EP2205587A2 - Nouveaux composés - Google Patents

Nouveaux composés

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Publication number
EP2205587A2
EP2205587A2 EP08804742A EP08804742A EP2205587A2 EP 2205587 A2 EP2205587 A2 EP 2205587A2 EP 08804742 A EP08804742 A EP 08804742A EP 08804742 A EP08804742 A EP 08804742A EP 2205587 A2 EP2205587 A2 EP 2205587A2
Authority
EP
European Patent Office
Prior art keywords
oxo
benzodiazepin
chloro
amino
tetrahydro
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.)
Withdrawn
Application number
EP08804742A
Other languages
German (de)
English (en)
Inventor
Kathrin Pachur
Uwe Joerg Ries
Sonja Sproll
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
Original Assignee
Boehringer Ingelheim International GmbH
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
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Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of EP2205587A2 publication Critical patent/EP2205587A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D401/14—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 three or more hetero rings
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • 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
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/12—Drugs for genital or sexual disorders; Contraceptives for climacteric disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/26—Androgens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/30—Oestrogens
    • 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

Definitions

  • the present invention relates to the novel salts AB of the base A.
  • a physiologically acceptable acid B selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid and salicylic acid and the polymorphs, the corresponding solvates and hydrates.
  • the present invention relates to CGRP antagonists, which are in the form of stable crystalline derivatives and are suitable for the treatment of headaches, in particular for the treatment of migraine.
  • the pharmacologically valuable properties of the compounds according to the invention represent the basic requirement for effective use of the compound as a medicament. However, an active ingredient must still meet other requirements in order to be used as a medicament. 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 drug used to prepare the drug compositions should therefore have a high stability which must be guaranteed under different 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 drug during manufacture if the drug is exposed to the environment without any protection from moisture.
  • a drug should only be slightly hygroscopic.
  • a first object of the present invention relates to the novel salts AB of the base A.
  • a physiologically acceptable acid B selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid and salicylic acid and the polymorphs, the corresponding solvates and hydrates.
  • a preferred first aspect of the present invention relates to the above salts in crystalline form.
  • 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 preferred second aspect of the present invention relates to the above compounds in crystalline form.
  • the crystalline salts are each characterized by a characteristic melting point which was determined by means of differential scanning calorimetry (DSC: evaluation via onset temperature or peak maximum, heating rate: 10 ° C./min).
  • DSC differential scanning calorimetry
  • the values of the individual compounds listed in Table 1 were determined by means of a DSC 821 from Mettler Toledo.
  • Table 1 Melting points of the crystalline salts according to the invention
  • a third 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 2a X-ray powder reflections and intensities (normalized) of compound (1a) - polymorph 1.
  • Table 2b X-ray powder reflections and intensities (normalized) of compound (1b) polymorph 2.
  • Table 2c X-ray powder reflections and intensities (normalized) of compound (1c) polymorph 3.
  • Table 3 X-ray powder reflections and intensities (normalized) of the compound (2).
  • 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).
  • Table 6a X-ray powder reflections and intensities (normalized) of compound (5a) Polymorph 1.
  • Table 6b X-ray powder reflections and intensities (standardized) of the compound (5b) ⁇ polymorph. 2
  • the compounds of general formula I are prepared by methods known in principle. The methods listed in the "Handbook of Pharmaceutical Salts” (Eds. P. Heinrich Stahl, Camille G. Wermuth, Wiley-VHC 2002) have proven particularly useful.
  • the preparation of the crystalline salt of the invention is 4- [4 - [(2R) -3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo 2 - [[[4- (1,2,4,5-tetrahydro-2-oxo-3 / - / -1,3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1 piperazinyl] piperidine-1-acetic acid ethyl ester difumarate (3), comprising the following steps:
  • the polar solvent used in steps (a) and (b) can be methanol, ethanol, propanol, isopropanol or a mixture of these solvents, ethanol or isopropanol or a 1: 1 mixture of ethanol and isopropanol being preferably used according to the invention can.
  • the same solvent is used in steps (a) and (b).
  • the solvent in step (a) may be used in an amount of 2 to 4 L / mol of base used, preferably in an amount of 3 to 4 L / mol of base used.
  • step (a) The reaction mixture formed in step (a) is then heated to the boiling point of the solvent used.
  • the solvent in step (b) may be used in an amount of 1 to 3 L / mol of fumaric acid used, preferably in an amount of 2 to 3 L / mol of fumaric acid used.
  • the solvent used in steps (a) and (b) it is particularly preferable for the solvent used in steps (a) and (b) to be ethanol.
  • a solvent in step (c) can be used according to the invention ethanol, propanol, isopropanol or a mixture of these solvents.
  • the production method described is also industrially applicable for the production of large amounts of substance.
  • Another object of the present invention is, due to the pharmaceutical activity of the novel salts, their use as medicaments.
  • the compounds according to the invention and their salts with physiologically tolerated acids are thus suitable for the acute and prophylactic treatment of headaches, in particular migraine, cluster headache and tension-type headaches. Furthermore, the compounds according to the invention also have a positive influence on the following diseases:
  • Non-insulin dependent diabetes mellitus (“NIDDM”), cardiovascular diseases, morphine tolerance, Clostridium toxin diarrheal diseases, skin disorders, in particular thermal and radiation related skin damage including sunburn, lesions, prurigo, prurigenic toxidermias and severe itching, inflammatory diseases, e.g. inflammatory joint diseases (osteoarthritis, rheumatoid arthritis, neurogenic arthritis), generalized soft tissue rheumatism (fibromyalgia), neurogenic inflammations of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, COPD, diseases associated with excessive vasodilation and consequent reduced tissue perfusion, e.g.
  • NIDDM Non-insulin dependent diabetes mellitus
  • cardiovascular diseases e.g. inflammatory joint diseases (osteoarthritis, rheumatoid arthritis, neurogenic arthritis), generalized soft tissue rheumatism (fibromyalgia), neurogenic inflammations of the oral mucosa
  • Shock and sepsis chronic pain disorders, e.g. diabetic neuropathies, chemotherapy-induced neuropathies, HIV-induced neuropathies, postherpetic neuropathies, tissue neuropathies induced by trauma, trigeminal neuralgia, temporomandibular dysfunctions, complex regional pain syndrome (CRPS), back pain, and visceral diseases, e.g. irritable bowel syndrome (IBS), inflammatory bowel syndrome.
  • the compounds according to the invention have a soothing effect on pain conditions in general.
  • the symptoms of menopausal, caused by vasodilation and increased blood flow hot flushes of estrogen-deficient women and hormone-treated prostate cancer patients and castrates is influenced by the CGRP antagonists of the present application preventively and acutely therapeutically favored, this therapy approach is characterized by hormone substitution by side effect poverty.
  • the compounds according to the invention are preferably suitable for the acute and prophylactic treatment of migraine and cluster headache, for the treatment irritable bowel syndrome (IBS) and for the preventive and acute therapeutic treatment of hot flashes of women with estrogen deficiency.
  • IBS irritable bowel syndrome
  • the dosage required to achieve a corresponding effect is advantageously from 0.0001 to 3 mg / kg body weight, preferably 0.01 to 1 mg / kg body weight, when administered intravenously or subcutaneously, and 0.01 to 10 mg / kg body weight when administered orally, nasally or by inhalation, preferably 0.1 to 10 mg / kg of body weight, one to three times daily.
  • CGRP antagonists or / and CGRP-release inhibitors are in addition to a conventional hormone substitution, it is recommended to reduce the dosages given above, the dosage then being 1/5 of the lower limits specified above up to 1/1 of the above may be upper limits.
  • Another object of the invention is the use of the compounds of the invention as valuable tools for the generation and purification (affinity chromatography) of antibodies and, after appropriate radioactive labeling, for example by tritiation of suitable precursors, for example by catalytic hydrogenation with trithium or replacement of halogen atoms by tritium, in RIA and ELISA assays and as diagnostic and analytical tools in neurotransmitter research.
  • Possible combinations of agents include antiemetics, prokinetics, neuroleptics, antidepressants, neurokinin antagonists, anticonvulsants, histamine H1 receptor antagonists, ⁇ -blockers, ⁇ -agonists and ⁇ -antagonists, ergot alkaloids, weak analgesics, non-steroidal anti-inflammatory drugs, corticosteroids, calcium Antagonists, 5-HT 1B / i D agonists or other antimigraine agents, together with one or more inert customary carriers and / or diluents, for example corn starch, milk sugar, 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, carboxymethyl cellulose or fatty substances such as hard fat or its suitable Mixtures, in common pharmaceutical preparation
  • the non-steroidal anti-inflammatory drugs aceclofenac, acemetacin, acetylsalicylic acid, acetaminophen (paracetamol), azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid are thus used as further active substances , Naproxen, phenylbutazone, piroxicam, sulfasalazine, zomepirac or their pharmaceutically acceptable salts, as well as meloxicam and other selective COX2 inhibitors, such as rofecoxib, valdecoxib, parecoxib, etoricoxib and celecoxib, as well as substances which inhibit earlier or later steps in prostaglandin. Inhibit synthesis
  • CGRP antagonists may be useful with vanilloid receptor antagonists such as VR-1 antagonists, glutamate receptor antagonists such as mGlu5 receptor antagonists, mGlui receptor antagonists, iGlu5 receptor antagonists, AMPA receptor antagonists, purine receptor blockers such as P2X3 Antagonists, NO synthase inhibitors such as iNOS inhibitors, calcium channel blockers such as PQ-type blockers, N-type blockers, potassium channel openers such as KCNQ channel openers, sodium channel blockers such as PN3 channel blockers, NMDA receptor antagonists, acid -sensing ion channel antagonists such as ASIC3 antagonists, bradykinin receptor antagonists such as B1 receptor antagonists, cannabinoid receptor agonists such as CB2 agonists, CB1 agonists nisten, somatostatin receptor agonists, such as sst2 receptor agonists are given.
  • vanilloid receptor antagonists such as VR-1 antagonists, glutamate receptor antagonists such
  • the dose for these active substances is expediently 1/5 of the usual recommended lowest dosage up to 1/1 of the normally recommended dosage, so for example 20 to 100 mg sumatriptan.
  • the compounds according to the invention may be administered either alone or optionally in combination with other active substances for the treatment of migraine intravenously, subcutaneously, intramuscularly, intraarticularly, intrarectally, intranasally, by inhalation, topically, transdermally or orally, in particular aerosol formulations being suitable for inhalation.
  • the combinations may be administered either simultaneously or sequentially.
  • Suitable application forms are, for example, tablets, capsules, solutions, juices, emulsions or inhalable powders or aerosols.
  • the proportion of the pharmaceutically active compound (s) in each case in the range of 0.1 to 90 wt .-%, preferably 0.5 to 50 wt .-% of the total composition, i. in amounts sufficient to achieve the above dosage range.
  • Oral administration may be in the form of a tablet, as a powder, as a powder in a capsule (e.g., hard gelatin capsule), as a solution or suspension.
  • the active substance combination can be carried out as a powder, as an aqueous or aqueous-ethanolic solution or by means of a propellant gas formulation.
  • compositions are preferably characterized by the content of one or more of the compounds of the invention.
  • Corresponding tablets can be prepared, for example, by mixing the active substance (s) with known auxiliaries, for example inert diluents, such as calcium carbonate, or calcium lactate, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or depot effecting agents such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • auxiliaries for example inert diluents, such as calcium carbonate, or calcium lactate, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and / or depot effecting agents such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate.
  • auxiliaries for example inert diluents, such as calcium carbonate, or calcium lac
  • Coated tablets can accordingly be produced by coating cores produced analogously to the tablets with agents customarily used in tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar.
  • the core can also consist of several layers.
  • the dragee sheath to achieve a depot effect of several layers may consist of the above mentioned in the tablets excipients can be used.
  • Juices of the active compounds or active compound combinations according to the invention may additionally contain a sweetening agent, such as saccharin, cyclamate, glycerol or sugar, and a taste-improving agent, e.g. Flavorings such as vanillin or orange extract. They may also contain suspending aids or thickening agents, such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • a sweetening agent such as saccharin, cyclamate, glycerol or sugar
  • a taste-improving agent e.g. Flavorings such as vanillin or orange extract.
  • suspending aids or thickening agents such as sodium carboxymethylcellulose, wetting agents, for example condensation products of fatty alcohols with ethylene oxide, or protective agents, such as p-hydroxybenzoates.
  • the capsules containing one or more active ingredients or combinations of active substances can be prepared, for example, by mixing the active ingredients with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatine capsules.
  • inert carriers such as lactose or sorbitol
  • Suitable suppositories can be prepared, for example, by mixing with suitable carriers, such as neutral fats or polyethylene glycol or its derivatives.
  • auxiliaries for example, water, pharmaceutically acceptable organic solvents such as paraffins (eg petroleum fractions), oils of vegetable origin (eg peanut or sesame oil), mono- or polyfunctional alcohols (eg ethanol or glycerol), excipients such as natural minerals (eg kaolin, Clays, talc, chalk) synthetic minerals (eg highly disperse silicic acid and silicates), sugars (eg Pipe, milk and dextrose) emulsifiers (eg lignin, liquors, methyl cellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate) mentioned.
  • paraffins eg petroleum fractions
  • oils of vegetable origin eg peanut or sesame oil
  • mono- or polyfunctional alcohols eg ethanol or glycerol
  • excipients such as natural minerals (eg kaolin, Clays, tal
  • the tablets may also contain additives other than those mentioned.
  • Sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatin and the like.
  • lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tableting.
  • the active ingredients may be added to the abovementioned excipients with various flavor enhancers or dyes.
  • the compounds according to the invention are administered by inhalation, it is particularly preferred if the administration takes place once or twice daily.
  • the compounds according to the invention must be provided in inhalable dosage forms. Suitable inhalable dosage forms are inhalable powders, propellant-containing metered-dose inhalers or propellant-free inhalable solutions which, if appropriate, are present in admixture with conventional physiologically compatible excipients.
  • the solution is heated to 80 0 C and treated with 98 .mu.l of isopropanolic hydrochloric acid (3.2 mol / l, 0.316 mmol). The temperature is lowered by 5 ° C every 30 minutes. The resulting suspension is stirred for 12 hours at room temperature. The resulting solid is filtered off, washed with a little ethyl acetate and dried at 35 ° C for 12 hours.
  • Example 2 4- [4 - [(2R) -3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4- (1 2 4,5-tetrahydro! -2-oxo-3 / - / - 1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1-piperazinyl] -piperidine-1-acetic acid ethyl ester hydrobromide (2)
  • Example 4 4- [4 - [(2R) -3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4- (1 2 4,5-tetrahydro! -2-oxo-3 / - / - 1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1-piperazinyl] -piperidine-1-acetic acid ethyl ester sulfate (4)
  • the solution is heated to 80 0 C and treated with a solution of 43 mg of salicylic acid (0.361 mmol) in 1.5 ml of ethanol. The temperature is lowered by 5 ° C every 30 minutes. Subsequently, the solution is stirred for 12 hours at room temperature. Since no precipitate has formed, the solvent is distilled off and the residue is dissolved in 2.5 ml of methyl isobutyl ketone at 80 ° C. The temperature is lowered by 5 ° C every 30 minutes. Subsequently, the solution is stirred for 12 hours at room temperature. Thereafter, the solution is stirred in an open vessel for a further 24 hours, whereby the solvent evaporates. The solid thus formed is filtered off, washed with methyl isobutyl ketone and dried at 35 ° C for 12 hours. Yield: 190 mg (65% of theory)
  • FIG. 1 shows the X-ray powder diffractogram of the crystalline compound 4- [4 - [(2 /?) - 3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4-] (1, 2,4,5-tetrahydro-2-oxo-3 / - / - 1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1-piperazinyl] -piperidine-1 acetic acid ethyl ester hydrochloride (1a, polymorph 1).
  • FIG. 2 shows the X-ray powder diffractogram of the crystalline compound 4- [4 - [(2 /?) - 3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4] (1, 2,4,5-tetrahydro-2-oxo-3 / - / - 1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1-piperazinyl] -piperidine-1 acetic acid ethyl ester hydrochloride (1b, polymorph 2).
  • FIG. 3 shows the X-ray powder diffractogram of the crystalline compound 4- [4 - [(2 /?) - 3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4-] (1, 2,4,5-tetrahydro-2-oxo-3 / - / - 1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1-piperazinyl] -piperidine-1 acetic acid ethyl ester hydrochloride (1c, polymorph 3).
  • FIG. 4 shows the X-ray powder diffractogram of the crystalline compound 4- [4 - [(2 /?) - 3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4-] (1, 2,4,5-tetrahydro-2-oxo-3 / - / - 1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1-piperazinyl] -piperidine-1 acetic acid ethyl ester hydrobromide (2).
  • FIG. 5 shows the X-ray powder diffractogram of the crystalline compound 4- [4 - [(2 /?) - 3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4] (1, 2,4,5-tetrahydro-2-oxo-3 / - / - 1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1-piperazinyl] -piperidine-1 acetic acid ethyl ester difumarate (3).
  • FIG. 6 shows the X-ray powder diffractogram of the crystalline compound 4- [4 - [(2 /?) - 3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4-] (1, 2,4,5-tetrahydro-2-oxo-3 / - / - 1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1-piperazinyl] -piperidine-1 acetic acid ethyl ester sulphate (4).
  • FIG. 6 shows the X-ray powder diffractogram of the crystalline compound 4- [4 - [(2 /?) - 3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4-] (1, 2,4,5-tetrahydro-2-oxo-3 /
  • FIG. 8 shows the X-ray powder diffractogram of the crystalline compound 4- [4 - [(2 /?) - 3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4-] (1, 2,4,5-tetrahydro-2-oxo-3 / - / - 1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1-piperazinyl] -piperidine-1 acetic acid ethyl ester salicylate (5b, polymorph 2).
  • FIG. 9 shows the X-ray powder diffractogram of the crystalline compound 4- [4 - [(2 /?) - 3- [4-amino-3-chloro-5- (trifluoromethyl) phenyl] -1-oxo-2 - [[[4] (1, 2,4,5-tetrahydro-2-oxo-3 / - / - 1, 3-benzodiazepin-3-yl) -1-piperidinyl] carbonyl] oxy] propyl] -1-piperazinyl] -piperidine-1 acetic acid ethyl ester salicylate (5c, polymorph 3).

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Abstract

L'invention concerne les nouveaux sels AB de base A,contenant un acide physiologiquement compatible B, sélectionné dans le groupe comprenant les acides de chlorhydrique, bromhydrique, sulfurique, fumarique et salicylique, ainsi que les polymorphes, et les solvates et hydrates correspondants.
EP08804742A 2007-09-28 2008-09-25 Nouveaux composés Withdrawn EP2205587A2 (fr)

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* Cited by examiner, † Cited by third party
Title
HEINRICH STAHL P ED - WERMUTH C G: "The Practice of Medicinal Chemistry; 35 Preparation of water-soluble compounds through salt formation", 1 January 2003, THE PRACTICE OF MEDICINAL CHEMISTRY, ELSEVIER, NL, PAGE(S) 601 - 615, ISBN: 978-0-12-744481-9, XP002566271 *

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AR068570A1 (es) 2009-11-18
CN101809015A (zh) 2010-08-18
US8551987B2 (en) 2013-10-08
AU2008306968A1 (en) 2009-04-09
MX2010003281A (es) 2010-04-09
WO2009043797A2 (fr) 2009-04-09
KR20100058598A (ko) 2010-06-03
BRPI0817585A2 (pt) 2015-03-31
UY31365A1 (es) 2009-04-30
PE20091206A1 (es) 2009-09-14
WO2009043797A3 (fr) 2009-07-02
CL2008002897A1 (es) 2010-03-05
US20120058994A1 (en) 2012-03-08

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