GB2048258A - Piperidine Derivatives - Google Patents
Piperidine Derivatives Download PDFInfo
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- GB2048258A GB2048258A GB8010997A GB8010997A GB2048258A GB 2048258 A GB2048258 A GB 2048258A GB 8010997 A GB8010997 A GB 8010997A GB 8010997 A GB8010997 A GB 8010997A GB 2048258 A GB2048258 A GB 2048258A
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- piperidinyl
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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
- C07D211/80—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 two double bonds between ring members or between ring members and non-ring members
- C07D211/82—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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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
- C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
- C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- Hydrogenated Pyridines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A compound of the formula <IMAGE> wherein Q is -CO- or -CHOH-; either R1 is hydrogen or hydroxy and R2 is hydrogen or R1 and R2 together form a second bond between the carbon atoms bearing R1 and R2; n is an integer of from 1 to 5; R3 is CH3, CH2OH, COOH or COO(C1-6 alkyl); and one of A and B is hydrogen and the other is hydrogen or hydroxy, with the proviso that one of A and B is hydroxy when R3 is CH3; or a pharmaceutically acceptable acid addition salt thereof. They are used as anti-histamines, anti- allergy agents and bronchodilators.
Description
SPECIFICATION
Piperidine Derivatives
This invention relates to novel piperidine derivatives which can have pharmaceutical utility.
Piperidine derivatives having antihistaminic properties are disclosed in US Patent Specification Nos.
3,806,526; 3,829,433; 3,862,173; 3,878,217; 3,931,197; 3,941,795; 3,946,022 and 3,965,257.
The novel compounds of this invention are of formula I
wherein Q is -CO- or -CHOH-; either R, is hydrogen or hydroxy and R2 is hydrogen or R1 and R2 together form a second bond between the carbon atoms bearing R, and R2; n is an integer of from 1 to 5;R3 is CHS, CH2OH,COO or COO(C,~6 alkyl); and one of A and B is hydrogen and the other is hydrogen or hydroxy, with the proviso that one of A and B is hydroxy when R3 is CH3; and include the pharmaceutically acceptable acid addition salts thereof.
Illustrative examples of C16 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl.
Preferred compounds of the invention in which Q is -CO- are those in which R3 is CH3 or
CH2OH. It is generally preferred that either R, is hydroxy and R2 is hydrogen or R, and R2 form a second bond. The combination of R, as hydroxy and R2 as hydrogen is particularly preferred, n is preferably 3 or 4.
The most preferred classes of compounds of the invention are those in which Q is -CO-, either
R, is hydroxy and R2 is hydrogen or R, and R2 form a second bond, n is 3 and B is hydrogen, with R3 as
COOH being particularly preferred in this context; and those in which Q is -CHOH-, either R, is hydroxy and R2 is hydrogen or R1 and R2 form a second bond, n is 3 and A and B are each hydrogen, R3 being COOH being particularly preferred in this context also.
As indicated above, this invention includes the pharmaceutically acceptable salts of the compounds of the invention, including those of the preferred groups identified above. Pharmaceutically acceptable acid addition salts of the compounds of this invention are those of any suitable inorganic or organic acid. Examples of suitable inorganic acids are hydrochloric, hydrobromic, sulfuric and phosphoric acids.Examples of suitable organic acids are carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, masonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acids, and sulfonic acids such as methanesulfonic, ethanesulfonic and /3-hydroxyethanesulfonic acids.Non-toxic salts of the compounds of the above-identified formulas formed with inorganic or organic bases are also included within the scope of this invention and include, for example, those of alkali metals such as sodium, potassium and lithium, alkaline earth metals such as calcium and magnesium, light metals of the group IIIA such as aluminium, tertiary amines, for example cyclohexylamine, ethylamine, pyridine, methylaminoethanol and piperazine. The salts are prepared by conventional means as, for example, by treating the free base of a compound of Formula I with an appropriate acid or, when R3 is COOH, with a base.
Illustrative examples of compounds of this invention in which 0 is -CO- are: 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oXobutyl]-ct,Xx-dimethylbenzeneacetic acid, 4-[4-[4-(diphenylmethyl)-2-piperidinyl]-1 oxobutyl]--dimethylbenzeneacetic acid, 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-oXobutyl]-a,-dimethylbenzeneacetic acid, 4-[4-[4-(hydroxydiphenylmethyl)-2-piperidinyl]-1 -oxobutyl]-,-dimethyl-(3- hydroxybenzene)acetic acid, 4-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidinyl]-1 -oxobutyl]-a,-dimethyl-(2- hydroxybenzene)acetic acid,
4-[4-[4-(diphenyl methylene)- 1 -piperidinyl]-l -oxobutyl]-a,c2 -dimethyl-(3-hydroxybenzene)acetic acid, 5-[4-[4-(diphenylmethylene)-1 -piperidinyl]- 1 -oxopentyl]-a,a-dimethylbenzeneacetic acid, 3-[4-[4-(hydroxydiphenylmeti,yl)- 1-piperidinyl]-1-oxopropyl]-a,c4-dimethylbenzeneacetic acid, 2-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxoethyl]-a,a-dimethylbenzeneacetic acid, ethyl 4-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-a,a-dimethylbenzeneacetate, n-pentyl 4-[4-[4-(diphenylmethyl)- 1 -piperidinyl]- 1 oxobutyl]-a,a-dimethylbenzeneacetate, ethyl 4-[4-[4-(diphenylmethylene)-l -piperidinyl]-l -oxobutyi]-a,a-dimethylbenzeneacetate, methyl 4-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-a,a-dimethylbenzeneacetate, ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]-α,α-dimethyl-(3- hydroxybenzene)acetate,
n-propyl 4-[4-[4-(hydroxydiphenyl methyl)- 1 -piperidinyl]- 1 -oxobutyl]-a-dimethyl-(2- hydroxybenzene)acetate,
n-hexyl 4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-oxobutyl]-α,α-dimethyl-(3- hydroxybenzene)acetate,
ethyl 5-[4-[4-(diphenylmethylene)-1 -piperidinyl]- 1 -oxopentyl]-α,α;-dimethylbenzeneacetate, 4'-tert-butyl-2'-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]butyrophenone, 4'-tert-butyl-3 '-hydroxy-4-[4-( hydroxydiphenylmethyl)- 1 piperidinyl]butyrophenone, 4'-tert-butyl-2'-hydroxy-4-[4-(diphenylmethylene)-1-piperidinyl]butyrophenone, 4'-tert-butyl-3'-hydroxy-4-[4-(diphenylmethyl)-1 -piperidinyl]butyrophenone,
4'-tert-butyl-2 '-hydroxy-3-[4-( hydroxydiphenylmethyl )-1 piperidinyl]propiophenone, 4'-tert-butyl-3'-hydroxy-2-[4-(diphenylmethylene)-1 -piperidinyl]acetophenone,
4'-(hydroxy-tert-butyl)-2'-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]butyrophenone, 4'-(hydroxy-tert-butyl)-3'-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]butyrophenone,
4'-(hydroxy-tert-butyl)-2'-hydroxy-4-[4-(diphenylmethylene)- 1 -piperidinyl]butyrophenone,
4'-(hydroxy-tert-butyl)-3'-hydroxy-4-[4-(diphenylmethylene)- 1 -piperidinyl]butyrophenone,
4'-(hydroxy-tert-butyl)-2'-hydroxy-3-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]propiophenone,
3'-hydroxy-4'-(hydroxy-tert-butyl)-2-[4-(diphenylmethylene)- 1 -piperidinyl)acetophenone,
4'-(hydroxy-tert-butyl)-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]butyrophenone,
4'-(hydroxy-tert-butyl)-4-[4-(diphenylmethylene)- 1 -piperidinyl]butyrophenone,
4'-(hydroxy-tert-butyl)-3-[4-(diphenylmethyl)- 1 -piperidinyl]propiophenone, and
tert-butyl-2-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxoethyl]-a,- dimethylbenzeneacetate.
Illustrative examples of compounds of this invention in which Q is -CHOH- are: 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]- 1 -hydroxybutyl]-α,α-dimethylbenzeneacetic acid, 4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α;-dimethylbenzeneacetic acid, 4-[4-[4-(diphenylmethylene)-1 -piperidinyl]- 1 hydrnxybutyl]-a,a-dimethylbenzeneacetic acid, 4-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidinyl]-1 -hydroxybutyl]-cg -dimethyl-(3- hydroxybenzene)acetic acid,
4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -hydroxybutyl]-,-dimethyl-(2- hydroxybenzene)acetic acid,
4-[4-[4-(diphenylmethylene)-1 -piperidinyl]-1 -hydroxybutyl]-a,-dimethyl-(3- hydroxybenzene)acetic acid, 5-[4-[4-(diphenylmethylene)- 1 -piperidinyl]-1 -hydroxypentyll-ct,cY-dimethylbenzeneac acid,
3-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -hydroxypropyl]-α,α;-dimethylbenzeneacetic acid, 2-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]- 1 hydrnxyethyl]-c',-dimethylbenzeneacetic acid,
ethyl 4-[4-[4-(hydroxydiphenyl methyl)- 1 -piperidinyl]- 1 -hydroxybutyl]-α,α;- dimethylbenzeneacetate,
n-pentyl 4-[4-[4-(diphenylmethyl)- 1 -piperidinyl]-1 -hydroxybutyl]-a,zx-di methylbenzeneacetate, ethyl 4-[4-[4-(diphenylrcethylene)- 1 -piperidinyl]-1 -hydroxybutyl]-a,-dimethylbenzeneacetate, methyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]- 1 -hydroxybutyl]-sx,cr- dimethylbenzeneacetate,
ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]- 1 -hydroxybutyl]-α,α;-dimethyl-(3- hydroxybenzene)acetate,
n-propyl 4-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidinyl]-1 -hydroxybutyl]-a,-di methyl-(2- hydroxybenzene)acetate, n-hexyl 4-[4-[4-(diphenylmethylene)- 1 -piperidinyl]-α -hydrnxybuWl]-a,a-dimethyl-(3- hydroxybenzene)acetate,
ethyl 5-[4-[4-(diphenyl methylene)-1 -piperidinyl]- 1 -hydroxypentyl]-cr,-dimethylbenzeneacetate, a,-diphenyl-1 -(4-(4-tert-butyl-2-hydroxy)phenyl)-4-hydroxybutyl-4-piperidinemethanol.
,sr-diphenyl-1 -(4-(4-tert-butyl-3-hydroxy)phenyl)-4-hydroxybutyl-4-piperidinemethanol, a,-diphenyl-1 -(3-(4-tert-butyl-2-hydroxy)phenyl)-3-hydroxypropyl-4-piperidinemethanol α,α-diphenyl-1 -(5-(4-tert-butyl-2-acetyloxy)phenyl)-5-hydroxypentyl-4-piperidinemethanol, a,ce-diphenyl-1 -(4-(4-hydroxy-tert-butyl-2-hydroxy)phenyl)-4-hydroxybutyl-4piperidinemethanol, a,a-diphenyl- 1 -(4-(4-hydroxy-tert-butyl-3-hydroxy) phenyl)-4-hydroxybutyl-4piperidinemethanol, α,α ;-diphenyl-1 -(3-(4-hydroxy-tert-butyl-2-hyd roxy)phenyl)-3-hydroxypropyl-4- piperidinemethanol, cr,-diphenyl-1 -(4-(4-hydroxy-tert-butyl)phenyl-4-hydroxybutyl-4-piperidinemethanol, 1 -(4-tert-butyl-2-hydroxyphenyl)-4-(4-diphenyl methylene)-1 -piperidinyl)butanol,
1 -(4-tert-butyl-3-hydroxyphenyl)-4-(4-(diphenylmethylene)-1 -piperidinyl)butanol,
1 -(4-tert-butyl-3-hydroxyphenyl)-2-(4-(diphenylmethylene)-1 -piperidinyl)ethanol.
1 -(4-tert-butyl-2-butyryloxyphenyl)-6-(4-(diphenylmethyl)-1 -piperdinyl)hexanol, 1 -(4-hydroxy-tert-butyl-2-hydroxyphenyl)- (diphenylmethylene)-1-diperidinyl)butanol, 1 -(4-hydroxy-tert-butyl-3-hydroxyphenyl)-4-(4-(diphenylmethylene)-1 -piperidinyl)butanol,
1 -(4-hydroxy-tert-butyl-3-hydroxyphenyl)-2-(4-(diphenylmethylene)-1 -piperidinyl)ethanol,
1 -(4-hydroxy-tert-butylphenyl)-4-(4-(diphenylmethylene)-1 -piperidinyl)butanol, 1-(4-hydroxy-tert-butylphenyl)-3-(4-diphenylmethyl)-1-piperidinyl)propanol, and
tert-butyl 2-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -hydroxyethyl]-a,- dimethylbenzeneacetate.
Compounds of formula I in which Q is -CO-, B is hydrogen and R3 is CH3 or COO(C1a alkyl) may be prepared by alkylating a piperidine derivative of formula II
wherein R, and R2 are as defined above, with an -haloalkyl phenyl ketone of formula Ill
wherein halo is a halogen atom such as chlorine, bromine or iodine, Z is hydrogen or
methoxyethoxymethyl (memoxy),-P6 is CH3 or COO(C1~6 alkyl) and n is as defined above. When Z is
memoxy, this group is cleaved in conventional manner, after the alkylation, to obtain the products in which A is hydroxy.The alkylation reaction is carried out in a suitable solvent, preferably in the presence of a base and optionally in the presence of a catalytic amount of potassium iodide for 4 to
1 20 hours and at 700C to the reflux temperature of the solvent. Suitable solvents for the alkylation reaction include alcohol solvents such as methanol, ethanol, isopropyl alcohol or butanol, ketone solvents such as methyl isobutyl ketone, hydrocarbon solvents such as benzene, toluene or xylene, and halogenated hydrocarbons such as chlorobenzene, methylene chloride or dimethylformamide. Suitable bases for the alkylation reaction include inorganic bases such as sodium bicarbonate, potassium carbonate or potassium bicarbonate, and organic bases, e.g. a trialkylamine such as triethylamine, or pyridine. Alternatively, an excess of a compound of formula II may be used.Cleavage of any memoxy group is achieved using trifluoroacetic acid at room temperature or 5 to 8 equivalents of powdered an hydros zinc bromide in methylene chloride at 25-400C by the general procedure of E. J. Corey et a/., Tetrahedron Letters 11,809-812(1976).
Compounds of formula I in which Q is -CO-, B is hydrogen and R3 is COOH may be prepared by base hydrolysis of a corresponding C16 alkyl ester. Base hydrolysis may be achieved by treatment with an inorganic base such as sodium hydroxy or potassium hydroxide in an aqueous C14 alcohol such as methanol, ethanol, isopropyl alcohol or n-butanol at reflux for T to 12 hours. When it is desired that A should be hydroxy, base hydrolysis of the corresponding ester in which the A group is protected as memoxy may be effected before hydrolysis, but hydrolysis subsequent to cleavage is preferred.
Compounds of formula I in which 0 is -CHOH, A is hydroxy, B is hydrogen and R3 is methyl may be prepared from the corresponding compounds in which 0 is -CO- by reduction. Reduction may be achieved by using sodium borohydride or potassium borohydride in a C14 alcohol. Alternatively, lithiun aluminium hydride or diborane may be used as the reducing agent, in which case suitable solvents are ethers such as ethyl ether, tetrahydrofuran or dioxane. These reduction reactions are carried out at from OOC to the reflux temperature of the system. The reaction time may be from T to 8 hours.
Catalytic reduction may also be used. Suitable systems include Raney nickel, palladium, platinum or rhodium catalysts in a C14 alcohol or acetic acid, optionally in admixture with water, or by using aluminium isopropoxide in isopropyl alcohol. Catalytic reduction is less preferred in the specific embodiment discussed above.
Compounds of formula I in which Q is -CHOH-, B is hydrogen and R3 is COO(C,~6 alkyl) may be prepared from the corresponding compounds in which 0 is -CO- by reduction, preferably using a borohydride or catalytic reduction.
Compounds of formula I in which Q is-CHOH-, B is hydrogen and R3 is COOH may be prepared from the corresponding compounds in which Q is -CO- by reduction, preferably using a borohydride or catalytic reduction. Alternatively, the same products may be prepared by base hydrolysis of the corresponding esters, using the conditions discussed above for base hydrolysis.
Compounds of formula I in which 0 is -CHOH-, B is hydrogen and R3 is CH2OH may be prepared from compounds of formula I in which B is hydrogen and R3 is COOH or COO(C,~6 alkyl) by reduction. Lithium aluminium hydride is the preferred reducing agent when, in the starting material, 0 is -CO- and R3 is COO(C,~6 alkyl). Diborane is the preferred reducing agent when R3 is COOH.
The starting materials for this sequence of reactions, i.e. the compounds of formulae II and Ill, are either known or can be prepared by procedures generally known in the art. For example, the compounds of formula Il in which P1 is hydrogen or hydroxy and R2 is hydrogen are commercially available. The corresponding compound in which R, and R2 form a second bond may be prepared by conventional dehydration of the compounds in which R, is hydroxy and R2 is hydrogen.
The compounds of formula Ill in which Z is memoxy may be prepared by reacting a phenol of formula V
wherein R6 is as defined above with an w-haloalkanoic acid of the formula halo-(CH2)-COOH wherein halo and n are as defined above in the presence of boron trifluoride by the procedure of
Delschager and Mousa, Arch. Pharm. 306, 807 (1973). The phenol and acid are melted together at about 500C and then cooled to about 1 00C, after which boron trifluoride is added in an amount about 2.2 times the molar amount of phenol employed. The mixture is heated at about 700C for about 2 hours, after which the reaction vessel is cooled, vented and treated with a 30% sodium acetate solution and extracted with ether.The organic layer is dried and the residue crystallised to give a hydroxy ketone corresponding to formula Ill but in which Z is hydroxy. The hydroxy ketone is then treated with a reagent of the formula CH30CH2CH20CH2NEt+3CI- in acetonitrile according to the general procedure of E. J. Corey et a/., Tetrahedron Letters 11,809-812(1967).
The compounds of formula III wherein Z is hydrogen are prepared by reacting a C16 alkyl ester of ,',c'-dimethylphenylacetic acid with a C16 co-haloalkanoyl halide under the general conditions of a
Friedel-Crafts acylation. The reaction is carried out in a solvent such as carbon disulfide (preferred), tetrachloroethane or nitrobenzene. The reaction time varies from T to 8, preferably 3 to 5, hours, and the reaction temperature varies from 0 to 250C. The esters and the acid halides are known or easily prepared by generally known methods.
The compound of formula V in which R6 is methyl is also commercially available. The compounds of formula V in which R6 is COO alkyl are prepared by treating a hot solution of 1 equivalent of a C,~6 alkyl ester of 3-trifluoroacetoxyphenylacetic acid in dimethoxyethane with a base such as sodium hydride under a nitrogen atmosphere, followed by the addition of 2.1 equivalents of methyl iodide in dimethoxyethane to the mixt- re over about 20 minutes. The mixture is refluxed for about 3 hours and then concentrated to remove most of the solvent, after which ethyl ether and then water are added cautiously. The organic layer is separated, extracted with ethyl ether, dried over magnesium sulfate and distilled to give the appropriate ester of (z,-dimethyl-3-trifluoroacetoxyphenylacetic acid.To a solution of the methylated ester in 50% alcohol/water is added 3x molar amount of potassium carbonate. The solution is stirred at about 250C for about 8 hours and then concentrated to a semi-solid at reduced pressure at about 500C. Upon cooling, water is added and the mixture is neutralised with dilute hydrochloric acid and then extracted with ether. The ether extract is dried over magnesium sulfate, filtered and concentrated to give the appropriate ester of 3-hydroxy-a,-dimethylphenylacetic acid. The esters of 3-trifluoroacetoxyphenylacetic acid are known in the art or may be prepared by procedures generally known in the art, for example, form ethyl m-hydroxyphenylacetate by treatment with trifluoroacetic anhydride.
Compounds of formula I in which Q is -CHOH-, B is hydroxy and R3 is CH3 or COOH may be prepared by treating a compound of formula IV
wherein either P9 is hydrogen or trifluoroacetoxy and P10 is hydrogen or P9 and P10 together form a second bond, and n and R6 are as defined above, with a slight excess of thallium trifluoroacetate in trifluoroacetic acid at reflux temperature (about 720C) for about 3 hours, after which 1 equivalent of lead tetraacetate in trifluoroacetic acid is added. The mixture is stirred for about T hour and then 1 equivalent of triphenylphosphine is added. Stirring is continued for about T hour, followed by removal of excess solvent at reduced pressure and the addition of cold dilute (6 N) hydrochloric acid.The lead chloride and thallium chloride are filtered off, and the filtrate is made alkaline with 10% NaOH solution and any precipitate is dissolved in a minimum amount of ethanol. The solution is refluxed for about 4 hours, neutralised, concentrated, extracted with toluene, dried, filtered and concentrated.
Compounds of formula I in which Q is -CHOH-, B is hydroxy and R3 is COO(C~6 alkyl) may be obtained by esterifying the corresponding acid in which R3 is COOH, using 2 or 3 equivalents of boron trifluoride etherate and 20 or 30 equivalents of a C18 alkanol. The mixture is refluxed for about 24 hours, according to the general procedure of Kadaba, J. Pharm. Sci. 63, 1333 (1974). Upon cooling, the mixture is added to about 100 ml of water, concentrated at reduced pressure on a water bath, and the product purified by crystallisation from alcohois or mixtures thereof with toluene.
Compounds of formula I in which Q is -CHOH-, B is hydroxy and R3 is CH2OH may be prepared from the corresponding compounds in which R is COOH or COO(C,~6 alkyl) by reduction, preferably using lithium aluminium hydride or diborane under the conditions described above.
Compounds of formula I in which 0 is -CO-, B is hydrogen and R3 is CH3, COOH or COO(C,~6 alkyl) may be prepared from the corresponding compound in which Q is -CHOH- by oxidation.
Various oxidising agents may be used. For example, chromium trioxide in pyridine or acetic acid at from 25 to 800C for 1 to 8 hours may be employed. Alternatively, aluminium isopropoxide or potassium tert-butoxide in acetone, cyclohexanone or benzophenone, usually with an aromatic solvent such as benzene or toluene, at 250C to reflux for 8 to 24 hours may be employed. Another procedure is to use potassium dichromate in dilute sulfuric acid at O to 250C, preferably 250C, for about 1 to 8 hours. A further oxidation method uses MnO2 in CH2CI2 at 0 to 400C for about 2 to 10 hours.
Compounds of formula I in which 0 is -CO- and R3 is CH2OH may be prepared from the corresponding compounds in which R3 is COOH or COO(C,~6 alkyl), by reduction. During the reduction, the 0 group must be protected as a ketal. The ketone may be converted to a ketal by treatment with a glycol such as ethylene glycol, propylene glycol or 2,2-dimethylpropylene glycol in a hydrocarbon solvent such as benzene or toluene and in the presence of a catalytic amount of an acid such asp- toluenesulfonic acid of methanesulfonic acid. During the ketalisation step, water is removed continuously, e.g. in a Dean-Stark apparatus, and the reaction is carried out at reflux for 4 to 24 hours.
Reduction of the ketalised derivative is achieved using, for example, lithium aluminium hydride or diborane in an ether solvent such as ethyl ether, tetrahydrofuran or dioxane at reflux for 1 5 minutes to 6 hours. When R3 is COOH, the preferred reducing reagent is diborane. When R3 is COO(C,~6 alkyl), the preferred reducing reagent is lithium aluminium hydride. Following the reduction, the carbonyl group is regenerated by treating the ketal with a dilute cold aqueous acid such as hydrochloric acid, sulfuric acid or trifluoroacetic acid.
The starting materials of formula IV in which P9 is trifluromethylacetoxy may be prepared by reacting a compound of formula I in which Q is -CO-, R, is hydroxy, R2 is hydrogen and R3 is CH3 or COO(C,~6 alkyl) with trifluoroacetic anhydride for 2 to 6 hours at 0 to 250C with stirring, followed by catalytic reduction using, for example, platinum oxide in methanol and 1 atmosphere hydrogen in a
Parr apparatus to take up an equivalent amount of hydrogen.
The following Examples 1 to 7 and 9 illustrate the preparation of compounds of formula I in which Q is -CO-. Examples 8 and 10 to 12 illustrate the preparation of compounds of formula I in which 0 is -CHOH-.
Example 1
Ethyl 4-[4-[4-( hydroxydiphenyl methyl)-I -piperidinyl]-I -oxobutyl]-a.a-di methylbenzeneacetate
Hydrochloride
(A) to 700 ml of carbon disulfide containing 36.5 g (0.254 mole) of 4-chlorobutyryl chloride are added 74.5 g (0.56 mole) of aluminium chloride with stirring in an ice bath (about -100C). Stirring is continued for about 1 5 minutes at about 25"C then the mixture is recooled to 50C and 48.4 g (0.294 mole) of ethyl a,a-dimethylphenylacetate in 100 ml of carbon disulfide are added. The reaction mixture is stirred on an ice bath for 3 7 hours then stirred for 15 hours at 250C then poured into HCI-ice water and extracted with chloroform.The extract is washed with dilute sodium carbonate solution, water and saturated sodium chloride solution, dried over magnesium sulfate, and evaporated giving as a solid ethyl 4-(4-ch loro-1 -oxobutyl)-a,-dimethylphenylacetate.
(B) A mixture of 4.5 g (0.0163 mole) of 4-(a,a-diphenyl)piperidinemethanol, 6.1 g (0.0205 mole) of ethyl 4-(4-chloro-1-oxobutyl)-a,-dimethylphenylacetate,5 g (0.05 mole of potassium bicarbonate and 0.05 g of potassium iodide in 50 ml of toluene is stirred and refluxed for 72 hours then filtered.
Ether, then ethereal hydrogen chloride, are added to the filtrate, and the resulting precipitate is collected and recrystallized several times from methanol/butanone and butanone to give ethyl 4-[4-[4 (hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-a,a-dimethylbenzeneacetate hydrochloride. M.P.
205.50--2080C.
Example 2 4-[4-[4-(Hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]-a,a-dimethylbenzeneaceric Acid
A mixture of 1 g of ethyl 4-[4-[4-(hydroxydiphenyimethyl)-1-piperidinyl]-1-oXobutyl]-,- dimethylbenzeneacetate hydrochloride, 25 ml of methanol and 5 ml of 25% sodium hydroxide solution is stirred and refluxed for 2 hours then concentrated to a solid, neutralized with dilute hydrochloric acid and extracted with hot toluene. The toluene extract is filtered and concentrated to a residue which is recrystallized from chloroform/toluene to give 4-[4-[4-(hydrnxydiphenylmethyl)-1 -piperidinyl]-l - oxobutyl]-a,-dimethylbenzeneacetic acid.
Example 3 4'-(hydroxy-tert-butyl)-4-[4-(hydroxydiphenyl methyl)-1 -piperidinyli butyrophenone A mixture of 1.5 g of the free base of the compound of Example 1 , that is, ethyl 4-[4-[4 (hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-,-di methyibenzeneacetate, and 25 ml of ethylene glycol containing 0.1 g of p-toluenesulfonic acid is stirred at 1 000C for four hours, then concentrated under vacuum to a residue. The residue is triturated with 5% sodium hydroxide solution, extracted with hot toluene, dried over sodium sulfate, filtered and concentrated to give the ketal as a solid. The ketal is added to a 3x excess of lithium aluminium hydride in tetrahydrofuran, stirred and refluxed for 18 hours.The excess lithium aluminium hydride is decomposed with water and the reaction mixture is concentrated to a solid residue. The residue is extracted with hot toluene, stirred over 10% aqueous HCI for 1 hour then made basic and extracted with chloroform, dried over magnesium sulfate, filtered and concentrated to give 4'-(hydroxy-tert-butyl)-4-[4 (hydroxydiphenylmethyl)-1 -piperidinyl]butyrophenone.
Example 4 4'-tert-Butyl-2'-hydroxy-4-[4-(hydroxydiphenylmethyl)- 1-pip eridinyl] butyrophenone
(A) A solution of 0.10 mole of 3-tert-butylphenol in 0.20 mole of o-chlorobutyric acid is heated
in a pressure vessel at 500C for about 1 hour, then cooled to 1 00C after which 0.35 mole of boron trifluoride is added. The vessel is sealed and the mixture is heated to about 700C for about 2 hours after which the mixture is cooled, the vessel vented and 200 ml of a 30% solution of sodium acetate is added followed by extraction with ether to give 4'-tert-butyl-2'-hydroxy-4-chlorobutyrophenone.The phenone is treated with a 10% excess of p-methoxyethoxymethyl triethylammonium chloride (CH3OCH2CH2OCH2N(C2Hs)+3C1) in 250 ml of dry acetonitrile with stirring for 1 8 hours at about 250C.
The precipitated triethylamine hydrochloride is filtered, and the filtrate concentrated to a semi-solid which is dissolved in dry ether. Residual amounts of triethylamine are removed by filtration.
Concentration of the ether solution gives 4'-tert-butyl-2'-memoxy-4-chlorobutyrophenone.
(B) When in the procedure of Example 1 (B) an appropriate amount of 4'-tert-butyl-4-chloro-2'memoxy-butyrophenone is substituted for ethyl 4-(4-chloro-1 -oxobutyl)-a,ar-dimethylphenylacetate, 4'-tert-butyl-2'-memoxy-4-[4-(hydroxydiphenylmethyl)- 1 -piperidinyl)butyrophenone is obtained and treated with excess trifluoroacetic acid at room temperatures for 0.2-1.0 hours, followed by removal of the trifluoroacetic acid at reduced pressure and then neutralized with dilute sodium bicarbonate solution. The organic layer is separated, dried (magnesium sulfate) and concentrated to give 4'-tertbutyl-2'-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]butyrophenone.
Example 5
When in the procedure of Example 1(B) an appropriate amount of 4 (diphenylmethylene)piperidine or 4-(diphenylmethyl)piperidine is substituted for 4-(a,- diphenyl)piperidinemethanol the following respective products are obtained: ethyl 4-[4-[4 (diphenylmethylene)-1 -piperidinyl]-1 -oxobutyl]-a,cg-di methylbenzeneacetate hydrochloride, and ethyl 4 [4-[4-(diphenylmethyl)- 1 -piperidinyl]- 1 oxobutyl]-c,a-dimethylbenzeneacetate hydrochloride.
Example 6
When in the procedure of Example 2 an appropriate amount of ethyl 4-[4-[4 (diphenylmethylene)-1 -piperidinyl]-1 -oxobutyl]-c',a-dimethylbenzeneacetate hydrochloride or ethyl 4 [4-[4-(diphenylmethyl)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetate hydrochloride is substituted for ethyl 4-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidinyl]-1 -oxobutyl]-a dimethylbenzeneacetate hydrochloride, the following respective products are obtained: 4-[4-[4 (diphenylmethylene)-1-piperidinyl]-1-oxobutyl]-,-dimethylbenzeneacetic acid and 4-[4-[4 (diphenylmethyl)-1 -piperidinyl]- 1 -oxobutyl]-ce,-di methylbenzeneacetic acid.
It is readily apparent to one skilled in the art that upon substitution of an appropriate amount of the free base of the products of Example 5 for the starting material free base of Example 3, the following respective products are obtained: 4'-(hydroxy-tert-butyl)-4-[4-(diphenylmethylene)-1- piperidinyl]butyrophenone, and 4'-(hydroxy-tert-butyl)-4-[4-(diphenylmethyl)- 1 - piperidinyl]butyrophenone.
Example 7
Ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]-a,a-dimethyl-3- hydroxyphenylacetate
(A) A hot solution of 1 equivalent of ethyl 3-trifluoroacetoxyphenylacetate in dimethoxyethane is treated with 2.1 equivalents in sodium hydride under a nitrogen atmosphere followed by the addition of 2.1 equivalents of methyliodide in dimethoxyethane over about a 20 minute period. The mixture is refluxed for about 3 hours, then concentrated to remove most of the solvent after which diethyl ether, then water are added cautiously. The organic layer is separated, extracted with ether, dried over magnesium sulfate, and distilled to give ethyl a -dimethyl-3-trifluoroacetoxyphenylacetate. To a solution of the methylated ester in 50% alcohol/water is added 3x molar amount of potassium carbonate.The solution is stirred at 250C for 8 hours then concentrated to a semi-solid at reduced pressure at 500C. Upon cooling water is added and the mixture is neutralized with dilute hydrochloric acid then extracted with ether. The ether extract is dried over magnesium sulfate, filtered and concentrated to give ethyl a,a-dimethyl-3-hydroxyphenylacetate.
When in the procedure of Example 4(A) an appropriate amount of ethyl a,-dimethyl-3- hydroxyphenylacetate is substituted for 3-tert-butylphenyl, ethyl 4-(4-chlorobutyryl)-3-memoxy-a,cg- dimethylphenylacetate is obtained.
(B) When in the procedure of Example 1(B) an appropriate amount of ethyl 4-(4-chlorobutyryl)-3 memoxy-a,-dimethylphenylacetate is substituted for ethyl 4-(4-chloro-1 -oxobutyl)-a,a- dimethylphenylacetate, ethyl 4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]-,cr-di methyl-3- memoxyphenylacetate is obtained. One equivalent of the memoxy acetate is treated with excess trifluoroacetic acid at room temperature for 0.5 hour. The resulting solution is concentrated to a solid at room temperature and reduced pressure.The residue is triturated with ethyl acetate and shaken over dilute sodium bicarbonate solution. the organic layer is separated, dried and concentrated to give ethyl 4-[4-[4-(hydroxydiphenylmethyl)- 1 -piperidinyl]-1 -oxobutyl]-a,a-dimethyl-3-hydrnxyphenylacetate.
The above obtained acetate derivative is converted to 4-[4-[4-(hydroxydiphenylmethyl)-1 - piperidinyl]-1-oxobutyl]-a,a-dimethyl-3-hydroxyphenylacetic acid by refluxing with 25% aqueous sodium hydroxide in methanol according to the procedure of Example 2 above.
Example 8 a,a-Diphenyl-1 -[4-(4-tert-butyl-3-hydroxyphenyl )-4-hydroxybutyl]-4-piperidinemethanol
A mixture of 0.1 mole of 4'-tert-butyl-4-[4-(hydroxydiphenylmethyl)piperidinyl]butyrophenone in 30 ml of trifluoroacetic anhydride is stirred for 4 hours at OOC, concentrated to a solid, then reduced catalytically in a Paar apparatus using platinum oxide in 200 ml of ethyl acetate until an equivalent amount of hydrogen is taken up to give a-(p-tert-butylphenyl)-4-(-trifluoroacetoxy--phenylbenzyl)- 1-piperidinebutanol which, after removal of catalyst and solvent, is treated with a slight excess of thallium trifluoroacetate in 50 ml of trifluoroacetic acid at 720C for 3 hours, after which 1 equivalent of lead tetraacetate in 10 ml of trifluoroacetic acid is added. The mixture is stirred for 30 minutes, then 1 equivalent of triphenylphosphine is added. Stirring is continued for 30 minutes, then the excess solvent is removed at reduced pressure. Cold and dilute (6 N) hydrochloric acid (100 ml) is added and the mixture is filtered. The filtrate is made basic using 10% aqueous NaOH and any precipitate is dissolved in a minimum amount of ethanol. The solution is refluxed 4 hours, neutralized with dilute HCI, concentrated, extracted with toluene dried, filtered and concentrated to give the title product.
Example 9 4'-tert-Butyl-3'-hydroxy-4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]butyrophenone
Hydrochloride
To 0.25 mole of potassium tert-butoxide are added 500 ml of toluene, 0.1 mole of a,-diphenyl- 1-(4-(4-tert-butyl-3-hydroxy)phenyl-4-hydroxy)butyl-4-piperidinemethanol and 0.5 mole of benzophenone. The mixture is flushed with dry nitrogen and refluxed for 10 hours. The reaction mixture is then cooled and neutralized using dilute hydrochloric acid. The organic phase is separated, dried over magnesium sulfate, filtered and treated with ethereal HCI. The resulting precipitate is collected and purified by recrystallization from methanol-butanone to give the title product.
Example 10 a,-Diphenyl-1 -[4-[4-{hydroxy-tert-butyl)phenyl]-4-hydroxybutyl]-4-piperidinemethanol A suspension of 2.1 5 g (0.0038 mole) of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 - hydrnxybutyl]-a,a-dimethylbenzeneacetate in 50 ml of tetrahydrofuran was slowly added to a suspension of 0.7 g (0.01 84 mole) of lithium aluminium hydride in 60 ml of tetrahydrofuran under a nitrogen atmosphere with stirring at such a rate to moderate the foaming. The mixture is stirred and heated at boiling for about 3 hours after which 30 ml of tetrahydrofuran are added. The mixture is refluxed for 4 hours and let stand overnight (about 16 hours). Stirring the mixture under a nitrogen atmosphere, 2 ml of water are added cautiously followed by 2 ml of 1 0% sodium hydroxide, 2 ml of water and 4 g of sodium sulfate. The mixture is warmed to 50-550C and stirred for 45 minutes, filtered and the solid material is washed with tetrahydrofuran. The combined filtrates are evaporated in vacuo, and the residue is recrystallized from ethanol to give c,a-diphenyl-1 -(4-(4-hydroxy-tert- butyl)phenyl)-4-hydroxybutyl-4-piperidinemethanol, M.P. 1 34-1 3 60C.
Example 11
Ethyl 4-[4-[4-(hydroxyd iphenyl methyl)-1 -piperidinyl]-1 -hydroxybutyl]-a,a- dimethylbenzeneacetate Hydrochloride
A solution of 5.64 g (0.01 mole) of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 - oxobutyl]-a,a-dimethylbenzeneacetate hydrochloride in 200 ml of absolute ethanol and 50 ml of methanol and 0.5 g of platinum oxide is hydrogenated at about 50 psi for about 1 hour until the infrared showed no evidence of a ketone carbonyl function. The solution is filtered and the filtrate concentrated leaving a residue which is recrystallized from butanone and methanol-butanone to give ethyl 4-[4-[4-(hydroxydiphenyl methyl 1 -piperidinyl]- 1 -hyd roxybutyl]-,-di methylbenzeneacetate
HCI, M.P. 185-1870C.
Example 12 4-[4-[4-( Hydroxydiphenyl methyl)-1 -piperidinyl]-1 hydroxybutyl]-a,a-dimethylbenzeneacetic Acid
To a solution of 0.6 g of ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -hydroxybutyl]- a,c;L-dimethylbenzeneacetate in 20 ml of absolute ethanol are added 10 ml of a 50% solution of sodium hydroxide. The mixture is refluxed for 3-1/2 hours and concentrated to a solid after which a minimum amount of methanol to dissolve the residue is added. 1 0% Aqueous HCI is added until pH 7 is reached, the methanol removed by evaporation and water (25 ml) is added.The resulting precipitate is recrystallized from methanol-butanone to give 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 - hydroxybutyl]-a,cg-dimethylbenzeneacetic acid, M.P. 1 95- 197 CC.
When in the procedure of Example 8 an appropriate amount of ethyl 4-[4-[4 (hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]-a,-dimethylbenzeneacetate is substituted for 4' tert-butyl-4-[4-(hydroxydiphenylmethyl)piperidinyi]-butyrophenone, ethyl 4-[4-[4 (hydroxydiphenylmethyl)-1 -piperidinyl]- 1 hydrnxybutyl]-a,a-dimethyl-(3-hydrnxybenzene)acetate is obtained.
When in the procedure of Example 11 an appropriate amount of 4'-tert-butyl-2'-hydroxy-4-[4 (hydroxydiphenylmethyl)-1 -piperidinyl]butyrophenone hydrochloride is substituted for 4-[4-[4 (hydroxydiphenylmethyl)-1 -piperidinyl]- 1 oxobutyl]-,a-dimethylbenzene acetate, a,sx-diphenyl-1-[4- (4-tert-butyl-2-hydroxyphenyl)-4-hyd roxybutyl]-4-piperidinemethanol hydrochloride is obtained.
When in the procedure of Example 11 an appropriate amount of ethyl 4-[3-(4 diphenylmethylene- 1 -piperidinyl)-1 -oxopropyl]-a,a-dimethylbenzeneacetate hydrochloride is substituted for ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]-1 -oxobutyl]-cz,- dimethylbenzeneacetate hydrochloride, ethyl 4-[3-[4-(hydroxydiphenylmethyl)-1 -piperidinyl]- 1 hydroxypropyl]-a,a-dimethylbenzeneacetate hydrochloride is obtained.
When in the procedure of Example 11 an appropriate amount of ethyl 4-[4-(4 hydroxydiphenylmethyl-1 -piperidinyl)-1 -oxobutyl]-,-di methyl-3-hydroxybenzeneacetate hydrochloride is substituted for ethyl 4-[4-(4-hydroxydiphenylmethyl-1 -piperidinyl)-1 -hydroxybutyl]- a,-dimethyl-3-hydroxybenzeneacetate is obtained and when an appropriate amount of this last compound is substituted for 4-[4-(4-hydroxydiphenylmethyl-1 -piperidinyl]-1 -hydroxybutyl]-a,c2- dimethylbenzeneacetate in the procedure of Example 12, 4-[4-[4-(hydroxydiphenylmethyl)-1 piperidinyl]- 1 -hydroxybutyl]-' s,a-dimethyl-3-hydrnxybenzeneacetic acid is obtained.
The compounds of this invention can have utility as anti-histamines, anti-allergy agents and bronchodilators. For these purposes, they may be administered alone or in composition form.
A pharmaceutical composition according to the invention comprises a compound of the invention in association with a physiologically acceptable excipient. Such compositions can be in solid or liquid form. Examples of such forms are tablets, capsules, powders, solutions, suspensions and emulsions.
The compounds of this invention can be administered orally, parenterally, for example, subcutaneously, intravenously, intramuscularly, intraperitoneally, by intranasal instillation or by application to mucous membranes such those of the nose, throat and bronchial tubes, for example, in an aerosol spray containing small particles of a compound of this invention in a spray or dry powder form.
The quantity of novel compound administered will vary depending on the patient and the mode of administration and can be any effective amount. The quantity of novel compound administered may vary over a wide range to provide in a unit dosage an effective amount of from about 0.01 to 20 mg/kg of body weight of the patient per day to achieve the desired effect. For example, the desired antihistamine, antiallergy and bronchodilator effects can be obtained by consumption of a unit dosage form such as a tablet containing 1 to 50 mg of a novel compound of this invention taken 1 to 4 times daily.
The solid unit dosage forms can be of the conventional type. Thus, the solid form can be a capsule which can be the ordinary gelatin type containing a novel compound of this invention and a carrier, for example, lubricants and inert fillers such as lactose, sucrose or cornstarch. In another embodiment the novel compounds are tableted with conventional tablet bases such as iactose, sucrose or cornstarch in combination with binders such as acacia, cornstarch or gelatin, disintegrating agents such as cornstarch,vpotato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate.
The compounds of this invention may also be administered in injectable dosages by solution or suspension of the compounds in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Illustrative oils are those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil or mineral oil. In general, water, saline, aqueous dextrose and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
For use as aerosols, the compounds of this invention in solution or suspension may be packaged in a pressurised aerosol container together with suitable propellants, for example, hydrocarbon propellants such as propane, butane or isobutane, or carbon dioxide or nitrogen or other environmentally acceptable propellants with the usual adjuvants as may be necessary or desirable. The compounds also may be administered in a non-pressurised form such as in a nebuliser or atomiser.
The compounds of the invention can be used to treat warm-blooded animals, birds and mammals. Examples of suitable subjects are humans, cats, dogs, horses, sheep, bovine cows, pigs, lambs, rats, mice and guinea pigs.
It is indicative of the utility of the compounds of this invention that ethyl 4-[4-(4 hydroxydiphenyl methyl-1 -piperidinyl)-1 -oxobutyl]-a,a-dimethylbenzeneacetate hydrochloride and 4 14-(hydroxydiphenyl methyl-l -piperidinyl)-l -hydrnxybutyl]-a,a-dimethylbenzeneacetic acid, each at a concentration of 1 x 10-7 M, give a significant reduction in histamine-induced isolated guinea pig ileal muscle contraction.
The following Examples 1 3 to 1 7 illustrate compositions of the invention.
Example 13
An illustrative composition for hard gelatin capsules is as follows:
(a) Ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -oxobutyl]-cr,a- dimethylbenzeneacetate hydrochloride 10 mg
(b) talc 5 mg
(c) lactose 100 mg
The formulation is prepared by passing the dry powders of (a) and (b) through a fine mesh screen and mixing them well. The powder is then filled into hard gelatin capsules at a net fill of 11 5 mg per capsules.
Example 14
An illustrative composition for tablets is as follows:
(a) Ethyl 4-[4-[4-(hydroxydiphenylmethyl)- 1 -oxobutyH-a,a- dimethylbenzeneacetate hydrochloride 5 mg
(b) starch 43 mg
(c) lactose 60 mg
(d) magnesium stearate 2 mg
The granulation obtained upon mixing the lactose with the compound (a) and part of the starch and granulated with starch paste is dried, screened, and mixed with the magnesium stearate. The mixture is compressed into tablets weighing 110 mg each.
Example 15
An illustrative composition for an aerosol solution is the following:
Weight percent
(a) 4'-(Hydroxy-tert-butyl)-4-[4-(hydroxydiphenylmethyl)-1
piperidinyl]butyrophenone 5.0
(b) ethanol 35.0
(c) isobutane 60.0
The materials (a), (b) and (c) are packaged in 1 5 ml stainless steel containers equipped with a metering valve designed to meter 0.2 grams per dose, an equivalent of 10 mg of novel compound (a).
Example 16
An illustrative composition for an aerosol suspension is the following:
Weight percent
(a) 4-[4-[4-(Hydroxydiphenylmethyl)- 1 -piperidinyl]- 1 -oxobutyl]-a,a- dimethylbenzeneacetic acid (Particle size < 10,u) 20.0
(b) sorbitan trioleate 0.5
(c) propane 79.5
The materials (a)-(c) are packaged in 1 5 ml stainless steel containers equipped with a metering valve designed to meter 50 mg per dose, an equivalent of 10 mg of novel compound (a).
Example 17
An illustrative composition for an injectable suspension is the following 1 ml ampoule for an intramuscular injection.
Weight percent
(a) Ethyl 4-[4-[4-(hydroxydiphenylmethyl)-1 -oxobutyl]-a,a- dimethylbenzeneacetate hydrochloride (particle size < 10,u) 1.0
(b) polyvinylpyrrolidone (M.W. 25000) 0.5
(c) lecithin 0.25
(d) water for injection to make 100.0
The materials (a)-(d) are mixed, homogenized, and filled into 1 ml ampoules which are sealed and autoclaved 20 minutes at 121 OC. Each ampoule contains 10 mg per ml of novel compound (a).
Other active compounds of the invention can be substituted for those given in Examples 1 3 to 1 7.
By way of further example [4-(4-hydroxy-tert-butyl)phenyl-4-hydroxybutyl]-4-piperidinemethanol may be substituted for compound (a) in each of Examples 13, 1 5 and 1 7. Ethyl 4-[4-(4 hydroxydiphenylmethyl-1 -piperidinyl)- 1 -hyd roxybutyl]= -dimethylbenzeneacetate may be substituted for compound (a) in Example 14. 4-[4-(4-hydroxydiphenylmethyl-1 -piperidinyl)-1 hydroxybutyl]-a,cg-dimethylbenzeneacetic acid (particle size < 1 0 ) may be substituted for compound (a) in Example 16.
Claims (29)
1. A compound of the formula
wherein Q is -CO- or -CHOH-; either P1 is hydrogen or hydroxy and R2 is hydrogen or R, and R2 together form a second bond between the carbon atoms bearing R1 and R2; n is an integer of from 1 to 5; R3 is CH3, CH2OH, COOH or COO(C1~6 alkyl); and one of A and B is hydrogen and the other is hydrogen or hydroxy, with the proviso that one of A and B is hydroxy when R3 is CH or a pharmaceutically acceptable acid addition salt thereof.
2. A compound as claimed in claim 1, wherein O is -CO-.
3. A compound as claimed in claim 1, wherein Q is -CHOH-.
4. A compound as claimed in claim 2, wherein R3 is CH3.
5. A compound as claimed in claim 2, wherein R3 is CH2OH.
6. A compound as claimed in any of claims 1 to 3, wherein R3 is COOH.
7. A compound as claimed in any of claims 1 to 3, wherein R3 is COO(C1~6 alkyl).
8. A compound as claimed in any preceding claim, wherein either R, is hydroxy and R2 is hydrogen or R1 and R2 form a second bond.
9. A compound as claimed in claim 8, wherein R1 is hydroxy and R2 is hydrogen.
10. A compound as claimed in any preceding claim, wherein n is 3 or 4.
11. A compound as claimed in claim 2, wherein either R, is hydroxy and R2 is hydrogen or R, and
R2 form a second bond, n is 3 and B is hydrogen.
12. A compound as claimed in claim 3, wherein either R, is hydroxy and R2 is hydrogen or R1 and
R2 form a second bond, n is 3 and A and B are each hydrogen.
13. A compound as claimed in claim 11 or claim 12, wherein R3 is COOH.
14. 4-[4-(4-Hydroxydiphenylmethyl- 1 -piperidinyl)- 1 -oxobutyl]-a,cr-di methylbenzeneacetic acid or a pharmaceutically acceptable salt thereof.
1 5. 4-[4-(4-Diphenylmethylene- 1 -piperidinyl)- 1 -oxobutyl]-c-dimethylbenzeneacetic acid or a pharmaceutically acceptable salt thereof.
1 6. Ethyl 4-[4-(4-hydroxydiphenylmethyl- 1 -piperidinyl)-1 -oxobutyl]-,cr-di methylbenzeneacetate or a pharmaceutically acceptable salt thereof.
17. Ethyl 4-[4-(4-diphenylmethylene-1 -piperidinyl)-1 -oxobutyl]-a,-dimethyíbenzeneacetate or a pharmaceutically acceptable salt thereof.
1 8. 4'-tert-Butyl-2'-hydroxy-4-(4-hydroxydiphenylmethyl-1 -piperidinyl)butyrophenone or a pharmaceutically acceptable salt thereof.
1 9. 4'-(Hydrnxy tert-butyl)-4-(4-hydroxydiphenylmethyl- 1 -piperidinyl)butyrophenone or a pharmaceutically acceptable salt thereof.
20. 4'-(Hydroxy-tert-butyl)-4-(4-diphenylmethylene- 1 -piperidinyl)butyrophenone or a pharmaceutically acceptable salt thereof.
21. Ethyl 4-[4-(4-hydroxydiphenylmethyl- 1 -piperidinyl)-1 -oxobutyl]-a,cY-dimethyl-3- hydroxyphenylacetate or a pharmaceutically acceptable salt thereof.
22. a,a-Diphenyl- 1 -[4-(4-hydroxy-tert-butyl)phenyl-4-hydroxybutyl]-4-piperidinemethanol or a pharmaceutically acceptable salt thereof.
23. Ethyl 4-[4-(4-hydroxydiphenylmethyl-l -piperidinyl)-l -hydroxybutyl]-a,- dimethylbenzeneacetate or a pharmaceutically acceptable salt thereof.
24. 4-[4-(4-Hydroxydiphenylmethyl- 1 -piperidinyl)- 1 -hydrnxybutyl]-a,a-dimethylbenzeneaceric acid or a pharmaceutically acceptable salt thereof.
25. a-Diphenyl-1 -[4-(4-tert-butyl-2-hydroxyphenyl)-4-hydroxybutyl]-4-piperidinemethanol or a pharmaceuticaily acceptable salt thereof.
26.4-[4-(4-Hydroxydiphenylmethyl-1-piperidinyl)-1-hydroxybutyl]-α,α-dimethyl-3- hydroxybenzeneacetic acid or a pharmaceutically acceptable salt thereof.
27. A compound as claimed in claim 1 substantially as described in any of Examples 1 to 7 and 9.
28. A compound as claimed in claim 1 substantially as described in any of Examples 8, 10, 11 and 12.
29. A pharmaceutical composition comprising a compound as claimed in any preceding claim in association with a physiologically acceptable excipient.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/028,872 US4254130A (en) | 1979-04-10 | 1979-04-10 | Piperidine derivatives |
| US06/028,813 US4254129A (en) | 1979-04-10 | 1979-04-10 | Piperidine derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2048258A true GB2048258A (en) | 1980-12-10 |
| GB2048258B GB2048258B (en) | 1983-03-30 |
Family
ID=26704108
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8010997A Expired GB2048258B (en) | 1979-04-10 | 1980-04-02 | Piperidine derivatives |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2048258B (en) |
| IE (1) | IE49672B1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2168974A (en) * | 1984-12-20 | 1986-07-02 | Procter & Gamble | Compounds and compositions having anti-inflammatory activity |
-
1980
- 1980-04-02 GB GB8010997A patent/GB2048258B/en not_active Expired
- 1980-04-09 IE IE72080A patent/IE49672B1/en not_active IP Right Cessation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2168974A (en) * | 1984-12-20 | 1986-07-02 | Procter & Gamble | Compounds and compositions having anti-inflammatory activity |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2048258B (en) | 1983-03-30 |
| IE800720L (en) | 1980-10-10 |
| IE49672B1 (en) | 1985-11-27 |
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