WO1996031500A1 - Composes heterocycliques nouveaux - Google Patents

Composes heterocycliques nouveaux Download PDF

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Publication number
WO1996031500A1
WO1996031500A1 PCT/DK1996/000143 DK9600143W WO9631500A1 WO 1996031500 A1 WO1996031500 A1 WO 1996031500A1 DK 9600143 W DK9600143 W DK 9600143W WO 9631500 A1 WO9631500 A1 WO 9631500A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
hydrogen
halogen
compound according
Prior art date
Application number
PCT/DK1996/000143
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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.)
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Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU52708/96A priority Critical patent/AU5270896A/en
Publication of WO1996031500A1 publication Critical patent/WO1996031500A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • 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.
  • 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. 1 967, 31 , 138-1 51 ) 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 inflam ⁇ matory responses in tissues like skin, joint, urinary tract, eye, meninges, gastro-intestinal and respiratory tracts.
  • inhibition of sensory nerve peptide release and/or activity may be useful in treatment of, for example arthritis, dermatitis, rhinitis, asthma, cystitis, gingivitis, thrombo-phlelitis, glaucoma, gastro-intestinal diseases or migraine.
  • T 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 conditions like NIDDM or aging-associated obesity (Melnyk et al. Obesity Res. 3_, 337- 344, 1995) where circulating plasma levels of CGRP are markedly increased.
  • inhibition of release and/or activity of the neuropeptide CGRP 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 carboxylic acids and esters thereof of formula I
  • R 1 and R 2 independently are hydrogen, halogen, trifluoromethyl, hydroxy, and
  • R 8 and R 9 independently are hydrogen or C ⁇ -alkyl; and q is 0 or 1 ; and p is 0 or 1 ; and r is 1 , 2 or 3; and Z is selected from R3
  • R 3 is -(CH 2 ) m OH or -(CH 2 ),COR 4 wherein m is 0, 1, 2, 3, 4, 5 or 6 and s is 0 or 1 and wherein R 4 is -OH, -NH 2 , -NHOH or C ⁇ -alkoxy; and R 5 is hydrogen, halogen, trifluoromethyl, hydroxy, and R 10 is hydrogen, C ⁇ -alkyl, C ⁇ ⁇ -alkoxy or phenyl optionally substituted with halogen, trifluoromethyl, hydroxy, C ⁇ -alky! or C ⁇ -alkoxy; and R 1 is hydrogen or C ⁇ ⁇ -alkyl; and - 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 L g-alkyl refers to a straight or branched, saturated hydrocarbon chain having 1 to 6 carbon atoms such as e.g.
  • the term as used herein, alone or in combination, refers to a straight or branched monovalent substituent comprising a 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.
  • 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.
  • the compounds of general formula I im ⁇ proves 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 I.
  • the compounds of formula I may be prepared by the following method:
  • a compound of formula II wherein R 1 , R 2 , X, Y, p, q 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 4 is alkoxy
  • compounds of formula I wherein R 4 is OH may be prepared by hydrolysis of the ester group, preferably at room tempera ⁇ ture 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.
  • 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).
  • 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. Reduced release of CGRP from pheripheral nervous endinos
  • mice 16 weeks of age, where injected glucose (2g/kg) subcu- taneously.
  • blood glucose was determined in tail venous blood by the glucose oxidase method.
  • glucose oxidase method was determined in tail venous blood by the glucose oxidase method.
  • Immunoreactive CGRP was determined in plasma by radio-immuno-assay. Two groups of animals were used. The one group was vehicle treated, whereas the other group received a compound of formula I via drinking water (100 mg/l) for five days before the test.
  • 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 acceptable acid addition salt form or where possible as a metal or a lower alkylammonium salt. Such salt forms exhibit approximately the same order of activity as the free base forms.
  • 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 compositions containing the compounds of this invention may be prepared by conventional 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.
  • 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 preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the 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 ora. or parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.
  • parenteral e.g. rectal, transdermal, subcutaneous, intranasal, intramuscular, topical, intravenous, intraurethral, ophthalmic solution or an ointment, the oral route being preferred.

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

Abstract

La présente invention porte sur un composé ayant pour formule (I), Z est choisi entre (a), (b), (c), (d), (e), (f), (g), (h), (i), (j) et (k). La présente invention concerne de nouveaux acides carboxyliques azahétérocycliques N-substitués, et des esters de ces acides, dans lesquels une chaîne alkyle substituée forme une partie du substituant N ou de sels de celui-ci; l'invention concerne aussi des procédés de préparation de ces composés, des compositions les contenant et leur emploi dans le traitement clinique d'états douloureux, hyperalgésiques ou inflammatoires, ou les uns et les autres, dans lesquels les fibres C jouent un rôle pathophysiologique en éliminant les douleurs ou l'inflammation neurogènes.
PCT/DK1996/000143 1995-04-07 1996-04-01 Composes heterocycliques nouveaux WO1996031500A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU52708/96A AU5270896A (en) 1995-04-07 1996-04-01 Novel heterocyclic compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DK0409/95 1995-04-07
DK40995 1995-04-07

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WO1996031500A1 true WO1996031500A1 (fr) 1996-10-10

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WO (1) WO1996031500A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999047517A1 (fr) * 1998-03-17 1999-09-23 Novo Nordisk A/S Nouveaux composes heterocycliques
US6214816B1 (en) 1998-03-17 2001-04-10 Novo Nordisk A/S Heterocyclic compounds
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US7723349B2 (en) 2003-04-24 2010-05-25 Incyte Corporation Aza spiro alkane derivatives as inhibitors of metalloproteases
US10029995B2 (en) 2015-09-03 2018-07-24 Forma Therapeutics, Inc. [6,6] fused bicyclic HDAC8 inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3079400A (en) * 1961-02-20 1963-02-26 Olin Mathieson Thiazocine compounds
US3514443A (en) * 1965-01-22 1970-05-26 Squibb & Sons Inc 5-(substituted amino-lower alkylene)-5,6-dihydrodibenz(b,f)azocines
US3567730A (en) * 1965-06-18 1971-03-02 Rhone Poulenc Sa Dibenzocycloheptatriene derivatives and their preparation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3079400A (en) * 1961-02-20 1963-02-26 Olin Mathieson Thiazocine compounds
US3514443A (en) * 1965-01-22 1970-05-26 Squibb & Sons Inc 5-(substituted amino-lower alkylene)-5,6-dihydrodibenz(b,f)azocines
US3567730A (en) * 1965-06-18 1971-03-02 Rhone Poulenc Sa Dibenzocycloheptatriene derivatives and their preparation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 70, No. 15, 14 April 1969, (Columbus, Ohio, USA), JEAN C.L. FOUCHE, "5,6,7,12-Tetrahydrodibenz(b,g)Azocines and Aminoalkylamine Derivatives", page 353, Abstract No. 68105p; & IND. CHIM. BELGE, 1967, 32, 226-233. *
CHEMICAL ABSTRACTS, Volume 86, No. 19, 9 May 1977, (Columbus, Ohio, USA), TOSHIHARU OHGOH et al., "Studies on Diphenyl Ether Derivatives. IX. Pharmacological Screening of Dibenz(b,g)(i,5)Oxazocine and Dibenzo(b,g)(1,5)Thiazocine Derivatives", page 17, Abstract No. 133360q; & YAKAGAKU ZASSHI, 1977, 97(1), 24-30. *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999047517A1 (fr) * 1998-03-17 1999-09-23 Novo Nordisk A/S Nouveaux composes heterocycliques
US6214816B1 (en) 1998-03-17 2001-04-10 Novo Nordisk A/S Heterocyclic compounds
US9403775B2 (en) 2003-04-24 2016-08-02 Incyte Corporation AZA spiro alkane derivatives as inhibitors of metalloproteases
US7723349B2 (en) 2003-04-24 2010-05-25 Incyte Corporation Aza spiro alkane derivatives as inhibitors of metalloproteases
US8039471B2 (en) 2003-04-24 2011-10-18 Incyte Corporation Aza spiro alkane derivatives as inhibitors of metalloproteases
US8637497B2 (en) 2003-04-24 2014-01-28 Incyte Corporation AZA spiro alkane derivatives as inhibitors of metalloproteases
US9801877B2 (en) 2003-04-24 2017-10-31 Incyte Corporation AZA spiro alkane derivatives as inhibitors of metalloproteases
US10226459B2 (en) 2003-04-24 2019-03-12 Incyte Holdings Corporation Aza spiro alkane derivatives as inhibitors of metalloproteases
US7417040B2 (en) 2004-03-01 2008-08-26 Bristol-Myers Squibb Company Fused tricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3
US10029995B2 (en) 2015-09-03 2018-07-24 Forma Therapeutics, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US10370343B2 (en) 2015-09-03 2019-08-06 Forma Therapeutics, Inc. [6,6] Fused bicyclic HDAC8 inhibitors
US10829460B2 (en) 2015-09-03 2020-11-10 Valo Early Discovery, Inc. [6,6] fused bicyclic HDAC8 inhibitors
US11414392B2 (en) 2015-09-03 2022-08-16 Valo Health, Inc. [6,6] fused bicyclic HDAC8 inhibitors

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