EP0506903A1 - Derives de 4-acetoxy-piperidine, procede servant a leur preparation, et leur utilisation comme antagonistes de recepteur m3 de muscarine - Google Patents

Derives de 4-acetoxy-piperidine, procede servant a leur preparation, et leur utilisation comme antagonistes de recepteur m3 de muscarine

Info

Publication number
EP0506903A1
EP0506903A1 EP91917741A EP91917741A EP0506903A1 EP 0506903 A1 EP0506903 A1 EP 0506903A1 EP 91917741 A EP91917741 A EP 91917741A EP 91917741 A EP91917741 A EP 91917741A EP 0506903 A1 EP0506903 A1 EP 0506903A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
group
quaternary ammonium
ammonium salt
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.)
Withdrawn
Application number
EP91917741A
Other languages
German (de)
English (en)
Inventor
Richard Bawden Ash Lea Cottage Barlow
Mark Anthony 4 Balmoral Close Veale
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.)
BTG International Ltd
Original Assignee
BTG International Ltd
British Technology Group Ltd
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 BTG International Ltd, British Technology Group Ltd filed Critical BTG International Ltd
Publication of EP0506903A1 publication Critical patent/EP0506903A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • 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
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • This invention relates to esters of N-substituted piperidin-4-ols and to their use as therapeutic agents.
  • a finding in a compound of such selectivity is of greater value than a finding of enhanced, but non-selective, anti-muscarinic receptor activity for a new compound.
  • the comprehensive literature on antimuscarinic N-substituted piperidin-4-ol esters includes the studies reported by Sugai et aj. (Che . Phar . Bull., 1984, 32(3) . 967 and 977, and Japanese Patent Application Number 27570/1979) on tertiary bases and quaternary ammonium salts which contain a substituted or unsubstituted 1 ,3-dioxolan-4-ylmethyl group substituted on the nitrogen atom of the piperidine ring. Accordingly the present invention compri ses a compound of formula ( I)
  • R and R2 are each separately selected from a phenyl group which is unsubstituted or substituted by one or more groups selected from alkyl, alkoxy, alkylenedioxy, halogeno, halogeno substituted alkyl, hydroxy and nitro
  • R3 and R4 are each hydrogen or together are an oxo group
  • R5 is an aromatic group, the compound optionally being in the form of a physiologically acceptable acid addition or quaternary ammonium salt, for use in therapy.
  • R] and R2 are each separately selected from a phenyl group which is unsubstituted or substituted by one or more groups selected from alkyl, alkoxy, alkylenedioxy, halogeno, halogeno substituted alkyl, hydroxy and nitro
  • R3 and R4 are each hydrogen or together are an oxo group and R5 is an aromatic group, the compound optionally being in the form of a physiologically acceptable acid addition or quaternary ammonium salt thereof, but excluding the compound in which R-
  • or R2 are C ⁇ — alkyl groups, for example methyl, ethyl, propyl and isopropyl, C _ alkoxy groups, for example methoxy and ethoxy, C-j_3 alkylenedioxy groups, for example methylenedioxy, fluoro, chloro, bro o and iodo groups, C- j — alkyl groups substituted by one or more halogeno groups, for example three fluoro groups as in trifluoromethyl , hydroxy and nitro.
  • substituents may be present, for example 1 , 2 or 3 monovalent substituents, preferably such substituted phenyl groups contain no more than one substituent (including one alkylenedioxy group) and conveniently the groups R ] and R are identical, especially with each being an unsubstituted phenyl group.
  • the aromatic group R5 may be carbocyclic or heterocyclic and unsubstituted or substituted, suitable heterocyclic groups consisting of a 5- or 6-membered ring system which contains one or two hetero atoms selected from the group consisting of oxygen, nitrogen and sulphur. Although suitable carbocyclic groups R5 are both phenyl and naphthyl, it is generally preferred that R5 is monocyclic.
  • R5 is a non-basic aromatic group so that among the heterocyclic groups thienyl is of greater interest than basic groups such as pyridyl, pyrimidyl, oxazolyl and thiazolyl, although such groups can be used as evidenced by the data presented herein on the compound containing a 2-pyridyl group R5.
  • Preferred groups R5 are thus 2- or 3-thienyl (thienyl indicates the univalent radical " i ⁇ " Jjderived from thiophene) and especially phenyl.
  • Such aromatic groups R5 may be substituted by one or more substituents but preferably no more than one substituent, especially in the case of naphthyl and particularly of phenyl groups.
  • Suitable substituents are broadly as described above for the substituted phenyl groups R- and R , for example methyl, methoxy, fluoro and nitro.
  • R5 halogeno and especially fluoro substituents are of the greatest interest.
  • Substitution may be present at various positions in the ring but in the case of substituted phenyl groups there is particular interest in substitution at the ortho and especially the para positions, substitution at the meta position being less preferred, especially in the case of a nitro group.
  • Unsubstituted groups R5 are, however, generally preferred.
  • tertiary bases (I) can be used in the form of physiologically acceptable salts which may be formed with various suitable inorganic and organic acids.
  • inorganic acids examples include phosphonic acid, nitric acid, sulphuric acid and particularly the hydrohalic acids hydrochloric acid, hydrobromic acid and hydroiodic acid.
  • organic acids examples include citric acid, oxalic acid, fumaric acid, maleic acid, lactic acid, succinic acid, malic acid, tartaric acid and methane sulphonic acid.
  • Formation of such an acid addition salt provides a particularly suitable method of formulating the basic compounds (I).
  • the quaternary salts may contain a variety of groups RX but particularly preferred are those which contain a group R which is an alkyl group substituted by a phenyl group which may optionally itself be substituted, for example as described in relation to the groups R-
  • alkyl groups R may conveniently be as described hereinbefore in relation to alkyl substituents on substituted phenyl groups R- and Rg, for example being isopropyl, propyl, ethyl or particularly methyl.
  • the group X may be of a variety of types, for example corresponding to the anions present in the acid addition salts described hereinbefore. Preferred groups X are however the halogeno groups, for example bromo or chloro.
  • and R2 are as defined for the compound of formula (1) or are groups convertible thereto, with a compound of formula (III).
  • R3 and R4 are as defined for the compound of formula (I) and R5 is as defined for the compound of formula (I) or is a group convertible thereto
  • Y is a suitable leaving group, in particular a halogeno group, for example a chloro or especially a bromo group.
  • the reaction is conveniently effected in solution in a suitable organic solvent such as chloroform using an appropriate temperature and time, for example at room temperature over a period of up to 24 hours.
  • R- and R2 are as defined for the compound of formula (I) or are groups convertible thereto, and Y is a suitable leaving group, with a compound of formula (V)
  • R3 and R4 are as defined for the compound of formula (I) and R5 is as defined for the compound of formula (I) or is a group convertible thereto.
  • Y is in particular a halogeno group, for example a bromo or especially a chloro group, or alternatively an alkoxy group, for example one containing an alkyl group as described hereinbefore in relation to alkyl substituents on substituted phenyl groups R-
  • the reaction is conveniently effected in solution in a suitable organic solvent such as toluene using an appropriate temperature and time, for example at 80°C over a period of up to 24 hours.
  • the free bases (I) often do not form crystalline solids and it is therefore usually convenient to isolate the compound (I) in the form of an acid addition salt by reaction with an acid, for example a monobasic acid. It is also usually preferable to .formulate the compound (I) as a salt, for example with one of the acids described hereinbefore, for example HBr or HC1, and in such an instance the compound may suitably be isolated directly in the form of the acid addition salt which is to be used therapeutically.
  • the compounds (I) may be formulated as a quaternary ammonium salt containing a cation (la) as indicated hereinbefore, although such salts do have disadvantages in terms of oral absorption and ability to cross the blood brain barrier.
  • Such salts may conveniently be formed in several ways. Firstly the compound (1) may be reacted with a compound RX in which R is the additional group present on the nitrogen atom in the quaternary ammonium salt and X ⁇ is the anion present therein. Alternatively a compound of formula (Ha)
  • R3, R4 and R5 are as defined above for formula (III) and X provides the anion present in the quaternary ammonium salt.
  • the quaternary ammonium salts contain an anion which is not a halogeno anion
  • an alkali metal salt for example a sodium or potassium salt
  • R- , R2 and R5 in the compounds of formulae (II), (IV), (V), (III), (Ila) and (Ilia) are identical with those groups in the compound of formula (I) but in some instances it may be convenient for this not to be the case, particularly where these groups are substituted groups and the compounds (II) to (V), (Ila) and (Ilia) contain a substituent or substituents convertible to those present in (I) .
  • the invention encompasses compounds (I) in the various stereochemical forms in which they exist, certain of which may be of particular value by virtue of their level of therapeutic activity and/or physical properties such as greater aqueous solubility, etc.
  • R- and R2 when R- and R2 are different the compounds will contain at least one asymmetric carbon atom and will be resolvable into optically active iso ers.
  • the quaternary ammonium salts can exist in different stereoisomeric forms depending on the relative orientation of the groups -C(R3)(R4)-Rs and R to the rest of the molecule. Such stereochemistry is described in detail by Sugai et al_, ibid, particularly in the Japanese patent application.
  • the antagonist activity of the compounds of the present invention against the uscarinic receptors, particularly against the M3 receptor, renders them of value as spasmolytics (or antispasmodics) which may be used in the treatment of patients with various conditions in which smooth muscle is in spasm.
  • Such conditions include gastrointestinal motility disorders such as the spastic condition of the gut, functional diarrhoea, irritable bowel syndrome, cardiospas , pylorospasm, gastro-oesophaegeal reflux, gastric and duodenal ulcers and also spasm of the bilary and particularly urinary tracts and urinary incontinence.
  • the compounds are of interest in the control of bronchospasm as M3 receptors are involved in cholinergic-induced bronchoconstriction.
  • the particular value of the compounds is their ability to block effects on M3 receptors in concentrations which do not have substantial effects on the beating of the heart.
  • the compounds are of further interest for their anti-secretory activity and in addition to their effects on gastric and intestinal secretion therefore have potential for use in reducing nasal secretion in colds, in reducing sweating and for reducing excessive excretions in conjunction with operative procedures.
  • cardiac-sparing substitutes for atropine as pre-operative medication, particularly in the elderly, and in preparations for suppressing nasal secretions and for reducing sweating.
  • antimuscarinics have been shown to be of value by virtue of a centrally acting effect in the treatment of defects of the central nervous system where the cholinergic or muscarinic mechanisms are malfunctioning, for example Parkinson's and Alzheimer's diseases and other conditions involving cognitive deficiencies.
  • the compounds of the present invention thus have further potential in this area.
  • the compounds (I) may be formulated with a physiologically acceptable diluent or carrier for use as pharmaceuticals for veterinary, for example in an avian or especially a mammalian context, and particularly for human use by a variety of methods.
  • a physiologically acceptable diluent or carrier for use as pharmaceuticals for veterinary, for example in an avian or especially a mammalian context, and particularly for human use by a variety of methods.
  • they may be applied as a composition incorporating a liquid diluent or carrier, for example an aqueous or oily solution, suspension or emulsion, which may often be employed in injectable form for parenteral administration and therefore may conveniently be sterile and pyrogen free.
  • Oral administration may also be used, particularly in the case of the free bases and their acid addition salts, and indeed is preferred.
  • compositions for this purpose may incorporate a liquid diluent or carrier
  • a solid for example a conventional solid carrier material such as starch, lactose, dextrin or magnesium stearate.
  • Such solid compositions may conveniently be of a formed type, for example as tablets, capsules (including spansules), etc.
  • Other forms of administration than by injection or through the oral route may also be considered in both human and veterinary contexts, for example the use of suppositories or pessaries.
  • Another form of pharmaceutical composition is one for baccal or nasal administration, for example lozenges, nose drops or an aerosol spray, or alternatively drops for administration into the eye which may conveniently contain a sterile liquid diluent or carrier.
  • the invention further includes a pharmaceutical composition
  • a pharmaceutical composition comprising a compound (I) as defined hereinbefore together with a physiologically acceptable diluent or carrier.
  • compositions may be formulated in unit dosage form, i.e. in the form of discrete portions each comprising a unit dose, or a multiple or sub-multiple of a unit dose.
  • dosage of active compound given will depend on various factors, including the particular compound which is employed in the composition and the condition treated, it may be stated by way of guidance that a satisfactory spasmolytic effect will often be achieved using a daily dosage of about 0.05 to 40 mg/kg, particularly of about 0.1 to 10 or 20 mg/kg, for example about 1 or 1.5 mg/kg. However, it will be appreciated that it may be appropriate under certain circumstances to give daily dosages either below or above these levels.
  • more than one compound (I) may be administered in the pharmaceutical composition or, indeed, other active compounds may be included in the composition.
  • the present invention therefore includes a compound of formula (I) as defined hereinbefore for use in therapy and also a method for the treatment of a patient in need of anti-spasmodic treatment which comprises administering to said patient a therapeutically effective amount of a compound of formula (I) as defined hereinbefore.
  • the invention is illustrated by the following Examples.
  • Example 2 Comparison of activity of compounds (I) against guinea-pig isolated atria and ileum The procedures used were essentially those described by Barlow and Shepherd, Br. J. Pharmac, 1986, 89., 837-843 as indicated below. (a) Guinea-pig isolated ileum
  • the guinea-pig ileum responses were recorded isotonically with a load of about 0.5 g.
  • the agonist, carbachol was allowed to act for 30 seconds and added once every 90 seconds by relays controlled from a PET microcomputer.
  • the tissue was suspended in Krebs solution aerated with a mixture of 95% O2 and 5% CO2, usually containing 5 yM norphenylephrine and experiments were carried out at 29.8 ⁇ 0.3°C.
  • the atria were set up in Krebs solution aerated with a mixture of 95% O2 and 5% CO2, usually containing 5 yM norphenylephrine (the same solution as was used for the ileum).
  • the temperature was 29.8 ⁇ 0.3°C and the spontaneous contractions were recorded isometrically with a load of about 0.2 g, action potentials also being recorded.
  • the agonist, carbachol was added by relays operated from a Commodore 128 microcomputer and allowed to act for 5 minutes. Doses were given once every 15 minutes with a second wash 10 minutes from the start of the cycle. The effects of the agonist were expressed as the percentage inhibition of the force of the contraction. As in the experiments on the ileum, the control responses were usually obtained with 0.1 and 0.2 ⁇ M carbachol. The tissue was then exposed to the antagonist and the experiment continued as with the ileum. The data obtained for the fourteen compounds (I) of Example 1 is given in Table 2. The dose-ratios obtained are used to calculate the affinity constants which are shown in log form.

Abstract

On décrit des composés de formule (I), dans lesquels R1 et R2 sont chacun séparément choisis à partir d'un alkyle, alcoxy, alkylènedioxy, halogéno, alkyle substitué par halogéno, hydroxy et nitro, R3 et R4 représentent chacun hydrogène ou représentent tous deux un groupe oxo et R5 représente un groupe aromatique, le composé se présentant éventuellement sous forme d'une addition d'acide physiologiquement acceptable ou d'un sel d'ammonium quaternaire. Ces composés sont utiles comme antagonistes sélectifs du récepteur M3 de muscarine.
EP91917741A 1990-10-23 1991-10-17 Derives de 4-acetoxy-piperidine, procede servant a leur preparation, et leur utilisation comme antagonistes de recepteur m3 de muscarine Withdrawn EP0506903A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9023023 1990-10-23
GB909023023A GB9023023D0 (en) 1990-10-23 1990-10-23 Pharmaceutical compositions

Publications (1)

Publication Number Publication Date
EP0506903A1 true EP0506903A1 (fr) 1992-10-07

Family

ID=10684199

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91917741A Withdrawn EP0506903A1 (fr) 1990-10-23 1991-10-17 Derives de 4-acetoxy-piperidine, procede servant a leur preparation, et leur utilisation comme antagonistes de recepteur m3 de muscarine

Country Status (9)

Country Link
EP (1) EP0506903A1 (fr)
JP (1) JPH05504578A (fr)
AU (1) AU8714991A (fr)
CA (1) CA2072598A1 (fr)
FI (1) FI922903A0 (fr)
GB (2) GB9023023D0 (fr)
PT (1) PT99299A (fr)
WO (1) WO1992006958A1 (fr)
ZA (1) ZA918381B (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995006635A1 (fr) * 1993-09-02 1995-03-09 Yamanouchi Pharmaceutical Co., Ltd. Derive de carbamate et medicament le contenant
NO2005012I1 (no) 1994-12-28 2005-06-06 Debio Rech Pharma Sa Triptorelin og farmasoytisk akseptable salter derav
CA2179574A1 (fr) * 1995-06-26 1996-12-27 Tomomi Okada Derive de substitution de la piperidine et medicament a base de ce derive
PE92198A1 (es) * 1996-08-01 1999-01-09 Banyu Pharma Co Ltd Derivados de 1,4-piperidina disustituida que contienen fluor
AR044851A1 (es) * 2003-06-24 2005-10-05 Novartis Ag Compuestos heterociclicos, antagonistas del receptor m3 muscarinico
GB0428418D0 (en) * 2004-12-24 2005-02-02 Novartis Ag Organic compounds
US10633336B2 (en) 2014-12-19 2020-04-28 The Broad Institute, Inc. Dopamine D2 receptor ligands
EP3233799B1 (fr) * 2014-12-19 2021-05-19 The Broad Institute, Inc. Ligands du récepteur d2 de la dopamine

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE792043A (fr) * 1971-11-30 1973-05-29 Ciba Geigy Derives de la piperidine utilisables pour stabiliser des matieres organiques
IT1231238B (it) * 1987-09-21 1991-11-26 Angeli Inst Spa Derivati ammidinici

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9206958A1 *

Also Published As

Publication number Publication date
JPH05504578A (ja) 1993-07-15
GB9122083D0 (en) 1991-11-27
FI922903A (fi) 1992-06-22
ZA918381B (en) 1993-04-21
GB9023023D0 (en) 1990-12-05
PT99299A (pt) 1992-08-31
AU8714991A (en) 1992-05-20
WO1992006958A1 (fr) 1992-04-30
CA2072598A1 (fr) 1992-04-24
FI922903A0 (fi) 1992-06-22
GB2249093A (en) 1992-04-29

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