EP0820442A1 - Novel heterocyclic compounds - Google Patents

Novel heterocyclic compounds

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Publication number
EP0820442A1
EP0820442A1 EP96909088A EP96909088A EP0820442A1 EP 0820442 A1 EP0820442 A1 EP 0820442A1 EP 96909088 A EP96909088 A EP 96909088A EP 96909088 A EP96909088 A EP 96909088A EP 0820442 A1 EP0820442 A1 EP 0820442A1
Authority
EP
European Patent Office
Prior art keywords
dibenzo
yloxy
ethyl
cyclohepten
dihydro
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.)
Ceased
Application number
EP96909088A
Other languages
German (de)
French (fr)
Inventor
Knud Erik Andersen
Uffe Bang Olsen
Henrik Sune Andersen
Rolf Hohlweg
Tine Krogh Joergensen
Peter Madsen
Polivka Zdenek
Silhánková ALEXANDRA
Sindelár KAREL
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.)
Novo Nordisk AS
Original Assignee
Novo Nordisk AS
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Filing date
Publication date
Application filed by Novo Nordisk AS filed Critical Novo Nordisk AS
Publication of EP0820442A1 publication Critical patent/EP0820442A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • 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
    • 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
    • C07D203/00—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D203/04—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D203/06—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D203/08—Heterocyclic compounds containing three-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
    • C07D203/10—Radicals substituted by singly bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/52—Oxygen atoms attached in position 4 having an aryl radical as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/15—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/30—Ortho- or ortho- and peri-condensed systems containing three rings containing seven-membered rings
    • C07C2603/32—Dibenzocycloheptenes; Hydrogenated dibenzocycloheptenes

Definitions

  • the present invention relates to novel N-substituted azaheterocyclic carbox- ylic acids and esters thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation.
  • the invention also relates to the use of the present compounds for the treatment of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) or aging, the present compounds knowing to interfere with neuropeptide con ⁇ taining C-fibres and hence inhibit the secretion and circulation of insulin an ⁇ tagonizing peptides like CGRP or amylin.
  • NIDDM non-insulin-dependent diabetes mellitus
  • the nervous system exerts a profound effect on the inflammatory response.
  • Antidromic stimulation of sensory nerves results in localized 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 postu- lated that peptides released from sensory nerve endings mediate many inflammatory responses in tissues like skin, joint, urinary tract, eye, menin- ges, 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 glycolytic and oxidative pathways (Rossetti et al. Am. J. Physiol. 264.
  • 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 condi ⁇ tions like NIDDM or aging-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995) where circulating plasma levels of CGRP are markedly increased. Hence inhibition of release and/or activity of the neuropeptide CGRP may be useful in the treatment of insulin resistance related to type 2 diabetes or aging.
  • the present invention relates to novel N-substituted azaheterocyclic carbo ⁇ xylic acids and esters thereof of formula I
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 independently are hydrogen, halogen, trifluoromethyl, hydroxy, -NR 7 R 8 or -SO 2 NR 7 R 8 wherein
  • R 7 and R 8 independently are hydrogen or C-.g-alkyl
  • Y is -O-, -S ⁇ O) q - wherein q is 0, 1 or 2, or -N(R 10 )- wherein R 10 is hydrogen or r is 1 , 2, 3 or 4;
  • n 1 or 2;
  • R 11 is -(CH 2 ) m OH or -(CH 2 ) t COR 12 wherein m is 0, 1 , 2, 3, 4, 5 or 6 and t is 0 or 1 and wherein R 12 is -OH, -NH 2 , -NHOH or C-. 6 -alkoxy; and R 3 is hydrogen, halogen, trifluoromethyl, hydroxy, or C-. g -alkoxy; and
  • R 14 is hydrogen, C.. ⁇ -alkyl, C ⁇ -alkoxy or phenyl optionally substituted with halogen, trifluoromethyl, hydroxy, C ⁇ -alkyl or C ⁇ -alkoxy; and R 15 is hydrogen or C ⁇ -alk ⁇ l; and a , is optionally a single bond or a double bond; or a pharmaceutically acceptable salt thereof.
  • the compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separ ⁇ ated by means of standard methods such as chromatographic techniques or fractional crystallization 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 pharma ⁇ ceutically acceptable acid addition salts or - when the carboxylic acid group is not esterified - as pharmaceutically acceptable metal salts or - optionally alkylated - ammonium salts.
  • salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically accept ⁇ able inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 ( 1977) which are hereby incorporated by reference.
  • C.. 6 -alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g.
  • C-.g-alkoxy refers to a straight or branched monovalent substituent comprising a C-. ⁇ -alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
  • halogen means fluorine, chlorine, bromine or iodine.
  • the term "patient” includes any mammal which could benefit from treatment of neurogenic pain or inflammation or insulin resistance in NIDDM.
  • the term particularly refers to a human patient, but is not intended to be so limited.
  • novel compounds of formula I inhibit neurogenic inflammation which involves the release of neuropeptides from peripheral and central endings of sensory C-fibres.
  • this can be demonstrated in animal models of formalin induced pain or paw oedema (Wheeler and Cowan, Agents Actions 1991 , 34, 264-269) 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-fibers 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 exemp ⁇ lified by various types of neuropathy (diabetic, post-traumatic, toxic), neural ⁇ gia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, chronic pancreatitis, inflammatory skin disease including psoriasis and autoimmune dermatoses, osteoporotic pain.
  • Acutely painful conditions exemplified by migraine, postoperative pain, burns, bruises, post-herpetic pain (Zoster) and
  • the compounds of general formula I improves the glucose tolerance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous endings.
  • the compounds of general formula I may be used in the treatment of NIDDM as well as aging-associated obesity.
  • this has been demonstrated by the subcutaneous administration of glucose into ob/ob mice with or without previous oral treatment with a compound of general formula 8
  • the compounds of formula I may be prepared by the following method:
  • a compound of formula II wherein R ⁇ R 2 , R 3 , R ⁇ R 5 , R ⁇ , X, Y and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an azaheterocyclic compound of formula III wherein Z is as defined above.
  • This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) or toluene in the presence of a base e.g. sodium hydride and a catalyst, e.g.
  • esters have been prepared in which R 12 is alkoxy
  • compounds of formula I wherein R 12 is OH may be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h.
  • mice About 20 g NMRI female mice were injected 20 ⁇ 1 % formalin into the left hind paw. The animals were then placed on a heated (31 °C) table, and the pain response was scored. After 1 h they were killed and bled. Left and right hind paws were removed and the weight difference between the paws was used as indication of the oedema response of the formalin injected paw.
  • mice 16 weeks of age, where injected glucose (2g/kg) subcutane- ously.
  • blood glucose was determined in tail venous blood by the glucose oxidase method.
  • the animals were decapita ⁇ ted and trunck blood collected.
  • 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.
  • dosages suitable for oral 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 pharmaceutical carrier or diluent.
  • the compounds of formula I may be administered in a pharmaceutically accept ⁇ able acid addition salt form or where possible as a metal or a lower alkylammo- nium salt.
  • Such salt forms exhibit approximately the same order of activity as the free base forms.
  • compositions comprising a com ⁇ pound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent.
  • the composi- tions containing the compounds of this invention may be prepared by conven ⁇ tional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
  • the pharmaceutical carrier employed may be a conventional solid or liquid carrier.
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid.
  • liquid carriers are syrup, peanut oil, olive oil and water.
  • the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the preparation can 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.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • the prepara ⁇ tion 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 compounds of this invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceuti ⁇ cally acceptable carrier per unit dosage.
  • the dosage of the compounds according to this invention is 1 -500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
  • a typical tablet which may be prepared by conventional tabletting techniques contains
  • Active compound (as free compound 100 mg or salt thereof)
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • TLC thin layer chromatography and THF is tetrahydrofuran
  • CDCI 3 is deuterio chloroform
  • DMSO-d ⁇ is 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.
  • ⁇ -NMR shifts (_> H ) are given in parts per million (ppm).
  • M.p. 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 com ⁇ pounds which can readily be prepared by methods known _e ⁇ se.

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  • Neurosurgery (AREA)
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  • Biomedical Technology (AREA)
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  • Emergency Medicine (AREA)
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  • Obesity (AREA)
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  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A compound of formula (I), in which Z is selected from (a), (b), (c), (d), (e), (f), (g), (h), (i), (j) and (k). The present invention relates to novel N-substituted azaheterocyclic carboxylic acids and esters thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation.

Description

Novel heterocvclic Compounds
Field of the Invention
The present invention relates to novel N-substituted azaheterocyclic carbox- ylic acids and esters thereof in which a substituted alkyl chain forms part of the N-substituent or salts thereof, to methods for their preparation, to compositions containing them, and to their use for the clinical treatment of painful, hyperalgesic and/or inflammatory conditions in which C-fibers play a pathophysiological role by eliciting neurogenic pain or inflammation. The invention also relates to the use of the present compounds for the treatment of insulin resistance in non-insulin-dependent diabetes mellitus (NIDDM) or aging, the present compounds knowing to interfere with neuropeptide con¬ taining C-fibres and hence inhibit the secretion and circulation of insulin an¬ tagonizing peptides like CGRP or amylin.
Background of the Invention
The nervous system exerts a profound effect on the inflammatory response. Antidromic stimulation of sensory nerves results in localized 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 postu- lated that peptides released from sensory nerve endings mediate many inflammatory responses in tissues like skin, joint, urinary tract, eye, menin- ges, gastro-intestinal and respiratory tracts. Hence 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. Further, the potent effects of CGRP on skeletal muscle glycogen synthase ac¬ tivity and muscle glucose metabolism, together with the notion that this peptide is released from the neuromuscular junction by nerve excitation, suggest that CGRP may play a physiological role in skeletal muscle glucose metabolism by directing the phosphorylated glucose away from glycogen storage and into the glycolytic 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 condi¬ tions like NIDDM or aging-associated obesity (Melnyk et al. Obesity Res. 3, 337-344, 1995) where circulating plasma levels of CGRP are markedly increased. Hence inhibition of release and/or activity of the neuropeptide CGRP may be useful in the treatment of insulin resistance related to type 2 diabetes or aging.
In US Patent No. 4,383,999 and No. 4,514,414 and in EP 236342 as well as in EP 231996 some derivatives of N-(4,4-disubstituted-3-butenyl)- azaheterocyclic carboxylic acids are claimed as inhibitors of GABA uptake. In EP 342635 and EP 374801 , N-substituted azaheterocyclic carboxylic acids in which an oxime ether group and vinyl ether group forms part of the N- substituent respectively are claimed as inhibitors of GABA uptake. Further, in WO 9107389 and WO 9220658, N-substituted azacyclic carboxylic acids are claimed as GABA uptake inhibitors. EP 221572 claims that 1 -aryloxyalkyl- pyridine-3-carboxylic acids are inhibitors of GABA uptake.
Description of the Invention
The present invention relates to novel N-substituted azaheterocyclic carbo¬ xylic acids and esters thereof of formula I
wherein R1, R2, R3, R4, R5 and R6 independently are hydrogen, halogen, trifluoromethyl, hydroxy, -NR7R8 or -SO2NR7R8 wherein
R7 and R8 independently are hydrogen or C-.g-alkyl; and
X is completion of an optional bond, -CH2-, -CH2CH2-, -CH = CH-, -O-,
-S(O)2- wherein z is 0, 1 or 2, or -N(R9)- wherein R9 is hydrogen or C-.β-alkyl; and
Y is -O-, -S{O)q- wherein q is 0, 1 or 2, or -N(R10)- wherein R10 is hydrogen or r is 1 , 2, 3 or 4; and
Z is selected from
wherein n is 1 or 2; and
R11 is -(CH2)mOH or -(CH2)tCOR12 wherein m is 0, 1 , 2, 3, 4, 5 or 6 and t is 0 or 1 and wherein R12 is -OH, -NH2, -NHOH or C-.6-alkoxy; and R 3 is hydrogen, halogen, trifluoromethyl, hydroxy, or C-.g-alkoxy; and
R14 is hydrogen, C..β-alkyl, C^-alkoxy or phenyl optionally substituted with halogen, trifluoromethyl, hydroxy, C^-alkyl or C^-alkoxy; and R15 is hydrogen or C β-alkγl; and a, is optionally a single bond or a double bond; or a pharmaceutically acceptable salt thereof.
The compounds of formula I may exist as geometric and optical isomers and all isomers and mixtures thereof are included herein. Isomers may be separ¬ ated by means of standard methods such as chromatographic techniques or fractional crystallization of suitable salts.
Preferably, the compounds of formula I exist as the individual geometric or optical isomers.
The compounds according to the invention may optionally exist as pharma¬ ceutically acceptable acid addition salts or - when the carboxylic acid group is not esterified - as pharmaceutically acceptable metal salts or - optionally alkylated - ammonium salts.
Examples of such salts include inorganic and organic acid addition salts such as hydrochloride, hydrobromide, sulphate, phosphate, acetate, fumarate, maleate, citrate, lactate, tartrate, oxalate or similar pharmaceutically accept¬ able inorganic or organic acid addition salts, and include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 ( 1977) which are hereby incorporated by reference. The term "C..6-alkyl" as used herein, alone or in combination, refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 4- methylpentyl, neopentyl, n-hexyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl and 1 ,2,2-trimethylpropyl.
The term "C-.g-alkoxy" as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a C-.β-alkyl group linked through an ether oxygen having its free valence bond from the ether oxygen and having 1 to 6 carbon atoms e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy.
The term "halogen" means fluorine, chlorine, bromine or iodine.
Illustrative examples of compounds encompassed by the present invention include:
1 -(2-.10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3- piperidinecarboxamide;
1 -(2-(10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4- piperidinecarboxyiic acid;
1 -(2-(10,1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2- piperidinecarboxylic acid;
(1 -(2-(10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)piperidin-3- yUmethanol;
4-(4-Chlorophenyl)-1-(2-(10,1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)- ethyl)-4-piperidinol;
4-(2-{10,11-Dihydro-5H-dibenzo[a,d_cyclohepten-5-yloxy)ethyl)-4- piperazinecarboxylic acid;
(2S,4R)-1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4- hydroxγ-2-pyrrolidinecarboxylic acid;
4-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-morpholine- carboxyiic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d.cyclohepten-5-yloxy)ethyl)-2- aziridinecarboxylic acid;
2-(2-(10,11-Dihydro-5H-dibenzo[a,d_cyclohepten-5-yloxy)ethyl)-1, 2,3,4- tetrahydro-4-isoquinolinecarboxylic acid;
1-(2-(10,11-Dihγdro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-methyl-1,4- diazepane-6-carboxylic acid;
2-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-1, 2,3,4- tetrahydro-3-isoquinolinecarboxylic acid;
1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3-piperidine- carboxylic acid hydroxamide;
(4-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)piperazin-1- yDacetic acid;
or a pharmaceutically acceptable salt thereof. As used herein, the term "patient" includes any mammal which could benefit from treatment of neurogenic pain or inflammation or insulin resistance in NIDDM. The term particularly refers to a human patient, but is not intended to be so limited.
It has been demonstrated that the 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 formalin induced pain or paw oedema (Wheeler and Cowan, Agents Actions 1991 , 34, 264-269) 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-fibers 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 exemp¬ lified by various types of neuropathy (diabetic, post-traumatic, toxic), neural¬ gia, rheumatoid arthritis, spondylitis, gout, inflammatory bowel disease, prostatitis, cancer pain, chronic headache, coughing, asthma, chronic pancreatitis, inflammatory skin disease including psoriasis and autoimmune dermatoses, osteoporotic pain.
Further, it has been demonstrated that the compounds of general formula I improves the glucose tolerance in diabetic ob/ob mice and that this may result from the reduced release of CGRP from peripheral nervous endings. Hence the compounds of general formula I may be used in the treatment of NIDDM as well as aging-associated obesity. Experimentally this has been demonstrated by the subcutaneous administration of glucose into ob/ob mice with or without previous oral treatment with a compound of general formula 8
The compounds of formula I may be prepared by the following method:
(II)
A compound of formula II wherein R\ R2, R3, R\ R5, Rβ, X, Y and r are as defined above and W is a suitable leaving group such as halogen, p-toluene sulphonate or mesylate may be reacted with an azaheterocyclic compound of formula III wherein Z is as defined above. This alkylation reaction may be carried out in a solvent such as acetone, dibutylether, 2-butanone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran (THF) 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. If esters have been prepared in which R12 is alkoxy, compounds of formula I wherein R12 is OH may be prepared by hydrolysis of the ester group, preferably at room temperature in a mixture of an aqueous alkali metal hydroxide solution and an alcohol such as methanol or ethanol, for example, for about 0.5 to 6 h.
Compounds of formula II and III may readily be prepared by methods familiar to those skilled in the art.
Under certain circumstances it may be necessary to protect the intermediates used in the above methods e.g. a compound of formula III with suitable protecting groups. The carboxylic acid group can, for example, be esterified. Introduction and removal of such groups is described in "Protective Groups in Organic Chemistry" J.F.W. McOrnie ed. (New York, 1973). Pharmacological Methods
Release of neurooeptides from pheripheral and central endings of sensory
C-fibers
Values for ]n vivo inhibition of formalin induced pain or oedema for the com- pounds of the present invention were assessed in mice essentially by the method of Wheeler-Aceto and Cowan (Agents Action 1991 , 34, 265-269).
About 20 g NMRI female mice were injected 20 μ\ 1 % formalin into the left hind paw. The animals were then placed on a heated (31 °C) table, and the pain response was scored. After 1 h they were killed and bled. Left and right hind paws were removed and the weight difference between the paws was used as indication of the oedema response of the formalin injected paw.
Reduced release of CGRP from pheripheral nervous endings
ob/ob female mice, 16 weeks of age, where injected glucose (2g/kg) subcutane- ously. At times hereafter blood glucose was determined in tail venous blood by the glucose oxidase method. At the end of the study the animals were decapita¬ ted and trunck blood collected. 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.
For the above indications the dosage will vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired. However, in general, satisfactory results are obtained with a dosage of from about 0.5 mg to about 1000 mg, preferably from about 1 mg to about 500 mg of compounds of formula I, conveniently given from 1 to 5 times daily, optionally in sustained release form. Usually, dosage forms suitable for oral 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 pharmaceutical carrier or diluent.
The compounds of formula I may be administered in a pharmaceutically accept¬ able acid addition salt form or where possible as a metal or a lower alkylammo- nium salt. Such salt forms exhibit approximately the same order of activity as the free base forms.
This invention also relates to pharmaceutical compositions comprising a com¬ pound of formula I or a pharmaceutically acceptable salt thereof and, usually, such compositions also contain a pharmaceutical carrier or diluent. The composi- tions containing the compounds of this invention may be prepared by conven¬ tional techniques and appear in conventional forms, for example capsules, tablets, solutions or suspensions.
The pharmaceutical carrier employed may be a conventional solid or liquid carrier. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Examples of liquid carriers are syrup, peanut oil, olive oil and water.
Similarly, the carrier or diluent may include any time delay material known to the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
If a solid carrier for oral administration is used, the preparation can 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. The amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g. If a liquid carrier is used, the prepara¬ tion 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. Generally, the compounds of this invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient in or together with a pharmaceuti¬ cally acceptable carrier per unit dosage.
The dosage of the compounds according to this invention is 1 -500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
A typical tablet which may be prepared by conventional tabletting techniques contains
Core:
Active compound (as free compound 100 mg or salt thereof)
Colloidal silicon dioxide (Areosif) 1.5 mg
Cellulose, microcryst. (Avicef*) 70 mg
Modified cellulose gum (Ac-Di-Sol*) 7.5 mg
Magnesium stearate
Coating:
HPMC approx. 9 mg
"Mywacett* 9-40 T approx. 0.9 mg
"Acylated monoglyceride used as plasticizer for film coating.
The route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
EXAMPLES The process for preparing compounds of formula I and preparations containing them is further illustrated in the following examples, which, however, are not to be construed as limiting.
Hereinafter, TLC is thin layer chromatography and THF is tetrahydrofuran, CDCI3 is deuterio chloroform and DMSO-dβ is 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. ^-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 com¬ pounds which can readily be prepared by methods known _eτ se.
EXAMPLE 1
1 -(2-{10,1 1 -Dihydro-5H-dibenzo_a,d]cyclohepten-5-yloxy)-1 -ethyl)-4-piperidine- carboxylic acid hydrochloride
A mixture of 10,1 1 -dihydro-5H-dibenzo[a,d]cyclohepten-5-ol (10.0 g, 0.047 mol), 2-bromoethanol (8.6 g, 0.069 mol) and concentrated sulphuric acid (1 .4 ml) in benzene (120 ml) was stirred for 0.5 h at room temperature. After cooling (water/ice), crude 5-(2-bromoethoxy-10,1 1 -dihydro-5H-dibenzo[a,d]cyclohepten was filtered off, washed with petroleum ether and dried. This afforded 10.7 g (72 %), which was used without purification for further reaction.
M.p. 62 - 70 °C.
A mixture of 5-(2-bromoethoxy)-10,1 1 -dihydro-5H-dibenzo[a,d]cycloheptene (9.5 g, 0.03 mol), ethyl 4-piperidinecarboxylate (4.7 g, 0.03 mol), potassium carbonate (8.1 g, 0.06 mol) and dimethylsulfoxide (120 ml) was stirred on a water bath at 40 - 50°C for 4 h. The mixture was cooled, filtered and the solid was washed with dimethylsulfoxide (10 ml). The combined filtrates were diluted with water (720 ml) and extracted with diethyl ether (2 x 200 ml). The ether extract was washed with water, dried (MgSO4), and the solvent was evaporated under vacuum. The residue was dissolved in 2-propanol, and a hot solution of oxalic acid (4.0 g) in 2-propanol was added. After cooling, crystals of ethyl 1 -(10, 1 1 dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)-1 -ethyl-4-piperidinecar- boxylate hydrogen oxalate precipitated. This afforded after filtration and drying 8.3 g (57 %), which was used for further reaction without purification.
The above oxalate suspension (7.3 g, 0.015 mol) in water was made alkaline with a 25 % ammonia solution and extracted with diethyl ether (2 x 100 ml).
The organic layer was washed with water (2 x 50 ml), dried (MgSO4 ) and evaporated in vacuum. This afforded 5.7 g (96 %) of free ethyl ester as an oil.
A mixture of the above ester 2.01 g (0.005 mol), 2.4 ml 20 % aqueous sodium hydroxide and ethanol (15 ml) was stirred at room temperature for 4 h and overnight. Dichloromethane (250 ml) was added, and under magnetic stirring and cooling (water/ice bath), ~ 2.5 N HCI was carefully added dropwise to pH 1 . The water layer was separated, and the organic layer was dried (MgSO4) and evaporated under vacuum. The solid residue was re-evaporated twice with acetone. This afforded 1.68 g (83 %) the title compound after crystallisation from a mixture of ethanol and ether. Dichloromethane, which was present in the crystalline sample was removed under vacuum at elevated temperature.
M.p.1 ?2 -194°C.
'H NMR (DMSO-dβ): 7.42 (bd, 2 H); 7.19 (m, 6 H); 5.62 (s, 1 H); 3.83 (t, 2 H); 3.28 (t, 1 H); 4.96 (d, 1 H); 2.53 (m, 1 H); 3.37 (m, 6 H); 3.00 (m, 4 H); 1.99 (m, 4H).

Claims

1 . A compound of formula I
wherein R\ R2, R3, R4, R5 and Rβ independently are hydrogen, halogen, trifluoro¬ methyl, hydroxy, C^β-alkyl, C,.β-alkoxy, -NR7R8 or -SO2NR7R8 wherein R7 and R8 independently are hydrogen or C^β-alkyl; and
X is completion of an optional bond, -CH2-, -CH2CH2-, -CH = CH-, -O-, -S(O)2- wherein z is 0, 1 or 2, or -N(R9)- wherein R9 is hydrogen or C β-alkyl; and Y is -O-, -S(O)q- wherein q is 0, 1 or 2, or -N(R10)- wherein R10 is hydrogen or C β-alkyl; and r is 1 , 2, 3 or 4; and Z is selected from
wherein n is 1 or 2; and
R11 is -(CH2)mOH or -(CH2)tCOR12 wherein m is 0, 1 , 2, 3, 4, 5 or 6 and t is 0 or 1 and wherein R12 is -OH, -NH2, -NHOH or C-.6-alkoxy; and R13 is hydrogen, halogen, trifluoromethyl, hydroxy, C^-alkyl or C..6-alkoxy; and R14 is hydrogen, C β-alkyl, C^e-alkoxy or phenyl optionally substituted with halogen, trifluoromethyl, hydroxy, C-.g-alkyl or C..6-alkoxy; and R1S is hydrogen or C-.g-alkyl; and j_. is optionally a single bond or a double bond; or a pharmaceutically acceptable salt thereof.
2_ A compound according to claim 1 selected from the following:
1-.2-.10, 11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3- piperidinecarboxamide;
1 -(2- (10,11 -Dihγdro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4- piperidinecarboxylic acid;
1-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclo he pten-5-yloxy) ethyl )-2- piperidinecarboxylic acid;
(1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)piperidin-3- yDmethanol;
4-(4-Chlorophenyl)-1-(2-(10,11 -Dihydro-5H-dibenzo[a,d]cyclohepten-5- yloxy)ethyl)-4-piperidinol;
4-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4- piperazinecarboxylic acid;
(2S,4R)-1-(2-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyi)-4- hydroxy-2-pyrrolidinecarboxylic acid;
4-(2-(10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2-morpholinecar- boxylic acid;
1 -(2-(10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-2- aziridinecarboxylic acid;
2-(2-( 1 0, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-1 ,2,3,4- tetrahydro-4-isoquinolinecarboxylic acid;
1 -(2-(10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-4-methyl-1 ,4- diazepane-6-carboxylic acid;
2-(2-( 10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-1 ,2,3,4- tetrahydro-3-isoquinolinecarboxylic acid;
1-(2-(10,1 1-Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)-3-piperidinecar- boxylic acid hydroxamide;
(4-(2-(10, 1 1 -Dihydro-5H-dibenzo[a,d]cyclohepten-5-yloxy)ethyl)piperazin-1 - yDacetic acid;
or a pharmaceutically acceptable salt thereof.
3^ A method of preparing a compound according to claim 1 ,
CHARACTERIZED in
a) reacting a compound of formula II wherein R1 , R2, R3, R4, R5, R6, X, Y and r are as defined above and W is a suit¬ able leaving group such as halogen, p-toluene sulphonate or mesylate, with a compound of formula III
HZ (III)
wherein Z is as defined above to form a compound of formula I; or
b) hydrolyzing a compound of formula I, wherein R12 is to form a compound of formula I wherein R12 is OH.
4_ A pharmaceutical composition comprising as active component a compound according to claim 1 together with a pharmaceutically carrier or diluent.
5__ A pharmaceutical composition suitable for treating neurogenic inflammation comprising an effective amount of a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent.
6_i The pharmaceutical composition according to claim 4 or 5 comprising between 0.5 mg and 1000 mg of the compound according to claim 1 per unit dose.
7. A method of treating neurogenic inflammation in a subject in need of such treatment comprising administering to said subject an effective amount of a compound according to claim 1 .
8^. A method of treating neurogenic inflammation in a subject in need of such treatment comprising administering to said subject a pharmaceutical composition according to claim 5.
9_i The use of a compound according to claim 1 for preparing a medic¬ ament for treatment of neurogenic inflammation.
EP96909088A 1995-04-07 1996-04-01 Novel heterocyclic compounds Ceased EP0820442A1 (en)

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