HK1125382B - Antihistaminic piperidine derivatives and intermediates for the preparation thereof - Google Patents

Description

Antihistaminic piperidine derivatives and intermediates for the preparation thereof

This application is a divisional application of divisional application 200610003627.8 of chinese patent application 99808132.9 entitled "novel antihistaminic piperidine derivatives and intermediates for the preparation thereof", filed on 17.6.1999.

Technical Field

The invention relates to novel piperidine derivatives of formula (I) and to processes for their preparation,

wherein

R₁Is H or C₁～C₆Alkyl radical, C thereof₁～C₆The alkyl moiety is straight or branched;

R₂is-COOH or-COO alkyl, the alkyl part of which has 1 to 6 carbon atoms and is straight-chain or branched; or

Stereoisomers or pharmaceutically acceptable acid addition salts thereof.

Background

Terfenadine, alpha- [4- (1,1-dimethylethyl) phenyl]-4- (hydroxybenzhydryl) -1-piperidinebutanol, a known antihistamine currently on the market under the trade nameThe recommended dose is 60mg twice daily (see Physician's Desk Reference, 52nd Edition, 1998, pp.1238-1244, Medical Economics Data, a division of Medical Economics company, Inc. Montvale, N.J.). Terfenadine is disclosed in U.S. p.no.3,878,217, granted on 4/15 of 1975. A review of the pharmacokinetic and therapeutic properties of terfenadine has been given by Sorken and Heel [ Drugs29，34～56(1985)]。

Terfenadine is metabolized via a broad (99%) first pass into two primary metabolites (fexofenadine) and one inactive dealkylated metabolite. Fexofenadine, also known as 4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl]Butyl radical]- α, α -dimethyl-phenylacetic acid, as an antihistamine with oral activity, has been disclosed in U.S. patent No.4,254,129, granted 3 months 3 in 1981. It is currently commercially available under the trade name(see Physician's Desk Reference, 52nd edition, 1998, pp.1189-1190, Medical Economics Data, a division of Medical Economics Company, Inc. Montvale, N.J.).

Disclosure of Invention

It is an object of the present invention to provide novel piperidine derivatives of formula (I) for use in the treatment of allergic disorders, and further to provide processes for the preparation of such derivatives and novel intermediates useful in the preparation of such derivatives.

In addition, it is an object of the present invention to provide a method of treating a patient suffering from an allergic disorder, comprising administering to said 10 patients (said 10 patient) an effective antiallergic amount of a compound of formula (I).

It is also an object of the present invention to provide a composition comprising an analytically acceptable amount of a compound of formula (I) in admixture or otherwise in association with one or more pharmaceutically acceptable carriers or excipients.

It is another object of the present invention to provide novel processes for the preparation of intermediates useful in the synthesis of fexofenadine and related compounds.

Further objects and advantages of the present invention will become apparent to those skilled in the art from a study of the specification and appended claims.

Drawings

FIG. 1 shows a scheme A which illustrates a novel process for the preparation of piperidine derivatives of formula (I).

FIG. 2 shows a scheme B which illustrates a novel process for the preparation of 4- (cyclopropylcarbonyl) phenylacetic acid.

Figure 3 shows scheme C, which lists a process for the preparation of compounds of formula (7) wherein 4- (cyclopropylcarbonyl) phenylacetic acid is used as an intermediate.

Detailed Description

Compounds of formula (I) may be prepared by techniques and methods recognized and well known to those of ordinary skill in the art.

Straight-chain or branched alkyl groups containing 1 to 6 carbon atoms as used herein refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and straight-chain and branched pentyl and hexyl groups.

Piperidine derivatives of formula (I) may form pharmaceutically acceptable salts. Pharmaceutically acceptable acid addition salts of the compounds of the present invention are those with any suitable inorganic or organic acid. Suitable inorganic acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Suitable organic acids include carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclohexanesulfamic, ascorbic, maleic, hydroxymaleic and dihydroxymaleic acids, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetylbenzoic, mandelic, sulfonic acids such as methanesulfonic, ethanesulfonic and β -hydroxyethanesulfonic. Non-toxic salts of compounds of the formula with inorganic or organic bases are also included within the scope of the invention, and include, for example, salts with alkali metals such as sodium, potassium and lithium, salts with alkaline earth metals such as calcium and magnesium, salts with group IIIA light metals such as aluminum, salts with organic amines such as primary, secondary and tertiary amines, e.g., cyclohexylamine, ethylamine, pyridine, methylaminoethanol and piperazine. These salts may be prepared by conventional means, for example by treating a piperidine derivative of formula (I) with a suitable acid or base.

Scheme A illustrates a novel process for the preparation of piperidine derivatives of formula (I). In scheme A, R₁And R₂Is C₁～C₆Alkyl radical, C thereof₁～C₆The alkyl moiety is straight or branched; r₃Is H or C₁～C₆Alkyl radical, C thereof₁～C₆The alkyl moiety is straight or branched; x is Cl, Br or I.

Scheme a provides a general synthetic method for preparing compounds of formula (I).

In step A, phenylacetic acid halide (1), wherein X is Cl, Br or I, is reacted with N-O-dimethylhydroxylamine hydrochloride to produce N-methoxy-N-methylphenylacetamide (2).

For example, the appropriate phenylacetyl halide (1) is contacted with a molar excess of potassium carbonate in a suitable solvent such as toluene. Suitable phenylacetyl halides include phenylacetyl chloride, phenylacetyl bromide, or phenylacetyl iodide. The preferred phenylacetyl halide is phenylacetyl chloride. Then an equimolar amount of N-O-dimethylhydroxylamine hydrochloride dissolved in water was added. The reaction mixture is stirred at a temperature in the range of 0 ℃ to 66 ℃ for 1 to 24 hours. The preferred stirring time is 3 hours. The preferred temperature is 25 ℃. N-methoxy-N-methyl-phenylacetamide (2) is recovered from the reaction layer by extraction methods known in the art.

In step B, N-methoxy-N-methyl-phenylacetamide (2) is acylated with a 4-halo-substituted butyryl halide of the appropriate formula under Friedel-Crafts conditions to produce a mixture of para-and meta-substituted omega-halo-alpha-keto-phenylacetamides (3),

wherein each X independently represents Cl, Br or I. Surprisingly, the para isomer is easily isolated by crystallization as described in the next step C.

For example, in step B, N-methoxy-N-methylphenylacetamide (2) is contacted with the appropriate 4-halo-substituted butyryl halide with the appropriate Lewis acid under typical Friedel-Crafts acylation conditions. Examples of suitable 4-halo-substituted butanoyl halides include 4-chlorobutanoyl chloride, 4-bromobutanoyl bromide, and the like. A preferred 4-halo-substituted butyryl halide is 4-chlorobutyryl chloride. The reaction is carried out in a solvent such as carbon disulfide, 1, 2-dichloroethane, n-hexane, acetonitrile, 1-nitropropane, nitromethane, diethyl ether, carbon tetrachloride, dichloromethane, tetrachloroethane or nitrobenzene, with dichloromethane being the preferred solvent. The reaction may be carried out at a temperature ranging from 0 ℃ to 40 ℃ for 1/2 to 25 hours. The preferred stirring time is 6 hours. The preferred temperature is 40 ℃. The mixture of para-and meta-substituted omega-halo-alpha-keto-phenylacetamides (3) is recovered from the reaction layer by water quenching and extraction methods known in the art.

Suitable Lewis acids for the acylation reaction described in step B are known and known in the art. Examples of suitable Lewis acids are boron trichloride, aluminum chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride and zinc chloride. The selection and use of suitable lewis acids for the acylation reaction of step B is well known and recognized by those of ordinary skill in the art.

The para-substituted omega-halo-alpha-keto-phenylacetamide (3) is purified by the recrystallization technique described in step C.

For example, the product of the extraction process described in step B is stirred and collected in a suitable organic solvent, such as a heptane/ethyl acetate (about 4: 1) mixture. The solid is dissolved in a suitable solvent such as ethyl acetate at a temperature in the range of 25 ℃ to 76 ℃. The preferred temperature is 76 ℃. The solution is then contacted with activated carbon. The mixture is filtered and diluted with a suitable solvent such as heptane. The resulting slurry was heated to obtain a homogeneous solution. Crystallization of the substantially pure para-substituted omega-halo-alpha-keto-phenylacetamide (4) upon standing at room temperature.

In step D, the substantially pure para-substituted ω -halo- α -keto-phenylacetamide (4) is hydrolyzed to produce 4- (cyclopropylcarbonyl) phenylacetic acid (5).

For example, substantially pure para-substituted omega-halo-alpha-keto-phenylacetamide (4) is contacted with a molar excess of a suitable base, such as potassium hydroxide, in a suitable solvent, such as ethanol. The reactants are generally stirred together at a temperature in the range of 0 ℃ to 78 ℃ for 1 to 24 hours. The preferred stirring time is 18 hours. The preferred temperature is 25 ℃. 4- (cyclopropylcarbonyl) phenylacetic acid (5) is recovered from the reaction layer by acidification and extraction methods known in the art.

In step E, 4- (cyclopropylcarbonyl) phenylacetic acid (5) is esterified to the corresponding 4- (cyclopropylcarbonyl) phenylacetic acid ester (6).

For example, 4- (cyclopropylcarbonyl) phenylacetic acid (5) is reacted with an excess amount of a compound having a structure represented by the following formula (I) at a temperature in the range of 25 ℃ to 78 ℃Suitably straight or branched C₁～C₆The alcohol is reacted in the presence of a catalytic amount of a mineral acid such as hydrochloric acid or sulfuric acid, with hydrochloric acid being preferred. The reactants are typically stirred together for 2 to 72 hours. The preferred stirring time is 24 hours. The preferred temperature is 25 ℃. The corresponding 4- (cyclopropylcarbonyl) phenylacetate (6) was recovered from the reaction layer by basification and extraction methods known in the art. It can be purified by silica gel chromatography.

In step F, 4- (cyclopropylcarbonyl) phenylacetate (6) is acylated with an appropriate acylating agent to produce the corresponding [4- (cyclopropylcarbonyl) phenyl ] malonic acid diester (7).

For example, 4- (cyclopropylcarbonyl) phenylacetate (6) is reacted with a slight molar excess of the appropriate acylating agent. Suitable acylating agents include dialkyl carbonates such as dimethyl carbonate or diethyl carbonate, or chloroformates such as methyl chloroformate or ethyl chloroformate. The reaction is carried out in the presence of a non-nucleophilic base in a suitable aprotic solvent at a temperature of from 0 ℃ to the reflux temperature of the solvent for from 0.5 hours to 7 days. The preferred stirring time is 3 days. The preferred temperature is 25 ℃. Suitable solvents for the acylation reaction include tetrahydrofuran, dioxane, or tert-butyl methyl ether. The preferred solvent is tetrahydrofuran. Suitable non-nucleophilic bases for the acylation reaction include inorganic bases such as sodium bicarbonate, potassium bicarbonate, or hydrides such as sodium or potassium hydride, or alkoxides such as potassium tert-butoxide. The preferred base is sodium bis (trimethylsilyl) amide.

After acylation, the derivative formed by the acylation is optionally alkylated in situ with a suitable alkylating agent. Suitable alkylating agents include alkyl halides such as methyl iodide, methyl chloride or methyl bromide, or dialkyl sulfates such as dimethyl sulfate or diethyl sulfate. The reactants are generally stirred together at a temperature in the range of 0 ℃ to 30 ℃ for 1 to 48 hours. The preferred stirring time is 24 hours. The preferred temperature is 25 ℃.

The corresponding [4- (cyclopropylcarbonyl) phenyl ] malonic acid diester (7) was recovered from the reaction layer by extraction methods known in the art. It can be purified by chromatography on silica gel and/or recrystallization.

The keto function of 4- (endocarbonyl) phenylacetate (6) may be protected with a suitable protecting group, although this is not necessary in the acylation and subsequent alkylation in step F. The selection and use of appropriate protecting Groups for protecting the keto group of formula (6) is well known to those of ordinary skill in the art and is described in "Protective Groups in Organic synthesis", Theodora W.Greene, Wiley (1981). For example, suitable protecting groups for protecting keto functionality include aliphatic ketals such as dimethyl ketal, cyclic ketals such as 1, 3-dioxane and 1, 3-dioxanone, aliphatic dithioketals such as S, S-dimethyl ketal, cyclic dithioketals such as 1, 3-dithiane and 1, 3-dithiane derivatives, aliphatic monothioketals, cyclic monothioketals such as 1, 3-oxathiolanes.

In step G, [4- (cyclopropylcarbonyl) phenyl ] malonic acid diester (7) is ring-opened to give the corresponding [4- (4-halo-1-oxo-butyl) phenyl ] malonic acid diester (8).

For example, [4- (cyclopropylcarbonyl) phenyl ] malonic acid diester (7) is contacted with a suitable hydrogen halide such as hydrogen chloride, hydrogen bromide or hydrogen iodide in a suitable organic solvent or in the absence of a solvent. Suitable organic solvents include, in the temperature range from 0 ℃ to 100 ℃, alcoholic solvents such as ethanol, methanol, isopropanol or n-butanol, hydrocarbon solvents such as benzene, toluene or xylene, halogenated hydrocarbons such as chlorobenzene, chloroform or dichloromethane, or dimethylformamide, or acetic acid, or dioxane. Preferably, no solvent is used. The reactants are generally stirred together for 1 to 24 hours. The preferred stirring time is 4 to 16 hours. The preferred temperature range is 60 ℃ to 80 ℃. If solvent is present, [4- (4-halo-1-oxo-butyl) phenyl ] malonic acid diester (8) is recovered from the reaction layer by extraction methods known in the art and then the solvent is distilled off.

In step H, the halogen function of [4- (4-halo-1-oxo-butyl) phenyl ] malonic acid diester (8) is alkylated with α - (4-pyridyl) diphenylmethanol (commercially available from Aldrich Chemicals) to produce the corresponding [4- [4- [4- (hydroxybenzyl) -1-piperidinyl ] -1-oxobutyl ] phenyl ] malonic acid diester (9).

For example, the alkylation reaction is carried out in a suitable solvent, preferably in the presence of a non-nucleophilic base, optionally in the presence of a catalytic amount of an iodide source such as potassium iodide or sodium iodide. The reaction time is about 4 hours to 7 days, and the reaction temperature is 25 ℃ to the reflux temperature of the solvent. The preferred stirring time is 3 days. The preferred temperature is the solvent reflux temperature. Suitable solvents for the alkylation include alcoholic solvents such as methanol, ethanol, isopropanol or n-butanol, ketone solvents such as methyl isobutyl ketone, hydrocarbon solvents such as benzene, toluene or xylene and mixtures thereof with water, halogenated hydrocarbons such as chlorobenzene or dichloromethane, or dimethylformamide. A preferred solvent is toluene/water (10: 4). Suitable non-nucleophilic bases for the alkylation reaction include inorganic bases such as sodium, potassium or potassium bicarbonate or carbonate, or organic bases such as trialkylamines such as triethylamine or pyridine, or an excess of alpha- (4-pyridyl) diphenylmethanol may be used. The preferred base is potassium carbonate.

The corresponding [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -1-oxobutyl ] phenylmalonic acid diester (9) is recovered from the reaction layer by extraction methods known in the art. It can be purified by silica gel chromatography.

Although not necessary in the alkylation of step H, the keto function in [4- (4-halo-1-oxo-butyl) phenyl ] malonic acid diester (8) may be protected with a suitable protecting group. The selection and use of suitable protecting Groups for protecting the keto group of formula (8) is well known to those of ordinary skill in the art and is described in Protective Groups in Organic synthesis, Theodora W.Greene, Wiley (1981). For example, suitable protecting groups for the keto functionality include aliphatic ketals such as dimethyl ketals, cyclic ketals such as 1, 3-dioxane and 1, 3-dioxanones, aliphatic dithioketals such as S, S-dimethyl ketal, cyclic dithioketals such as 1, 3-dithiane and 1, 3-dithiane derivatives, aliphatic monothioketals, cyclic monothioketals such as 1, 3-oxathiolanes.

In step I, [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -1-oxobutyl ] phenyl ] malonic acid diester (9) is selectively reduced to the corresponding 4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] - α - (hydroxymethyl) -phenylacetic acid ester (10). This is accomplished by using an appropriate selective reducing agent. A suitable selective reducing agent is an agent or combination of agents that selectively reduces only one ester group in a malonate functional group to the corresponding hydroxymethyl moiety without reducing a second ester group in the malonate functional group. Suitable selective reduction agents include lithium tri-tert-butoxyaluminum hydride, or a combination of a suitable silane and a suitable titanocene-based catalyst.

For example, [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -1-oxobutyl ] phenyl ] propanedioic acid diester (9) is contacted with a suitable selective reducing agent such as lithium tri-tert-butoxyaluminum hydride in a suitable solvent such as tetrahydrofuran, diethyl ether or dioxane. The preferred solvent is tetrahydrofuran. The reactants are generally stirred together at a temperature in the range of 0 ℃ to 65 ℃ for 0.5 to 168 hours. The preferred stirring time is 48 hours. The preferred temperature is 25 ℃.

Is prepared from [4- [4- [4- (hydroxydiphenylmethyl) -1-piperidyl]-1-oxobutyl group]Phenyl radical]Preparation of 4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl using malonic acid diester (9)]Butyl radical]-alpha- (hydroxymethyl) -phenylacetic acid ester (10), catalytic reduction can also be employed using, for example, a suitable titanocene-based catalyst with a suitable silane, such as polymethylhydrosilane, as the stoichiometric amount of reducing agent. Suitable titanocene-based catalysts include the activated commonly known "Cp₂TiH "catalytic species. By, for example, adding 1 equivalent of Cp in a suitable solvent such as tetrahydrofuran₂TiCl₂To which 2 equivalents of ethylmagnesium bromide were added to synthesize the activated catalytic species "Cp₂TiH ", is well known to those of ordinary skill in the art.

For example, the catalytic reduction is carried out in a suitable solvent such as tetrahydrofuran or diethyl ether or dioxane at a temperature range of about 25 ℃ to the reflux temperature of the solvent. The preferred temperature for catalytic reduction is 65 ℃. The reaction time is 8 to 24 hours. The preferred stirring time is 18 hours. 4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl group]Butyl radical]The (alpha) - (hydroxymethyl) -benzeneacetic acid ester (10) can be prepared by reacting with Bu₄The NF is recovered from the reaction layer after the action by extraction methods known in the art. It can be purified by silica gel chromatography.

Alternatively, [4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl]-1-oxobutyl group]Phenyl radical]Preparation of optically pure 4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl group from malonic acid diester (9)]Butyl radical]-alpha- (hydroxymethyl) -phenylacetic acid ester (10) which can be reduced by chiral catalysis using a suitable chiral titanocene system, such as the Journal of American Chemical Society,11611667 to 11670 (1994).

It will be appreciated by those skilled in the art that the keto-protected [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -1-oxobutyl ] phenylmalonic acid diester (9) must be reacted with an appropriate deprotection reagent prior to the reduction reaction described in step I. The selection and use of appropriate deprotecting agents is well known to those of ordinary skill in the art and is described in "Protective Groups in Organic synthesis", Theodora W.Greene, Wiley (1981). For example, cleavage of the dimethyl ketal protecting group on the [4- [4- [4- (hydroxybenzyl) -1-piperidinyl ] -1-oxobutyl ] phenyl ] malonic acid diester (9) keto function can be accomplished by using iodotrimethylsilane or dilute acids known in the art.

In step J, 4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] - α - (hydroxymethyl) -phenylacetic acid ester (10) is optionally hydrolyzed to yield the corresponding 4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] - α - (hydroxymethyl) -phenylacetic acid (11).

For example, hydrolysis may be accomplished by methods known in the art, such as potassium carbonate in methanol, methanolic ammonium, potassium carbonate, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, sodium/pyridine in methanol, potassium cyanide in ethanol, and sodium hydroxide in aqueous alcohols, with sodium hydroxide being preferred. The reaction is usually carried out in an aqueous lower alcohol solvent such as methanol, ethanol, isopropanol, n-butanol, 2-ethoxyethanol or ethylene glycol or pyridine. A preferred solvent is a tetrahydrofuran/methanol/water (3: 2: 1) mixture. The reaction is usually carried out at a temperature ranging from room temperature to the reflux temperature of the solvent. The preferred temperature is 65 ℃. The reactants are generally stirred together for 1 to 24 hours. The preferred stirring time is 4 hours. 4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -phenylacetic acid (11) is recovered from the reaction layer by acidification and extraction methods known in the art.

Of course, the compounds of formula (I) may exist as a number of stereoisomers. The compound has more than one chiral center. For example, carboxy, hydroxymethyl, and methyl-linked benzylic carbons may exist in either the (R) or (S) form. In addition, the hydroxyl group, the hydrogen atom, the alkylamino group-attached benzylic carbon may exist in the (R) or (S) form. It will be further understood that the present invention encompasses various structural and stereoisomeric configurations of the compounds of formula (I), i.e., including individual isomers and mixtures of isomers.

Scheme B illustrates another novel process for the preparation of 4- (cyclopropylcarbonyl) phenylacetic acid. The compounds are useful for the synthesis of compounds of formula (I) and fexofenadine and related compounds. In scheme B, R₁Is C₁～C₆Alkyl radical, C thereof₁～C₆The alkyl moiety is straight or branched.

In step a of scheme B, phenylacetate (1), R thereof₁Is C₁～C₆Alkyl radical, C thereof₁～C₆The alkyl moiety is straight or branched chain and acylated with a 4-halo substituted butyryl halide of the appropriate formula under Friedel-Crafts conditions to form the corresponding para and meta substituted omega-halo-alpha-keto-phenylacetate (2) wherein X is Cl, Br or I,

wherein each X independently represents Cl, Br or I.

For example, in step a, phenylacetate (1) is contacted with a 4-halo-substituted butyryl halide under the general conditions of Friedel-Crafts acylation with an appropriate Lewis acid. Examples of suitable 4-halo-substituted butanoyl halides include 4-chlorobutanoyl chloride, 4-bromobutanoyl bromide, and the like. A preferred 4-halo-substituted butyryl halide is 4-chlorobutyryl chloride. The reaction is carried out in a solvent such as carbon disulfide, 1, 2-dichloroethane, n-hexane, acetonitrile, 1-nitropropane, nitromethane, diethyl ether, carbon tetrachloride, dichloromethane, tetrachloroethane or nitrobenzene, with dichloromethane being the preferred solvent. The reaction time is between about 1/2 and 25 hours and the reaction temperature is between 0 ℃ and 40 ℃. The para-meta substituted omega-halo-alpha-keto-phenylacetate (2) is recovered from the reaction layer by quenching with water and subsequent extraction as known in the art.

Suitable lewis acids for the acylation reaction described in step a are known and known in the art. Examples of suitable Lewis acids are boron trichloride, aluminum chloride, titanium tetrachloride, boron trifluoride, tin tetrachloride and zinc chloride. The selection and use of suitable lewis acids for acylation in step a is well known and recognized by those of ordinary skill in the art.

In step B of scheme B, the meta-and para-substituted ω -halo- α -keto-phenylacetate (2) mixture is hydrolyzed to produce a meta-and para-substituted (cyclopropylcarbonyl) phenylacetic acid (3) mixture.

For example, a mixture of meta-and para-substituted ω -halo- α -keto-phenylacetate (2) is contacted with a molar excess of a suitable base such as lithium hydroxide or potassium hydroxide in a suitable solvent such as ethanol. The reactants are generally stirred together at a temperature in the range of 0 ℃ to 78 ℃ for 1 to 24 hours. The preferred stirring time is 18 hours. The preferred temperature is 25 ℃. The meta-and para-substituted (cyclopropylcarbonyl) phenylacetic acid (3) can be recovered from the reaction layer by acidification and extraction methods known in the art.

Surprisingly, the substantially pure para isomer can be readily isolated by crystallization as outlined in step c of scheme B, which follows.

For example, the product of the extraction process outlined in step b is heated to reflux and dissolved in a suitable organic solvent such as a heptane/ethyl acetate (about 4: 1) mixture. The solution was treated with activated carbon and filtered. After cooling, the resulting solid is collected and recrystallized from a suitable organic solvent such as ethyl acetate/heptane. Substantially pure para-substituted (cyclopropylcarbonyl) phenylacetic acid (4) is obtained by crystallization at room temperature.

As shown hereinbefore, 4- (cyclopropylcarbonyl) phenylacetic acid is useful as an intermediate in the synthesis of compounds of formula (I). As shown in scheme C, 4- (cyclopropylcarbonyl) phenylacetic acid can also be used as an intermediate in a process for preparing a compound of the formula such as (7). Compounds of formula (7) include fexofenadine and related compounds.

In step a of scheme C, 4- (cyclopropylcarbonyl) phenylacetic acid (1) is esterified under the conditions set forth in step E of scheme A to the corresponding 4- (cyclopropylcarbonyl) phenylacetic acid ester (2) wherein R is₁Is C₁～C₆Alkyl radical, C thereof₁～C₆The alkyl moiety is straight or branched.

In scheme C, step b, the 4- (cyclopropylcarbonyl) phenylacetate (2) is alkylated with a suitable alkylating agent to produce the corresponding alkylated [4- (cyclopropylcarbonyl) phenyl ester]Phenylacetic acid ester (3) wherein R₁R is the same as defined in step a above₂And R₃Independently represents C₁～C₆Alkyl radical, C thereof₁～C₆The alkyl moiety is straight or branched.

For example, the reaction is typically carried out in a suitable aprotic solvent in the presence of a suitable non-nucleophilic base. Suitable solvents for the alkylation reaction include diglyme, tetrahydrofuran, dioxane t-butyl methyl ether. The preferred solvent is diglyme. Suitable non-nucleophilic bases for the alkylation reaction include sodium bis (trimethylsilyl) amide, inorganic bases such as sodium bicarbonate, potassium bicarbonate, or hydrides such as sodium or potassium hydride, or alkoxides such as potassium tert-butoxide. The preferred base is potassium tert-butoxide. Suitable alkylating agents include halogenated hydrocarbons such as methyl iodide, methyl chloride or methyl bromide, or dialkyl sulfates such as dimethyl sulfate or diethyl sulfate. The reactants are generally stirred together at a temperature in the range of 0 ℃ to 80 ℃ for 1 to 48 hours.

In step C of scheme C, alkylated [4- (cyclopropylcarbonyl) phenyl]Phenylacetic acid ester (3) is ring-opened to give the corresponding [4- (4-halo-1-oxo-butyl) phenyl ] ester]Phenylacetic acid ester (4) wherein R₁、R₂And R₃X is Cl, Br or I as defined in step b above. The reaction is carried out under the conditions set forth in step G of scheme A.

In step d, [4- (4-halo-1-oxo-butyl) phenyl]Phenylacetate (4) is alkylated with α - (4-pyridyl) diphenylmethanol under the conditions disclosed in U.S. p.no.4,254,129 to produce [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl]-1-oxobutyl group]Phenyl radical]Phenylacetic acid ester (5) wherein R₁、R₂And R₃The same as defined in step b above, which is incorporated herein by reference.

In step e of scheme C, [4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl group]-1-oxobutyl group]Phenyl radical]Phenylacetic acid ester (5) is reacted with a suitable reducing agent under the conditions disclosed in U.S. p.no.4,254,129 to produce 4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl]Butyl radical]Phenylacetic acid ester (6) wherein R₁、R₂And R₃As defined in step b above. Suitable reducing agents include, for example, sodium borohydride or potassium borohydride. Catalytic reduction using Raney nickel, palladium, platinum or rhodium catalysts may also be used in step e of scheme C.

In step f of scheme C, p-4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl]Butyl radical]Phenylacetic acid ester (6) is optionally hydrolyzed under the conditions disclosed in U.S. p.no.4,254,129 to produce 4- [ 1-hydroxy 4- [4- (hydroxybenzhydryl) -1-piperidinyl]Butyl radical]Phenylacetic acid (7) wherein R₂And R₃As defined in step b above.

Although not necessary in the alkylation steps b and d, the keto function of 4- (cyclopropylcarbonyl) phenylacetate (6) may be protected with a suitable protecting group. The selection and use of appropriate protecting Groups for protecting the keto group of formula (6) is well known to those of ordinary skill in the art and is described in "Protective Groups in Organic synthesis", Theodora W.Greene, Wiley (1981). For example, suitable protecting groups for protecting keto functionality include aliphatic ketals such as dimethyl ketal, cyclic ketals such as 1, 3-dioxane and 1, 3-dioxanone, aliphatic dithioketals such as S, S-dimethyl ketal, cyclic dithioketals such as 1, 3-dithiane and 1, 3-dithiane derivatives, aliphatic monothioketals, cyclic monothioketals such as 1, 3-oxathiolanes.

Representative examples of syntheses described in flow diagrams A, B and C are given below. The starting materials for schemes A, B and C are readily available to one of ordinary skill in the art. These examples are illustrative only and are not intended to limit the scope of the present invention in any way. The following terms are used herein (throughout the specification) to have the following meanings: "g" means g; "mmol" means millimole; "mL" refers to milliliters; "bp" refers to boiling point; "mp" means melting point; "° c" means degrees celsius; "mm Hg" refers to millimeter of mercury; "μ L" means microliter; "μ g" means micrograms; "μ M" means micromolar.

Synthetic examples set forth in scheme A

Step A: preparation of N-methoxy-N-methyl-phenylacetamide

Potassium carbonate (100g, 720mmol) was dissolved in water (100 ml). A solution of phenylacetyl chloride (50g, 320mmol) in toluene (250ml) was added. Then a solution of N-O-dimethylhydroxylamine hydrochloride (32g, 330mmol) in water (100mL) was added dropwise over 1 hour. After three hours, 10% hydrochloric acid (250mL) and t-butyl methyl ether (125mL) were carefully added. The organic phase was separated and washed with 10% hydrochloric acid and saturated sodium bicarbonate solution. Drying over anhydrous magnesium sulfate and concentration gave the title compound (55g, 95%).

And B: [4- (4-chloro-1-oxybutyl)]Preparation of (E) -N-methoxy-N-methylphenylacetamide

A slurry of aluminum chloride (87g, 650mmol) in dichloromethane (100mL) was cooled with an ice bath. 4-chlorobutyryl chloride (51g, 360mL) was added dropwise over 0.5 hours. N-methoxy-N-methylphenylacetamide (53g, 300mmol) was added over 0.5 hour. The reaction solution was allowed to warm to room temperature. Followed by heating and refluxing for 6 hours. After the solution was cooled to room temperature, it was poured into ice (1L) and dichloromethane (1L) was added. The organic phase was separated. The aqueous phase was extracted with dichloromethane (2X 500 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to give a solid containing the title compound and an approximately 1: 1 mixture of its stereoisomers.

And C: [4- (4-chloro-1-oxybutyl)]-N-methoxy-N-methyl-phenylacetamide crystals

The solid obtained in step B was slurried in heptane/ethyl acetate (about 4: 1) and then collected. The solid was dissolved in hot ethyl acetate and the resulting solution was treated with about 5g of activated carbon. Filtered through celite and heptane (60mL) was added. The slurry was heated until a homogeneous solution was obtained. The solution was left overnight at room temperature. The resulting crystalline solid was filtered and washed with heptane to give purified [4- (4-chloro-1-oxobutyl) ] -N-methoxy-N-methyl-phenylacetamide (20 g). The mother liquor was allowed to stand for 5 days and a second portion of the crystalline solid (3.0g) was collected, yielding a total of 23g (28%) of purified [4- (4-chloro-1-oxobutyl) ] -N-methoxy-N-methyl-phenylacetamide.

Step D: preparation of 4- (cyclopropylcarbonyl) phenylacetic acid

Purified [4- (4-chloro-1-oxobutyl) ] -N-methoxy-N-methyl-phenylacetamide (9.4g, 330mmol) was added to a solution of potassium hydroxide (22.0g) in ethanol (160 mL). Stirred for 18 hours. The solution was poured into dilute hydrochloric acid (30mL concentrated hydrochloric acid in 500mL water). The solution was extracted with three 500mL portions of ethyl acetate. The combined organic phases were dried over anhydrous magnesium sulfate and concentrated to give the title compound (6.4g, 95%).

Step E: preparation of ethyl 4- (cyclopropylcarbonyl) phenylacetate

4- (Cyclopropylcarbonyl) phenylacetic acid was dissolved in ethanol (150mL) containing concentrated sulfuric acid (10 drops). Stirred for 24 hours. Triethylamine (2mL) was added and the solution was concentrated. The residue was dissolved in water/ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. Purification by silica gel chromatography (400mL silica gel, 20% ethyl acetate in heptane as eluent) gave the title compound (7.0g, 88%).

Step E: preparation of methyl 4- (cyclopropylcarbonyl) phenylacetate

4- (Cyclopropylcarbonyl) phenylacetic acid was dissolved in methanol (100mL) containing concentrated sulfuric acid (10 drops). Stirred for 24 hours. Triethylamine (2mL) was added and the solution was concentrated. The residue was dissolved in water/ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated. Purification by silica gel chromatography (400mL silica gel, 20% ethyl acetate in heptane as eluent) gave the title compound (4.6g, 68%).

Step F: [4- (Cyclopropylcarbonyl) phenyl group]Preparation of methyl-malonic acid diethyl ester

Ethyl 4- (cyclopropylcarbonyl) phenylacetate (6.5g, 28mmol) and diethyl carbonate (4.0g, 34mmol) were dissolved in tetrahydrofuran (100 mL). 62mL (62mmol) of a 1.0 molar solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran was added over 0.5 h. Stirred for 28 hours. Methyl iodide (5.3g, 35mmol) was added. Stirring for 2 days. Water and ethyl acetate were added. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated. Purification by flash chromatography (200g silica gel, ethyl acetate/heptane as eluent) gave the title compound (1.43g, 17%).

Step F:[4- (Cyclopropylcarbonyl) phenyl group]Preparation of methyl-malonic acid dimethyl ester

Methyl 4- (cyclopropylcarbonyl) phenylacetate (1.5g, 6.0mmol) and dimethyl carbonate (930mg, 10.3mmol) were dissolved in tetrahydrofuran (10 mL). 20mL (20mmol) of a 1.0 molar solution of sodium bis (trimethylsilyl) amide in tetrahydrofuran are added over 0.5 h. Stirring for 3 days. Methyl iodide (5.3g, 35mmol) was added. Stirred for 24 hours. Water and ethyl acetate were added. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated. Purification by flash chromatography (50g silica gel, ethyl acetate/heptane as eluent) gave the title compound (315mg, 16%).

Alternatively, the following compounds may be prepared by the synthetic procedure described in step F:

[4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid, ethyl methyl diester

[4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid, methylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] methyl-malonic acid, butyl methyl diester

[4- (Cyclopropylcarbonyl) phenyl ] methyl-malonic acid, methyl amyl diester

[4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid, hexylmethyl diester

[4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid, ethylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] methyl-malonic acid, butylethyl diester

[4- (Cyclopropylcarbonyl) phenyl ] methyl-malonic acid, ethyl pentyl diester

[4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid, ethylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] methyl-malonic acid, dipropyl ester

[4- (Cyclopropylcarbonyl) phenyl ] methyl-malonic acid, butylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid, pentylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid, hexylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] methyl-malonic acid, dibutyl ester

[4- (Cyclopropylcarbonyl) phenyl ] methyl-malonic acid, butyl pentyl diester

[4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid, butylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] methyl-malonic acid, diamyl ester

[4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid, hexylpentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] methyl-malonic acid, dihexyl ester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, diethyl ester

[4- (cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, dimethyl ester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, ethyl methyl diester

[4- (cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, methylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, butyl methyl diester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, methyl amyl diester

[4- (cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, hexylmethyl diester

[4- (cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, ethylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, butylethyl diester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, ethylpentyl diester

[4- (cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, ethylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, dipropyl ester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, butylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, pentylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, hexylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, dibutyl ester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, butyl pentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, butylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, diamyl ester

[4- (cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, hexylpentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] ethyl-malonic acid, dihexyl ester

[4- (Cyclopropylcarbonyl) phenyl ] propyl-malonic acid, diethyl ester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, dimethyl ester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, ethyl methyl diester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, methylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] propyl-malonic acid, butyl methyl diester

[4- (Cyclopropylcarbonyl) phenyl ] propyl-malonic acid, methyl amyl diester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, hexylmethyl diester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, ethylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] propyl-malonic acid, butylethyl diester

[4- (Cyclopropylcarbonyl) phenyl ] propyl-malonic acid, ethylpentyl diester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, ethylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] propyl-malonic acid, dipropyl ester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, butylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, pentylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, hexylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] propyl-malonic acid, dibutyl ester

[4- (Cyclopropylcarbonyl) phenyl ] propyl-malonic acid, butyl pentyl diester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, butylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] propyl-malonic acid, diamyl ester

[4- (cyclopropylcarbonyl) phenyl ] propyl-malonic acid, hexylpentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] propyl-malonic acid, dihexyl ester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, diethyl ester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, dimethyl ester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, ethyl methyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, methylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, butyl methyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, methyl amyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, hexylmethyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, ethylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, butylethyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, ethyl pentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, ethylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, dipropyl ester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, butylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, pentylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] butyl-malonic acid, hexylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, dibutyl ester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, butyl pentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, butylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, diamyl ester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, hexylpentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] butyl-malonic acid, dihexyl ester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, diethyl ester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, dimethyl ester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, ethyl methyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, methylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, butyl methyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, methyl pentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, hexylmethyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, ethylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, butylethyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, ethyl pentyl diester

[4- (cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, ethylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, dipropyl ester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, butylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, pentylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, hexylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, dibutyl ester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, butylpentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, butylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, diamyl ester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, hexylpentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] pentyl-malonic acid, dihexyl ester

[4- (Cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, diethyl ester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, dimethyl ester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, ethyl methyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, methylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, butyl methyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, methyl pentyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, hexylmethyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, ethylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, butylethyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, ethylpentyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, ethylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, dipropyl ester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, butylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, pentylpropyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, hexylpropyl diester

[4- (Cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, dibutyl ester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, butylpentyl diester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, butylhexyl diester

[4- (Cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, diamyl ester

[4- (cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, hexylpentyl diester

[4- (Cyclopropylcarbonyl) phenyl ] hexyl-malonic acid, dihexyl ester

The method comprises the following steps: g: [4- (4-chloro-1-oxybutyl) phenyl]Preparation of methyl-malonic acid diethyl ester

Hydrogen chloride gas was bubbled through a solution of [4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid diethyl ester (570mg, 2.0mmol) in ethanol (4mL) for 5 minutes. The solution was heated to reflux. After 18 hours, the solution was cooled to room temperature and purged with nitrogen for 1 hour. To the residue were added ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The crude product was dissolved in ethanol (50mL) and hydrogen chloride gas was bubbled through the solution for 10 minutes. The solution was heated to reflux. After stirring for 2 days, the solution was concentrated. To the residue were added ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulfate and concentrated. Purification by flash chromatography (150g silica gel, 20% ethyl acetate in heptane as eluent) gave the title compound (409mg, 59%).

Step G:[4- (4-chloro-1-oxybutyl) phenyl]Preparation of methyl-malonic acid dimethyl ester

Hydrogen chloride gas was bubbled through a solution of [4- (cyclopropylcarbonyl) phenyl ] methyl-malonic acid dimethyl ester (315mg, 1.1mmol) in ethanol (3mL) -toluene (9mL) for 10 minutes. The solution was heated to 68C. After 4 hours, the solution was cooled to room temperature and purged with nitrogen for 1 hour. To the residue were added ethyl acetate and water. The organic phase was dried over anhydrous magnesium sulfate and concentrated to give the title compound (321mg, 91%).

Additionally, the following compounds may be prepared by the synthetic procedure described in step G:

[4- (4-bromo-1-oxybutyl) phenyl ] methyl-malonic acid, diethyl ester

[4- (4-iodo-1-oxybutyl) phenyl ] methyl-malonic acid, diethyl ester

[4- (4-bromo-1-oxybutyl) phenyl ] methyl-malonic acid, dimethyl ester

[4- (4-iodo-1-oxybutyl) phenyl ] methyl-malonic acid, dimethyl ester

Furthermore, all compounds derived from the change in position of substituents listed in the exemplary examples of step F can be prepared by the synthetic procedures described in step G.

Step H: [4- [4- [4- (Hydroxydiphenylmethyl) -1-piperidinyl group]-1-oxobutyl group]Phenyl radical]Preparation of methyl-malonic acid diethyl ester

[4- (4-chloro-1-oxobutyl) phenyl ] methyl-malonic acid diethyl ester (380mg, 1.1mmol), potassium carbonate (450mg, 3.2mmol), α - (4-pyridyl) diphenylmethanol (500mg, 1.9mmol), water (4mL) and toluene (10mL) were mixed together. The mixture was heated to reflux. After 7 days, the mixture was cooled to room temperature. Ethyl acetate and water were added. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated. Purification by flash chromatography (200g silica gel, 10% methanol/chloroform as eluent) gave the title compound (627mg, 99%).

Step H: [4- [4- [4- (Hydroxydiphenylmethyl) -1-piperidinyl group]-1-oxobutyl group]Phenyl radical]Methyl-malonic acidPreparation of dimethyl esters

[4- (4-chloro-1-oxobutyl) phenyl ] methyl-malonic acid dimethyl ester (300mg, 0.92mmol), potassium carbonate (350mg, 2.5mmol), α - (4-pyridyl) diphenylmethanol (500mg, 1.9mmol), water (3mL) and toluene (7mL) were mixed together. The mixture was heated to reflux. After 5 days, the mixture was cooled to room temperature. Ethyl acetate and water were added. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated. Purification by flash chromatography (150g silica gel, 10% methanol/chloroform as eluent) gave the title compound (387mg, 76%).

Furthermore, all compounds derived from the change in substituent position listed in the exemplary examples of step F can be prepared by the synthetic procedures described in step H.

Step I: 4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl group]Butyl radical]Preparation of (alpha) -alpha- (hydroxymethyl) -alpha-methyl-phenylacetic acid ethyl ester

[4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -1-oxobutyl ] phenyl ] methyl-malonic acid diethyl ester (515mg, 0.88mol) was dissolved in tetrahydrofuran (5mL) and the solution was cooled with an ice bath. Lithium tri-tert-butoxyaluminum hydride (10mL of a 1 molar solution in tetrahydrofuran, 10mmol) was added in portions over 20 minutes. After 2 hours, the solution was warmed to room temperature. After 48 hours, the solution was cooled with an ice bath and 10% aqueous potassium bisulfate (10mL) was added. The organic phase was washed with brine, dried over anhydrous magnesium sulfate and concentrated. Purification by flash chromatography (150g silica gel, 5% methanol/chloroform as eluent) gave the title compound (321mg, 67%).

In addition, the following compounds can be prepared by the synthetic procedure described in step I:

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-methyl-phenylacetic acid, methyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-methyl-phenylacetic acid, propyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-methyl-phenylacetic acid, butyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-methyl-phenylacetic acid, pentyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-methyl-phenylacetic acid, hexyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-ethyl-benzoic acid, methyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-ethyl-benzeneacetic acid, ethyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-ethyl-benzeneacetic acid, propyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-ethyl-benzeneacetic acid, butyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-ethyl-benzeneacetic acid, pentyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-ethyl-phenylacetic acid, hexyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-propyl-benzeneacetic acid, methyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-propyl-benzeneacetic acid, ethyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-propyl-phenylacetic acid, propyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-propyl-benzeneacetic acid, butyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-propyl-phenylacetic acid, pentyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-propyl-phenylacetic acid, hexyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-butyl-phenylacetic acid, methyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-butyl-benzeneacetic acid, ethyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-butyl-phenylacetic acid, propyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-butyl-phenylacetic acid, butyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-butyl-phenylacetic acid, pentyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-butyl-phenylacetic acid, hexyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-pentyl-phenylacetic acid methyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-pentyl-phenylacetic acid, ethyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-pentyl-phenylacetic acid, propyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-pentyl-phenylacetic acid, butyl ester

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-pentyl-phenylacetic acid, pentyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-pentyl-phenylacetic acid, hexyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-hexyl-phenylacetic acid, methyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-hexyl-phenylacetic acid, ethyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-hexyl-phenylacetic acid, propyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-hexyl-phenylacetic acid, butyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-hexyl-phenylacetic acid, pentyl ester

4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-hexyl-phenylacetic acid, hexyl ester

Step J: 4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl group]Butyl radical]Preparation of (alpha) -alpha- (hydroxymethyl) -alpha-methyl-phenylacetic acid

Ethyl 4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-methyl-phenylacetate (200mg, 0.37mmol) was dissolved in methanol (8mL) and tetrahydrofuran (12mL) and 1.6mL (1.6mmol) of a 1 molar aqueous solution of sodium hydroxide was added. After 4 hours, the solution was cooled to room temperature and 10% hydrochloric acid (about 1mL) was added dropwise to a pH of 5-6. The solution was concentrated and purified by flash chromatography (50g silica gel, methanol/chloroform gradient elution) to give the title compound (127mg, 66%).

In addition, the following compounds can be prepared by the synthetic procedure described in step J:

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-ethyl-phenylacetic acid

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-propyl-phenylacetic acid

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-butyl-phenylacetic acid

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-pentyl-phenylacetic acid

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-hexyl-phenylacetic acid

Synthetic examples set forth in scheme B

To a slurry of aluminum chloride (210g, 1.6mol) in dichloromethane (200mL) cooled in an ice bath was added 4-chlorobutyryl chloride (121g) dropwise while maintaining the vessel temperature below 10 ℃. After 10 minutes, ethyl phenylacetic acid (118g, 0.72mol) was added dropwise while maintaining the vessel temperature below 10 ℃. The mixture was stirred at room temperature for 1 hour, then heated to 40 ℃. After 4 hours, the solution was cooled to room temperature and poured onto crushed ice (2L). Dichloromethane (1L) was added. The organic phase was separated. The aqueous phase is extracted with 2 portions of dichloromethane, 1L each. The combined organic phases were dried (MgSO)₄) And concentrated. Toluene (1L) was added and the solution was concentrated to about 500 mL. Ethanol (500mL) was added. The solution was heated to 70 ℃ and HCl (g) bubbled for 20 minutes. The solution was sparged with nitrogen and concentrated. A1: 1 mixture of m-and p-ethyl (4-chloro-1-oxobutyl) phenylacetic acid (119g) was obtained by chromatography on silica gel (2.5L) using an ethyl acetate/heptane gradient. To a slurry of lithium hydroxide (23.5g, 0.56mol) in water (100mL) and ethanol (100mL) was added a 1: 1 mixture of meta, para-ethyl (4-chloro-1-oxobutyl) phenylacetic acid (50g, 0.19 mol). The reaction exothermed and was cooled with an ice bath. After 1 hour, the solution was warmed to room temperature. After 18 hours, the mixture was concentrated. Water (400mL) and concentrated hydrochloric acid (to pH4) were added. Ethyl acetate (600mL) was added. The organic phase was separated, washed with brine and dried (MgSO)₄). The solution was heated on a steam bath and activated carbon (about 3g) was added. The mixture was filtered through Celite and concentrated. The residue was dissolved in ethyl acetate (300mL) and heptane (600mL) with heating. Seed crystals are added. Upon cooling, an organic oil appeared. Heptane (500mL) was added and the mixture heated to reflux and treated with activated carbon (ca. 5g), filtered and seeded (seed). The solid was collected.¹H NMR showed it to be para: an approximately 4: 1 mixture of meta isomers. Recrystallization from ethyl acetate/heptane yielded 4- (cyclopropylcarbonyl) phenylacetic acid (4.3g, 11%).

Synthetic examples set forth in scheme C

Step a: preparation of ethyl 4- (cyclopropylcarbonyl) phenylacetate

See the preparation described in scheme A, step E, supra

Step b: [4- (cyclopropylcarbonyl)]Preparation of ethyl (alpha-dimethylphenylacetate)

A2L glass jacketed reactor was charged with ethyl 4- (cyclopropylcarbonyl) phenylacetate (232g, 1 mol), diglyme (150mL) and methyl chloride (127g, 2.5 mol). A heated additional vessel was charged with potassium tert-butoxide (182.4g, 1.6 moles) and diglyme (1050 mL). The reactor jacket was set at-10 ℃ and the contents of the additional vessel were heated to 60 ℃. The base solution is added at a rate to maintain the internal temperature of the reaction below 25 ℃. After the addition of the base solution was completed, an ethanol solution of 21% sodium ethoxide (86g, 0.3 mol) was added to remove the excess methyl chloride. Next, the entire reaction mixture was stirred with toluene (900mL) containing sodium bicarbonate (8.4g) and water (1200 mL). After phase separation the organic phase was washed with additional water (200mL) to remove the remaining potassium chloride salt. The whole solution was then acidified to pH 3 with concentrated hydrochloric acid without phase separation. The organic phase was freed of the solvent to give the title compound.

Step c: preparation of ethyl 4- (4-chloro-1-oxybutyl) -alpha-dimethylphenylacetate

To a 4L reactor equipped with a gas-line, overhead stirrer and temperature control was added ethyl [4- (cyclopropylcarbonyl) ] - α - α -dimethylphenylacetate (500 g). The oil was heated to 60 ℃ and the headspace evacuated. HCl was then added and the pressure was raised to 10 psig. After 4 hours, the excess HCl was drained off and the oil was purged with nitrogen for 5 minutes.

Step d: ethyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl radical]-1-oxobutyl group]Preparation of (alpha) -alpha-dimethyl phenylacetyl hydrogen chloride

A mixture of 4.5g (0.0163 moles) of α - α -diphenyl-4-piperidinemethanol, 6.1g (0.0205 moles) of ethyl 4- (4-chloro-1-oxybutyl) - α -xylyl acetate, 5g (0.05 moles) of potassium bicarbonate and 0.05g of potassium iodide in 50mL of toluene was stirred at reflux for 72 hours, followed by filtration, according to the procedure described by Carr et al in U.S. P. No.4,254,129. Then, ether and gaseous hydrogen chloride were added to the filtrate, and the resulting precipitate was collected and recrystallized in methanol-butanone and butanone several times to give ethyl 4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -1-oxobutyl ] - α - α -dimethylbenzylacetyl hydrochloride. M and P.205.5-208 ℃.

Step e: ethyl 4- [4[4- (hydroxydiphenylmethyl) -1-piperidinyl group]-1-hydroxybutyl radical]Preparation of-alpha-dimethylphenylacetic acid ester

According to the procedure described by Carr et al in U.S. P.No.4,254,129, 5.64g (0.01 mole) of ethyl 4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -1-oxobutyl ] -a-dimethylbenzylacetyl hydrochloride was hydrogenated with 0.5g of platinum oxide in 200mL of absolute ethanol and 50mL of methanol at about 50psi for about 1 hour until the infrared indicated that no ketone carbonyl functionality was present. The solution was filtered, the filtrate was concentrated, and the residue was recrystallized from butanone and methanol-butanone to give ethyl 4- [4- [4- (hydroxybenzhydryl) -1-piperidinyl ] -1-hydroxybutyl ] - α - α -dimethylbenzoyl hydrogen chloride, m.p.185 ° -187 ℃.

Step f: 4- [4[4- (hydroxydiphenylmethyl) -1-piperidinyl group]-1-hydroxybutyl radical]-alpha-dimethylphenylacetic acid

To 0.6g of ethyl 4- [4[4- (hydroxybenzhydryl) -1-piperidinyl ] -1-hydroxybutyl ] - α -dimethylbenzeneacetate in 20mL of pure ethanol was added 10mL of 50% sodium hydroxide solution according to the procedure described by Carr et al in U.S. P.No.4,254,129. The mixture was refluxed for 3.5 hours and concentrated to a solid, and a minimum amount of methanol was added to dissolve the residue. A10% hydrochloric acid solution was added until the pH reached 7, the methanol was removed by evaporation and water (25mL) was added. The generated precipitate is recrystallized in methyl ethyl ketone to obtain 4- [4- (hydroxybenzyl methyl) -1-piperidyl ] -1-hydroxybutyl ] -alpha-dimethyl phenylacetic acid with the temperature of M.P. of 195-197 ℃.

According to the invention, piperidine derivatives of formula (I) are used as histamine H₁-a receptor antagonist to alleviate symptoms in patients with histamine-mediated allergic disorders. Histamine-mediated allergic disorders are diseases or conditions having histamine-mediated allergic factors, such as seasonal allergic rhinitis, recurrent rhinitis, idiopathic nettle, asthma, and the like. The reduction of symptoms of an allergic disorder treated according to the invention refers to a reduction in the severity of the symptoms compared to when no treatment is performed, and does not necessarily indicate complete elimination of the disease.

Antihistaminic potential is measured by the test compound and H in the meninges of animals₁Linked to an antagonistic component of the histamine receptor³H]Affinity assay for the binding site of pyrenamine (pyrilamine). The affinity for this receptor may indicate that the test compound binds to central and peripheral H₁The potential for histamine receptor interactions.

The following method is used to determine the extent of binding of the test compound to the cortex of rat³H]Affinity of the binding site for pyramine.

Brain tissue of young male rats was removed. The cortex was dissected and stored at-20 ℃ or used immediately. Tissues in 10mL ice-cold 50nM K/NaPO₄The buffer (pH7.4) was homogenized with Polytron (set-up 6, 15 min). The homogenate was centrifuged at 40,000g for 15 minutes at 4 ℃. The pellet was resuspended in the same buffer to obtain 100mg wet weight/mL buffer. The culture tubes contained 50mM K// NaPO₄Buffer solution, promethazine (final concentration of 2.10-6M) or test compound,³H Pyramine (Final)Concentration of 2nM) and homogenate (10 mg wet weight per tube), the volume of solution in the final tube is 250-1000 mL. After incubation for 30 minutes at room temperature, the incubation was terminated by rapid filtration through a Whatman GF/B glass fiber filter, which was either pre-impregnated with water when using a Brandel cell harvester or not pre-impregnated with water when filtering through a 96-well Skraren cell harvester. The filters were rinsed with 3X 3mL of 0.9% NaCl (Brandel) or pre-wetted with NaCl (Skatron) and rinsed for 10 seconds. The filters were either transferred to scintillation vials and 10mL of Quickshafe A was added for liquid scintillation spectrometry, or a thin layer of solid scintillator was melted onto the filter, which was then counted with a beta plate (betaplate) beta counter.³Specific binding of H pirimid is determined by an amount that is higher than the blank value in the presence of 2.10-6M promethazine. Protein content of the membrane by the method of Lowry et al,J.Biol.Chem.193, 265 to 275 (1951). The Hill slope and IC are obtained by analysis of the displacement curves using GraphPad (GraphPad Software, Inc.) or similar programs₅₀The value is obtained. K_iThe value is given by Cheng et al inBiochem.Pharmacol.22, 3099-3108 (1973) using the Cheng-Prusoff formula obtained from the preceding saturation experiments carried out under the same conditions³H pyridoxamine K_DAnd (4) calculating the value.

4- [ 1-hydroxy-4- [4- (hydroxydiphenylmethyl) -1-piperidinyl group]Butyl radical]K of (alpha- (hydroxymethyl) -alpha-methyl-phenylacetic acid_iIs 3.6X 10^-7Piperidine derivatives of formula (I) are indicated to be useful in the treatment of histamine-mediated allergic disorders.

The term "patient" as used herein refers to an adult suffering from a histamine-mediated allergic disorder. For the purposes of the present invention, the term "adult" refers to a person 12 years old or older and may generally treat his allergic disorder using the amount of antihistamine recommended for adults.

Determining which patients would benefit from the present invention is well within the ability and knowledge of those skilled in the art. Those patients suffering from histamine-mediated allergic disorders are readily identified by clinicians in the art through clinical examination, physical examination, and medical/family history.

The amount of the novel compounds will vary depending on the mode of administration and may be any effective antiallergic amount. The amount of the novel compounds employed may vary widely and is provided in unit dosage form in an amount effective to provide the desired effect in an amount of from about 0.01 to about 20mg/kg of patient body weight per day. For example, the desired antihistaminic, antiallergic and bronchodilatory effects may be achieved by administering to the patient about 10mg to about 50mg daily of a piperidine derivative of formula (I). A preferred daily dosage is from about 20mg to about 40 mg. The most preferred daily dose is about 30 mg.

It will be appreciated that the daily dosage may be given to the patient in a single dose or in a multiple dose regimen. For example, a daily dose may be administered in the form of one, two, three or four doses. Typically, these unit doses are of equal strength and will be taken on a timed schedule such that the time intervals between each administration are approximately equal throughout the day. For example, once a day administration is about 1 time every 24 hours; twice a day administration is about 1 time every 12 hours; three times a day is about every 8 hours; four times a day is administered about every 6 hours.

In accordance with the present invention, the piperidine derivatives of formula (I) may be administered in any form or manner, including orally or parenterally, in an amount effective to ensure bioavailability. For example, the piperidine derivative of formula (I) may be administered orally, subcutaneously, transdermally, intranasally, etc. Oral administration is preferred. One skilled in the art of formulation can readily select the appropriate form and mode of administration depending on the identity of the compound selected, the state of the disease to be treated, the stage of the disease, and other relevant conditions.

The compounds may be administered alone or in pharmaceutical compositions together with pharmaceutically acceptable carriers or excipients, the proportions and nature of which are determined in accordance with the chosen route of administration and standard pharmaceutical practice. Although the piperidine derivative of formula (I) is effective as such, it may be formulated and administered in the form of a pharmaceutically acceptable acid addition salt for the purpose of stability, ease of crystallization, improved solubility, and the like. In addition, individual polymorphs, solvates or individual stereoisomers of piperidine derivatives of formula (I) [ i.e. (R, R) -4- [ 1-hydroxy-4- [4- (hydroxybenzyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-methyl-phenylacetic acid, (R, S) -4- [ 1-hydroxy-4- [4- (hydroxybenzyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-methyl-phenylacetic acid, (S, S) -4- [ 1-hydroxy-4- [4- (hydroxybenzyl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-methyl-phenylacetic acid and (S, r) -4- [ 1-hydroxy-4- [4- (hydroxybenzhydryl) -1-piperidinyl ] butyl ] -a- (hydroxymethyl) -a-methyl-phenylacetic acid ] can be used.

The invention encompasses compositions comprising a mixture or combination of piperidine derivatives of formula (I) with one or more inert carriers. These compositions can be used, for example, as analytical standards, as a convenient means of bulk transport (compliance means of making bulk transfers), or as pharmaceutical compositions. Analyzable amounts of piperidine derivatives of formula (I) are those amounts which can be readily determined using standard analytical procedures and techniques known and well known to those skilled in the art. The analyzable amount of the piperidine derivative of formula (I) is typically from about 0.001% to about 75% by weight of the composition. The inert carrier may be any material which does not degrade or covalently react with the piperidine derivative of formula (I). Examples of suitable inert carriers are water, aqueous buffers such as those typically used for High Performance Liquid Chromatography (HPLC) analysis in organic solvents such as acetonitrile, ethyl acetate, hexane, and the like, and pharmaceutically acceptable carriers or excipients.

More particularly, the present invention comprises a pharmaceutical composition in solid unit dosage form comprising from about 15mg to about 30mg of a piperidine derivative of formula (I) in admixture with a pharmaceutically acceptable carrier. The term "solid unit dosage form" as used herein encompasses solid dosage forms for oral administration, such as tablets, capsules and the like, as well as solid dosage forms for parenteral administration, such as transdermal patches for the ocular route and the like.

The pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid, or liquid material that can serve as a carrier or medium for the active ingredient. Suitable carriers or excipients are well known in the art. The pharmaceutical composition can be administered orally or parenterally, and can be administered in the form of tablets, capsules, solutions, suspensions, transdermal patches, and the like.

The piperidine derivatives of formula (I) may be administered orally, for example in admixture with an inert diluent or an edible carrier. It may be encapsulated in a gelatin capsule or compressed into tablets. For oral therapeutic administration, the piperidine derivative of formula (I) may be incorporated with excipients and used in the form of tablets, capsules, elixirs, suspensions, syrups, wafers, gums, and the like. These formulations should contain at least 4% of the compound of the invention, i.e. the active ingredient, but may vary from about 4% to about 70% of the weight of the unit depending on the particular form. The amount of compound present in the composition is such that the appropriate dosage is administered. Preferred compositions and formulations according to the present invention are prepared in such amounts that the oral unit dosage form contains from about 15mg to about 30 mg. The most preferred oral unit dose is a dose containing about 15mg to 30 mg.

Tablets, pills, capsules and the like may also contain one or more of the following adjuvants: binder such as microcrystalline cellulose, tragacanth or gelatin, excipient such as starch or lactose, disintegrant such as alginic acid, Primogel^TMCorn starch, carbonates such as sodium bicarbonate or calcium carbonate, lubricants such as magnesium stearate or Sterotex^TMGlidants such as colloidal silicon dioxide, sweetening agents such as sucrose or saccharin may be added, or flavoring agents such as peppermint, methyl salicylate or orange flavoring may be added. When the preparation is a capsule, it may contain, in addition to the above-mentioned types of materials, a liquid carrier such as polyethylene glycol or fatty oil. Other dosage forms may contain other various materials for modifying the physical form of the formulation, such as coatings. Thus, tablets or pills may be coated with sugar, shellac or other enteric coatingAnd (4) coating. Syrups may contain, in addition to conventional compounds, sucrose as a sweetening agent, certain preservatives, dyes, colors and flavors. The materials used to prepare these compositions must be pharmaceutically pure and non-toxic in the amounts used. Preferred excipients are corn starch, gelatin, lactose, magnesium stearate and sodium bicarbonate.

Oral unit dosage forms may be formulated for immediate release or sustained release. These forms can be formulated according to conventional techniques and procedures to achieve the desired solubility and bioavailability.

Alternatively, the piperidine derivatives of formula (I) may be formulated as solutions or suspensions for oral or parenteral administration. These preparations should contain at least 0.1% by weight of the piperidine derivative of formula (I), but may vary from 0.1 to about 50%. The amount of piperidine derivative of formula (I) in such compositions is such that the appropriate dosage is obtained following oral or parenteral administration.

The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents, antibacterial agents such as benzyl alcohol or methyl parabens, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffer salts such as acetates, citrates or phosphates, and tonicity adjusting agents such as sodium chloride or dextrose.

Transdermal dosage forms of the piperidine derivatives of formula (I) may be prepared by conventional techniques well known in the pharmaceutical arts, for example by incorporating the piperidine derivatives of formula (I) into various polymeric reservoir matrix materials. These polymeric reservoir matrix materials may include pressure sensitive acrylics, silicones, polyurethanes, ethylene vinyl acetate copolymers, polyolefins, as well as rubber adhesive matrices, medical grade silicone fluids, and medical grade silicone elastomers, which are common in the art to form drug transdermal delivery reservoirs.

It will also be appreciated that the piperidine derivatives of formula (I) according to the present invention may be formulated with a wide variety of active ingredients commonly used in combination with antihistamines, such as decongestants including pseudoephedrine and the like, analgesics such as paracetamol and the like, non-steroidal anti-inflammatory drugs such as ibuprofen and the like.

Claims (2)

1. A compound of the formula,

wherein

R₁Is H or C₁～C₆Alkyl radical, and said C₁～C₆The alkyl moiety is straight or branched;

R₂and R₃Independently represent C₁～C₆Alkyl radical, and said C₁～C₆The alkyl moiety is straight or branched; or

A pharmaceutically acceptable acid addition salt thereof.

2. The compound of claim 1, wherein R₁Is methyl, and R₂And R₃Is ethyl.