WO1993007122A1

WO1993007122A1 - 4-diphenylacetoxy-n-substituted piperidines with antimuscarinic activity

Info

Publication number: WO1993007122A1
Application number: PCT/GB1992/001829
Authority: WO
Inventors: Richard Bawden Barlow; Mark Anthony Veale
Original assignee: British Technology Group Ltd.
Priority date: 1991-10-11
Filing date: 1992-10-08
Publication date: 1993-04-15
Also published as: AU2673892A; GB2260323A; GB9121631D0; GB9221212D0

Abstract

Compounds of formula (I) in which R1 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 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, are of value as selective antagonists of the M3 muscarinic receptor.

Description

-r-D__PH__N-___AC^_X)XY-- -Sϋ_-b l TJ^,l_^ PIPERIDINES WITH

ANΠ ISCARINIC ACTIVITY

This invention relates to esters of N-substituted piperidin-4-ols and to their use as therapeutic agents.

Studies have been reported in the literature on the activity of large numbers of esters of N-substituted piperidin-4-ols as anti uscarinic drugs. Several muscarinic receptors exist, those concerned with actions at atria now being classified as M and those concerned with the contraction of ileum now being classified as M3. There is a particular need for compounds which show selective activity between the M₂ and M3 receptors in order to provide drugs which have activity at the M3 receptor but with a significantly lower activity at the M₂ receptor, thereby reducing the level of undesirable side effects on the heart.

The search for suitable selective antagonists at the M and M3 receptors has continued for many years as indicated by Barlow and Shepherd, Br. J. Phar ac, 1986, 89, 837-843, who describe further attempts to produce alternative antagonists to 4-diphenylacetoxy-N- methylpiperidine(4-DAMP) methobromide. However, it has now been found that a group of N-substituted 4-piperidinol esters, which has never previously been studied, possesses fully acceptable levels of antimuscarinic activity and shows enhanced activity for the M3 receptors as compared with the M₂ receptors, with a level of selectivity which in general is better than that of 4-DAMP methobromide.

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. Thus, 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. However, these documents are silent upon the question of the relative activity between M₂ and M3 receptors of the compounds which they describe.

Accordingly the present invention comprises a compound of formula (I)

in which R-_| 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-|_ alkyl groups, for example methyl, ethyl, propyl and isopropyl, Cτ_6 alkoxy groups, for example methoxy and ethoxy, Cι_3 alkylenedioxy groups, for example methylenedioxy, fluoro, chloro, bromo and iodo groups, Cι_6 alkyl groups substituted by one or more halogeno groups, for example three fluoro groups as in trifluoromethyl, hydroxy and nitro. Although various numbers of 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). Although the groups R-j and R₂ may be different they are conveniently identical, especially with each being an unsubstituted phenyl group.

Although 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. As regards 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. However, substituted groups, for example 2-, 3- or 4-methylcyclohexyl, are of less interest than the unsubstituted groups, for example cyclopentyl, cycloheptyl and especially cyclohexyl.

Specific compounds (I) according to the present invention are l-cyclohexylcarbonyl-4-diphenylacetoxy-piperidine (R-j = R₂ = C6H5, R3 + R4 = 0, R5 = C_βH-_]-_j) and l-cyclohexylmethyl-4-diphenylacetoxy- piperidine (R-| = R₂ = C6H5, R₃ = R₄ = H, R5 = C₆H-|-|).

As indicated, 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. Examples of such inorganic acids are phosphonic acid, nitric acid, sulphuric acid and particularly the hydrohalic acids hydrochloric acid, hydrobromic acid and hydroiodic acid. Examples of such 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). In addition, however, it is possible to prepare quaternary ammonium salts in which the nitrogen atom of the piperidine ring is substituted by an additional group R to provide a salt as shown below in which a cation (la) is associated with one of various physiologically acceptable anions X~.

(la) 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 R₂, 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 R₂, 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.

The compounds of formula (I) are most conveniently prepared by reaction of a compound of formula (II)

CHCOY (II)

R2 y

in which R-j 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 (III)

in which 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 R₂, 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.

An alternative route to the compounds of formula (I) involves reacting a compound of formula (IV)

in which R-_j and R₂ are as defined for the compound of formula (I) or are groups convertible thereto, with a compound of formula (V)

in which 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, and 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. 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.

As an alternative to the use of the compounds (I) as the free base or an acid addition salt they 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)

in which R-_] and R₂ 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)

R₄

in which R3, R4 and R5 are as defined above for formula (V) and X provides the anion present in the quaternary ammonium salt.

Particularly where 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.

Most commonly R-| , R₂ 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. In particular, when R-j and R₂ are different the compounds will contain at least one asymmetric carbon atom and will be resolvable into optically active isomers. Moreover 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 R₂ 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. In addition 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. Thus there is a role for cardiac-sparing substitutes for atropine as pre-operative medication, particularly in the elderly, and in preparations for suppressing nasal secretions and for reducing sweating.

It should also be noted that other 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. For instance, 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. Although compositions for this purpose may incorporate a liquid diluent or carrier, it is more usual to use 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. Thus, 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. Whilst the 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. Where desired, 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. EXAMPLES

Example 1 : Preparation of l-cyclohexylmethyl-4-diphenylacetoxy- piperidine hvdrochloride

(1) 1-Cyc1ohexylmethyl-4-hydroxypiperidine

A solution of cylohexylmethylbromide (9.92 g, 56 mmol) and 4-hydroxypiperidine (5.66 g, 56 mmol) in dry acetonitrile (56 ml) is heated at reflux in the presence of potassium carbonate (7.74 g, 56 mmol) for 16 hours. The cooled reaction mixture is filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in dichloromethane (100 ml) and washed with water (2 x 50 ml). The organic layer is dried over sodium sulphate and evaporated under reduced pressure to give crude 1-cyclohexylmethyl- 4-hydroxypiperidine as an oil (4.8 g). This is distilled in a kugelrohr apparatus. Starting material is obtained at 40°C (bath temperature)/0.2mm Hg and the pure l-cyclohexylmethyl-4- hydroxypiperidine distils over at 105°C/0.1mm Hg (3.2g).

(2) l-Cyclohexylmethyl-4-diphenylacetoxypiperidine hydrochloride

A solution of l-cyclohexylmethyl-4-hydroxypiperidine (3.2 g, 16.2 mmol) in dry toluene (25 ml) is added dropwise to a stirred solution of diphenylacetylchloride (3.74 g, 16.2 mmol) in dry toluene (10 ml) at room temperature under argon. The mixture is heated at 80°C for 18.5 hours by which time a precipitate has formed. The solid material is collected by filtration, washed successively with toluene and hexane and dried under vacuum to give the crude hydrochloride (5.6 g). 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). The free base is dissolved in dry dichloromethane (20 ml) and treated with pyridine hydrochloride (1.34 g, 11.6 mmol) under argon at room temperature. The mixture is stirred for 4.5 hours. The solvent is evaporated under reduced pressure and the residue is recrystallised from acetone to give l-cyclohexylmethyl-4-diphenylacetoxypiperidine hydrochloride (4.1 g) as white crystals, m.p. 195.3-199. °C (corrected), δ(CDCl₃) 0.8-2.0 (m, 11H, 5xCH₂ + CH), 2.0-3.6 (m, 10H, 5xCH₂), 5.10 (s, 1H, ArCH), 5.15 (s, 1H, CH-0), 7.32 (m, 10H, ArH), 11.7 (broad s, 1H, NH).

Note The 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% 0₂ and 5% C0 , usually containing 5 yM norphenylephrine and experiments were carried out at 29.8 ± 0.3°C.

Alternate small and large control responses were obtained, usually to 0.1 and 0.2 yM carbachol. When these were regular the tissue was exposed to a solution of the antagonist and the concentration of agonist was increased to try to obtain responses which roughly matched the controls. When these were regular the approximate dose-ratio was given by the ratio of the concentrations of agonist used in the presence and in the absence of the antagonist and an exact dose-ratio was calculated from the size of the responses by a calculation similar to a 4-point assay, (b) Guinea-pig isolated atria

The atria were set up in Krebs solution aerated with a mixture of 95% 0₂ and 5% C0₂, 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.

Claims

CLAIMS 1 . A compound of formula ( I)

in which R-_j 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.

2. A compound according to Claim 1 or 2, in which R5 is a cyclopentyl, cyclohexyl or cycloheptyl group.

3. A compound according to Claim 1, in which R5 is cyclohexyl.

4. A compound according to Claim 1, 2 or 3, in which R-| and R₂ are each phenyl.

5. A compound according to any of the preceding claims, in which R3 and R4 are each hydrogen.

6. A compound according to Claim 1, which is l-cyclohexylmethyl-4- diphenylacetoxypiperidine.

7. A compound according to any of the preceding claims which is in the form of the free base or an acid addition salt.

8. A compound according to any of Claims 1 to 6, which is in the form of a quaternary ammonium salt wherein the additional group substituted on the nitrogen atom of the ring is an alkyl group.

9. A compound according to Claim 1, which is the quaternary ammonium salt of l-cyclohexylmethyl-4-diphenylacetoxypiperidine having an additional methyl group substituted on the nitrogen atom of the ring.

10. A compound of formula (I) as defined in any of Claims 1 to 9, for use in therapy.

11. A process for the preparation of a compound of formula (I) as defined in Claim 1 which comprises: (1) reacting a compound of formula (II)

CHCOY (II)

in which R-j 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 (III)

in which 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, and where appropriate in either order converting one or more of R-j , R₂ and R5 to the groups present in the compound (I) and/or converting the compound to an acid addition or quaternary ammonium salt;

(2) reacting a compound of formula (IV)

in which R-j and R₂ are as defined for the compound of formula (I), or are groups convertible thereto, with a compound of formula (V)

? Y- C—R₅ (V)

R4 in which 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, and Y is a suitable leaving group, and where appropriate in either order converting one or more of R-j , R₂ and R5 to the groups present in the compound (I) and/or converting the compound to an acid addition or quaternary ammonium salt; or in the case of the preparation of a quaternary ammonium salt: (3) reacting a compound of formula (IVa)

in which R] and R₂ are as defined above for formula (IV) and R is the additional group present in the quaternary ammonium salt, with a compound of formula (Va)

^R3

X — C— R5 (Va)

R₄

in which R3, R4 and R5 are as defined above for formula (V) and X provides the anion present in the quaternary ammonium salt, and where appropriate converting one or more of R-_j , R₂ and R5 to the groups present in the compound (I); or

(4) reacting a quaternary ammonium salt produced by any of routes (1), (2) and (3) with an alkali metal salt to replace the anion present in the quaternary ammonium salt by that present in the alkali metal salt and where appropriate converting one or more of R] , R₂ and R5 to the groups present in the compound (I).

12. A pharmaceutical composition comprising a compound of formula (I) as defined in any of Claims 1 to 9, together with a physiologically acceptable diluent or carrier.

13. The use in the manufacture of a medicament for use as an antispasmodic of a compound of formula (I) as defined in any of Claims 1 to 9.

14. A method for the treatment of a patient in need of antispasmodic treatment which comprises administering to said patient a therapeutically effective amount of a compound of formula (I) as defined in any of Claims 1 to 9.