WO1995021843A1 - Derives azacycliques - Google Patents

Derives azacycliques Download PDF

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Publication number
WO1995021843A1
WO1995021843A1 PCT/EP1995/000345 EP9500345W WO9521843A1 WO 1995021843 A1 WO1995021843 A1 WO 1995021843A1 EP 9500345 W EP9500345 W EP 9500345W WO 9521843 A1 WO9521843 A1 WO 9521843A1
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alkyl
formula
hydrogen
compound according
group
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PCT/EP1995/000345
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English (en)
Inventor
Giuseppe Giardina
Mario Grugni
Roberto Colle
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Smithkline Beecham Farmaceutici S.P.A.
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Priority to JP07520934A priority Critical patent/JP3135577B2/ja
Priority to EP95908236A priority patent/EP0743944A1/fr
Publication of WO1995021843A1 publication Critical patent/WO1995021843A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • A61P11/06—Antiasthmatics
    • 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
    • A61P11/14—Antitussive agents
    • 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
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • 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
    • 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
    • A61P9/06—Antiarrhythmics
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This invention is concerned with novel substituted azacyclic condensed piperazines, processes for their preparation, and their use in medicine, particularly as diuretics and anti-ischaemics.
  • kappa receptor agonists Compounds which are kappa receptor agonists have mainly been studied as analgesics through interaction with kappa opioid receptors.
  • EP-A-343900 and EP-A-398720 disclose groups of piperazine derivatives which are said to exhibit kappa receptor agonism and are therefore said to be useful as analgesics, as diuretics and in the treatment of cerebral ischaemia.
  • a novel class of structurally related azacyclic condensed piperazine derivatives has now been discovered which also exhibit potent kappa receptor agonism and are particularly useful as diuretics for the treatment of hyponatraemic disease states in mammals and anti- ischaemics, in particular for the treatment of cerebral ischaemia.
  • This novel class of derivatives also possess analgesic activity which indicates that they are of potential use in the treatment of pain, without some of the undesirable behavioural effects of morphine and morphine analogues.
  • the novel class of derivatives are also of potential use in the treatment of other conditions which respond to administration of kappa agonists, in particular convulsions, cough, asthma, inflammation (including inflammation pain), pancreatitis, arrhythmia's and skin disorders.
  • each of X and Y is independently CH or N;
  • RCO is an acyl group in which the group R contains a substituted or unsubstituted carbocyclic aromatic or heterocyclic aromatic ring;
  • each of Ri and R2 which may be the same or different, is C -Q alkyl optionally substituted by at least one of halogen, (preferably fluorine or chlorine), hydroxy, Cj.g alkoxy (preferably methoxy), acyloxy (preferably acetoxy), thiol, C ⁇ .g alkyl thio (preferably methylthio), acylthio (preferably acetylthio) halo-C ⁇ _g alkoxy (preferably fluoro-alkoxy), CORh, COOR , CONHRh or NHCORh where Rh is hydrogen or Cj.g alkyl, preferably methyl or ethyl;
  • each of Rj and R2 is hydrogen, C2-6 alkenyl, 03.5 cycloalkyl, or C4.12 cycloalkylalkyl; or Rj and R2 together form an optionally substituted C2-8 branched or linear polymethylene or C2-6 alkenylene group, the polymethylene group, with the attached nitrogen, preferably being of the formula
  • Rb which may be attached to the same or different carbon atom as Re, is hydrogen, hydroxy, C ⁇ .g alkoxy (preferably methoxy) or halogen (preferably fluorine), and Re is hydrogen, C- . ⁇ alkyl (preferably methyl) or together with Rb forms a keto-group or a cyclic ether containing from 1 to 4 carbon atoms, and a is 1 or 2.
  • NR1R2 examples are 1-pyrrolidinyl, 3-hydroxy-l-pyrrolidinyl and 3-fluoro-l- pyrrolidinyl.
  • the term 'carbocyclic aromatic group' includes single or fused rings, having 6 to 12 ring carbon atoms, and the term 'heterocyclic aromatic group' includes single or fused rings having 5 to 12 ring atoms, comprising up to four hetero-atoms in the or each ring, selected from oxygen, nitrogen and sulphur.
  • the carbocyclic or heterocyclic group is a fused two ring system, one or both rings may be aromatic in character.
  • one of the rings is aromatic and the other is non-aromatic.
  • the group R preferably has the formula (II):
  • X is a direct bond, or O, S or NRs in which
  • Rg is hydrogen or C ⁇ .Q alkyl
  • Ar is a substituted or unsubstituted carbocyclic or heterocyclic group
  • each of Rg and Rga is C ⁇ .g alkyl, C2-g alkenyl, C2- alkynyl, C ⁇ _g haloalkyl, C I -g haloalkenyl, C2-g haloalkynyl, optionally substituted phenyl or heterocyclyl, optionally substituted phenyl C ⁇ .g alkyl, hydroxy, C ⁇ .
  • Rg or Rga is heterocyclyl, it is preferably an aromatic or non-aromatic single or fused ring system having from 5 to 12 ring atoms, comprising up to 4 hetero-atoms in the or each ring, selected from oxygen, nitrogen and sulphur.
  • Preferred halogens are F, Cl and Br.
  • Rg's When two Rg's are linked they preferably form a fused cyclopentyl or cyclohexyl ring.
  • Ar is phenyl and Rg or Rg a is preferably in the meta- and/or para- position.
  • Ar are naphthyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl,
  • Rg or Rga is bromine, chlorine, CF3, 2-furanyl, 2-pyrryl, 2-thiazolyl, 2-imidazolyl or 2-thienyl, partictdarly, when Ar is phenyl, in the meta and/or para position.
  • X is typically oxygen or a direct bond
  • n is typically 0 or 1.
  • a further preferred group R has the formula (Ha)
  • Rx and Ry are linked together and Rx represents -(Z m )- where m is 0 or 1 and Z is O, S or NR Z where R z is hydrogen or C ⁇ _g alkyl, and Ry represents -(CH2)q- where q is an integer of from 1 to 4, preferably 2 or 3.
  • a preferred sub-group of formula (Ila) is a group of formula (lib)
  • q is 2 when Z is oxygen and m is 1, and q is 3 when m is 0.
  • a further preferred sub-group of formula (Ila) is the group of formula (lie)
  • each of Rx and Ry is Cj.g alkyl, preferably methyl, and the position of -CH2- is as defined in formula (Ha)
  • a further preferred group R has the formula (lid)
  • Het is the remainder of a single aromatic heterocyclic ring, containing from 5 to 6 ring atoms and comprising up to 3 heteroatoms in the ring selected from O, S and N; and R7, X, Y, Z, m and q are as defined in formula (Ila)
  • R are 3,4-dichlorobenzyl or 4- trifluoromethylbenzyl .
  • the compounds of formula (I) or their salts or solvates are preferably in pharmaceutically acceptable or substantially pure form.
  • pharmaceutically acceptable form is meant, inter alia, of a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and including no material considered toxic at normal dosage levels.
  • a substantially pure form will generally contain at least 50% (excluding normal pharmaceutical additives), preferably 75%, more preferably 90% and still more preferably 95% of the compound of formula (I) or its salt or solvate.
  • One preferred pharmaceutically acceptable form is the crystalline form, including such form in a pharmaceutical composition.
  • the additional ionic and solvent moieties must also be non-toxic.
  • Examples of a pharmaceutically acceptable salt of a compound of formula (I) include the acid addition salts with the conventional pharmaceutical acids, for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicyclic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • conventional pharmaceutical acids for example, maleic, hydrochloric, hydrobromic, phosphoric, acetic, fumaric, salicyclic, citric, lactic, mandelic, tartaric, succinic, benzoic, ascorbic and methanesulphonic.
  • Examples of a pharmaceutically acceptable solvate of a compound of formula (I) include the hydrate.
  • the compounds of formula (I) have at least one asymmetric centre and therefore exist in more than one stereoisomeric form.
  • the invention extends to all such forms and to mixtures thereof, including racemates.
  • the present invention also provides a process for the preparation of a compound of formula (I) which comprises treating a compound of formula (III)
  • Suitable active derivatives of RCOOH are acid chlorides or acid anhydrides.
  • Another suitable derivative is a mixed anhydride formed between the acid and an alkyl chloroformate.
  • the compound of formula ( ⁇ i) may be coupled:
  • the compounds of formula (I ) may be converted into their pharmaceutically acceptable acid addition salts by reaction with the appropriate organic or mineral acids.
  • Solvates of the compounds of formula (I) may be formed by crystallization or recrystallization from the appropriate solvent.
  • hydrates may be formed by crystallization or recrystallization from aqueous solutions, or solutions in organic solvents containing water.
  • salts or solvates of the compounds of formula (I) which are not pharmaceutically acceptable may be useful as intermediates in the production of pharmaceutically acceptable salts or solvates. Accordingly such salts or solvates also form part of this invention.
  • the compounds of formula (I) exist in more than one stereoisomeric form and the process of the invention produces mixtures thereof.
  • the individual isomers may be separated one from another by resolution using an optically active acid such as tartaric acid.
  • an asymmetric synthesis would offer a route to the individual form.
  • a compound of formula (VI) is prepared from the known compound (VII) (J. Am. Chem. Soc. 1945, 67, 1711) by reaction with an excess of the appropriate amine in the absence or presence of solvent such as MeOH.
  • Compound (VI) is thereafter treated with a haloacetaldehyde such as chloro acetaldehyde or bromoacetaldehyde in a dioxane/water mixture at a temperature of 90°C for a prolonged period of time (from 8 to 48 hours), and the resulting compound of formula (V) is hydrogenated over a suitable catalyst such as PtO2 or 5% Pt C in the presence of calcium oxide in an appropriate solvent such as ethanol or 2-methoxyethanol.
  • a haloacetaldehyde such as chloro acetaldehyde or bromoacetaldehyde in a dioxane/water mixture at a temperature of 90°C for a prolonged period of time (from 8 to 48 hours
  • a suitable catalyst such as PtO2 or 5% Pt C in the presence of calcium oxide in an appropriate solvent such as ethanol or 2-methoxyethanol.
  • the known compound of formula (XII) (U.S. Patent 4,578,378) is N-protected with an alkylation procedure and the resulting compound of formula -11- (XIII) is treated with a selective reductive agent such as lithium borohydride in refluxing THF to obtain the compound of formula (XIV).
  • This intermediate is activated with methanesulphonyl chloride or p-toluene sulphonyl chloride in dichloromethane as solvent and subsequently treated with the appropriate amine.
  • the resulting compound of formula (XV) is transformed into the corresponding imidoyl chloride by treatment with PCI5 in dichloromethane.
  • the compound of formula (XX) is submitted to a reductive amination procedure with phthalimido acetaldehyde in the presence of an alkali metal hydride such as NaBH4 or NaCNBH3 in a suitable alchoholic solvent.
  • an alkali metal hydride such as NaBH4 or NaCNBH3 in a suitable alchoholic solvent.
  • the obtained compound of formula (XXV) is selectively reduced by hydrogenation over Pt ⁇ 2 in the presence of calcium oxide in a suitable solvent such as 2-methoxyethanol to obtain a compound of formula (XXVI).
  • the compound of general formula (XXIII) can be obtained from a known compound using known methods, for example as described in J. Heterocycl. Chem. 1979, 16(1), 193-4 and in Heterocycles 1984, 22 (2), 299-301.
  • the activity of the compounds of formula (I) in standard tests indicates that they are of potential therapeutic utility in the treatment of pain, cerebral ischaemia, hyponatraemic disease states, convulsions, cough, asthma, inflammation (including inflammation pain) pancreatitis, arrythmias and skin disorders (hereinafter referred to as the Conditions).
  • the present invention also provides a compound of fo ⁇ nula (I), or a pharmaceutically acceptable salt or solvate thereof, for use as an active therapeutic substance.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • the present invention also provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, (hereinafter referred to as the Compounds) in the manufacture of a medicament for the treatment of the Conditions.
  • the present invention also provides a method for the treatment and/or prophylaxis of the Conditions in mammals, particularly humans, which comprises administering to the mammal in need of such treatment and/or prophylaxis an effective amount of the Compound.
  • Medicaments and compositions containing the Compounds may be prepared by admixture of a Compound with an appropriate carrier, which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • an appropriate carrier which may contain a diluent, binder, filler, disintegrant, flavouring agent, colouring agent, lubricant or preservative in conventional manner.
  • a medicament or pharmaceutical composition of the invention is in unit dosage form and in a form adapted for use in the medical or veterinarial fields.
  • preparations may be in a pack form accompanied by written or printed instructions for use as an agent for the treatment of each of the Conditions.
  • the suitable dosage range for a Compound depends on the Compound to be employed, the Condition to be treated, and on the condition of the patient. It will also depend, inter alia, upon the relation of potency to absorbability and the frequency and route of administration.
  • the Compound may be formulated for administration by any route, and is preferably in unit dosage form or in a form that a human patient may administer to himself in a single dosage.
  • the composition is suitable for oral, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may be designed to give slow release of the active ingredient.
  • Compositions may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • compositions may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpy ⁇ olidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable setting agents such as sodium lauryl sulphate.
  • binding agents for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpy ⁇ olidone
  • fillers for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine
  • tabletting lubricants for example magnesium stearate
  • disintegrants for example starch, polyvinylpyrrolidone
  • Solid compositions may be obtained by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers.
  • any carrier suitable for formulating solid pharmaceutical compositions may be used, examples being magnesium stearate, starch, glucose, lactose, sucrose, rice flour and chalk. Tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating.
  • the composition may also be in the form of an ingestible capsule, for example of gelatin containing the compound, if desired with a carrier or other excipients.
  • compositions for oral administration as liquids may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid compositions may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminium stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; aqueous or non-aqueous vehicles, which include edible oils, for example almond oil, fractionated coconut oil, oily esters, for example esters of glycerine, or propylene glycol, or ethyl alcohol, glycerine, water or normal saline; preservatives, for , example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavouring
  • compositions may be formulated, for example, for rectal administration as a suppository or for topical administration as a cream or lotion. They may also be formulated for presentation in an injectable form in an aqueous or non-aqueous solution, suspension or emulsion in a pharmaceutically acceptable liquid, e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • a pharmaceutically acceptable liquid e.g. sterile pyrogen-free water or a parenterally acceptable oil or a mixture of liquids.
  • the liquid may contain bacteriostatic agents, anti-oxidants or other preservatives, buffers or solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Such forms will be presented in unit dose form such as ampoules or disposable injection devices or in multi- dose forms such as a bottle from which the appropriate dose may be withdrawn or a solid form or concentrate which can be used to prepare an inject
  • the Compounds may also be administered by inhalation, via the nasal or oral routes.
  • administration can be carried out with a spray formulation comprising a Compound and a suitable carrier, optionally suspended in, for example, a hydrocarbon propellant.
  • Preferred spray formulations comprise micronised Compound particles in combination with a surfactant, solvent or a dispersing agent to prevent the sedimentation of suspended particles.
  • the Compound particle size is from about 2 to 10 microns.
  • a further mode of administration of the Compounds comprises transdermal delivery utilising a skin-patch formulation.
  • a prefe ⁇ ed formulation comprises a Compound dispersed in a pressure sensitive adhesive which adheres to the skin, thereby permitting the Compound to diffuse from the adhesive through the skin for delivery to the patient.
  • pressure sensitive adhesives known in the art such as natural rubber or silicone can be used.
  • the effective dose of Compound depends on the particular Compound employed, the Condition to be treated, the condition of the patient and on the frequency and route of administration.
  • a unit dose will generally contain from 20 to 1000 mg and preferably will contain from 30 to 500 mg, in particular 50, 100, 150, 200, 250, 300, 350, 400, 450, or 500 mg.
  • the composition may be administered once or more times a day for example 2, 3 or 4 times daily, and the total daily dose for a 70 kg adult will normally be in the range 100 to 3000 mg.
  • the unit dose will contain from 2 to 20mg of active ingredient and be administered in multiples, if desired, to give the preceding daily dose.
  • the kappa receptor affinity of the Compounds may be demonstrated by in vitro binding experiments using a kappa selective radioligand (Sbacchi et al., Excerpta Medica, Vol. 914,211-212, 1990).
  • the diuretic activity of the compounds may be evaluated by measuring the urine volume in normally hydrated or water loaded rats, in agreement with the methods described by J .D. Leander, J. Pharmacol. Exp. Ther., 1983, Vol. 224, 89 and by A.G. Hayes, J. Pharmacol. Exp., 1987, Vol. 240, 984.
  • the activity of the Compounds in treating cerebral ischaemia may be evaluated by using the gerbil model of ischaemic stroke, as described by P. Lysko et al., Stroke, 1992, Vol. 23(3).
  • the analgesic activity of the Compounds may be demonstrated using the p- phenylquinone-induced abdominal constriction test in mice (Siegmund et al, Proe. Soc. Exp. Biol. 95, 729-, 1957, modified by Milne and Twomey, Agents and Actions, 10, 31-, 1980).
  • the effects of the Compounds in protecting against inflammation pain may be demonstrated using the paw pressure test in the monoarthritic rat as described in Eur. J. Pharmacol. 155, 255-264, 1988.
  • the Compounds produce an enhanced analgesic effect in the inflamed paw compared to the non-inflamed paw.
  • the analgesic effect in the inflamed paw is completely reversed by a low intraplantar dose of the opioid antagonist, naloxone, but not by a similar dose of naloxone administered subcutaneously.
  • peripheral analgesic action of Compounds may be obtained by a modification of the abdominal constriction test as described in Br. J. Pharmacol. 73, 325-332, 1981. After administration of PPQ or acetylcholine, intraperitoneal administration of the Compounds produce a decrease in the number of abdominal constrictions.
  • 8-(1-Pyrrolidinylmethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine 2.1 g (9.53 mmoles) of 8-(1-pyrrolidinylcarbonyl)-5,6,7,8-tetra- hydroimidazo[l,2-a]pyrazine were dissolved in 60 ml of dry THF. The solution was warmed to 60°C and 2.8 ml of a 10 M solution of borane dimethylsulfide complex were added dropwise under nitrogen and mechanical stirring.
  • reaction mixture was allowed to reflux for 6 hours, cooled to -10°C, carefully treated with 6N HC1 and warmed again for 3 hours at 70°C.
  • the crude product was purified by silica gel flash column chro atography, eluting with CH 2 Cl 2 /MeOH/28% NH 4 OH, 94:3:0.3 respectively, to yield 1.3 g of the title compound as white crystals from ethyl acetate.
  • Example n° 1 Prepared as described in Example n° 1, starting from 1 g (4.85 mmoles) of the compound of Description n° 4 and 1.2 g (5.40 mmoles) of (4-trifluoromethylphenyl)acetyl chloride in 30 ml of dry CH C1 .
  • the crude product was purified by silica gel flash column chromatography, eluting with a mixture of CH2Cl2/MeOH/28% NH4OH, 86:10:0.6 respectively, to yield 0.4 g of the title compound which was recrystallized from ethyl acetate.
  • Example n° 1 Prepared as described in Example n° 1, starting from 1.5 g (7.24 mmoles) of the compound of Description n° 9 and 1.86 g (8.32 mmoles) of (3 ,4-dichlorophenyl)acetyl chloride in 50 ml of dry CH C1 .
  • the crude product was purified by silica gel flash column chromatography, eluting with CH 2 Cl 2 /MeOH/28% NH 4 OH, 86:12:0.6 respectively, to yield 1.0 g of the title compound.
  • Example n° 1 Prepared as described in Example n° 1, from 1.5 g (7.24 mmoles) of the compound of Description n° 9 and 1.85 g (8.32 mmoles) of (4-trifluoromethylphenyl)acetyl chloride in 50 ml of dry CH2CI2.
  • the crude product was purified by silica gel flash column chromatography, eluting with CH 2 Cl 2 /MeOH/28% NH 4 OH, 86:15:0.7 respectively, to yield 1.2 g of the pure free base which was transformed into the dihydrochloride salt recrystallized from EtOAc/acetone.

Abstract

Dérivés azacycliques répondant à la formule (I), dans laquelle X et Y, indépendamment l'un de l'autre, représentent CH ou N; RCO représente un groupe acyle dans lequel le groupe R renferme un cycle aromatique carbocyclique, ou aromatique hétérocyclique éventuellement substitué; R1 et R2, identiques ou différents, représentent alkyle C1-6 éventuellement substitué par l'un au moins des éléments suivants: halogène, hydroxy, alcoxy C1-6, acyloxy, thiol, alkylthio C1-6, acylthio, haloalcoxy C1-6, CORh, COORh, CONHRh ou NCHORh où Rh représente hydrogène ou alkyle C1-6; ou R1 et R2, représentent chacun hydrogène, alcényle C2-6, cycloalkyle C3-6 ou cycloalkylalkyle C4-12; ou bien R1 et R2, pris ensemble, forment un groupe alcénylène C2-6 ou polyméthylène linéaire ou ramifié C2-8 éventuellement substitué. Ces dérivés sont des antagonistes des récepteurs kappa, et ils sont utilisables dans le traitement des algies, des convulsions, de la toux, de l'asthme, de l'inflammation, de la pancréatite, des arythmies, des états pathologiques hyponatrémiques, de l'ischémie cérébrale ou des affections cutanées.
PCT/EP1995/000345 1994-02-11 1995-01-31 Derives azacycliques WO1995021843A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP07520934A JP3135577B2 (ja) 1994-02-11 1995-01-31 アザ環式誘導体
EP95908236A EP0743944A1 (fr) 1994-02-11 1995-01-31 Derives azacycliques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI94A000238 1994-02-11
ITMI940238A IT1273751B (it) 1994-02-11 1994-02-11 Derivati azaciclici

Publications (1)

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WO1995021843A1 true WO1995021843A1 (fr) 1995-08-17

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IT (1) IT1273751B (fr)
WO (1) WO1995021843A1 (fr)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998023290A1 (fr) * 1996-11-25 1998-06-04 Toray Industries, Inc. Agent antiprurigineux
US6387924B2 (en) 1994-09-13 2002-05-14 G.D. Searle & Co. Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6420417B1 (en) 1994-09-13 2002-07-16 G. D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors
US6458851B1 (en) 1998-12-23 2002-10-01 G. D. Searle, Llc Combinations of ileal bile acid transport inhibitors and cholesteryl ester transfer protein inhibitors for cardiovascular indications
US6458850B1 (en) 1998-12-23 2002-10-01 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications
US6462091B1 (en) 1998-12-23 2002-10-08 G.D. Searle & Co. Combinations of cholesteryl ester transfer protein inhibitors and HMG coA reductase inhibitors for cardiovascular indications
US6489366B1 (en) 1998-12-23 2002-12-03 G. D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
US6562860B1 (en) 1998-12-23 2003-05-13 G. D. Searle & Co. Combinations of ileal bile acid transport inhibitors and bile acid sequestering agents for cardiovascular indications
US6569905B1 (en) 1998-12-23 2003-05-27 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and bile acid sequestering agents for cardiovascular indications
US6586434B2 (en) 2000-03-10 2003-07-01 G.D. Searle, Llc Method for the preparation of tetrahydrobenzothiepines
US6638969B1 (en) 1998-12-23 2003-10-28 G.D. Searle, Llc Combinations of ileal bile acid transport inhibitors and fibric acid derivatives for cardiovascular indications
US6642268B2 (en) 1994-09-13 2003-11-04 G.D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors
US6740663B2 (en) 2001-11-02 2004-05-25 G.D. Searle, Llc Mono- and di-fluorinated benzothiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
US6852753B2 (en) 2002-01-17 2005-02-08 Pharmacia Corporation Alkyl/aryl hydroxy or keto thiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
US7709468B2 (en) 2005-09-02 2010-05-04 Abbott Laboratories Imidazo based heterocycles

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3080088B2 (ja) 1999-02-01 2000-08-21 ミノルタ株式会社 電子写真感光体
JP2001034003A (ja) 1999-07-19 2001-02-09 Minolta Co Ltd 電子写真感光体

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EP0330469A2 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Dérivés de la tétrahydroisoquinoléine
EP0343900A2 (fr) * 1988-05-23 1989-11-29 Glaxo Group Limited Composés pipéraziniques
EP0356247A1 (fr) * 1988-08-24 1990-02-28 Sankyo Company Limited Dérivés analgésiques des amides d'acides carboxyliques
EP0366327A1 (fr) * 1988-10-18 1990-05-02 Glaxo Group Limited Furo- et thiéno[3,2-c]pyridines et compositions pharmaceutiques les contenant
EP0398720A2 (fr) * 1989-05-18 1990-11-22 Glaxo Group Limited Dérivés de pipérazine

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Publication number Priority date Publication date Assignee Title
EP0330469A2 (fr) * 1988-02-23 1989-08-30 Glaxo Group Limited Dérivés de la tétrahydroisoquinoléine
EP0343900A2 (fr) * 1988-05-23 1989-11-29 Glaxo Group Limited Composés pipéraziniques
EP0356247A1 (fr) * 1988-08-24 1990-02-28 Sankyo Company Limited Dérivés analgésiques des amides d'acides carboxyliques
EP0366327A1 (fr) * 1988-10-18 1990-05-02 Glaxo Group Limited Furo- et thiéno[3,2-c]pyridines et compositions pharmaceutiques les contenant
EP0398720A2 (fr) * 1989-05-18 1990-11-22 Glaxo Group Limited Dérivés de pipérazine

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6387924B2 (en) 1994-09-13 2002-05-14 G.D. Searle & Co. Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6420417B1 (en) 1994-09-13 2002-07-16 G. D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothiepines and HMG Co-A reductase inhibitors
US6784201B2 (en) 1994-09-13 2004-08-31 G.D. Searle & Company Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake
US6642268B2 (en) 1994-09-13 2003-11-04 G.D. Searle & Co. Combination therapy employing ileal bile acid transport inhibiting benzothipines and HMG Co-A reductase inhibitors
WO1998023290A1 (fr) * 1996-11-25 1998-06-04 Toray Industries, Inc. Agent antiprurigineux
US6174891B1 (en) 1996-11-25 2001-01-16 Toray Industries, Inc. Antipruritic agent
US6316461B1 (en) 1996-11-25 2001-11-13 Toray Industries, Inc. Antipruritic
US6489366B1 (en) 1998-12-23 2002-12-03 G. D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
US6462091B1 (en) 1998-12-23 2002-10-08 G.D. Searle & Co. Combinations of cholesteryl ester transfer protein inhibitors and HMG coA reductase inhibitors for cardiovascular indications
US6562860B1 (en) 1998-12-23 2003-05-13 G. D. Searle & Co. Combinations of ileal bile acid transport inhibitors and bile acid sequestering agents for cardiovascular indications
US6569905B1 (en) 1998-12-23 2003-05-27 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and bile acid sequestering agents for cardiovascular indications
US6638969B1 (en) 1998-12-23 2003-10-28 G.D. Searle, Llc Combinations of ileal bile acid transport inhibitors and fibric acid derivatives for cardiovascular indications
US6458850B1 (en) 1998-12-23 2002-10-01 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and fibric acid derivatives for cardiovascular indications
US6458851B1 (en) 1998-12-23 2002-10-01 G. D. Searle, Llc Combinations of ileal bile acid transport inhibitors and cholesteryl ester transfer protein inhibitors for cardiovascular indications
US6890958B2 (en) 1998-12-23 2005-05-10 G.D. Searle, Llc Combinations of cholesteryl ester transfer protein inhibitors and nicotinic acid derivatives for cardiovascular indications
US6586434B2 (en) 2000-03-10 2003-07-01 G.D. Searle, Llc Method for the preparation of tetrahydrobenzothiepines
US6740663B2 (en) 2001-11-02 2004-05-25 G.D. Searle, Llc Mono- and di-fluorinated benzothiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
US6852753B2 (en) 2002-01-17 2005-02-08 Pharmacia Corporation Alkyl/aryl hydroxy or keto thiepine compounds as inhibitors of apical sodium co-dependent bile acid transport (ASBT) and taurocholate uptake
US7709468B2 (en) 2005-09-02 2010-05-04 Abbott Laboratories Imidazo based heterocycles

Also Published As

Publication number Publication date
EP0743944A1 (fr) 1996-11-27
ITMI940238A0 (it) 1994-02-11
IT1273751B (it) 1997-07-10
ITMI940238A1 (it) 1995-08-11
JPH09508635A (ja) 1997-09-02
JP3135577B2 (ja) 2001-02-19

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