EP2601181A1 - Sels d'addition d'acide du 2-[2-[[(4-méthoxy-2,6-diméthylphényl)sulfonyl]-(méthyl)amino]éthoxy]-n-méthyl-n-[3-(4-méthylpipérazine-1-yl)cyclohexyl]acétamide, et leur utilisation en tant qu'antagonistes du récepteur de la bradykinine-b1 - Google Patents

Sels d'addition d'acide du 2-[2-[[(4-méthoxy-2,6-diméthylphényl)sulfonyl]-(méthyl)amino]éthoxy]-n-méthyl-n-[3-(4-méthylpipérazine-1-yl)cyclohexyl]acétamide, et leur utilisation en tant qu'antagonistes du récepteur de la bradykinine-b1

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Publication number
EP2601181A1
EP2601181A1 EP11741454.0A EP11741454A EP2601181A1 EP 2601181 A1 EP2601181 A1 EP 2601181A1 EP 11741454 A EP11741454 A EP 11741454A EP 2601181 A1 EP2601181 A1 EP 2601181A1
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EP
European Patent Office
Prior art keywords
methyl
methoxy
pain
compound
ethoxy
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP11741454.0A
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German (de)
English (en)
Inventor
Thorsten Pachur
Waldemar Pfrengle
Manfred Birk
Juergen Schnaubelt
Ulrike Werthmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
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Boehringer Ingelheim International GmbH
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Priority to EP11741454.0A priority Critical patent/EP2601181A1/fr
Publication of EP2601181A1 publication Critical patent/EP2601181A1/fr
Withdrawn legal-status Critical Current

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    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • the present invention relates to the novel acid addition salts AB of the following free base of the formula A.
  • a physiologically acceptable acid B selected from the group consisting of hydrochloric acid, fumaric acid and tartaric acid, as well as their polymorphs, hydrates and solvates.
  • the acid addition salts according to the invention are in crystalline form.
  • the present invention relates to B1 antagonists, which are in the form of stable crystalline derivatives and for the treatment or prevention of acute
  • Pain, intestinal pain, neuropathic pain, inflammatory and pain receptor-mediated pain, cancer pain and headache are suitable.
  • the pharmacologically valuable properties of the compounds according to the invention represent the basic requirement for the effective use of the compound as a medicament.
  • an active ingredient must meet even further requirements to be used as a medicine. These parameters are largely related to the physicochemical nature of the drug.
  • examples of these parameters are the effective stability of the starting material under various environmental conditions, stability in the course of preparation of the pharmaceutical formulation, and stability in the final compositions of the drug.
  • the active ingredient used in the preparation of the pharmaceutical compositions should therefore have a high stability, which must be ensured even under various changing environmental conditions. This is absolutely necessary in order to prevent the use of pharmaceutical compositions in which, in addition to the actual active substance, for example, degradation products thereof are contained. In such a case, an active ingredient content found in pharmaceutical formulations could be lower than specified.
  • Moisture-prone drugs must be protected from moisture during storage, for example by adding suitable drying agents or by storing the drug in a humidity protected environment.
  • the ingestion of moisture may reduce the level of active ingredient during manufacture if the drug is exposed to the environment without any protection from moisture.
  • a drug should only be slightly hygroscopic.
  • solubility of the drug If, for example, drug solutions (for example for infusions) are provided, sufficient solubility of the active substance in physiologically acceptable solvents is indispensable. Also for orally administered drugs sufficient solubility of the drug is of great importance.
  • the acid addition salts of the invention are characterized primarily by their stable crystalline form, while the free base is present as an oil.
  • a first object of the present invention relates to the novel acid addition salts AB of the following free base of the formula A.
  • a physiologically acceptable acid B selected from the group consisting of hydrochloric acid, fumaric acid and tartaric acid, as well as their polymorphs, hydrates and solvates.
  • the acid addition salts of the present invention are obtained in enantiomerically pure form.
  • enantiomerically pure in the context of the present invention describes compounds of the formula A with a physiologically acceptable acid B which are present in an enantiomeric purity of at least 85% ee, preferably at least 90% ee, particularly preferably> 95% ee.
  • ee enantiomeric excess
  • a second subject of the present invention relates to the following compounds:
  • the compounds of the invention are characterized by a high degree of stability and very readily soluble in physiologically acceptable solvents.
  • a third object of the present invention relates to the above compounds in crystalline form.
  • the crystalline salts (3), (4), (5) and (6) are each characterized by a characteristic melting point, which by means of differential scanning calorimetry (DSC:
  • Table 1 Melting points of the crystalline salts according to the invention
  • a fourth object of the present invention relates to the crystalline salts according to the invention, each characterized by their characteristic melting point.
  • the melting point depends on the degree of purity of a compound and increases with increasing purity. This means that the compounds of the present invention may well have a higher or lower melting point than those specified.
  • Table 2 X-ray powder reflections and intensities (normalized) of the compound (1).
  • Table 3 X-ray powder reflections and intensities (normalized) of the compound (2). d-value 2-theta relative intensity
  • Table 4 X-ray powder reflections and intensities (normalized) of the compound (3).
  • Table 5 X-ray powder reflections and intensities (normalized) of compound (4).
  • the present invention relates to crystalline 2- ⁇ 2 - [[(4-methoxy-2,6-dimethylphenyl) sulfonyl] - (methyl) amino] ethoxy ⁇ - / - / - methyl- / V- [(1S, 3f?) - 3- (4-methylpiperazin-1-yl) cyclohexyl] acetamide (L) tartrate (3), characterized in that it is described in the X-ray powder diagram, among others the
  • the present invention relates to crystalline 2- ⁇ 2 - [[(4-methoxy-2,6-dimethylphenyl) sulfonyl] - (methyl) amino] ethoxy ⁇ - / - / - methyl- / V- [(1 f, 3S) -3- (4-methylpiperazin-1-yl) cyclohexyl] acetamide (D) tartrate (4), characterized in that it is included in the X-ray powder diagram, among others the
  • the crystalline form of compound (3) is further characterized by the following lattice parameters:
  • the values were obtained by indexing a reddening powder diagram taken at room temperature and using CuK 2 radiation.
  • Table 6 lists the indexed peaks ( ⁇ 0.05 ° 2 ⁇ ) with their relative intensities. Table 6: Indexed XRPD peaks (up to 40 ° 2 ⁇ ) including relative intensities of compound (3)
  • Another object of the present invention relates to crystalline 2- ⁇ 2 - [[(4-methoxy-2,6-dimethylphenyl) sulfonyl] - (methyl) amino] ethoxy ⁇ -A / -methyl-A / - [(1 S, 3) -3- (4-m-piperazin-1-yl) cyclohexyl] acetamide (L) tartrate (3), characterized in that the crystals are present in an orthorhombic system.
  • compositions characterized in that they contain the inventive crystalline, enantiomerically pure compound AB. These compositions are preferred for the treatment of acute pain, intestinal pain, neuropathic
  • the present invention further relates to the use of the crystalline, enantiomerically pure compound AB for the manufacture of a medicament for the treatment of acute pain, intestinal pain, neuropathic pain, inflammatory and pain receptor mediated
  • the present invention preferably relates to the use of the above-mentioned crystalline and enantiomerically pure compounds of formula AB for the manufacture of a medicament for the treatment of acute pain, intestinal pain, neuropathic pain, inflammatory and pain receptor mediated
  • a further subject matter of the present invention relates to a process for the preparation of the acid addition salts according to the invention, comprising the following steps:
  • X is a hydrogen atom, an alkali metal such as lithium, sodium or potassium, or a CI_ 4 alkyl group, but preferably sodium
  • Y is a halogen atom, for example chlorine or bromine, preferably chlorine; optionally recrystallization of a compound of general formula VII obtained in step (c)
  • X is a hydrogen atom, an alkali metal such as lithium, sodium or potassium, or a CI_ 4 alkyl group, but preferably sodium, in a solvent;
  • X is a hydrogen atom, an alkali metal such as lithium, sodium or potassium, or a CI_ 4 alkyl group, but preferably sodium, with a Verbindun of the formula IX
  • n represents one of the numbers 0, 1, 2 or 3; optionally isolating a compound obtained in step (d) of
  • step (a) preferably 1.0 equivalents of 3,5-dimethylanisole of the formula II are reacted with 1.5 to 2.5 equivalents, preferably 1.8 to 2.2 equivalents, of chlorosulfonic acid.
  • the reaction can be carried out in a solvent which is selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride and
  • the solvent may be used in an amount of 0.25 to 1.25 L / mol, preferably 0.60 to 0.90 L / mol of 3,5-dimethylanisole used.
  • the reaction is carried out at a low temperature, for example between -45 ° C and 0 ° C, preferably between -40 ° C and 0 ° C, more preferably between -35 ° C and -10 ° C.
  • step (b) preferably 1.0 equivalents of 2,6-dimethyl-4-methoxysulfonyl chloride of the formula III are reacted with from 1.5 to 2.5 equivalents, preferably from 1.8 to 2.2 equivalents, of a compound of the general formula IV.
  • the reaction may be carried out in a solvent selected from the group consisting of dichloromethane, chloroform, carbon tetrachloride and 1, 2-dichloroethane.
  • the solvent may be used in an amount of 0.25 to 1.25 L / mol, preferably 0.5 to 1.0 L / mol of 2,6-dimethyl-4-methoxysulfonyl chloride used.
  • the reaction is carried out at a temperature below room temperature, for example between -0 ° C and 20 ° C, preferably between 5 ° C and 15 ° C.
  • step (c) preferably 1.0 equivalents of a compound of general formula V are reacted with 1.1 to 2.5 equivalents, preferably 1.4 to 1.7 equivalents, of a compound of general formula VI.
  • the reaction may be carried out in a solvent selected from the group consisting of acetonitrile, tetrahydrofuran, methyltetrahydrofuran, acetone, toluene, xylene, dichloromethane and chloroform.
  • the solvent can be used in an amount of 0.5 to 3 L / mol, preferably 1.2 to 1.7 L / mol of the compound of the general formula V used.
  • the reaction mixture may further be added to a base.
  • the base may be selected from the group consisting of potassium tert-butylate, potassium carbonate, sodium carbonate, lithium carbonate, sodium hydride, sodium methoxide and sodium ethoxide, preferably potassium tert-butylate. It can be added in an amount of 1.2 to 2.0 equivalents, preferably 1.3 to 1.6 equivalents, based on the amount of compound of general formula V used.
  • the compound of general formula VII obtained in step (c) may be purified by recrystallization prior to the reaction described in step (e) from a solvent selected from the group consisting of water, tetrahydrofuran, methyltetrahydrofuran, acetone or mixtures thereof.
  • 1.0 equivalents of a compound of general formula VIII are reacted with 1.0 to 1.5 equivalents, preferably 1.0 to 1.2 equivalents, of a compound of general formula IX or its enantiomer.
  • the reaction may be carried out in a solvent selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, dichloromethane, chloroform, toluene, ethyl acetate, isopropyl acetate and dioxane.
  • the solvent can be in an amount from 1.2 to 2 L / mol, preferably 1.4 to 1.8 L / mol of the compound of general formula VIII used.
  • the reaction mixture may further be added to a base.
  • the base may be selected from the group consisting of potassium tert -butylate, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, triethylamine, diisopropylethylamine and diazabicyclo [5.4.0] undec-7-ene (DBU), preferably potassium tert -butylate. It can be added in an amount of 3 to 4 equivalents, preferably 3.3 to 3.8 equivalents, based on the amount of compound of general formula VIII used. Furthermore, a coupling reagent can be added to the reaction mixture.
  • the coupling reagent may be selected from the group consisting of propane phosphonic anhydride, thionyl chloride, N, N, N ', N'-tetramethyl-O- (benzotriazol-1-yl) uronium tetrafluoroborate, carbodiimide and 1, 1' carbonyldiimidazole; Propanephosphonic anhydride is preferably used according to the invention.
  • the reaction is carried out at elevated temperature, for example between 40 ° C and 60 ° C.
  • the compound of the general formula IX or its enantiomer can be prepared according to a process as described in WO 2010/017850.
  • Enantiomer is preferably carried out by concentration to dryness or crystallization from water or dichloromethane, methanol, ethanol, propanol, butanol, isopropyl acetate, ethyl acetate, tetrahydrofuran, methyltetrahydrofuran, dioxane, methyl isobutyl ketone, toluene, xylene or mixtures of these solvents, water, ethanol, tetrahydrofuran, ethyl acetate , Methylisobutylketon and toluene or mixtures thereof are preferably used.
  • Dissolving a compound of the formula A or its enantiomer obtained under step (e) or (f) is carried out in a polar or unploused solvent, preferably in water or methanol, ethanol, isopropanol, 1-butanol, acetonitrile, acetone, tetrahydrofuran, ethyl acetate, Methyl isobutyl ketone, toluene or mixtures of these solvents.
  • a polar or unploused solvent preferably in water or methanol, ethanol, isopropanol, 1-butanol, acetonitrile, acetone, tetrahydrofuran, ethyl acetate, Methyl isobutyl ketone, toluene or mixtures of these solvents.
  • a physiologically acceptable acid B described in step (h), which is selected from the group consisting of hydrogen chloride, fumaric acid and D- or L-tartaric acid can be carried out in bulk or dissolved in a solvent.
  • the acid B may be in an amount of 1.0 to 2.4 equivalents, preferably 2.0 to 2.2
  • the solvent may be selected from the group consisting of water, methanol, ethanol, isopropanol, 1-butanol, acetonitrile, acetone, tetrahydrofuran, ethyl acetate, methyl isobutyl ketone or toluene and mixtures thereof. It can be used in an amount of 0.01 to 10.0 L / mol, preferably 0.02 to 5.0 L / mol of the compound of the formula A used or its enantiomer.
  • step (i) The crystallization described in step (i) is carried out according to the invention under controlled and stepwise lowering of the temperature and can be carried out with or without seeding.
  • Ci -4 alkyl (including those which are part of other groups) alkyl groups having 1, 2, 3 or 4 carbon atoms are understood. Examples include: methyl, ethyl, n-propyl, / ' so-propyl, n-butyl, / ' so-butyl, sec-butyl and tert-butyl. Unless otherwise stated, the definitions of propyl and butyl include all conceivable isomeric forms of the respective radicals. Thus, for example, includes propyl n-propyl and / 'so-propyl, butyl includes /' so-butyl, sec-butyl and te / f-butyl.
  • Another object of the present invention is, due to the pharmaceutical activity of the novel salts, their use as medicaments.
  • CHO cells expressing the cynomolgus B1 receptor are cultured in "HAM ' S F-12 medium.” Confluent cultures are used to remove the medium, wash the cells with PBS buffer, shave or peel off and pass through Centrifuging isolated. Subsequently, the cells are homogenized in suspension, the homogenate is centrifuged and resuspended. After determining the protein content, 200 ⁇ l of the homogenate (50 to 250 ⁇ g protein / assay) are added for 60-180 minutes
  • the acid addition salts of the present invention are useful in the treatment of diseases and disease symptoms that are at least partially due to the stimulation of bradykinin B1 receptors
  • bradykinin-1 receptor in which antagonizing the bradykinin-1 receptor can cause symptom improvement.
  • a further subject of the present invention comprises the acid addition salts AB according to the invention for use as medicaments.
  • the substances are suitable for treatment
  • Gastrointestinal pain such as chronic pelvic pain, gynecological pain, pain before and during menstruation, pain in pancreatitis, peptic ulcer, interstitial cystitis, renal colic, cholecystitis, prostatitis, angina pectoris, pain in colonic irritable, ulcerative dyspepsia and in gastritis, prostatitis, non- cardiac chest pain and pain in myocardial ischemia and myocardial infarction;
  • neuropathic pain such as painful
  • Polyneuropathy pain in diabetic neuropathy, AIDS-associated neuropathic pain, non-herpes-associated neuralgia, post-zoster neuralgia, nerve injury, traumatic brain injury, pain due to nerve damage due to toxins or chemotherapy,
  • Phantom pain multiple sclerosis pain, nerve root detachment and painful traumatic single nerve damage, as well as central pain such as after stroke, spinal cord injury or tumors;
  • osteoarthritis Associated with diseases such as osteoarthritis, rheumatoid arthritis, rheumatic fever, Tendo synovitis, bursitis, tendonitis, gout and gouty arthritis, traumatic arthritis, vulvodynia, damage and diseases of the muscles and fascia, juvenile arthritis, spondylitis, psoriatic arthritis, myositides , Dental diseases, influenza and other viral infections such as colds, systemic lupus erythematosus or pain in burns;
  • lymphoid or myeloid leukemia for example lymphoid or myeloid leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, lymphogranulomatosis, lymphosarcoma, solid malignant tumors and extensive metastases;
  • Headache disorders of various causes such as cluster headache, migraine (with or without aura), and tension-type headache;
  • Back pain including lumbago, or fibromyalgia.
  • the compounds are suitable for treatment
  • Irritable bowel syndrome pancreatitis, nephritis, cystitis (interstitial cystitis), uveitis; inflammatory diseases of the skin (such as psoriasis and eczema), vascular connective tissue diseases, strains and fractures, as well as musculoskeletal diseases with inflammatory phenomena such as acute rheumatic fever, polymyalgia rheumatica, reactive arthritis, rheumatoid arthritis, spondylarthritis, but also osseoarthritis, as well as inflammatory
  • bronchial asthma including allergic asthma (atopic and non-atopic) and bronchospasm on exertion, occupational asthma, viral or bacterial exacerbation of existing asthma, and other non-allergic asthmatic conditions ; chronic bronchitis and chronic obstructive pulmonary disease (COPD) including pulmonary emphysema, viral or bacterial exacerbation of chronic bronchitis or chronic obstructive bronchitis, acute
  • COPD chronic obstructive pulmonary disease
  • ARDS Adult respiratory distress syndrome
  • bronchitis bronchitis
  • pneumonia allergic rhinitis (seasonal and perennial)
  • vasomotor rhinitis and pneumoconiosis diseases such as aluminosis, anthracosis, asbestosis, chalicosis, siderosis, silicosis, tobaccoosis, byssinosis, exogenous allergic alveolitis, pulmonary fibrosis, bronchiectasis, Pulmonary diseases with alpha-antritrypsin deficiency and cough;
  • diabetes mellitus and its consequences (such as diabetic).
  • Vasculopathy diabetic neuropathy, diabetic retinopathy
  • diabetic symptoms of insulitis eg hyperglycemia, diuresis,
  • vascular diseases such as panarteritis nodosa, polyarthritis nodosa, periarteritis nodosa, temporal arteritis, Wegner's granulomatosis,
  • Giant cell atritis arteriosclerosis, erythema nodosum
  • hypertension for example, hypertension and related diseases
  • the substances are suitable for causal treatment in terms of slowing down or stopping the progression of chronic progressive diseases, in particular osteoarthritis, rheumatoid arthritis and spondylarthritis.
  • Another object of the present invention comprises the use of the acid addition salts according to the invention for the preparation of a medicament for a therapeutic application in the indications mentioned above.
  • the acid addition salts according to the invention are preferably used for the treatment of osteoarthritis, rheumatoid arthritis or COPD.
  • treatment or “therapy” is to be understood as a therapeutic treatment of patients with a manifest, acute or chronic indication, on the one hand the symptomatic (palliative) treatment for the alleviation of the disease symptoms and on the other hand the causal or curative treatment of the indication with the
  • the aim is to terminate the pathological condition, to reduce the severity of the pathological condition or to delay the progression of the pathological condition, depending on the type or severity of the indication included.
  • Another object of the present invention is the use of the
  • Acid addition salts according to the invention for the manufacture of a medicament for the acute and prophylactic treatment of acute pain, intestinal pain, neuropathic pain, inflammatory / pain receptor-mediated pain, tumor pain, headache disorders and pain conditions of mixed cause and other of the aforementioned diseases. It is the
  • patient is preferably understood to mean a human.
  • these substances are also useful in the veterinary treatment of pets, exotic animals and livestock.
  • Non-steroidal anti-inflammatory drugs such as propionic acid derivatives, which may be selected from the group consisting of
  • Fenamic acid derivatives which may be selected from the group consisting of meclofenamic acid, mefenamic acid and tolfenamic acid; Biphenyl-carboxylic acid derivatives; Oxicams, which may be selected from the group consisting of meloxicam, piroxicam and tenoxicam; Salicylic acid derivatives which may be selected from the group consisting of acetylsalicylic acid and sulfasalazine; Pyrazolones, which may be selected from the group consisting of apazone and feprazone); Coxibs, which may be selected from the group consisting of celecoxib and etoricoxib.
  • Opiate receptor agonists which may be selected, for example, from the group consisting of such as morphine, darvon, tramadol and buprenorphine.
  • Cannabinoid agonists such as GW-1000.
  • Sodium channel blockers which may be selected, for example, from the group consisting of carbamazepine, mexiletine, pregabalin, tectin and ralfinamide.
  • N-type calcium channel blockers such as ziconotide.
  • Serotonergic and noradrenergic modulators which may be selected, for example, from the group consisting of duloxetine and amitriptyline.
  • Corticosteroids which may be selected, for example, from the group consisting of betamethasone, budesonide, cortisone, dexamethasone,
  • Hydrocortisone methylprednisolone, prednisolone, prednisone and triamcinolone.
  • Histamine H1 receptor antagonists which may for example be selected from the group consisting of brompheniramine, chlorpheniramine,
  • Leukotriene antagonists and 5-lipoxygenase inhibitors which may for example be selected from the group consisting of zafirlukast, montelukast, pranlukast and zileuton.
  • Local anesthetics which may be selected, for example, from the group consisting of ambroxol and lidocaine.
  • TRPV1 antagonists which may be selected, for example, from the group consisting of AZD-1386, JTS-653 and PHE-377.
  • Nicotine receptor agonists such as A-366833.
  • P2X3 receptor antagonists such as A-317491.
  • anti-NGF antibodies and NGF antagonists which may for example be selected from the group consisting of JNJ-42160443 and PPH 207.
  • NK1 and NK2 antagonists such as CP-728663.
  • NMDA antagonists which may for example be selected from the group consisting of CNS-5161, AZ-756 and V-3381.
  • Potassium channel modulators such as CL-888.
  • GABA modulators such as baclofen.
  • Anti-migraine therapeutics which may be selected, for example, from the group consisting of sumatriptan, zolmitriptan, naratriptan and eletriptan.
  • the dose required to produce an analgesic effect is advantageously 0.01 to 3 mg / kg body weight, preferably 0.1 to 1 mg / kg when given intravenously, and 0.1 to 8 mg / kg body weight, preferably 0.5 to 3 mg / kg, respectively, when given orally 1 to 3 times a day.
  • the compounds prepared according to the invention can be administered intravenously, subcutaneously, intramuscularly, intrarectally, intranasally, by inhalation, transdermally or orally, in particular aerosol formulations being suitable for inhalation.
  • customary carriers and / or diluents for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbitol , Water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or their suitable
  • Example 3a 2- ⁇ 2 - [(4-Methoxy-2,6-dimethyl-benzenesulfonyl) -methyl-amino-1-ethoxy) -
  • Example 3b 2- ⁇ 2 - [(4-Methoxy-2,6-dimethyl-benzenesulfonyl) -methyl-amino-1-ethoxy) - / V-methyl-N - [(1f?, 3S) -3- (4 -methylpiperazin-1-yl) -cyclohexyl-1-acetamide (G ”)
  • Plasticizer A water / 0.1% formic acid
  • Plasticizer B acetonitrile / 0.1% formic acid
  • Example 9 2- ⁇ 2 - [[(4-Methoxy-2,6-dimethylphenyl) sulfonyl-1- (methyl) amino-1-ethoxy) - / - / - methyl- / V - [(1f, 3S) -3- ( 4-methylpiperazin-1-yl) cvclohexyl1acetamid- (D) -
  • Example 1 2- ⁇ 2 - [[(4-Methoxy-2,6-dimethylphenyl) sulfonyl-1-methyl-amino-1-ethoxy) - / - / - methyl- / V - [(1f?, 3s) -3- (4-methylpiperazin-1-yl) cvclohexylacetamide difumarate ⁇ 1
  • Figure 1 shows the X-ray powder diffractogram of the crystalline compound 2- ⁇ 2 - [[(4-methoxy-2,6-dimethylphenyl) sulfonyl] - (methyl) amino] ethoxy ⁇ - / ⁇ / - methyl - / ⁇ / - [(1 f,, 3S) -3- (4-methylpiperazin-1-yl) cyclohexyl] acetamide dihydrochloride (1).
  • Figure 2 shows the X-ray powder diffractogram of the crystalline compound 2- ⁇ 2 - [[(4-methoxy-2,6-dimethylphenyl) sulfonyl] - (methyl) amino] ethoxy ⁇ - / ⁇ / - methyl - / ⁇ / - [(1 S, 3f?) - 3- (4-methylpiperazin-1-yl) cyclohexyl] acetamide dihydrochloride (2).
  • FIG. 3 shows the X-ray powder diffractogram of the crystalline compound 2- ⁇ 2 - [[(4-methoxy-2,6-dimethylphenyl) sulfonyl] - (methyl) amino] ethoxy ⁇ - / - / - methyl - / ⁇ / - [(1 S, 3f?) - 3- (4-methylpiperazin-1-yl) cyclohexyl] acetamide (L) tartrate (3).
  • Figure 4 shows the X-ray powder diffractogram of the crystalline compound 2- ⁇ 2 - [[(4-methoxy-2,6-dimethylphenyl) sulfonyl] - (methyl) amino] ethoxy ⁇ - / ⁇ / - methyl - / ⁇ / - [(1 f, 3S) -3- (4-methylpiperazin-1-yl) cyclohexyl] acetamide (D) tartrate (4).

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Abstract

L'invention concerne les nouveaux sels d'addition d'acide AB des bases libres suivantes de formule (A) ou de leurs énantiomères avec un acide B physiologiquement compatible, qui est choisi dans le groupe comprenant l'acide chlorhydrique, l'acide fumarique et l'acide tartrique, ainsi que leurs polymorphes, hydrates et solvates.
EP11741454.0A 2010-08-05 2011-08-04 Sels d'addition d'acide du 2-[2-[[(4-méthoxy-2,6-diméthylphényl)sulfonyl]-(méthyl)amino]éthoxy]-n-méthyl-n-[3-(4-méthylpipérazine-1-yl)cyclohexyl]acétamide, et leur utilisation en tant qu'antagonistes du récepteur de la bradykinine-b1 Withdrawn EP2601181A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11741454.0A EP2601181A1 (fr) 2010-08-05 2011-08-04 Sels d'addition d'acide du 2-[2-[[(4-méthoxy-2,6-diméthylphényl)sulfonyl]-(méthyl)amino]éthoxy]-n-méthyl-n-[3-(4-méthylpipérazine-1-yl)cyclohexyl]acétamide, et leur utilisation en tant qu'antagonistes du récepteur de la bradykinine-b1

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP10172018 2010-08-05
EP11741454.0A EP2601181A1 (fr) 2010-08-05 2011-08-04 Sels d'addition d'acide du 2-[2-[[(4-méthoxy-2,6-diméthylphényl)sulfonyl]-(méthyl)amino]éthoxy]-n-méthyl-n-[3-(4-méthylpipérazine-1-yl)cyclohexyl]acétamide, et leur utilisation en tant qu'antagonistes du récepteur de la bradykinine-b1
PCT/EP2011/063413 WO2012017027A1 (fr) 2010-08-05 2011-08-04 Sels d'addition d'acide du 2-[2-[[(4-méthoxy-2,6-diméthylphényl)sulfonyl]-(méthyl)amino]éthoxy]-n-méthyl-n-[3-(4-méthylpipérazine-1-yl)cyclohexyl]acétamide, et leur utilisation en tant qu'antagonistes du récepteur de la bradykinine-b1

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EP2601181A1 true EP2601181A1 (fr) 2013-06-12

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EP11741454.0A Withdrawn EP2601181A1 (fr) 2010-08-05 2011-08-04 Sels d'addition d'acide du 2-[2-[[(4-méthoxy-2,6-diméthylphényl)sulfonyl]-(méthyl)amino]éthoxy]-n-méthyl-n-[3-(4-méthylpipérazine-1-yl)cyclohexyl]acétamide, et leur utilisation en tant qu'antagonistes du récepteur de la bradykinine-b1

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US (1) US20130289049A1 (fr)
EP (1) EP2601181A1 (fr)
JP (1) JP2013535480A (fr)
CN (1) CN103003253A (fr)
AU (1) AU2011287581A1 (fr)
CA (1) CA2807078A1 (fr)
MX (1) MX2013000978A (fr)
WO (1) WO2012017027A1 (fr)

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AU2018359017A1 (en) * 2017-11-02 2020-06-18 Sportswrap Australia Pty Ltd Covered sporting instrument

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EP1953151A4 (fr) * 2005-11-18 2010-06-02 Eisai R&D Man Co Ltd Sels de composé cynamide ou solvates de ces derniers
EP2062886B1 (fr) * 2006-08-23 2011-11-30 Eisai R&D Management Co., Ltd. Sel de derive de phenoxypyridine ou son cristal et procede de production
CL2007002499A1 (es) * 2006-08-30 2008-03-14 Phenomix Corp Sales citrato y tartrato de compuestos derivados de acido pirrolidinilaminoacetilpirrolidinboronico, inhibidores de dpp-iv; metodo de preparacion; forma solida; combinacion farmaceutica, util para el tratamiento de diabetes.
US8394805B2 (en) * 2007-08-14 2013-03-12 Boehringer Ingelheim International Gmbh Compounds
EP2025673A1 (fr) 2007-08-14 2009-02-18 Boehringer Ingelheim International GmbH Arylsulfonamides ayant activité analgésique
BRPI0914556A2 (pt) 2008-08-12 2015-08-04 Boehringer Ingelheim Int Processo para a preparação de compostos de piperazina substituídos por cicloalquila
JP2012512885A (ja) * 2008-12-18 2012-06-07 ノバルティス アーゲー 新規な塩
US8207335B2 (en) * 2009-02-13 2012-06-26 Boehringer Ingelheim International Gmbh Process for making certain compounds having B1 antagonistic activity

Non-Patent Citations (1)

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Title
See references of WO2012017027A1 *

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JP2013535480A (ja) 2013-09-12
MX2013000978A (es) 2013-02-15
CA2807078A1 (fr) 2012-02-09
AU2011287581A1 (en) 2013-02-14
US20130289049A1 (en) 2013-10-31
WO2012017027A1 (fr) 2012-02-09

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