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WO1993007122A1 - Piperidines de 4-diphenylacetoxy a substitution n presentant une activite antimuscarinique - Google Patents

Piperidines de 4-diphenylacetoxy a substitution n presentant une activite antimuscarinique Download PDF

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Publication number
WO1993007122A1
WO1993007122A1 PCT/GB1992/001829 GB9201829W WO9307122A1 WO 1993007122 A1 WO1993007122 A1 WO 1993007122A1 GB 9201829 W GB9201829 W GB 9201829W WO 9307122 A1 WO9307122 A1 WO 9307122A1
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WO
WIPO (PCT)
Prior art keywords
compound
formula
group
quaternary ammonium
ammonium salt
Prior art date
Application number
PCT/GB1992/001829
Other languages
English (en)
Inventor
Richard Bawden Barlow
Mark Anthony Veale
Original Assignee
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 British Technology Group Ltd. filed Critical British Technology Group Ltd.
Publication of WO1993007122A1 publication Critical patent/WO1993007122A1/fr

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Classifications

    • 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

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 (Chem. Pharm. 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 l,3-dioxolan-4-ylmethyl group substituted on the nitrogen atom of the piperidine ring.
  • these documents are silent upon the question of the relative activity between M 2 and M3 receptors of the compounds which they describe.
  • the present invention comprises a compound of formula (I)
  • and R 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 alicyclic hydrocarbyl group containing from 3 to 9 carbon atoms in the ring, the compound optionally being in the form of a physiologically acceptable acid addition or quaternary ammonium salt.
  • Particularly suitable substituents on a substituted phenyl group R] or R are C-
  • 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).
  • groups R-j and R 2 may be different they are conveniently identical, especially with each being an unsubstituted phenyl group.
  • the grouping -C(R3)(R )-R5 may be an acyl group it is preferred that R3 and R4 are each hydrogen rather than together being an oxo group.
  • the alicyclic (cycloaliphatic) hydrocarbyl group R5 this preferably has 5 to 7 and especially 6 carbon atoms in the ring and is a saturated group.
  • the ring of the group R5, which is attached directly to the group -C(R3)(R4)- f may optionally be substituted by aliphatic hydrocarbon groups, particularly by one or more alkyl groups, for example C-j_5 alkyl groups such as ethyl, propyl, isopropyl, and especially methyl, but again is preferably unsubstituted.
  • Preferred groups R5 are thus of > ⁇ the form (CH ) n CH-, in which n is an integer from 2 to 8 but is preferanly 4, 6 or especially 5, and which may optionally be substituted by one or more alkyl groups.
  • substituted groups for example 2-, 3- or 4-methylcyclohexyl, are of less interest than the unsubstituted groups, for example cyclopentyl, cycloheptyl and especially cyclohexyl.
  • the tertiary bases (I) can be used in the form of physiologically acceptable salts which may be formed with various suitable inorganic and organic acids.
  • suitable inorganic acids are phosphonic acid, nitric acid, sulphuric acid and particularly the hydrohalic acids hydrochloric acid, hydrobromic acid and hydroiodic acid.
  • organic acids are 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-j and R 2 , and particularly those which contain a group R which is an alkyl group.
  • Such unsubstituted and substituted alkyl groups R may conveniently be as described hereinbefore in relation to alkyl substituents on substituted phenyl groups R-j and R 2 , 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.
  • 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-j and R 2 , such as methoxy.
  • 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.
  • R- j and R 2 are as defined for the compound of formula (I) or are groups convertible thereto, with a compound of formula (V)
  • R3 and R4 are as defined for the compound of formula (I)
  • 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.
  • 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.
  • the compound (I) 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 (I) 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 (IVa)
  • R- ] and R 2 are as defined above for formula (IV) and R is the additional group present in the quaternary ammonium salt may be reacted with a compound of formula (Va)
  • R3, R4 and R5 are as defined above for formula (V) and X provides the anion present in the quaternary ammonium salt.
  • the quaternary ammonium salts contain , an anion which is not a halogeno anion, it may be convenient to prepare the salt by reaction of a quaternary ammonium salt containing such a halogeno anion with an alkali metal salt, for example a sodium or potassium salt, containing the alternative anion which it is desired to introduce.
  • an alkali metal salt for example a sodium or potassium salt
  • , R 2 and R5 in the compounds of formulae (II), (III), (IV), (V), (IVa) and (Va) 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 (Va) contain a substituent or substituents convertible to those present in (I). It will be appreciated that 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.
  • the compounds when R-j and R 2 are different the compounds will contain at least one asymmetric carbon atom and will be resolvable into optically active isomers.
  • 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. It will be appreciated, however, that the absence of stereoisomerism in a compound (I) can simplify synthetic procedures and for that reason free bases and acid addition salts (I) in which R- ⁇ and R 2 are identical and which do not contain other asymmetric carbon atoms have an advantage.
  • 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, cardiospasm, 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 bronchospas 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 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 g/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.
  • This material is not susceptible to purification by recrystallisation but instead is purified as the free base, being converted thereto by partition between dichloromethane (50 ml) and 2M sodium hydroxide solution (50 ml). The organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue is "flash” chromatographed on silica eluting with methanol-chloroform (1:9 v/v) to give pure l-cyclohexylmethyl-4-diphenylacetoxypiperidine as a white crystalline solid (4.54 g).
  • l-cyclohexylmethyl-4-diphenylacetoxypiperidine free base may alternatively be converted to a quaternary salt, for example the methobromide being obtained by reaction of the free base with an excess (> 1 equivalent) of methylbromide.
  • 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% 0 2 and 5% C0 , 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% 0 2 and 5% C0 2 , 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 yM carbachol. The tissue was then exposed to the antagonist and the experiment continued as with the ileum. These procedures were applied to the compound of Example 1. The dose-ratios obtained were used to calculate the log affinity constants which were found to be 7.17 for the ileum but only 4.88 for the atria. It will be seen that there is therefore a marked selective M3 receptor antagonist effect.

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

Abstract

Composés de la formule (I) dans laquelle R1 et R2 sont séparément choisis à partir d'un groupe phényle non substitué ou substitué par un ou plusieurs groupes choisis entre alkyle, alcoxy, alkylènedioxy, halogéno, alkyle substitué par halogéno, hydroxy et nitro, R3 et R4 représentent chacun hydrogène ou représentent ensemble un groupe oxo, et R5 représente un groupe hydrocarbyle alicyclique contenant entre 3 et 9 atomes de carbone dans le cycle, le composé se présentant éventuellement sous la forme d'un sel d'addition acide ou d'un sel d'ammonium quaternaire physiologiquement acceptables. Ces composés peuvent être utilisés comme antagonistes sélectifs du récepteur muscarinique M3.
PCT/GB1992/001829 1991-10-11 1992-10-08 Piperidines de 4-diphenylacetoxy a substitution n presentant une activite antimuscarinique WO1993007122A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9121631.7 1991-10-11
GB919121631A GB9121631D0 (en) 1991-10-11 1991-10-11 Pharmaceutical compositions

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WO1993007122A1 true WO1993007122A1 (fr) 1993-04-15

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Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9400600D0 (en) * 1994-01-14 1994-03-09 Pfizer Ltd Treatment of motion seckness
CA2296329A1 (fr) * 1997-07-24 1999-02-04 Masakazu Nakano Composes d'aminocycloalcane
WO1999032443A1 (fr) * 1997-12-23 1999-07-01 Alcon Laboratories, Inc. Agents muscariniques et leur utilisation pour traiter le glaucome, la myopie, et d'autres dysfonctionnements

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB688354A (en) * 1950-04-07 1953-03-04 Nopco Chem Co Improvements relating to compounds of the benzhydryl ether type
JPS5427570A (en) * 1977-07-30 1979-03-01 Ota Pharma Stereoisomer of 44acyloxyy11 alkyll11*1*33dioxolanee44 ylmethyl* pideridinium salt derivative
JPS58208270A (ja) * 1982-05-28 1983-12-03 Dainippon Pharmaceut Co Ltd α−環状アミノフエニル酢酸エステル類並びにその酸付加塩類及び第４級アンモニウム塩類

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB688354A (en) * 1950-04-07 1953-03-04 Nopco Chem Co Improvements relating to compounds of the benzhydryl ether type
JPS5427570A (en) * 1977-07-30 1979-03-01 Ota Pharma Stereoisomer of 44acyloxyy11 alkyll11*1*33dioxolanee44 ylmethyl* pideridinium salt derivative
JPS58208270A (ja) * 1982-05-28 1983-12-03 Dainippon Pharmaceut Co Ltd α−環状アミノフエニル酢酸エステル類並びにその酸付加塩類及び第４級アンモニウム塩類

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
CHEMICAL AND PHARMACEUTICAL BULLETIN. vol. 32, no. 3, 1984, TOKYO JP pages 967 - 976 S. SUGAI ET. AL. 'Studies on Spasmolytics.' cited in the application *
CHEMICAL AND PHARMACEUTICAL BULLETIN. vol. 32, no. 3, 1984, TOKYO JP pages 977 - 985 S. SUGAI ET. AL. 'Studies on Spasmolytics' cited in the application *
DATABASE WPIL Week 7914, Derwent Publications Ltd., London, GB; AN 79-27185 & JP,A,54 027 570 (OHTA SEIYAKU KK) 1 March 1979 cited in the application *
DATABASE WPIL Week 8403, Derwent Publications Ltd., London, GB; AN 84-014937 & JP,A,58 208 270 (DAINIPPON) 3 December 1983 cited in the application *
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. vol. 65, no. 2, 11 February 1943, GASTON, PA US pages 262 - 267 R. R. BURTNER, J. W. CUSIC 'Antispasmodics. I. Basic Esters of Some Arylacetic acids.' *
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY. vol. 74, 20 March 1952, GASTON, PA US pages 1485 - 1488 J. H. BIEL ET. AL. 'Antispasmodics. I. Substituted Acetic Acid Esters of 1-Alkyl-3-hydroxypiperidine' *

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GB9221212D0 (en) 1992-11-25
GB9121631D0 (en) 1991-11-27
GB2260323A (en) 1993-04-14
AU2673892A (en) 1993-05-03

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