CA2072598A1 - Pharmaceutical compositions - Google Patents
Pharmaceutical compositionsInfo
- Publication number
- CA2072598A1 CA2072598A1 CA002072598A CA2072598A CA2072598A1 CA 2072598 A1 CA2072598 A1 CA 2072598A1 CA 002072598 A CA002072598 A CA 002072598A CA 2072598 A CA2072598 A CA 2072598A CA 2072598 A1 CA2072598 A1 CA 2072598A1
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- ammonium salt
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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
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- 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
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- 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
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- 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
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- 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
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
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 aromatic group, 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
W O 92iO6958 2 ~ 7 ~ P ~ /GB91/01810 4-acetoxy-plper1dine derivat1Yes, process for thelr preparation and use as a muscarlnlc M3-receptor antagonlst.
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 1arge numbers of esters of N-substituted piperidin-4-ols as OS antimuscarinic drugs. Several muscarinic receptors exist, those concerned with actions at atria now being classified as M2 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 M2 and M3 receptors has continued for many years as indicated by Barlow and Shepherd, Br. J. Pharmac., lg~6, 89, 837-843, who describe further attempts to produce alternative antagonists to 4-diphenylacetoxy-N-methylpiperidine(4-DAMP) methobromide. I~owever, tt has now been found that a group of N-substituted 4-piperidinol esters 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-UAMP methobromide. lhis group of compounds has never previously been studied as antimuscarinic drugs, although one compound is reported as an intermediate, only, in a patent application relating to such drugs.
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-o1 esters includes the studies reported by Sugai et a1 (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 1,3-dioxolan-4-ylmethyl group substituted on the nitrogen atom of the piperidine ring.
W O 92/06958 2 ~ 7 2 ~ 9 ~ pc~rtGB9l/ol8lo Accordingly the present invention comprises a compound of formula (I) Rl \ IR3 / CHC00 ~ - C - Rs (I) in which Rl and R2 are each separately selected from a phenyl group which is unsubstituted or substituted by one or more groups 05 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 Rs 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.
These compounds are novel apart from the disclosure of l-benzyl-4-diphenylacetoxypiperidine hydrochloride as an intermediate in Example 5 of European Patent Application A-0309424.
The present invent~on therefore further comprises a compound of formula (I) Rl~ IR3 / CHC00 ~ N - C - R5 (I) in which Rl 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 Rs is an aromatic group, the compound optionally being in the form of a phys;ologically acceptable acid addition or quaternary ammonium salt thereof, but excluding the compound in which Rl = R2 = Rs = phenyl and R3 - R4 = hydrogen and physiologically acceptable acid addition salts thereof.
W O 92/06958 2 ~ 7 ,~ ~ 9 8 PCT/GB91/01810 Particularly suitable substituents on a substituted phenyl group Rl or R2 are C1_6 alkyl groups, for example methyl, ethyl, propyl and isopropyl, C1_6 alkoxy groups, for example methoxy and ethoxy, C1_3 alkylenedioxy groups, for example methylenedioxy, 05 fluoro, chloro, bromo and iodo groups, C1_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) and conveniently the groups Rl and R2 are identical, especially with each being an unsubstituted phenyl group.
Although the grouping -C(R3)(R4)-R5 may be an acyl group it is preferred that R3 and R4 are each hydrogen rather than together being an oxo group. rhe aromatic group R5 may be carbocyclic or heterocyclic and unsubstituted or substituted, suitable heterocyclic groups consisting of a S- 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 Rs are both phenyl and naphthyl, it is generally preferred that Rs is monocyclic. Moreover, it is further preferred that Rs 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 Rs. Preferred groups R5 are thus 2- or 3-thienyl (thienyl indicates the univalent radical ~ derived from thiophene) and especially phenyl.
Such aromatic groups Rs 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 Rl and R2, for example methyl, methoxy, fluoro and nitro. However, in the case of Rs, halogeno 2 0 ~ 2 ~ ~ 3 PCI'/GB91/01810 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, 05 substitution at the meta position being less preferred, especially in the case of a nitro group. Unsubstituted groups Rs are, however, generally preferred.
Specific compounds (I) according to the present invention are 4-diphenylacetoxy-1-phenacylpiperidine (Rl = R2 = R5 = C6Hs, R3 + R4 = 0), 1-benzyl-4-diphenylacetoxypiperidine (Rl = R2 = Rs = C6H5- R3 = R4 = H), 4-diphenylacetoxy-1-(2-thienylmethyl)-piperidine (Rl = R2 = C6H5, R3 = R4 = H, R5 = 2-C4H3S) and 4-diphenylacetoxy-1-(3-thienylmethyl)-piperidine ~Rl = R2 = C6H5. R3 = R4 = H, Rs = 2-C4H3S).
As indicated, the tertiary bases (I) can be used in the form of physiologically acceptable salts which may be for0ed with various suitable inorganic and organic acids. Examples of such inorganic acids are phosphonic acid, nitric acid, sulphuric acid and part~cularly the hydrohalic acids hydrochloric acid, hydrobromic acid and hydroiodic ac;d. 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 (Ia) is associated with one of various physiologically acceptable anions X~.
Rl / C(R3)(R4)-R5 \ CHC00 ~ N \ X~
(Ia) W O 92/06958 2 ~ 7 2 ~ 9 8 P~r/GB91/01810 The quaternary salts may contain a variety of groups R~ 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 05 groups Rl and R2, and particularly those which contain a group R
which is an alkyl group. Such alkyl groups R may conveniently be as described hereinbefore in relation to alkyl substituents on substituted phenyl groups Rl 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) Rl~
/ Cl~C00 ~ N-l~ (II) in which Rl and R2 are as defined for the compound of formula (1) or are groups convertible thereto, with a compound of formula (III) Y - C - RS (III) in which R3 and R4 are as defined for the compound of formula (I) and Rs 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 per;od of up to 24 hours.
W o 92/06958 2 ~ 7 2 S ~ 8 P~r/GB91/01810 An alternative route to the compounds of formula (I) involves reacting a compound of formula (IV) Rl~
~CHCOY ( IV) in which Rl and R2 are as defined for the compound of formula tI) or are groups convertible thereto, and Y is a suitable leaving 05 group, with a compound of formula (V) H0 ~ N - C - R5 (V) in which R3 and R4 are as defined for the compound of formula ~I) and Rs 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 Rl and R2, such as methoxy. The reaction is conveniently effected in solution ;n a suitable organic solvent such as toluene using an appropriate temperature and time, for lS example at 80OC 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 HCl, and in such an instance the compound may suitably be isolated directly ;n the form of the acid addition salt which is to be used therapeutically.
W O 92/06958 2 ~ g P ~ /GB91/01810 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 (Ia) as indicated hereinbefore, although such salts do have disadvantages in terms of 05 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 (lIa) Rl~
/CHC00 ~ N-R (IIa) in which Rl and R2 are as defined above for formula (Il) and R is the additional group present in the quaternary ammonium salt may be reacted with a compound of formula (lIla) X - C - RS (IIIa) in which R3, R4 and Rs are as defined above for formula ( III) 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 Rl, R2 and Rs in the compounds of formulae (II), (IV), (V), (lII), (IIa) and (llIa) 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 W O 92/06958 2 ~ ~ 2 ~ 9 8 P ~ /GB91/01810 groups are substituted groups and the compounds (Il) to (V), (Ila) and (IIIa) contain a substituent or substituents convertible to those present in (1).
lt will be appreciated that the invention encompasses 05 compounds (I) in the various stereochemical forms in which they extst, 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 Rl 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)-R5 and R to the rest of the molecule. Such stereochemistry is described in detail by Sugai et al, ibid, lS particularly in the Japanese patent application. It will be appreciated, however, that the absence of steresisomerism in a compound (I) can simplify synthetic procedures and for that reason free bases and acid addition salts ~I) in which Rl and R2 are identical and which do not contain other asymmetric carbon atoms have an advantage.
Ihe antagonist activity of the compounds of the present invention against the muscarinic 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 bronchospasm as M3 receptors are involved in cholinergic-induced bronchoconstriction.
W 0 92/06958 2 ~ ~ 2 ~ 9 ~ pc~r/GB9l/ol8l~
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 05 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 inventlon 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.
W O 92/06958 2 ~ ~ 2 ~ ~ 8 PCT/GB91/01810 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 05 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 act,ve 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 lO or 20 mg/kg, for example about l or l.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.
w O 92/06958 2 ~ 7 2 ~ 9 8 P ~ /GB9l/0181 The invention is illustrated by the following Examples.
EXAMPLES
Example 1 : PreParation of comDounds (I) ~Q~ The compounds are prepared by reacting equimolar amounts of OS the appropriate unsubstituted or substituted 4-diphenylacetoxY-piperidine free base RlR2CI~C00 ~ Nl~ and the appropriate bromo compound Br-C(R3)(R4)-Rs. The reactants are dissolved in chloroform and stirred at room temperature overnight. 'I'he solution is then washed with saturated aqueous sodium carbonate and the chloroform layer is dried with magnesium sulphate. After filtration, the solvent is distilled off, the last traces of chloroform being removed by evaporation with ethanol. l'he residue is triturated with ether and this often yields the base as a white powder. The product from the trituration is dissolved in a mixture of acetone and ether (3:1 by volume) and a slight excess of 50%
aqueous HBr is added with stirring. Stirring of the mixture is continued overnight, the hydrobromide of the base often appearing after only about 5 minutes as a white so1id. The mi%ture is then filtered and the solid washed with ether and recrystallized usually from butanone or mixtures of butanone and ethanol with the addition of ether if necessary.
Details of the crystallization solvent and melting point for fourteen compounds (I) prepared in this way are given in Table l.
These contain as R5 a substituted or unsubstituted phenyl group, an ~- or ~-naphthyl group or a 2- or 3-thienyl group. In addition similar data on a fifteenth compound containing a 2-pyridyl group R5 prepared as described under (B) below is also given in the table. In the case of compound 7 the free base was obtained by crystallization from ethanol/water of the product obtained by trituration of the reaction residue. In the case of compound 2 the methobromide was formed by reaction of the free base in butanone with an excess (>1 equivalent) of methyl bromide.
,, o 7 ,, 5 9 ~ P ~ /GB9t/01810 (B) The above procedure can be varied slightly so that in the case of the compound containing a 2-pyridyl group R5 the reactant 2-chloromethylpyridine ma~ be used as follows.
4-(Uiphenylacetoxy)piperidine (2,37 g, 8,03 mmol), potassium 05 carbonate (2.222 9, 16.1 mmol), 2-(chloromethyl)pyridine hydrochloride (1.31 9, 7.99 mmol) and catalytic sodium iodide (65 mg) are stirred together in boiling acetonitrile ~30 ml) for 15 hours, The solvent is evaporated under reduced pressure.
The residue is partitioned between water (30 ml) and chlorofom (3 x S0 ml). lhe combined organic portions are dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue is "flash" chromatographed on silica eluting with acetone-petrol (bp 40-600C) 1/1 to give the free base as a pale yellow solid. This is dissolved in acetone (20 ml) and treated with 48X l~Br aqueous solution (1 ml), The solvents are evaporated under reduced pressure and the residue is co-evaporated under reduced pressure with toluene (30 ml). The residue is recrystallised from ethanol to give the 4-(diphenylacetoxy)-1-~2-p~rid~lmethyl)piperidine bis-hydrobromide salt as a white powder ~0 (2.15 9), A similar variation may be used with other compounds, WO 92/06958 2 ~ 7 2 ~ 9 ~ pcr/GB91/ot8to Table Compounds of formula (C6Hs)2CHC00{~,N-C-R5 Compound R3,R4 R5 Salt M.p. crystallization oc solvent ..
1 H,H C6H5 HBr 194.2 butanone/
ethanol/ether 2 H,H C6H5 CH3Br 195.5 ,.
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 1arge numbers of esters of N-substituted piperidin-4-ols as OS antimuscarinic drugs. Several muscarinic receptors exist, those concerned with actions at atria now being classified as M2 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 M2 and M3 receptors has continued for many years as indicated by Barlow and Shepherd, Br. J. Pharmac., lg~6, 89, 837-843, who describe further attempts to produce alternative antagonists to 4-diphenylacetoxy-N-methylpiperidine(4-DAMP) methobromide. I~owever, tt has now been found that a group of N-substituted 4-piperidinol esters 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-UAMP methobromide. lhis group of compounds has never previously been studied as antimuscarinic drugs, although one compound is reported as an intermediate, only, in a patent application relating to such drugs.
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-o1 esters includes the studies reported by Sugai et a1 (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 1,3-dioxolan-4-ylmethyl group substituted on the nitrogen atom of the piperidine ring.
W O 92/06958 2 ~ 7 2 ~ 9 ~ pc~rtGB9l/ol8lo Accordingly the present invention comprises a compound of formula (I) Rl \ IR3 / CHC00 ~ - C - Rs (I) in which Rl and R2 are each separately selected from a phenyl group which is unsubstituted or substituted by one or more groups 05 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 Rs 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.
These compounds are novel apart from the disclosure of l-benzyl-4-diphenylacetoxypiperidine hydrochloride as an intermediate in Example 5 of European Patent Application A-0309424.
The present invent~on therefore further comprises a compound of formula (I) Rl~ IR3 / CHC00 ~ N - C - R5 (I) in which Rl 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 Rs is an aromatic group, the compound optionally being in the form of a phys;ologically acceptable acid addition or quaternary ammonium salt thereof, but excluding the compound in which Rl = R2 = Rs = phenyl and R3 - R4 = hydrogen and physiologically acceptable acid addition salts thereof.
W O 92/06958 2 ~ 7 ,~ ~ 9 8 PCT/GB91/01810 Particularly suitable substituents on a substituted phenyl group Rl or R2 are C1_6 alkyl groups, for example methyl, ethyl, propyl and isopropyl, C1_6 alkoxy groups, for example methoxy and ethoxy, C1_3 alkylenedioxy groups, for example methylenedioxy, 05 fluoro, chloro, bromo and iodo groups, C1_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) and conveniently the groups Rl and R2 are identical, especially with each being an unsubstituted phenyl group.
Although the grouping -C(R3)(R4)-R5 may be an acyl group it is preferred that R3 and R4 are each hydrogen rather than together being an oxo group. rhe aromatic group R5 may be carbocyclic or heterocyclic and unsubstituted or substituted, suitable heterocyclic groups consisting of a S- 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 Rs are both phenyl and naphthyl, it is generally preferred that Rs is monocyclic. Moreover, it is further preferred that Rs 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 Rs. Preferred groups R5 are thus 2- or 3-thienyl (thienyl indicates the univalent radical ~ derived from thiophene) and especially phenyl.
Such aromatic groups Rs 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 Rl and R2, for example methyl, methoxy, fluoro and nitro. However, in the case of Rs, halogeno 2 0 ~ 2 ~ ~ 3 PCI'/GB91/01810 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, 05 substitution at the meta position being less preferred, especially in the case of a nitro group. Unsubstituted groups Rs are, however, generally preferred.
Specific compounds (I) according to the present invention are 4-diphenylacetoxy-1-phenacylpiperidine (Rl = R2 = R5 = C6Hs, R3 + R4 = 0), 1-benzyl-4-diphenylacetoxypiperidine (Rl = R2 = Rs = C6H5- R3 = R4 = H), 4-diphenylacetoxy-1-(2-thienylmethyl)-piperidine (Rl = R2 = C6H5, R3 = R4 = H, R5 = 2-C4H3S) and 4-diphenylacetoxy-1-(3-thienylmethyl)-piperidine ~Rl = R2 = C6H5. R3 = R4 = H, Rs = 2-C4H3S).
As indicated, the tertiary bases (I) can be used in the form of physiologically acceptable salts which may be for0ed with various suitable inorganic and organic acids. Examples of such inorganic acids are phosphonic acid, nitric acid, sulphuric acid and part~cularly the hydrohalic acids hydrochloric acid, hydrobromic acid and hydroiodic ac;d. 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 (Ia) is associated with one of various physiologically acceptable anions X~.
Rl / C(R3)(R4)-R5 \ CHC00 ~ N \ X~
(Ia) W O 92/06958 2 ~ 7 2 ~ 9 8 P~r/GB91/01810 The quaternary salts may contain a variety of groups R~ 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 05 groups Rl and R2, and particularly those which contain a group R
which is an alkyl group. Such alkyl groups R may conveniently be as described hereinbefore in relation to alkyl substituents on substituted phenyl groups Rl 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) Rl~
/ Cl~C00 ~ N-l~ (II) in which Rl and R2 are as defined for the compound of formula (1) or are groups convertible thereto, with a compound of formula (III) Y - C - RS (III) in which R3 and R4 are as defined for the compound of formula (I) and Rs 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 per;od of up to 24 hours.
W o 92/06958 2 ~ 7 2 S ~ 8 P~r/GB91/01810 An alternative route to the compounds of formula (I) involves reacting a compound of formula (IV) Rl~
~CHCOY ( IV) in which Rl and R2 are as defined for the compound of formula tI) or are groups convertible thereto, and Y is a suitable leaving 05 group, with a compound of formula (V) H0 ~ N - C - R5 (V) in which R3 and R4 are as defined for the compound of formula ~I) and Rs 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 Rl and R2, such as methoxy. The reaction is conveniently effected in solution ;n a suitable organic solvent such as toluene using an appropriate temperature and time, for lS example at 80OC 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 HCl, and in such an instance the compound may suitably be isolated directly ;n the form of the acid addition salt which is to be used therapeutically.
W O 92/06958 2 ~ g P ~ /GB91/01810 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 (Ia) as indicated hereinbefore, although such salts do have disadvantages in terms of 05 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 (lIa) Rl~
/CHC00 ~ N-R (IIa) in which Rl and R2 are as defined above for formula (Il) and R is the additional group present in the quaternary ammonium salt may be reacted with a compound of formula (lIla) X - C - RS (IIIa) in which R3, R4 and Rs are as defined above for formula ( III) 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 Rl, R2 and Rs in the compounds of formulae (II), (IV), (V), (lII), (IIa) and (llIa) 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 W O 92/06958 2 ~ ~ 2 ~ 9 8 P ~ /GB91/01810 groups are substituted groups and the compounds (Il) to (V), (Ila) and (IIIa) contain a substituent or substituents convertible to those present in (1).
lt will be appreciated that the invention encompasses 05 compounds (I) in the various stereochemical forms in which they extst, 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 Rl 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)-R5 and R to the rest of the molecule. Such stereochemistry is described in detail by Sugai et al, ibid, lS particularly in the Japanese patent application. It will be appreciated, however, that the absence of steresisomerism in a compound (I) can simplify synthetic procedures and for that reason free bases and acid addition salts ~I) in which Rl and R2 are identical and which do not contain other asymmetric carbon atoms have an advantage.
Ihe antagonist activity of the compounds of the present invention against the muscarinic 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 bronchospasm as M3 receptors are involved in cholinergic-induced bronchoconstriction.
W 0 92/06958 2 ~ ~ 2 ~ 9 ~ pc~r/GB9l/ol8l~
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 05 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 inventlon 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.
W O 92/06958 2 ~ ~ 2 ~ ~ 8 PCT/GB91/01810 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 05 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 act,ve 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 lO or 20 mg/kg, for example about l or l.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.
w O 92/06958 2 ~ 7 2 ~ 9 8 P ~ /GB9l/0181 The invention is illustrated by the following Examples.
EXAMPLES
Example 1 : PreParation of comDounds (I) ~Q~ The compounds are prepared by reacting equimolar amounts of OS the appropriate unsubstituted or substituted 4-diphenylacetoxY-piperidine free base RlR2CI~C00 ~ Nl~ and the appropriate bromo compound Br-C(R3)(R4)-Rs. The reactants are dissolved in chloroform and stirred at room temperature overnight. 'I'he solution is then washed with saturated aqueous sodium carbonate and the chloroform layer is dried with magnesium sulphate. After filtration, the solvent is distilled off, the last traces of chloroform being removed by evaporation with ethanol. l'he residue is triturated with ether and this often yields the base as a white powder. The product from the trituration is dissolved in a mixture of acetone and ether (3:1 by volume) and a slight excess of 50%
aqueous HBr is added with stirring. Stirring of the mixture is continued overnight, the hydrobromide of the base often appearing after only about 5 minutes as a white so1id. The mi%ture is then filtered and the solid washed with ether and recrystallized usually from butanone or mixtures of butanone and ethanol with the addition of ether if necessary.
Details of the crystallization solvent and melting point for fourteen compounds (I) prepared in this way are given in Table l.
These contain as R5 a substituted or unsubstituted phenyl group, an ~- or ~-naphthyl group or a 2- or 3-thienyl group. In addition similar data on a fifteenth compound containing a 2-pyridyl group R5 prepared as described under (B) below is also given in the table. In the case of compound 7 the free base was obtained by crystallization from ethanol/water of the product obtained by trituration of the reaction residue. In the case of compound 2 the methobromide was formed by reaction of the free base in butanone with an excess (>1 equivalent) of methyl bromide.
,, o 7 ,, 5 9 ~ P ~ /GB9t/01810 (B) The above procedure can be varied slightly so that in the case of the compound containing a 2-pyridyl group R5 the reactant 2-chloromethylpyridine ma~ be used as follows.
4-(Uiphenylacetoxy)piperidine (2,37 g, 8,03 mmol), potassium 05 carbonate (2.222 9, 16.1 mmol), 2-(chloromethyl)pyridine hydrochloride (1.31 9, 7.99 mmol) and catalytic sodium iodide (65 mg) are stirred together in boiling acetonitrile ~30 ml) for 15 hours, The solvent is evaporated under reduced pressure.
The residue is partitioned between water (30 ml) and chlorofom (3 x S0 ml). lhe combined organic portions are dried over sodium sulphate and the solvent is evaporated under reduced pressure. The residue is "flash" chromatographed on silica eluting with acetone-petrol (bp 40-600C) 1/1 to give the free base as a pale yellow solid. This is dissolved in acetone (20 ml) and treated with 48X l~Br aqueous solution (1 ml), The solvents are evaporated under reduced pressure and the residue is co-evaporated under reduced pressure with toluene (30 ml). The residue is recrystallised from ethanol to give the 4-(diphenylacetoxy)-1-~2-p~rid~lmethyl)piperidine bis-hydrobromide salt as a white powder ~0 (2.15 9), A similar variation may be used with other compounds, WO 92/06958 2 ~ 7 2 ~ 9 ~ pcr/GB91/ot8to Table Compounds of formula (C6Hs)2CHC00{~,N-C-R5 Compound R3,R4 R5 Salt M.p. crystallization oc solvent ..
1 H,H C6H5 HBr 194.2 butanone/
ethanol/ether 2 H,H C6H5 CH3Br 195.5 ,.
3 H,H ~-C10l~7 HBr 189.6 ll 4 H,H I~-ClOH7 HBr 220.4 butanone/ethanol H,H 2-C4l~3S HBr 192.8-193.2 ,l 6 H,H 3-C4H3S HBr 175.5-176.2 butanone 7 H,H p-CI~3-C6l~4 base 99.1 ethanol/water B H,H o-F-C6H4 HBr 176.3 butanone/
. ethanol/ether g H,H m-F-C6l14 HBr 197.6 butanone/ethanol H,H p-F-C6l~4 HBr 186.5 11 H,H m-N02-C6l~4 HBr 185.2 ,l 12 H,H p-NO2-C6H4 HBr not butanone/
. determined ethanol/ether 13 0= C6H5 HBr not butanone/ethanol determined 14 0= m-CH30-C6H4 HBr 206.7 ll H,H 2-C5H4N 2HBr 199.6-201.0 ethanol . , , W O 92/06958 2 ~ 7 2 5 9 8 P ~ /GB91/01810 - l4 Example 2 : comParison of activitv of comPounds (I) aqainst - quinea-~iq isolated atria and ileum The procedures used were essentially those described by Barlow and Shepherd, Br. J. Pharmac., 1986, 89, B37-843 as indicated below.
05 (a) Guinea-Diq isolated ileum The guinea-pig ileum responses were recorded isotonically with a load of about 0.5 9. 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% 2 and SX C02, usually containing 5 ~M norphenylephrine and experiments were carried out at 29.8 + 0.30C.
Alternate small and large control responses were obtained, usually to O.l and 0.2 ~M 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-Diq isolated atria The atria were set up in Krebs solution aerated with a mixture of 95% 2 and 5% C02, usually containing 5 ~M norphenylephrine (the same solution as was used for the ileum). The temperature was 29.8 + 0.3OC and the spontaneous contractions were recorded isometrically with a load of about 0.2 9, action potentials also being recorded.
The agonist, carbachol, was added by relays operated from a Commodore l28 microcomputer and allowed to act for S minutes. Doses were given once every l5 minutes with a second wash lO 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 O.l and 0.2 ~M carbachol. lhe tissue was then exposed to the antagonist and the experiment continued as with the ileum.
W 0 92/06958 2 ~ 9 ~ PCT/GB91/01810 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. In some cases the mean estimate of log affinity constant, K, is shown 05 (+ s,e.) with the number of experiménts carried out indicated in brackets. In the other cases only one experiment was carried out.
It wil1 be seen that for every compound there is a selective M3 receptor antagonist effect with the effect against the atria being less than that against the ileum. On the basis of these results the highest level of selectivity was shown by 1-benzyl-4-diphenyl-acetoxypiperidine hydrobromide but nearly similar levels were shown by the hydrobromides of 1-(3-thienylmethyl) -4-diphenyl-- acetoxypiperidine and particularly 1-(2-thienylmethyl)-4-diphenylacetoxypiperidine (compounds 1, 6 and 5 respectively).
Table 2 Atria and ileum loq affinitv constants for comDounds (I) Compound Atria Ileum 1 5.65 ~ 0.18 (4)7.65 ~ 0.07 (5) 2 6.64 ~ 0.02 (4)1.82 + 0.03 (5) 3 4.30 5.74 4 4.78 6.75 5.69 ~ 0.21 (2)7.47 ~ 0.06 (3) 6 5.96 + 0.08 (3)7.'50 + 0.06 (3) 78 5.54 76 1687 9 5.90 7.22, 7.46 5.48 7.07 11 5.70 6.48 12 5.87 7.07 13 6.03 6.87 14 5.26 6.12 5.07 7.10 _
. ethanol/ether g H,H m-F-C6l14 HBr 197.6 butanone/ethanol H,H p-F-C6l~4 HBr 186.5 11 H,H m-N02-C6l~4 HBr 185.2 ,l 12 H,H p-NO2-C6H4 HBr not butanone/
. determined ethanol/ether 13 0= C6H5 HBr not butanone/ethanol determined 14 0= m-CH30-C6H4 HBr 206.7 ll H,H 2-C5H4N 2HBr 199.6-201.0 ethanol . , , W O 92/06958 2 ~ 7 2 5 9 8 P ~ /GB91/01810 - l4 Example 2 : comParison of activitv of comPounds (I) aqainst - quinea-~iq isolated atria and ileum The procedures used were essentially those described by Barlow and Shepherd, Br. J. Pharmac., 1986, 89, B37-843 as indicated below.
05 (a) Guinea-Diq isolated ileum The guinea-pig ileum responses were recorded isotonically with a load of about 0.5 9. 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% 2 and SX C02, usually containing 5 ~M norphenylephrine and experiments were carried out at 29.8 + 0.30C.
Alternate small and large control responses were obtained, usually to O.l and 0.2 ~M 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-Diq isolated atria The atria were set up in Krebs solution aerated with a mixture of 95% 2 and 5% C02, usually containing 5 ~M norphenylephrine (the same solution as was used for the ileum). The temperature was 29.8 + 0.3OC and the spontaneous contractions were recorded isometrically with a load of about 0.2 9, action potentials also being recorded.
The agonist, carbachol, was added by relays operated from a Commodore l28 microcomputer and allowed to act for S minutes. Doses were given once every l5 minutes with a second wash lO 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 O.l and 0.2 ~M carbachol. lhe tissue was then exposed to the antagonist and the experiment continued as with the ileum.
W 0 92/06958 2 ~ 9 ~ PCT/GB91/01810 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. In some cases the mean estimate of log affinity constant, K, is shown 05 (+ s,e.) with the number of experiménts carried out indicated in brackets. In the other cases only one experiment was carried out.
It wil1 be seen that for every compound there is a selective M3 receptor antagonist effect with the effect against the atria being less than that against the ileum. On the basis of these results the highest level of selectivity was shown by 1-benzyl-4-diphenyl-acetoxypiperidine hydrobromide but nearly similar levels were shown by the hydrobromides of 1-(3-thienylmethyl) -4-diphenyl-- acetoxypiperidine and particularly 1-(2-thienylmethyl)-4-diphenylacetoxypiperidine (compounds 1, 6 and 5 respectively).
Table 2 Atria and ileum loq affinitv constants for comDounds (I) Compound Atria Ileum 1 5.65 ~ 0.18 (4)7.65 ~ 0.07 (5) 2 6.64 ~ 0.02 (4)1.82 + 0.03 (5) 3 4.30 5.74 4 4.78 6.75 5.69 ~ 0.21 (2)7.47 ~ 0.06 (3) 6 5.96 + 0.08 (3)7.'50 + 0.06 (3) 78 5.54 76 1687 9 5.90 7.22, 7.46 5.48 7.07 11 5.70 6.48 12 5.87 7.07 13 6.03 6.87 14 5.26 6.12 5.07 7.10 _
Claims (15)
1. A compound of formula (I) (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 aromatic group, the compound optionally being in the form of a physiologically acceptable acid addition or quaternary ammonium salt, for use in therapy.
2. A compound of formula (I) (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 a1kyl, 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 R1 = R2 = R5 = phenyl and R3 = R4 = hydrogen and physiologically acceptable acid addition salts thereof.
3. A compound according to Claim 1 or 2, in which R5 is a phenyl or thienyl group which is unsubstituted or substituted by one or more groups selected from alkyl, alkoxy, alkylenedioxy, halogeno, halogeno substituted alkyl, hydroxy and nitro.
4. A compound according to Claim 3, in which R5 is phenyl, 2-thienyl or 3-thienyl.
5. A compound according to any of Claims 1 to 4, in which R1 and R2 are each phenyl.
6. A compound according to any of Claims 1 to 5, in which R3 and R4 are each hydrogen.
7. A compound according to Claim 1, which is 1-benzyl-4-diphenyl-acetoxypiperidine, 4-diphenylacetoxy-1-(2-thienylmethyl)-piperidine or 4-diphenylacetoxy-1-(3-thienylmethyl)-piperidine.
8. A compound according to Claim 2, which is 1-(2-thienylmethyl-4-diphenylacetoxypiperidine or 1-(3-thienylmethyl)-4-diphenylacetoxy-piperidine.
9. A compound according to any of the preceding claims, which is in the form of the free base or an acid addition salt.
10. A compound according to any of Claims 1 to 8, 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.
11. A compound according to Claim 1 or 2, which is a quaternary ammonium salt of l-benzyl-4-diphenylacetoxypiperidine, 4-diphenylacetoxy-1-(2-thienylmethyl)-piperidine or 4-diphenylacetoxy-1-(3-thienylmethyl)-piperidine having an additional methyl group substituted on the nitrogen atom of the ring.
12. 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) (II) in which R1 and R2 are as defined for the compound of formula (I), or are groups convertible thereto, with a compound of formula (III) (III) 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 R1, 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) (IV) in which R1 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) (V) 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 R1, 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 (IIa) (IIa) in which R1 and R2 are as defined above for formula (II) and R is the additional group present in the quaternary ammonium salt with a compound of formula (IIIa) (IIIa) in which R3, R4 and R5 are as defined above for formula (III) and X
provides the anion present in the quaternary ammonium salt, and where appropriate converting one or more of R1, R2 and R5 to the groups present tn the compound (I); or (4) reacting a quaternary ammonium salt produced by any of the three procedures 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 R1, R2 and R5 to the groups present in the compound (I).
(1) reacting a compound of formula (II) (II) in which R1 and R2 are as defined for the compound of formula (I), or are groups convertible thereto, with a compound of formula (III) (III) 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 R1, 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) (IV) in which R1 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) (V) 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 R1, 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 (IIa) (IIa) in which R1 and R2 are as defined above for formula (II) and R is the additional group present in the quaternary ammonium salt with a compound of formula (IIIa) (IIIa) in which R3, R4 and R5 are as defined above for formula (III) and X
provides the anion present in the quaternary ammonium salt, and where appropriate converting one or more of R1, R2 and R5 to the groups present tn the compound (I); or (4) reacting a quaternary ammonium salt produced by any of the three procedures 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 R1, R2 and R5 to the groups present in the compound (I).
13. A process according to Claim 12, in which the procedure (1), (3) or (4) is used.
14. A pharmaceutical composition comprising a compound of formula (I) as defined in any of Claims 1 to ll, together with a physiologically acceptable diluent or carrier.
15. 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 in any of Claims 1 to 11.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB909023023A GB9023023D0 (en) | 1990-10-23 | 1990-10-23 | Pharmaceutical compositions |
| GB9023023.6 | 1990-10-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2072598A1 true CA2072598A1 (en) | 1992-04-24 |
Family
ID=10684199
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002072598A Abandoned CA2072598A1 (en) | 1990-10-23 | 1991-10-17 | Pharmaceutical compositions |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0506903A1 (en) |
| JP (1) | JPH05504578A (en) |
| AU (1) | AU8714991A (en) |
| CA (1) | CA2072598A1 (en) |
| FI (1) | FI922903A0 (en) |
| GB (2) | GB9023023D0 (en) |
| PT (1) | PT99299A (en) |
| WO (1) | WO1992006958A1 (en) |
| ZA (1) | ZA918381B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995006635A1 (en) * | 1993-09-02 | 1995-03-09 | Yamanouchi Pharmaceutical Co., Ltd. | Carbamate derivative and medicine containing the same |
| NO2005012I1 (en) * | 1994-12-28 | 2005-06-06 | Debio Rech Pharma Sa | Triptorelin and pharmaceutically acceptable salts thereof |
| CA2179574A1 (en) * | 1995-06-26 | 1996-12-27 | Tomomi Okada | Substituted piperidine derivative and medicine comprising the same |
| PE92198A1 (en) * | 1996-08-01 | 1999-01-09 | Banyu Pharma Co Ltd | DERIVATIVES OF FLUORINE-CONTAINED 1,4-PIPERIDINE |
| PE20050231A1 (en) * | 2003-06-24 | 2005-05-20 | Novartis Ag | DERIVATIVES OF PIPERIDINIUM AND PYRROLIDINIUM AS ANTAGONISTS OF THE MUSCARINIC M3 RECEPTOR |
| GB0428418D0 (en) | 2004-12-24 | 2005-02-02 | Novartis Ag | Organic compounds |
| WO2016100940A1 (en) | 2014-12-19 | 2016-06-23 | The Broad Institute, Inc. | Dopamine d2 receptor ligands |
| EP3233799B1 (en) * | 2014-12-19 | 2021-05-19 | The Broad Institute, Inc. | Dopamine d2 receptor ligands |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE792043A (en) * | 1971-11-30 | 1973-05-29 | Ciba Geigy | PIPERIDINE DERIVATIVES USED TO STABILIZE ORGANIC MATERIALS |
| IT1231238B (en) * | 1987-09-21 | 1991-11-26 | Angeli Inst Spa | AMIDIDIC DERIVATIVES |
-
1990
- 1990-10-23 GB GB909023023A patent/GB9023023D0/en active Pending
-
1991
- 1991-10-17 JP JP3516505A patent/JPH05504578A/en active Pending
- 1991-10-17 GB GB9122083A patent/GB2249093A/en not_active Withdrawn
- 1991-10-17 CA CA002072598A patent/CA2072598A1/en not_active Abandoned
- 1991-10-17 AU AU87149/91A patent/AU8714991A/en not_active Abandoned
- 1991-10-17 EP EP91917741A patent/EP0506903A1/en not_active Withdrawn
- 1991-10-17 WO PCT/GB1991/001810 patent/WO1992006958A1/en not_active Application Discontinuation
- 1991-10-21 ZA ZA918381A patent/ZA918381B/en unknown
- 1991-10-22 PT PT99299A patent/PT99299A/en not_active Application Discontinuation
-
1992
- 1992-06-22 FI FI922903A patent/FI922903A0/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| AU8714991A (en) | 1992-05-20 |
| GB2249093A (en) | 1992-04-29 |
| FI922903A (en) | 1992-06-22 |
| ZA918381B (en) | 1993-04-21 |
| GB9122083D0 (en) | 1991-11-27 |
| WO1992006958A1 (en) | 1992-04-30 |
| GB9023023D0 (en) | 1990-12-05 |
| EP0506903A1 (en) | 1992-10-07 |
| JPH05504578A (en) | 1993-07-15 |
| FI922903A0 (en) | 1992-06-22 |
| PT99299A (en) | 1992-08-31 |
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