EP1071679A1 - Nouveaux composes heterocycliques - Google Patents

Nouveaux composes heterocycliques

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Publication number
EP1071679A1
EP1071679A1 EP99908771A EP99908771A EP1071679A1 EP 1071679 A1 EP1071679 A1 EP 1071679A1 EP 99908771 A EP99908771 A EP 99908771A EP 99908771 A EP99908771 A EP 99908771A EP 1071679 A1 EP1071679 A1 EP 1071679A1
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European Patent Office
Prior art keywords
compound
compound according
formula
pharmaceutical composition
defined above
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
EP99908771A
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German (de)
English (en)
Inventor
Rolf Hohlweg
Tine Krogh Jorgensen
Knud Erik Andersen
Uffe Bang Olsen
Zdenék Polivka
Karel Sindelar
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Novo Nordisk AS
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Novo Nordisk AS
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Publication of EP1071679A1 publication Critical patent/EP1071679A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to novel N-substituted azaheterocyclic compounds in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, to the use of the compounds for preparing compositions for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, and to methods of treating said painful, hyperalgesic and/or inflammatory conditions.
  • the invention also relates to the use of the present compounds for reducing blood glucose and/or inhibit the secretion, circulation or effect of insulin antagonizing peptides like CGRP or amylin, the present compounds being known to iterfere with neuropeptide containing C-fibres.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the nervous system exerts a profound effect on the inflammatory response.
  • Antidromic stimulation of sensory nerves results in localised vasodilation and increased vascular permeability (Janecso et al. Br. J. Pharmacol. 1967, 31 , 138-151), and a similar response is observed following injection of peptides known to be present in sensory nerves. From this and other data it is postulated that peptides released from sensory nerve endings mediate many inflammatory responses in tissues like skin, joint, urinary tract, eye, meninges, gastro- intestinal and respiratory tracts.
  • inhibition of sensory nerve peptide release and/or activity may be useful in treatment of for example arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis, glaucoma, gastro-intestinal diseases or migraine.
  • CGRP may play a physiological role in skeletal muscle glucose metabolism by directing the phosphorylated glucose away from glycogen storage and into the giycolytic and oxidative pathways (Rossetti et al. Am. J. Physiol. 264, E1-E10, 1993).
  • This peptide may represent an important physiological modulator of intracellular glucose trafficking in physiological conditions, such as exercise, and may also contribute to the decreased insulin action and skeletal muscle glycogen synthase in pathophysiological conditions like NIDDM or ageing-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995) where circulating plasma levels of CGRP are markedly increased.
  • inhibition of release and/or activity of the neuropeptide CGRP and other sensory neuropeptides may be useful in the treatment of insulin resistance related to type 2 diabetes or ageing.
  • GABA uptake inhibitors EP 221572 claims that 1-aryloxyalkylpyridine-3-carboxylic acids are inhibitors of GABA uptake.
  • WO 9518793 discloses N-substituted azaheterocyclic carboxylic acids and esters thereof.
  • the present invention relates to compounds of the general formula I, wherein X, Y, R ⁇ R 2 , Z and r are as defined in the detailed part of the present description.
  • the present compounds are useful for the treatment, prevention, elimination, alleviation or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides and other peptides derived from the sensory nervous system, e.g. non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance and ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • a method of treating painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis
  • C-fibres play a pathophysiological role
  • a pathophysiological role e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis
  • indications caused by or related to the secretion and circulation of insulin antagonising peptides e.g. non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance and ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the method of treatment may be described as the treatment, prevention, elimination, alleviation or amelioration of one of the above indications, which comprises the step of administering to the said subject a neurologically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
  • a further aspect of the invention relates to the use of a compound of the present invention for the preparation of a pharmaceutical composition for the treatment of all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role, e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as for the treatment of indications caused by or related to the secretion and circulation of insulin antagonising peptides and other peptides derived from the sensory nervous system, e.g. non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance and ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the present invention relates to novel N-substituted azaheterocyclic compounds of the general formula I
  • R 1 and R 2 independently are hydrogen, halogen, trifluoromethyl, hydroxy, C ⁇ -alkyl or C 1-6 -alkoxy;
  • A is -CH 2 -, -O-, -S- or -N(R 5 )- wherein R 5 is H or C ⁇ -alkyl;
  • R 3 is -(CH 2 ) m OH or -(CH 2 ) p COR 4 wherein m and p independently are 1 , 2, 3 or 4 and R 4 is OH, NH 2 , NHOH or C 1-6 -alkoxy; or a pharmaceutically acceptable salt thereof.
  • the compounds of formula I may exist as geometric and optical isomers and all isomers, as separeted, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention. Isomers may be separated by means of standard methods such as chromatographic techniques or fractional crystallisation of suitable salts.
  • the compounds of formula I exist as the individual geometric or optical isomers.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable acid addition salts, metal salts or, optionally alkylated, ammonium salts.
  • salts examples include inorganic and organic acid addition salts such as hydrochlo- ride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tar- trate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • inorganic and organic acid addition salts such as hydrochlo- ride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tar- trate, oxalate or similar pharmaceutically acceptable inorganic or organic acid addition salts.
  • pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science. 66, 2 (1977) which are known to the skilled artisan.
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid, and the salt isolated by evaporating the solvent or by precipitation or crystallisation.
  • the compounds of formula I may be administered in a pharmaceutically acceptable acid addition salt form or where possible as a metal or a lower alkylammonium salt. Such salt forms exhibit approximately the same order of activity as the free base forms.
  • C 1-6 -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms.
  • Examples of such groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, iso-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, iso-hexyl, 4- methylpentyl, neopentyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1 ,2,2-trimethylpropyl and the like.
  • halogen means fluorine, chlorine, bromine or iodine.
  • C 1-6 -alkoxy as used herein, alone or in combination is intended to include those C 1-6 - alkyl groups of the designated length in either a linear or branched or cyclic configuration linked through an ether oxygen having its free valence bond from the ether oxygen.
  • linear alkoxy groups are methoxy, ethoxy, propoxy, butoxy, pentoxy and hexoxy.
  • branched alkoxy are isoprpoxy, sec-butoxy, tert-butoxy, isopentoxy and isohexoxy.
  • cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
  • R 1 and R 2 are selected from hydrogen, halogen, trifluoromethyl or C 1-6 -alkyl.
  • R 1 and R 2 are hydrogen.
  • X is -CH 2 CH 2 -.
  • Y is >N-CH 2 - .
  • r is 0, 1 or 2.
  • R 3 is -(CH 2 ) p COOH wherein p is 1 , 2, 3 or 4.
  • Preferred compounds of the present invention include:
  • novel compounds of formula I inhibit neurogenic inflammation which involves the release of neuropeptides from peripheral and central endings of sensory C-fibres. Experimentally this can be demonstrated in animal models of histamine induced paw oedema Amann et al. (Europ. J. Pharmacol. 279, 227-231 , 1995) in which the novel compounds of formula I exhibit a potent inhibitory effect.
  • Compounds of formula I may be used to treat all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role by eliciting neurogenic pain or inflammation, i.e.:
  • Acutely painful conditions exemplified by migraine, postoperative pain, burns, bruises, post- herpetic pain (Zoster) and pain as it is generally associated with acute inflammation; chronic, painful and/or inflammatory conditions exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, itching, chronic pancreatitis, inflammatory skin disease including psoriasis and autoimmune dermatoses, osteoporotic pain.
  • neuropathy diabetic, post-traumatic, toxic
  • neuralgia rheumatoid arthritis
  • spondylitis gout
  • inflammatory bowel disease exemplified by various types of neuropathy (diabetic, post-traumatic, toxic), neuralgia, rheumatoid arthritis, spondylitis, g
  • the compounds of general formula I lower the glucose levels in diabetic rodents (ob/ob mice and diabetic fat Zucker rats) as well as improve the glucose tolerance and that this may result from the reduced release of CGRP from peripheral nervous endings and other peptides derived from the sensory nervous system.
  • the compounds of general formula I may be used in the treatment of NIDDM, insulin resistance as well as ageing-associated obesity. Experimentally this can be demonstrated by the administration of histamine chloride icv into NMRI mice with previous treatment ip of a compound of formula I.
  • the compounds of formula I may be prepared by the following method A:
  • a compound of formula II wherein R 1 , R 2 and X are as defined above may be reacted with a compound of formula III wherein r is as defined above, W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate, PG is a suitable N-protecting group, e.g. benzyl, and U is selected from
  • A is as defined above, to form a compound of formula IV wherein R 1 , R 2 , X, r, U and PG are as defined above.
  • This alkylation reaction may be carried out in a solvent such as N,N-dimethylformamide, acetone, dibutylether, 2-butanone, tetrahydrofuran (THF), dioxane or toluene in the presence of a base e.g. sodium hydride and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h.
  • the compound of formula IV may be N-deprotected, e.g.
  • debenzylated to give a compound of formula V wherein R 1 , R 2 , X, r and U are as defined above.
  • the debenzylation reaction may be carried out in a solvent or a mixture of solvents such as methanol, ethanol or toluene in the presence a catalyst, e.g. Pd/C under a hydrogen atmosphere.
  • the compound of formula V may be N-alkylated with a compound of formula VI wherein R 3 is as defined above and V is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate, to give a compound of formula I.
  • This alkylation reaction may be carried out in a solvent such as N,N- dimethylformamide, acetone, dibutylether, 2-butanone, tetrahydrofuran (THF), dioxane or toluene in the presence of a base e.g. potassium carbonate or sodium hydride and a catalyst, e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h.
  • a base e.g. potassium carbonate or sodium hydride
  • a catalyst e.g. an alkali metal iodide at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h.
  • esters have been prepared in which R 4 is alkoxy
  • compounds of formula I wherein R 4 is OH may be prepared by hydrolysis of the ester group, prefarably at room temperature in a mixture of an aqueous alkali metal hydroxide and an alcohol such as methanol or ethanol, for e.g. about 0.5 to 48 h.
  • the compounds of formula I may be prepared by the following method B:
  • a compound of formula II wherein R ⁇ R 2 and X are as defined above may be reacted with a compound of formula VII wherein r is as defined above, W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate, PG is a suitable N-protecting group, e.g. benzyl, and U is selected from
  • A is as defined above, to form a compound of formula VIII wherein R ⁇ R 2 , X, r, U and PG are as defined above.
  • This acylation reaction may be carried out in a solvent such as N,N-dimethylformamide, acetonitrile, acetone, 2-butanone or toluene in the presence of an assisting agent or base such as triethylamine or N,N-dimethylaniline at a temperature up to reflux temperature for the solvent used for e.g. 1 to 120 h.
  • the compound of formula VIII may be reduced to give a compound of formula IV wherein R 1 , R 2 , X, r, U and PG are as defined above.
  • the reduction may take place in a solvent such as tetrahydrofuran using sodium boron hydride and boron trifluoride ethyl etherate.
  • the compound of formula IV may be N- deprotected, e.g. debenzylated to give a compound of formula V wherein R 1 , R 2 , X, r and U are as defined above.
  • the debenzylation reaction may be carried out in a solvent or a mixture of solvents such as methanol, ethanol or toluene in the presence of a catalyst, e.g. Pd/C under a hydrogen atmosphere.
  • the compound of formula V may be transformed to a compound of formula I as described under method A.
  • the rat histamine paw oedema test was performed essentially as described by Amann et al. (Europ. J. Pharmacol. 279, 227-231 , 1995). In brief 250-300 g male Sprague-Dawley rats were anaesthetized with pentobarbital sodium, and placed on a 32 degree Celsius heated table. Ten minutes later histamine (50 micoliter, 3 mg/ml) was injected in the right hind paw and 20 minutes hereafter the paw swelling was determined by water plethysmography (Ugo Basile). Test compounds were administered intraperitoneally at 15 minutes before the anaesthetics.
  • Conscious unfasted 25 g male NMRI mice are administered histamine chloride (90 nmol) icv according to the method of Nishibori et al. (J. Pharmacol. Exp. Therap. 241 , 582-286, 1987). Blood glucose is determined at time 0 and 40 min after the histamine injection. Test compounds are administered at 1.0 mg/kg ip 30 min before the histamine injection, and % inhibition refers to the capacity of the compounds to inhibit the histamine induced blood glucose rise.
  • mice 16 weeks of age, where injected glucose (2g/kg) subcutaneously.
  • blood glucose was determined in tail venous blood by the glucose oxidase method.
  • glucose oxidase method was determined in tail venous blood by the glucose oxidase method.
  • Immunoreactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, whereas the other group received a compound of formula I via drinking water (100 mg/l) for five days before the test.
  • the present invention also relates to pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutically acceptable carrier or diluent.
  • compositions comprising a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practise of Pharmacy. 19 th Ed.. 1995.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, associated with a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent or be diluted by a carrier, or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a ampoule, capsule, sachet, paper, or other container.
  • the carrier When the carrier serves as a diluent, it may be solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid container for example in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, syrup, peanut oil, olive oil, gelatine, lactose, terra alba, sucrose, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglyce des and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the formulations may also include wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents or flavouring agents.
  • the formulations of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • compositions can be sterilized and mixed, if desired, with auxiliary agents, emulsifiers, salt for influencing osmotic pressure, buffers and/or colouring substances and the like, which do not deleteriously react with the active compounds.
  • the route of administration may be any route, which effectively transports the active com- pound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transder- mal or parenteral e.g. rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, topical, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • a liquid carrier in particular an aqueous carrier
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain: Core:
  • Active compound (as free compound or salt thereof) 100 mg
  • the compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of an indication related to all painful, hyperalgesic and/or inflammatory conditions in which C-fibres play a pathophysiological role such as e.g. neurogenic pain, neurogenic inflammation, migraine, neuropathy, itching and rheumatoid arthritis, as well as indications caused by or related to the secretion and circulation of insulin antagonising peptides, such as non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance or ageing-associated obesity.
  • NIDDM non-insulin-dependent diabetes mellitus
  • Such mammals include also animals, both domestic animals, e.g. household pets, and non-domestic animals such as wildlife.
  • the compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, in an effective amount.
  • the compounds of the invention are effective over a wide dosage range.
  • dosages from about 0.5 to about 1000 mg, preferably from about 1 to about 500 mg of compounds of formula I, conveniently given from 1 to 5 times daily.
  • a most preferable dosage is from about 50 to about 200 mg per dose when administered to e.g. a human.
  • the exact dosage will depend upon the mode of administration, on the therapy de- sired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • the compounds of the present invention are dispensed in unit dosage form comprising from about 50 to about 200 mg of active ingredient in or together with a pharmaceutically acceptable carrier per unit dosage.
  • dosage forms suitable for oral, nasal, pulmonal or transdermal administration comprise from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.
  • TLC thin layer chromatography
  • CDCI 3 deuterio chloroform
  • DMSO-d 6 hexadeuterio dimethylsulfoxide.
  • the structures of the compounds are confirmed by either elemental analysis or NMR, where peaks assigned to characteristic protons in the title compounds are presented where appropriate.
  • 1 H NMR shifts ( ⁇ H ) are given in parts per million (ppm).
  • M.p. is melting point and is given in °C and is not corrected.
  • Column chromatography was carried out using the technique described by W.C. Still et al, J. Org. Chem. (1978), 43, 2923-2925 on Merck silica gel 60 (Art. 9385).
  • Compounds used as starting materials are either known compounds or compounds which can readily be prepared by methods known per se.
  • 10,11-Dihydro-5H-dibenzo[b,f]azepine (4.88 g, 25 mmol) was added to a stirred suspension of 60% sodium hydride (1.1 g, 27 mmol) in dry N,N-dimethylformamide (15 ml). The mixture was slowly heated to 80 °C, maintained at that temperature until the evolution of hydrogen ceased (30 minutes) and cooled to room temperature. A solution of 1-benzyl-3-chloromethylpyrrolidine (5.24 g, 25 mmol, prepared similarly as described in J.Org.Chem., 26, 1519,(1961)) in dry N,N- dimethylformamide (15 ml) was added, followed by sodium iodide (3.75 g, 25 mmol).
  • HPLC retention time 17.25 minutes (5 ⁇ m C18 4 x 250 mm column, eluting with a 20-80 % gradient of 0.1 % trifluoroacetic acid/acetonitrile and 0.1 % trifluoroacetic acid/water over 25 minutes at 35 °C).
  • the free base (7.0 g, 17.65 mmol) was released from the above oxalate using aqueous ammonia, and extracted with dichloromethane. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (60 ml). After addition of sodium borohydride (1.25 g) the mixture was stirred for 30 minutes and a solution of boron trifluoride ethyl etherate (5.4 g) in tetrahydrofuran (20 ml) was added dropwise. The mixture was stirred for 5 h at room temperature, 20 % hydrochloric acid (40 ml) was added and the mixture was heated at reflux temperature for 7 h.
  • the aqueous phase was extracted with dichloromethane (3 x 30 ml), and the combined dichloromethane phases were washed with water (30 ml), brine (20 ml), dried (MgSO 4 ) and evaporated in vacuo.
  • the residue was purified by chromatography (100 g) using benzene, chloroform and chloroform saturated with ammonia, gradually, as eluents, affording oily 2-(3-(10,11-dihydro- 5H-dibenz[b,f]azepin-5-yl)-1-propyl)piperidine (2.95 g, 88 %).
  • the base was librated from the above oxalate using aqueous ammonia, extracting with dichloromethane and evaporating the solvent.
  • the residue was dissolved in a mixture of methanol (40 ml), acetic acid (60 ml) and toluene (20 ml). 10 % Pd/C (4.5 g, suspension in toluene) was added and the mixture was hydrogenated at 50 C C and 5 MPa.
  • the catalyst was filtered off and the solvents were evaporated, affording a residue, which was made alkaline using 10 % ammonia and extracted with dichloromethane (2 x 50 ml).

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  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
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  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux composés azahétérocycliques N-substitués de la formule générale (I) dans laquelle X, Y, R1, R2, Z et r sont comme défini dans la partie détaillée de la présente description; ou alors des sels de ces composés. L'invention concerne également leurs procédés de préparation, des compositions les contenant et leur utilisation dans le traitement clinique de troubles douloureux, hyperalgiques et/ou inflammatoires dans lesquels les fibres C jouent un rôle pathopsychologique, les composés permettant d'éliciter une douleur ou une inflammation neurogène. L'invention concerne en outre leur utilisation dans des traitements d'affections dues ou liées à la sécrétion et à la circulation de peptides d'antagonisation de l'insuline, comme par exemple le diabète non insulino-dépendant (NIDDM) et l'obésité associée au vieillissement.
EP99908771A 1998-03-17 1999-03-16 Nouveaux composes heterocycliques Withdrawn EP1071679A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DK36698 1998-03-17
DK36698 1998-03-17
PCT/DK1999/000135 WO1999047517A1 (fr) 1998-03-17 1999-03-16 Nouveaux composes heterocycliques

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EP1071679A1 true EP1071679A1 (fr) 2001-01-31

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EP (1) EP1071679A1 (fr)
JP (1) JP2002506863A (fr)
AU (1) AU2825999A (fr)
WO (1) WO1999047517A1 (fr)

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DE19952147A1 (de) * 1999-10-29 2001-05-03 Boehringer Ingelheim Pharma Neue Cyclopropane, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung

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CH379507A (de) * 1962-02-01 1964-07-15 Cilag Chemie Aktiengesellschaf Verfahren zur Herstellung von neuen 10-(1'-Hydroxyalkyl-pyrrolidyl-(3')-methyl)-phenothiazinen
GB1043158A (en) * 1962-06-07 1966-09-21 Sandoz Ag Improvements in or relating to piperidylalkidene-5h-dibenzo(a,d)cycloheptenes
US4017621A (en) * 1974-12-09 1977-04-12 Sumitomo Chemical Company, Limited 2-Morpholinyl tricyclic dibenzazepine compounds
SE7514779L (sv) * 1975-01-06 1976-07-07 Sumitomo Chemical Co Nya morfolinderivat.
UA54385C2 (uk) * 1995-04-07 2003-03-17 Ново Нордіск А/С N-заміщені азагетероциклічні карбонові кислоти та їх ефіри, спосіб їх одержання, фармацевтична композиція та спосіб лікування
AU5270896A (en) * 1995-04-07 1996-10-23 Novo Nordisk A/S Novel heterocyclic compounds
US5698551A (en) * 1995-04-07 1997-12-16 Novo Nordisk A/S Heterocyclic compounds

Non-Patent Citations (1)

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Title
See references of WO9947517A1 *

Also Published As

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WO1999047517A1 (fr) 1999-09-23
WO1999047517A8 (fr) 1999-11-25
JP2002506863A (ja) 2002-03-05
AU2825999A (en) 1999-10-11

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