WO1996031483A1 - Nouveaux composes heterocycliques - Google Patents

Nouveaux composes heterocycliques Download PDF

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Publication number
WO1996031483A1
WO1996031483A1 PCT/DK1996/000156 DK9600156W WO9631483A1 WO 1996031483 A1 WO1996031483 A1 WO 1996031483A1 DK 9600156 W DK9600156 W DK 9600156W WO 9631483 A1 WO9631483 A1 WO 9631483A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
alkyl
hydrogen
alkoxy
Prior art date
Application number
PCT/DK1996/000156
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English (en)
Inventor
Knud Erik Andersen
Uffe Bang Olsen
Henrik Sune Andersen
Rolf Hohlweg
Tine Krogh JØRGENSEN
Peter Madsen
Original Assignee
Novo Nordisk A/S
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU52721/96A priority Critical patent/AU5272196A/en
Publication of WO1996031483A1 publication Critical patent/WO1996031483A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • the present invention relates to novel N-substituted amino 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 containing C-fibres and hence inhibit the secretion and circulation of insulin antagonizing 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 ( elnyk 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 may be useful in the treatment of insulin resistance related to type 2 diabetes or aging.
  • the present invention relates to novel N-substituted amino acids and esters thereof of formula I
  • R 1 and R 2 independently are hydrogen, halogen, trifluoromethyl, hydroxy, C.. ⁇ -alkyl, C*. ⁇ -alkoxy, -NR 7 R 8 or -SO 2 NR 7 R 8 wherein R 7 and R 8 independently are hydrogen or C.. ⁇ -alkyl;
  • R 9 is hydrogen or C*.
  • R 10 is C 1- ⁇ -alkyl or phenyl optionally substituted with halogen, CF 3 , hydroxy, C-. ⁇ -alkyl or C*.
  • ⁇ - alkoxy, and R 11 and R 12 independently are hydrogen or C*. ⁇ -alkyl;
  • Y is -O-, -S(O) q - wherein q is 0, 1 or 2, or -N(R 13 )- wherein R 13 is hydrogen or
  • n is 0 or 1 ;
  • R 3 is -(CH 2 ) m OH or -(CH 2 ) t COR 4 wherein m is 0, 1 , 2, 3, 4, 5 or 6 and t is 0 or 1 and wherein R 4 is -OH, -NH 2 , -NHOH or C*. ⁇ -alkoxy; and R 5 is hydrogen, halogen, trifluoromethyl, hydroxy, C ⁇ -alkyl or C-. ⁇ -alkoxy; and
  • R ⁇ is hydrogen, C-. ⁇ -alkyl
  • A is C-.g-alkylene, C 2 . ⁇ -alkenylene or C 2 . ⁇ -alkynylene; 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, 6_6_, 2 (1977) which are hereby incorporated by reference.
  • C ⁇ . ⁇ -alkyl 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-methylbut ⁇ l, 3-methylbutyl, n-hexyl, 4- methylpentyl, neopentyl, n-hexyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl and 1 ,2,2-trimethylpropyl.
  • C-. ⁇ -alkox ⁇ 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. 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
  • the compounds of formula I may be prepared by the following method:
  • a compound of formula II wherein R ⁇ R 2 , X, Y, p, s 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 amino 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 4 is alkoxy
  • compounds of formula I wherein R 4 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 yl 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. '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 com ⁇ pounds which can readily be prepared by methods known jjer s_e.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention décrit un composé de formule (I). Z est choisi parmi des composé de formule (a), (b), (c) et (d). La présente invention se rapporte à de nouveaux aminoacides N substitués et à leur esters dans lesquels une chaîne alkyle substituée fait partie du substituant N ou de ses sels, à leur procédé de fabrication, aux compositions les contenant et à leur utilisation pour le traitement clinique d'états douloureux, hyperalgésiques et/ou inflammatoires dans lesquels les fibres C jouent un rôle pathophysiologique en induisant une douleur ou inflammation neurogène.
PCT/DK1996/000156 1995-04-07 1996-04-01 Nouveaux composes heterocycliques WO1996031483A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU52721/96A AU5272196A (en) 1995-04-07 1996-04-01 Novel heterocyclic compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK0422/95 1995-04-07
DK42295 1995-04-07

Publications (1)

Publication Number Publication Date
WO1996031483A1 true WO1996031483A1 (fr) 1996-10-10

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WO (1) WO1996031483A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL6609437A (fr) * 1965-07-06 1967-01-09

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL6609437A (fr) * 1965-07-06 1967-01-09

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 67, No. 20, 13 November 1967, (Columbus, Ohio, USA), FARMOCHIMICA CUTOLOCALOSI S.P.A., "Dibenzosuberene Derivatives", page 8535, Abstract No. 90698u; & NL,A,66 09437, (1967). *

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Publication number Publication date
AU5272196A (en) 1996-10-23

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