la tyrosine kinase de bruton
CN104662024A (zh) * 2012-10-26 2015-05-27 弗·哈夫曼-拉罗切有限公司 酪氨酸激酶抑制剂
RU2619465C2 (ru) * 2012-10-26 2017-05-16 Ф. Хоффманн-Ля Рош Аг Ингибиторы тирозинкиназы брутона
JP2015535226A (ja) * 2012-10-26 2015-12-10 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ ブルートンチロシンキナーゼの阻害剤
WO2014064131A2 (fr) * 2012-10-26 2014-05-01 F. Hoffmann-La Roche Ag Inhibiteurs de la tyrosine kinase de bruton
US10093683B2 (en) 2014-04-22 2018-10-09 Merck Sharp & Dohme Corp. Factor XIa inhibitors
WO2015164308A1 (fr) * 2014-04-22 2015-10-29 Merck Sharp & Dohme Corp. Inhibiteurs du facteur xia
WO2016075224A1 (fr) 2014-11-14 2016-05-19 Nerviano Medical Sciences S.R.L. Dérivés 6-amino -7-bicyclo -7-déazapurine utiles en tant qu'inhibiteurs de protéine kinase
JP2018500349A (ja) * 2014-12-23 2018-01-11 ガルデルマ・リサーチ・アンド・デヴェロップメント 新規な複素環式化合物並びに医薬及び化粧品におけるその使用
WO2020249969A1 (fr) * 2019-06-12 2020-12-17 Heptares Therapeutics Limited Composés antagonistes de cgrp
CN114245798A (zh) * 2019-06-12 2022-03-25 赫普泰雅治疗有限公司 Cgrp拮抗剂化合物
WO2021005497A1 (fr) * 2019-07-05 2021-01-14 Allergan Pharmaceuticals International Limited Antagonistes du cgrp et dérivés de clostridium pour le traitement de troubles associés à la dépression corticale envahissante
CN113527308A (zh) * 2021-06-28 2021-10-22 上海应用技术大学 一种利用铁配合物催化合成7-脱氮嘌呤类化合物的方法

Also Published As

Publication number Publication date
GB0725103D0 (en) 2008-01-30

Similar Documents

Publication Publication Date Title
WO2009080682A1 (fr) Dérivés de pyrrolo[2,3-d]pyrimidine convenant comme antagonistes du récepteur gcrp
EP3752510B1 (fr) Macrocycles utilisés en tant que modulateurs du régulateur de la conductance transmembranaire de fibrose kystique, compositions pharmaceutiques de ceux-ci, leur utilisation dans le traitement de la fibrose kystique et procédé de fabrication associé
CN107660205B (zh) 作为lsd1抑制剂的杂环化合物
EP3201196B1 (fr) Dérivés d'imidazoles pentacyclic fusionnés
EP3080121B1 (fr) Dérivés de benzoimidazoles fusionnes tricycliques utilisables en tant que modulateurs de l'activité tnf
EP2763990B1 (fr) Inhibiteurs de kinase pyrrolopyrazine
US9273055B2 (en) Tyrosine kinase inhibitors
TWI487706B (zh) 六氫吡啶酮甲醯胺氮雜茚滿ｃｇｒｐ受體拮抗劑
EP3112370A1 (fr) Composés hétérocycliques tricycliques et inhibiteurs de jak
EP3191488B1 (fr) N-acyl-triazolopyrazines modulant le p2x7
EP3112366B1 (fr) Modulateurs p2x7
WO2015073767A1 (fr) Dérivés de 4,5,6,7-tétrahydropyrazolo[1,5-a]pyrazine substitués en tant qu'inhibiteurs de caséine kinase 1 d/e
US20040019057A1 (en) Imidazo-pyrazine derivatives as ligands for gaba receptors
WO2016007736A1 (fr) Imidazopyrazines en tant qu'inhibiteurs de lsd1
EP2955181B1 (fr) Composé pyrrolopyridine tricyclique et inhibiteur de jak
TW201350476A (zh) 用於調節表皮生長因子受體（ｅｇｆｒ）活性之化合物及組合物
EP3822273A1 (fr) Composés tricycliques substitués servant d'inhibiteurs des fgfr
KR20100014271A (ko) 면역 억제를 위한 7-치환된 퓨린 유도체
JPWO2004028524A1 (ja) 併用医薬
AU2013329097B2 (en) Urea and amide derivatives of aminoalkylpiperazines and use thereof
AU2020321956A1 (en) Heterobicyclic amides as inhibitors of CD38
EP1799691A1 (fr) Nouveaux derives bis-azaindoles, leur preparation et leur utilisation pharmaceutique comme inhibiteurs de kinases
KR20200046061A (ko) 스피로사이클 화합물 및 이를 제조하고 사용하는 방법
US6914060B2 (en) Imidazotriazinone derivatives as ligands for GABA receptors
EP4067358A1 (fr) Dérivés de (s)-1-(5-((pyridin-3-yl)thio)pyrazin-2-yl)-4'h,6'h-spiro[pipéridine-4,5'-pyrrolo[1,2-b]pyrazol]-4'-amine et composés similaires en tant qu'inhibiteurs de shp2 pour le traitement par ex. du cancer

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 08865083

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 08865083

Country of ref document: EP

Kind code of ref document: A1