MXPA98004894A

MXPA98004894A - Procedure for the production of piperid derivatives

Info

Publication number: MXPA98004894A
Application number: MXPA/A/1998/004894A
Authority: MX
Inventors: E D Ambra Thomas; M Pilling Garry
Original assignee: Albany Molecular Research Inc
Priority date: 1995-12-21
Filing date: 1998-06-18
Publication date: 1999-07-06

Abstract

The present invention relates to a process for the preparation of piperidine derivative compounds of the formulas (I, II), wherein n is 0 or 1; R1 is a hydrogen atom or a hydroxy group; R2 is a hydrogen atom or, when n is or, R1 and R2 taken together form a second bond between the carbon atoms carrying R1 and R2, provided that when n is 1, R1 and R2 are each hydrogen atom, R3 is -COOH0-COOR4; alkyl or aryl portion: A, B and D are substituents of the rings each of which may be the same or different and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy and other substituents. The process comprises obtaining a regioisomer of formula (III), wherein Z is -CG1G2G3 (VIoV), m is an integer from 1 to 6, Q and Y are the same or different and are selected from the group consisting of O, S and NR5; G1, G2 and G3 are the same or different and are selected from the group consisting of OR8, SR8 and NR8R9; R6 and R7 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion, a portion aryl, OR8, SR8 and NR8R9, and R5, R8 and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion and transforming the regioisomer into a piperidine derivative compound, with a piperidi

Description

PROCEDURE FOR THE PRODUCTION OF PIPERIDINE DERIVATIVES FIELD OF THE INVENTION The present invention relates to processes for the production of piperidine derivatives. BACKGROUND OF THE INVENTION Terfenadine, which is 1- (p-tert-butylphenyl) -4- [4'- (α-hydroxydiphenylmethyl) -1'-piperidinyl] -butanol, is a non-sedating antihistamine. It is reported to be a specific H receptor antagonist that is also devoid of any anticholinergic, antiserotoninergic, and antiadrenergic effects, both in vi tro and in vivo. See D. McTavish, K. L. Goa, M. Ferril, Drugs, 1990, 39, 552; C. R. Kingsolving, N. L. Monroe, A. A. Carr, Pharmacologist, 1973, 15, 221; J. K. Woodward, N. L. Munro, Arzneiirt-Forsch, 1982, 32, 1154; K.V. Mann, J. J. Tietze, Clin. Pharm. 1989, 6, 331. Great efforts have been made to investigate the structure-activity relationships of the terfenadine analogues and this is reflected in the large number of North American Patents described for this compound and their related structures, such as the following: US Patent 3,687,956 to Zivkovic REF: 27680 US Patent 3,806,526 to Carr et al. U.S. Patent No. 3,829,433 to Carr et al. US Patent 3,862,173 to Carr et al. U.S. Patent No. 3,878,217 to Carr et al. U.S. Patent No. 3,922,276 to Duncan et al.

U.S. Patent No. 3,931,197 to Carr et al. U.S. Patent No. 3,941,795 to Carr et al. U.S. Patent No. 3,946,022 to Carr et al. U.S. Patent No. 3,956,296 to Duncan et al. US Patent 3,965,257 to Carr et al. U.S. Patent No. 4,742,175 to Fawcett et al. In metabolic studies in humans and animals, it has been shown that terfenadine undergoes extensive first pass hepatic metabolism and after normal doses, it can not be detected in the plasma unless very sensitive assays are used. A specific liver enzyme, cytochrome P-450, transforms terfenadine into the main metabolite 4- [4- [4- (hydroxydiphenyl-ethyl) -1-piperidinyl] -1-hydroxybutyl] -aa-dimethylphenylacetic acid, also known as the metabolite carboxylic acid of terfenadine. This metabolite can be easily detected in plasma and is considered to be the active form of terfenadine administered orally.

The side effects reported for terfenadine are cardiac arrhythmias (ventricular tachyarrhythmias, spot torsion, ventricular fibrillation), sedative effect, gastrointestinal discomfort, dry mouth, constipation and / or diarrhea. The most serious of these and potentially life-threatening are cardiac arrhythmias, which are related to the ability of terfenadine to prolong the cardiac QT interval and have only been reported in patients with liver disease or in whom Once they are given drugs such as the antifungal agent ketoconazole or the antibiotic erythromycin and terfenadine. As a result of these adverse events, the FDA (Food and Drug Administration of the United States), in 1992, requested that terfenadine include a warning label. Although terfenadine OTC formulations have been developed, the potentially serious side effects observed in some patients will always be a significant obstacle to regulatory approval. As cardiac side effects of terfenadine have been reported in patients with impaired liver function, as well as in patients who are also taking antibiotics that are known to suppress the function of liver enzymes, it has been speculated that cardiac side effects should be to the accumulation of terfenadine and not to the accumulation of the terfenadine carboxylic acid metabolite. Patch studies in feline ventricular myocytes support the argument that terfenadine and not the carboxylic acid metabolite, is responsible for cardiac side effects. At a concentration of 1 μM, terfenadine caused more than 90% inhibition of the delayed rectifying potassium current. At concentrations of up to 5 μM, the terfenadine carboxylic acid metabolite had no significant effect on the potassium current in this assay (see R. L. Woosley, Y. Chen, J. P. Frieman, and R. A. Gillis, JAMA 1993, 269, 1532). Since inhibition of iron transport has been linked to cardiac abnormalities such as arrhythmias, these results indicate that terfenadine carboxylic acid is probably not capable of causing cardiac arrhythmias at the dose levels at which this side effect is caused by the terfenadine itself. Carebastine, which is 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-oxobutyl] -a, a-dimethyl-phenylacetic acid, is the carboxylic acid metabolite of ebastine, 1- (p. -tert-butylphenyl) -4- [4 '- (a-diphenylmethoxy) -1'-piperidinyl] -butanol. Both compounds have potent selective properties of the Hi receptor of histamine and calcium antagonist properties, and have proven useful in the treatment of a variety of respiratory, allergic and cardiovascular disease disorders. These compounds relax bronchial and vascular smooth muscle in vi tro and in vivo, and inhibit the constrictive influence of norepinephrine, potassium ions, and several other agonist drugs. The compounds also inhibit the responses of intestinal and tracheal preparations to histamine, acetylcholine and barium chloride, and block the bronchoconstriction induced by aerosolized histamine in guinea pigs, in doses lower than 1 mg / kg of body weight of the animal, administered by orally. They also possess antianaphylactic properties in rats, inhibit skin lesions against a variety of anaphylactic mediators (histamine, 5-hydroxytryptamine, bradykinin, LCD4, etc.) and antagonize the Schutz-Dale response in sensitive guinea pigs. The piperidine derivatives related to the terfenadine carboxylic acid metabolite are described in the following North American Patents: US Pat. No. 4,254,129 to Carr et al. U.S. Patent No. 4,254,130 to Carr et al.

U.S. Patent No. 4,285,957 to Carr et al. U.S. Patent No. 4,285,958 to Carr et al. In these patents, 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, α-dimethylbenzeneacetic acid and related compounds are prepared by the alkylation of a substituted piperidine derivative of the formula: with a phenylketone substituted with? -haloalkyl of the Formula: wherein the substituents halo, R, R, n, Z and R are described in column 6 of US Pat. No. 4,254,130. Similarly, the US Patent US 4,550,116 of Soto et al. , describes the preparation of piperidine derivatives related to carebastine, by reacting the phenylketone substituted with? -haloalkyl, with a substituted hydroxypiperidine derivative of the Formula: U.S. Patent No. 4,254,130 teaches that? -haloalkyl substituted phenylketones, wherein Z is hydrogen, are prepared by reacting a straight or branched chain C 1-6 lower alkyl ester of α-dimethylphenylacetic acid , with a compound of the following Formula: halo (CH2) m C halo under the conditions of an acylation of Friedel-Crafts, where halo and m radicals are described in column 11 of US Patent US 4,254,129. The reaction is carried out in carbon disulfide as the preferred solvent.

Other methods for the production of the terfenadine carboxylic acid metabolite are described in PCT Applications Nos. WO 95/00482, WO 94/03170 and WO 95/00480. The present invention relates to an improved process for the preparation of the carboxylic acid metabolite terfenadine and carebastine. BRIEF DESCRIPTION OF THE INVENTION The present invention relates to methods for preparing piperidine derivative compounds of the formulas: where n is 0 or 1; R1 is a hydrogen atom or a hydroxy radical; R2 is a hydrogen atom; or, when n is 0, R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2, provided that when n is 1, then R 1 and R are each hydrogen atoms; R3 is a radical -COOH or -COOR4; 4 R is an alkyl or aryl moiety; A, B and D are substituents of the rings, each of which may be the same or different, and are selected from the group consisting of hydrogen atoms, halogen, alkyl, hydroxy, alkoxy and other substituents, or a salt thereof. the same. The piperidine derivative compound is prepared from a regioisomer having the following Formula: where Z is a radical -CG 1G2G3, or m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S and NR; G 1, G2 and G3 are the same or different and are O Q selected from the group consisting of OR, SR and NR R; R and R are the same or different and are selected from the group consisting of hydrogen atoms, an alkyl portion, an aryl portion, radicals OR8, SR8 and NR8R9; and R 5, R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen atoms, an alkyl portion and an aryl portion. Then, the regioisomer is transformed into the piperidine derivative having a keto group with a piperidine compound. The present invention also relates to a regioisomer having the Formula: The present invention also relates to processes for preparing a regioisomer with the Formula: In one aspect of the present invention, the process for preparing the regioisomer includes acylating a disubstituted methylbenzene derivative in a, a, of the Formula: wherein X is a halogen, trialkyltin or triaryltin, trialkylborate or triarylborate, alkylhalosilicon, trialkylsilicon, a substituted sulphonic ester, or substituents useful in organometallic coupling reactions, with a compound of the formula: ? wherein X is a halogen; an alkali metal oxide; a portion having the Formula -OR, a portion having the Formula -SR; or an amine; and R is selected from the group consisting of hydn atoms, an alkyl portion and an aryl portion, under conditions effective to produce the regioisomer. In another aspect of the present invention, the process for preparing the regioisomer includes reacting a 4- (a, disubstituted) -tolucic acid derivative of the Formula: wherein 2 X is a hydn atom; a halogen, an alkali metal oxide; a portion of the Formula -OR; a portion of the Formula -SR 10; or an amine; and R is selected from the group consisting of hydn atoms, an alkyl portion and an aryl portion, with a compound of the Formula: X '~ < ] wherein X is a halogen, a trialkyltin or triaryltin radical, trialkylborate or triarylborate, alkylhalosilicon, trialkylsilicon, a substituted sulphonic ester, or substituents useful in organometallic coupling reactions, under conditions effective to produce the regioisomer. In another aspect of the present invention, the process for preparing a regioisomer includes preparing a regioisomer without a-position substitutions, a, precursor, having the following Formula: and methylating the non-substituted regioisomer precursor in position a, under effective conditions to produce the regioisomer. The present invention also relates to a disubstituted methylbenzene derivative in a, a position of the Formula: CH- and an unsubstituted methylbenzene derivative in position a, a of the formula: A The present invention also relates to an oxobutyl derivative of the Formula: as well as precursors of piperidine derivatives of the Formulas: DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for preparing piperidine derivative compounds of the formulas: CH, O where n is 0 or 1; R is a hydn atom or a hydroxy radical; 2 R is a hydn atom; or, when n is 0, R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2, provided that when n is 1, then R 1 and R are each hydn atoms; R3 is a radical -COOH or -COOR4; R is an alkyl or aplo moiety; A, B and D are substituents of the rings, each of which may be the same or different, and are selected from the group consisting of hydn atoms, halogen, alkyl, hydroxy, alkoxy and other substituents, or a salt thereof. the same. These piperidine derivative compounds may be in the form of 4-diphenylmethylpiperidine derivatives represented by the following Formulas: CH, where A, B, D and R are as previously defined. The piperidine derivative compounds also include 4- (hydroxydiphenylmethyl) -piperidine derivatives in accordance with the following Formulas: Or where A, B, D and R are as previously defined. Another useful class of piperidine derivatives are the 4-diphenylmethylenepiperidine derivatives according to the following formulas: CH, O CH, where A, B, D and R are as previously defined. Another useful class of piperidine derivative compounds are the 4-diphenylmethoxypiperidine derivatives of the following Formulas: or where A, B, D and R are as previously defined. Examples of radicals R are substituted or unsubstituted, straight or branched chain alkyl groups, including methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl , benzyl and 4-methylbenzyl, and substituted or unsubstituted aryl groups, including phenyl, tolyl and xylyl. Illustrative examples of the compounds prepared by the process of the present invention are the following: 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- hydroxybutyl] -a, α-dimethylbenzenacetic acid; 4- [4- [4- (diphenylmethyl) -1-piperidinyl] -1- hydroxybutyl] -a, α-dimethylbenzeneacetic acid; 4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1- hydroxybutyl] -a, α-dimethylbenzeneacetic acid; 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- hydroxybutyl] -a, α-dimethyl-3-hydroxybenzenacetic acid; - 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- hydroxybutyl] -a, a-dimethyl-2-hydroxybenzenacetic acid; 4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1- hydroxybutyl] -a, α-dimethyl-3-hydroxybenzenacetic acid; 4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1- hydroxybutyl] -a, α-dimethylbenzeneacetic acid; 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- hydroxybutyl] -a, ethyl-a-dimethylbenzenacetate; 4- [4- [4- (diphenylmethyl) -1-piperidinyl] -1-hydroxy-butyl] -a, n-pentylacetate-n-pentylacetate;4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1-hydroxybutyl] -a, ethyl-dimethylbenzene acetate; 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- hydroxy-butyl] -a, methyl-dimethylbenzeneacetate; 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- hydroxybutyl] -a, a-dimethyl- (3-hydroxybenzene) -acetic acid ethyl ester; 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1- hydroxybutyl] -a, a-dimethyl- (2-hydroxybenzene) -n-propyl acetate; 4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1-hydroxy-butyl] -a, [alpha] -dimethyl- (3-hydroxybenzene) n-hexyl acetate; 4- [4- [4- (diphenylmethylene) -1-piperidinyl] -1-hydroxybutyl] -a, ethyl-dimethylbenzene acetate; 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1- hydroxybutyl] -a, α-dimethylbenzeneacetic acid; 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1- hydroxybutyl] -a, α-dimethyl-3-hydroxybenzeneacetic acid; - 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1- hydroxybutyl] -a, a-dimethyl-2-hydroxybenzeneacetic acid; 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1- hydroxybutyl] -a, α-dimethyl-3-hydroxybenzeneacetic acid; 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1- hydroxybutyl] -a, α-dimethylbenzeneacetic acid; 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxy-butyl] -a, n-pentylacetate-dimethylbenzenacetate; 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -a, ethyl a-dimethylbenzeneacetate; 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxy-butyl] -a, a-dimethyl- (3-hydroxybenzene) -acetic acid ethyl ester; 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethyl- (2-hydroxybenzene) -n-propyl acetate; 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethyl- (3-hydroxybenzene) -hexyl acetate; and - ethyl 4- [4- [4- (diphenylmethoxy) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylbenzeneacetate; Particularly preferred are the compounds of the formulas: Optionally, both diphenyl groups of the piperidine compound can be substituted with alkyl (eg, methyl) radicals in the para position, with respect to methylene, such as OR The compounds prepared by the methods of the present invention can be pharmaceutically acceptable salts in the form of acid or basic addition salts, organic or inorganic, of the above compounds. Suitable inorganic acids are, for example, hydrochloric, hydrobromic, sulfuric and phosphoric acids. Suitable organic acids include carboxylic acids such as acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymelic, dihydroxymethic, benzoic, phenylacetic, 4-aminobenzoic, anthranilic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic. Also suitable are sulfonic acids such as methanesulfonic acid, ethanesulfonic acid and β-hydroxyethane sulfonic acid. Non-toxic salts of the compounds of the above-identified Formulas can be formed with organic or inorganic bases including, for example, alkali metal salts such as sodium, potassium and lithium, alkaline earth metals eg calcium and magnesium, light metals of the group IIIA, for example aluminum, organic amines such as primary, secondary or tertiary amines, for example cyclohexylamine, ethylamine, pyridine, methylaminoethanol and piperazine. These salts are prepared by conventional means, for example by treating the piperidine derivative compounds of the Formulas: or 1 2 3 where A, B, D, n, R, R and R are as previously defined, with an appropriate acid or base. The piperidine derivative compounds prepared by the methods of the present invention can be used as biologically active compounds in pharmaceutical compositions. These compounds are useful as antihistamines, antiallergic agents and bronchodilators. They can be administered alone or with suitable pharmaceutical vehicles, they can be in solid or liquid form such as tablets, capsules, powders, solutions, suspensions or emulsions. The compounds prepared by the methods of the present invention can be administered orally, parenterally, for example subcutaneously, intravenously, intramuscularly, intraperitoneally, by transnasal instillation or by application to mucous membranes, such as those of the nose, throat and bronchial tube. . The application to the mucous membranes is carried out with an aerosol containing small particles of a compound of the present invention in the form of a spray or dry powder. The amount of the compound administered will vary depending on the patient and the mode of administration and can be any effective amount. The amount of the compound administered can vary over a wide range to provide, in a unit dose, an effective amount of about 0.01 to 20 mg / kg of body weight of the patient, per day, to achieve the desired effect. For example, antihistaminic, antiallergic and bronchodilator effects can be obtained by consuming a dosage unit in a form such as a tablet containing from 1 to 50 mg of the compound of the present invention, from 1 to 4 times a day. The solid dosage unit forms can be of the conventional type. This solid form can be a capsule, such as an ordinary gelatin capsule containing the compound of the present invention and a carrier, for example inert lubricants and fillers such as lactose, sucrose or corn starch. In another embodiment, the compounds are tableted with conventional tablet bases such as lactose, sucrose or corn starch, in combination with binders such as acacia gum, corn starch or gelatin, disintegrating agents such as corn starch, potato starch or alginic acid, and a lubricant such as stearic acid or magnesium stearate. The compounds prepared according to the present invention can also be administered in injectable doses, by placing in solution or suspension the compounds of the present invention in a physiologically acceptable diluent, with a pharmaceutical carrier. Such vehicles include sterile liquids such as water and oil, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants. Some illustrative oils are petroleum oil, oils of animal origin, vegetable oils or oils of synthetic origin, for example peanut oil, soybean oil or mineral oil. In general, water, saline, aqueous dextrose solution and related sugar solutions, glycols such as propylene glycol or polyethylene glycol, are preferred liquid carriers, particularly for injectable solutions. For use as aerosols, the compounds in solution or suspension can be packaged in a pressurized aerosol container, together with suitable propellants, for example hydrocarbon propellants such as propane, butane or isobutane, with conventional adjuvants. These compounds can be administered in a non-pressurized form, such as a nebulizer or atomizer. The compounds prepared according to the present invention can be used for the treatment of warm-blooded animals, birds and mammals. Examples of such beings include humans, cats, dogs, horses, sheep, cows, pigs, rams, mice and guinea pigs. In accordance with one aspect of the present invention, the piperidine derivative compounds are prepared by obtaining a regioisomer of the following Formula: and transforming the regioisomer into the piperidine derivative compounds of the present invention having a keto group with a piperidine compound. Subsequently, the resulting piperidine compounds with a keto group can be transformed by reduction to the above-described piperidine compounds, with a hydroxyl group. A is the ring substituent, each of which may be different or may be the same and is selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy or other substituents. Z can be a carbon atom to which three electron-rich groups are linked, such as portions having the formula CG 1 G 2 G 3. G1, G2 and G3 they may be the same or different and are selected, for example, from the group consisting of OR, SR and O Q fi Q NR R, where R and R are the same or different and can be hydrogen; an alkyl portion, including substituted or unsubstituted, branched or straight-chain nickel portions, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; or an aryl portion, including substituted or unsubstituted aryl moieties such as phenyl, tolyl and xylyl. Examples of the Z groups include triethoxymethyl or trimethoxymethyl portions. Z may also be a heterocyclic portion of the following Formula: wherein m is an integer from l to 6 and Q and Y are independently oxygen, sulfur or a substituted or unsubstituted amine of the formula NR. R can be hydrogen; an alkyl portion including substituted or unsubstituted, branched or straight chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl , benzyl and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; or an aryl portion, including substituted or unsubstituted aryl moieties such as phenyl, tolyl and xylyl. It should be understood that R and R, which are the two substituents linked to each methylene (ie to each CH2 group), of which there are m in the above formulas, are independently selected from each other. Furthermore, it should be understood that the R and R groups in a methylene may be the same or different as those of the other methylenes. Each R and R may be hydrogen, an alkyl portion including substituted or unsubstituted, branched or straight chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n -pentyl, neopentyl, n-hexyl, 2-methylpentyl, cyclohexyl, benzyl and 4-methylbenzyl, preferably having 1 to 7 carbon atoms; an aryl portion including substituted or unsubstituted aryl moieties, such as phenyl, tolyl, xylyl and naphthyl; or a portion having the Formulas OR, SR8 or NR 8R9, wherein R8 and R9 are as previously defined where Z had the Formula CGG G3. Preferred examples of Z include isoxazoline portions of the Formula wherein R, R, R and R are the same or different and can be hydrogen; an alkyl portion including substituted or unsubstituted, branched or straight chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl , 2-methylpentyl, cyclohexyl, benzyl and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; an aryl portion including substituted or unsubstituted aryl portions such as phenyl, tolyl, xylyl and p-naphthyl; or a portion having the Formulas OR, SR or p Q fi Q NR R, where R and R are as previously defined. Preferably, m is 2 and R12 and R13 are hydrogen. More preferably, R 12 and R 13 are hydrogen and R and R are each an alkyl portion of 1 to 7 carbon atoms. More preferably, Z is 4,4-dimethylisoxazolin-2-yl, wherein each R12 and R13 are hydrogen, and R and R are methyl. A variety of methods can be used to obtain these regioisomers. Procedure to Produce the Regioisomer. In one embodiment of the present invention, the regioisomer is produced by acylating a disubstituted methylbenzene derivative in the a, a position of the Formula: CH3 with a compound of the formula: X2 curro? under effective conditions to produce the regioisomer of the Formula: In this embodiment, the acylating agent is a cyclopropyl derivative. In another embodiment of the present invention, the acylating agent is a derivative of 4- (a, α-disubstituted) -tolucic acid. In this embodiment, the regioisomer is produced by reacting a 4- (a, disubstituted) -tolucic acid derivative of the Formula: with a compound of the formula: under effective conditions to acylate the compound, producing the regioisomer. Regardless of whether the regioisomer is produced using the process with an acylation agent derived from cyclopropyl or the process with a derivative of 4- (a, α-disubstituted) -tolucic acid, X can be a halogen; a trialkyltin or triaryltin radical; trialkylborate or triarylborate; alkylhalosilicon; trialkylsilicon; or a substituted sulfonic ester such as tosylate, mesylate or triflate, with any straight or branched chain alkyl group and preferably having from 1 to 4 carbon atoms. Alternatively, X can be a useful substituent in organometallic coupling reactions, including lithium or magnesium compounds derived from bromine or iodine. As used herein, the alkylhalosilicon is a tetravalent silicon atom bonded to at least one halogen and at least one alkyl group. The remaining valence of the silicon is linked either to a second halogen, or to a second alkyl. A particularly useful alkylhalosilicon has the formula -SÍCH3F2. X, in any of the embodiments, can be a hydrogen atom; a halogen group; an alkali metal oxide; a portion of the Formula -OR 10; a portion of the Formula -SR; or an amine. Suitable amines are those having the Formula -NR R or -NR (OR); saturated cyclic amines, such as those of the Formulas: -N (CH2) p DO NOT or heteroarylamines, such as imidazole, pyrazole and the like. R 10 and R 11 are the same or different and are selected from the group consisting of hydrogen; an alkyl portion, including substituted or unsubstituted, branched or straight chain alkyl moieties, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n- hexyl, benzyl and 4-methylbenzyl, preferably having from 1 to 7 carbon atoms; and an aryl portion including substituted or unsubstituted aryl portions such as phenyl, tolyl and xylyl; p is an integer, preferably from 2 to 8. In the practice of the process using an acylation agent derived from cyclopropyl, suitable acylating agents include cyclopropylcarboxylic acid halides, alkali metal salts of cyclopropylcarboxylic acid, esters of cyclopropylcarboxylic acid or cyclopropylcarboxylic acid amides. Cyclopropylcarboxylic acid halides include cyclopropylcarboxylic acid fluoride, cyclopropylcarboxylic acid chloride and cyclopropylcarboxylic acid bromide. When an alkali metal salt of cyclopropylcarboxylic acid is used as the acylating agent, suitable alkali metals include lithium, sodium and potassium. The cyclopropylcarboxylic acid amides can be N-unsubstituted amides such as cyclopropylcarboxylic acid amide; an N-monosubstituted amide such as cyclopropylcarboxylic acid N-methylamide, cyclopropylcarboxylic acid N-ethylamide, cyclopropylcarboxylic acid N-propylamide and cyclopropylcarboxylic acid N-hexyl ida; or a N, N-disubstituted amide. Suitable N, N-disubstituted amides include the N, N-dimethylamide of cyclopropylcarboxylic acid, N-methyl-N-ethylamide of cyclopropylcarboxylic acid, N-methyl-N-propylamide of cyclopropylcarboxylic acid, N-methyl-N-hexylamide of the acid cyclopropylcarboxylic acid, N, N-diethylamide of cyclopropylcarboxylic acid, N-ethyl-N-propylamide of cyclopropylcarboxylic acid, N-ethyl-N-hexylamide of cyclopropylcarboxylic acid, N, -dipropylamide of cyclopropylcarboxylic acid, N-propyl-N-hexylamide of cyclopropylcarboxylic acid and N, N-dihexylamide of cyclopropylcarboxylic acid . Particularly useful are N, N-disubstituted cyclopropylcarboxylic acid amides of the Formula -NR (OR), such as N-methyl-N-methoxyamide of cyclopropylcarboxylic acid, N-methyl-N-ethoxyamide of cyclopropylcarboxylic acid, N-ethyl-N - cyclopropylcarboxylic acid methoxyamide and cyclopropylcarboxylic acid N-ethyl-N-ethoxyamide. Suitable N, N-disubstituted amides also include cyclic amides such as cyclopropylcarboxylic acid morpholinamide, cyclopropylcarboxylic acid piperazinamide, cyclopropylcarboxylic acid imidazolamide, and cyclopropylcarboxylic acid pyrazololamide, as well as those of the Formula: O -C- (CH2) p wherein p is an integer, preferably from 2 to 8, examples of which include N, N-ethylenamide of cyclopropylcarboxylic acid, N, N-propyleneamide of cyclopropylcarboxylic acid, N, N-butyleneamide of cyclopropylcarboxylic acid and N, N-Pentylenamide of cyclopropylcarboxylic acid. Regardless of whether the regioisomer is produced using the process with an acylation agent derived from cyclopropyl or using an acylating agent derived from 4- (a, α-disubstituted) -tolucic acid, the acylation reactions are carried out in a solvent suitable in the presence of an appropriate catalyst, for about 1 to 120 hours and at temperatures from about -78 ° C to the reflux temperature of the solvent. Suitable solvents for acylation include: hydrocarbon solvents, such as benzene, toluene, xylene or cyclohexane; halogenated hydrocarbons such chlorobenzene, dichloroethane, methylene chloride, chloroform or carbon tetrachloride; carbon disulfide; dimethylformamide; ethereal solvents such as tetrahydrofuran and diethyl ether; or dioxane. In the practice of any of the foregoing procedures, a variety of catalysts can be used when A is hydrogen. Suitable catalysts include palladium catalysts such as palladium chloride, palladium acetate, tetrakis- (triphenylphosphine) palladium (0), dichlorobis (triphenylphosphine) -palladium (II) or benzylchlorobis (triphenylphosphine) palladium (II); or nickel-phosphine catalysts. The acylation can also be carried out in the presence of lithium chloride or triphenylphosphine. This latter acylation reaction is known in the art as an organometallic cross coupling reaction and is carried out by the general procedures of D. Milstein, et al. , J. Org. Chem., 1979, 44, 1613; J. W. Labadie, et al. , J. Org. Chem., 1983, 48, 4634; C. Sahlberg, et al. , Tetrahedron Letters, 1983, 24, 5137; D, Milstein, et al. , J. Am. Chem. Soc, 1978, 100, 3636; and K. Tamao, et al. , Tetrahedron, 1982, 38, 3347, all of which are incorporated herein by reference. When acylation is carried out using the process with an acylation agent derived from cyclopropyl, the reaction can also be promoted by the addition of an acylation promoter, which, when reacted with the methylbenzene derivative, displaces X from the ring benzene, forming a reactive carbanion. A suitable acylation promoter is butyllithium, which is particularly effective when X 2 is an amine. When X is chlorine, the preferred acylation promoters are metallic magnesium or tetraalkyltin. Acylation promoters, especially organometallic ones such as butyllithium, are highly reactive with carbonyl groups. For this reason, the Z-portion is selected in such a way as to minimize the reactivity of the beta-carbon of the benzene ring. In particular, when an acylation promoter is used, Z portions of the Formula are preferred: m such as isoxazolidinium groups. The disubstituted methylbenzene derivative in position a, a of the Formula: it can be obtained by reacting a disubstituted methylbenzene derivative in position a, a of Formula: A with a methylating agent under conditions effective to produce the disubstituted methylbenzene derivative at a, a. The methylation reaction is carried out in a suitable solvent and in the presence of a suitable non-nucleophilic base, such as potassium t-butoxide, sodium hydride, lithium diisopropylamide ("LDA"), lithium hexamethyldisilazide ("LHMDS"), potassium hexamethyldisilazide ("KHMDS"), sodium or lithium tetramethylpiperidine, or related strong bases, for about 1 to about 120 hours at temperatures from about -78 °. C up to room temperature. Preferably, the reaction is carried out under a dry inert atmosphere, such as N 2 or Ar gaseous, in an anhydrous inert solvent. Suitable solvents for methylation include: hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane; halogenated hydrocarbons such as chlorobenzene, dichloroethane, methylene chloride or carbon tetrachloride; carbon disulfide; dimethylformamide; ethereal solvents such as tetrahydrofuran, t-butyl methyl ether and diethyl ether; or dioxane. At least 2 molar equivalents and preferably between 2.1 and 3 molar equivalents of the methylating agent are used and are added in the course of the reaction, either continuously or in two or more slurries. Suitable methylation agents include iodomethane, bromomethane, chloromethane, dimethyl sulfate, and the like. Methylbenzene derivatives not disubstituted in position a, a of the formula: they can be prepared by reacting the corresponding undisubstituted benzyl acid in position a, a of the Formula: with an appropriate aminoalkyl derivative of the Formula: H2N- (CR6R7) m-Q-H Under conditions effective to produce the non-disubstituted methylbenzene derivative at a, a. This reaction is carried out in a suitable solvent for about 1 to about 120 hours and at a temperature ranging from 0 ° C to the reflux temperature of the solvent. Suitable solvents for this reaction include: hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane; halogenated hydrocarbons such as chlorobenzene, dichloroethane, methylene chloride, chloroform or carbon tetrachloride; carbon disulfide; dimethylformamide; ethereal solvents such as tetrahydrofuran and diethyl ether; or dioxane. Preferably, the solvent is refluxed in an apparatus with a mechanism for removing water, such as a Dean-Stark trap. In many cases it is advantageous to transform the undisubstituted benzyl acid derivative in position a, a to the corresponding acid halide, for example by treatment with thionyl chloride, before reacting it with the aminoalkyl derivative. Alternatively, the methylbenzene derivative disubstituted in the a, a position of Formula: can be prepared from the corresponding disubstituted benzyl acid in the a, a position of the Formula: CH, 3 by reacting the disubstituted benzyl acid derivative in a, a position with the above aminoalkyl derivative, under the conditions described above with respect to the transformation of the undisubstituted benzyl acid in a, a position. The benzyl acid derivative disubstituted in position a, to be used to prepare the disubstituted methylbenzene derivative in a, a, can be synthesized by methylation of the corresponding undisubstituted benzyl acid derivative in a, a position. The conditions suitable for carrying out this methylation are the same as those described above with respect to the methylation of the non-disubstituted methylbenzene derivatives in position a, a. In case the acylation is carried out with a derivative of the 4- (a, disubstituted) toluic acid of the formula: the 4- (a, α-disubstituted) -tolucic acid derivative can be obtained by reacting a 4- (a, non-disubstituted) -tolucic acid derivative of the Formula: with a methylating agent under conditions effective to produce the 4- (α, α-disubstituted) -tolucic acid derivative. The appropriate methylation conditions are the same as described above. The 4- (a, non-disubstituted) -tolucic acid derivatives of the Formula: < CR6R7), can be prepared by reacting the corresponding 4- (α-carboxy-a, non-disubstituted) -tolucic acid derivative of the Formula: with an appropriate aminoalkyl derivative of the Formula: H2N- (CR6R7) m-Q-H under conditions effective to produce the 4- (a, non-disubstituted) -tolucic acid derivative. The conditions suitable for carrying out this reaction are the same as those given above for the reaction of the non-disubstituted methylbenzene derivatives in the a, a, position with aminoalkyl derivatives. Alternatively, the 4- (a, α-disubstituted) -tolucic acid derivative of the Formula: it can be prepared from the corresponding 4- (α-carboxy-a, disubstituted) -tolucic acid derivative of the Formula: CH, by reacting the 4- (α-carboxy-a, disubstituted) -tolucic acid derivative with the above aminoalkyl derivative, under the conditions described above with respect to the reaction of the non-disubstituted benzyl acid derivatives in position a , a, with aminoalkyl derivatives. The 4- (α-carboxy, α, α-disubstituted) -tolucic acid derivative used to prepare the 4- (a, α-disubstituted) -tolucic acid derivative can be synthesized by methylation of the corresponding acid derivative - (α-carboxy-a, non-disubstituted) -tolucic. The conditions suitable for carrying out this methylation are the same as described above with respect to the methylation of the non-disubstituted methylbenzene derivatives in position a, a. The regioisomer of the present invention of the Formula: it can also be prepared from a corresponding precursor of the non-disubstituted regioisomer in position a, a of the Formula: by methylation using the reagents and conditions described above with respect to the methylation of non-disubstituted methylbenzene derivatives in a, a. When this route is used, the precursor of the non-disubstituted regioisomer in position a, a is conveniently prepared from a non-disubstituted methylbenzene derivative in the a, a position of the formula: by acylation of the non-disubstituted methylbenzene derivative in a, a, position with an acylating agent of the Formula: ? under conditions effective to produce the precursor of the non-disubstituted regioisomer in position a, a. Suitable acylation conditions for this reaction are the same as those described above with respect to the acylation of disubstituted methylbenzene derivatives in a, a position. Procedure for the Transformation of the Regioisomer to Piperidine Derivatives with a Keto Group. Once the regioisomer is obtained, it is transformed into the piperidine derivative with a piperidine compound. In one aspect of the present invention, the regioisomer of the Formula: it is reacted with a piperidine compound of the Formula: 1"7 1 fi where R and R may be the same or different and are selected from the group consisting of an alkyl portion, including substituted or unsubstituted, branched or straight-chain alkyl portions, such as methyl, ethyl, n-propyl , isopropyl, n-butyl sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, benzyl and 4-methylbenzyl, preferably having 1 to 7 carbon atoms, and an aryl portion including substituted aryl moieties or unsubstituted, such as phenyl, tolyl and xylyl Preferably, the reaction is carried out under a dry inert atmosphere, for example with nitrogen or argon, in an anhydrous inert solvent, at temperatures from about -50 ° C to about reflux temperature of the solvent Suitable solvents include hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane, dimethylformamide, ethereal solvents such as tetrahydrofuran, t-butyl methyl ether and diethyl ether or dioxane. In another aspect of the present invention, the transformation of the regioisomer to the piperidine derivative is effected by halogenation, hydroxylation, alkoxylation or aryloxylation of the regioisomer under conditions effective to form a first intermediate compound of the Formula: wherein X is a halogen group or a hydroxy, alkoxy or aryloxy moiety. Suitable halogens include chlorine, bromine and iodine. Suitable conditions for carrying out the halogenation include reacting the regioisomer with a halogen nucleophile and a Lewis acid. The halogenation reaction is carried out in a suitable solvent, optionally in the presence of a catalytic amount of a base, for example for about 0.5 to 24 hours and at a temperature from about -40 ° C to the reflux temperature of the solvent. Suitable halogen nucleophiles include sodium iodide, sodium bromide, potassium iodide, potassium bromide, cesium iodide, cesium bromide, trimethylsilyl iodide, manganese iodide, cerium iodide, magnesium bromide, magnesium iodide, magnesium carbonate, calcium bromide and calcium iodide. Suitable Lewis acids include silicon compounds such as trimethylsilyl chloride and trimethylsilyl iodide; aluminum compounds such as aluminum chloride, trimethylaluminum, diethylaluminum chloride, ethylaluminum dichloride and diethylaluminum cyanide; magnesium salts and boron salts. Suitable solvents for the halogenation reaction include alcohols such as methanol, ethanol, isopropanol and various glycols; hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane; ethereal solvents such as ether, tetrahydrofuran, dioxane or dimethoxyethane; or halogenated hydrocarbons such as chlorobenzene, methylene chloride, carbon tetrachloride, chloroform or dichloroethane. The halogenation reaction can be carried out in a mixture of organic solvents and mineral acids, such as hydrochloric acid, hydrobromic acid or hydroiodic acid. In this manner, in addition to breaking the cyclopropyl ring, the portion referred to herein as Z is also broken, obtaining the first intermediate compound. Alternatively, the above halogenation may comprise two separate steps. In the first step, the regioisomer of the present invention is deciclized (open) under conditions effective to produce an oxobutyl derivative of the Formula: The deciclization (opening) can be carried out with a halogen nucleophile and a Lewis acid under the conditions described above. At this point, the oxobutyl derivative, optionally, can be purified to remove excess decyclization reagent (opening reagent). The oxobutyl derivative is transformed into the first intermediate compound by treating the oxobutyl derivative with a mineral acid, such as hydrochloric acid, hydrobromic acid or hydroiodic acid. It is preferred that the acid treatment be carried out separately from the opening. Furthermore, it is preferred that the treatment with the acid be carried out on a purified oxobutyl derivative, instead of the oxobutyl derivative contaminated with an excess of the opening agent.

As indicated above, the regioisomer can also be transformed into an oxobutyl derivative by hydroxylation, alkoxylation or aryloxylation. In such cases, X3 is OR19, wherein R1 may be a hydrogen atom, an alkyl group or an aryl group. The alkoxylation or aryloxylation is carried out by reacting the regioisomer with mineral acids in a solution of the appropriate alcohol, such as methanol when R 19 is methyl, ethanol when R 19 is ethyl and phenol when R 19 is phenyl. The hydroxylation can be carried out by treating the regioisomer with mineral acids in aqueous solution. Then, the intermediate hydroxy compound can be transformed into a sulfonate ester such as tosylate ester or mesylate ester, by reaction with a sulfonyl halide such as p-toluenesulfonyl chloride or methanesulfonyl chloride. If desired, the acid group of the first intermediate compound can be esterified by techniques known to those skilled in the art, such as by evaporating an alcoholic solution of the acid and a mineral acid, for example a methanolic, ethanolic, propanolic or butanolic solution. of hydrochloric, hydrobromic or hydroiodic acid, to dryness, to form an ester of the Formula: After halogenation, alkoxylation or aryloxylation and optional esterification, the first intermediate compound or ester thereof can be reacted with a piperidine compound of the formula: under effective conditions for forming the piperidine derivative compound with a keto group of the Formula: This 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 about 4 to 120 hours at a temperature from about 70 ° C to the reflux temperature of the solvent. Suitable solvents for the alkylation reaction include alcohol solvents such as methanol, ethanol, isopropyl alcohol or n-butanol; ketone solvents such as methyl isobutyl ketone and methyl ethyl ketone; hydrocarbon solvents such as benzene, toluene or xylene; halogenated hydrocarbons such as chlorobenzene or methylene chloride; or dimethylformamide. Suitable bases for the alkylation reaction include inorganic bases, for example, sodium bicarbonate, potassium carbonate or potassium bicarbonate; or organic bases such as trialkylamine, for example triethylamine or pyridine; or an excess of the piperidine compound can be used. When the piperidine derivative is in the form of an ester, it can be hydrolyzed to obtain a carboxylic acid. It is also possible to prepare piperidine derivative compounds of the present invention having n equal to 1, by the following alternative alkylation process. After halogenation and optional esterification, the first intermediate compound of the Formula: is reacted with 4-hydroxypiperidine in an organic solvent such as toluene, dioxane, xylene, methyl ethyl ketone, methyl isobutyl ketone or N, N-dimethylfor amide, at a temperature between 80 and 140 ° C and in the presence of an acid scavenger, such as an alkali metal carbonate or bicarbonate, to form an N-substituted hydroxypiperidine of the Formula: The N-substituted hydroxypiperidine is subsequently reacted with a diphenylmonohalomethane of the Formula: wherein X .1 is a halogen group, under conditions effective to form the piperidine derivative compound of the Formula: The preferred reaction is carried out in an inert organic solvent, for example toluene, xylene, dioxane, methylisobutyl ketone or N, N-dimethylformamide, at a temperature between 80 and 140 ° C in the presence of an acid scavenger, such as a carbonate or alkali metal bicarbonate. The diphenylmonohalomethanes can be obtained commercially, or they can be prepared by methods in the art, for example by reacting the corresponding diphenylmethanol with a phosphorus bromide or thionyl chloride, in an inert organic solvent. This alternative alkylation method is preferred when R in the first intermediate compound is a -COOH group. Regardless of the alkylation process employed, when R is -COOalkyl, the alkylation reaction can be followed by a hydrolysis in basic medium, to transform the substituents R which are -COOalkyl groups into -COOH groups. Such basic hydrolysis involves the treatment of the piperidine derivative with an inorganic base such as sodium hydroxide, in an alcoholic solvent with little water, such as methanol, ethanol, isopropyl alcohol or aqueous n-butanol, at reflux temperature for about 1 / 2 hours to 12 hours. The piperidine compounds where n = 0 and each of R1 and R2 is hydrogen or where n = 0 and R1 is 2-hydroxy and hydrogen R, can be obtained commercially or can be prepared in accordance with procedures already known in the art (eg FJ McCarty, CH Tilford, MG Van Campen, J. Am. Chem. Soc., 1961, 26 , 4084, which is incorporated herein by reference). The piperidine compounds wherein n = 0 and R 1 and R 2 form a second bond between the carbon atoms carrying R 1 and R 2, can be prepared by dehydrating the corresponding compound wherein R is hydroxy, by procedures generally known in the art. The technique. The piperidine compounds wherein n = 1 and R 1 and R 2 are hydrogen, are prepared by the condensation of an appropriately substituted diphenylmonohalomethane, such as diphenylchloromethane, diphenyl bromide and di (p-tolyl) -chloromethane, with a 1-alkoxycarbonyl-4 -hydroxypiperidine in a suitable solvent, such as toluene, xylene, dioxane, methyl isobutyl ketone or N, N-dimethylformamide. The reaction is carried out at a temperature between 80 and 140 ° C and in the presence of a base such as an alkali metal carbonate or bicarbonate. After the reaction, hydrolysis is carried out with an alkali metal hydroxide in an organic solvent, such as ethanol or isopropanol, at the boiling point of the solvent, obtaining 4- (diarylmethoxy) -piperidine in free base form. In still another aspect of the present invention, the piperidine derivative compound is produced by the deciclization (opening) of the regioisomer of the present invention, under conditions effective to produce an oxobutyl derivative compound of the Formula: The opening can be carried out by reacting the regioisomer with a halogen nucleophile and a Lewis acid. The opening is carried out in a suitable solvent, optionally in the presence of a catalytic amount of an optional nucleophile, for about 0.5 to 24 hours and at a temperature from about -40 ° C to the reflux temperature of the solvent. Suitable halogen, Lewis acids and solvents include those that were described above with respect to the halogenation of the regioisomer. The oxobutyl derivative compound is transformed into a piperidine derivative precursor of the Formula: by reacting the oxobutyl derivative with a piperidine compound of the Formula: under effective conditions to form the precursor of the piperidine derivative. This 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 about 4 to 120 hours, at a temperature of about 70 ° C. the reflux temperature of the solvent. Suitable solvents for the alkylation reaction include alcoholic solvents such as methanol, ethanol, isopropyl alcohol or n-butanol; ketone solvents such as methyl isobutyl ketone and methyl ethyl ketone; hydrocarbon solvents such as benzene, toluene or xylene; halogenated hydrocarbons such as chlorobenzene or methylene chloride; or dimethylformamide. Suitable bases for the alkylation reaction include organic bases for example sodium bicarbonate, potassium carbonate or potassium bicarbonate; or organic bases such as trialkylamine for example triethylamine or pyridine, or an excess of the piperidine compound can be used. Alternatively, the precursors of the piperidine derivative of the present invention with n = 1, can also be prepared by reacting the oxobutyl derivative of the Formula: with a 4-hydroxypiperidine in an organic solvent such as toluene, dioxane, xylene, methyl isobutyl ketone or N, N-dimethylformamide, at a temperature between 80 and 140 ° C and a presence of an acid scavenger, such as a carbonate or bicarbonate of alkali metal, to form an N-substituted hydroxypiperidine of the Formula: then, the N-substituted hydroxypiperidine is reacted with a diphenylmonohalornet or Formula: 4 wherein X is a halogen, under conditions effective to form the precursor of the piperidine derivative of the Formula: The preferred reaction is carried out in an inert organic solvent, for example toluene, xylene, dioxane, methyl isobutyl ketone or N, N-dimethylformamide, at a temperature between 80 and 140 ° C in the presence of an acid scavenger such as a carbonate or alkali metal bicarbonate. Regardless of the procedure of the alkylation employed, the precursor of the piperidine derivative is subsequently transformed into the piperidine derivative of the Formula: This transformation can be effected by treating the precursor of the piperidine derivative with a mineral acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, in a suitable organic solvent, for about 0.5 to 24 hours and at a temperature of about -40 ° C. to the reflux temperature of the solvent. Suitable solvents include alcohols such methanol, ethanol, isopropanol and various glycols; hydrocarbon solvents such as benzene, toluene, xylene or cyclohexane; ethereal solvents such as ether, tetrahydrofuran, dioxane or dimethoxyethane; or halogenated hydrocarbons such as chlorobenzene, methylene chloride, carbon tetrachloride, chloroform or dichloroethane. Alternatively, this transformation can be effected in vivo by administering the piperidine derivative precursor to a subject and allowing the subject to metabolize the piperidine derivative precursor to obtain the piperidine derivative compound. The precursors of the piperidine derivative of the present invention can be used for the treatment of patients suffering from allergic reactions such as asthma, allergic rhinitis and other disorders that can be treated with the piperidine derivative compounds. The treatment includes administering to the patient an effective amount of the precursor of the piperidine derivative. The amounts and modes of administration are the same as those described above for the administration of piperidine derivative compounds. Procedure for the reduction of the Keto Group in Piperidine and Precursors Derivatives. As described above, the process of the present invention is useful in the production of piperidine derivatives with either a keto group or a hydroxyl group. The derivatives with keto groups can be transformed into similar compounds with hydroxyl groups, by reduction reactions which are known in the art. The reduction can be carried out with sodium borohydride or potassium borohydride in lower alcoholic solvents such as methanol, ethanol, isopropyl alcohol or n-butanol. When lithium aluminum hydride or diborate is used as a reducing agent, suitable solvents are ethers, for example diethyl ether, tetrahydrofuran or dioxane. These reduction reactions are carried out at temperatures ranging from about 0 ° C to the reflux temperature of the solvent and the reaction time varies from about 0.5 to 8 hours. The catalytic reduction with hydrogen can also be used employing, for example, catalysts such as Raney nickel, palladium, platinum or rhodium in lower alcoholic solvents such as methanol, ethanol, isopropyl alcohol or n-butanol or acetic acid or their aqueous mixtures, or by the use of aluminum isopropoxide in isopropyl alcohol. Generally, reduction is preferred using sodium borohydride over catalytic reduction when carboxylic acids or esters are formed. The piperidine derivative containing a hydroxy group prepared in this way, optionally it can be separated into its enantiomerically pure components by conventional methods. For example, the racemic mixture of piperidine-derived enantiomers can be transformed into a racemic mixture of diastereoisomers with a reactive chiral agent. Then, the diastereoisomers are separated, for example, by recrystallization or chromatography and the pure enantiomer is recovered by separating it from the reactive chiral agent. Alternatively, the racemic mixture of piperidine-derived enantiomers can be separated by chromatography using chiral stationary phases or by recrystallization using chiral solvents. The piperidine derivatives with keto groups can also be transformed into enantiomerically pure piperidine derivatives with hydroxy groups, using chiral reducing agents. For example, reduction using (+) - B-chlorodiisopropycamphenylborane produces the piperidine derivative with a chirality R at the carbon to which the hydroxy group is linked. Alternatively, using (-) - B-chlorodiisopropinocanphenylborane the S-enantiomer is produced. Other suitable chiral reducing agents are (R) and (S) -oxazaborolidine / BH3, 9- 0- (1, 2: 5, 6-di-O-isopropilidin-aD-glucofuranosyl) -9-boratebicyclo [3.3.1] -non-potassium, (R) and (S) -B-3-phenylane-9- borobicyclo [3.3.1] -nonano, NB-enantride, (R) - (+) and (S) - (-) -2,2'-dihydroxy-l, lithium aluminum-l-binaphthylalkoxydhydride, complex (R ) - (+) and (S) - (-) -2, 2'-dihydroxy-6, '-dimethylbiphenylborane-amine, tris (((lS, 2S, 5R) -2-isopropyl-5-methylcyclohex-1- il) methyl) -aluminium, (((IR, 3R) -2, 2-dimethylbicyclo- [2.2.1] -hept-3-yl) ethyl) beryllium chloride, complex (R) -BINAP-ruthenium / H2 and 6,6'-bis (diphenylphosphino) -3,3'-dimethoxy-2, 2 ', 4,4'-tetramethyl-1,1'-biphenyl. When esters with hydroxyl groups have formed, a hydrolysis of basic medium can be used to produce a carboxylic acid. Such processes are known and generally include treatment with an inorganic base such as sodium hydroxide or potassium hydroxide, in an aqueous lower alcohol solvent such as methanol, ethanol, isopropyl alcohol or aqueous n-butanol. The hydrolysis in basic medium is carried out at a temperature from about room temperature to about the reflux temperature of the solvent, for a period of about 1/2 hour to 12 hours. Similarly, the precursors of the piperidine derivative bearing a keto group and having the Formula: they can be reduced to obtain precursors of the piperidine derivative bearing a hydroxyl group with the Formula: The precursors of the piperidine derivative bearing a hydroxyl group can be transformed into the piperidine derivative of the Formula: in vi tro, for example by treating the precursor of the piperidine derivative bearing a hydroxyl group, with a strong acid as described above, or alternatively, in vivo, by administering the precursor of the piperidine derivative carrying a hydroxyl group to a subject. The hydroxyl group-carrying piperidine derivative precursors, similarly to the precursors of the piperidine derivative bearing keto groups, can be used for the treatment of allergic reactions such as asthma or allergic rhinitis. The present invention will be further illustrated with the following Examples. EXAMPLES Example 1 - Preparation of 4-bromo-a- (4,4-dimethyl-isoxazolin-2-yl) -toluene A mixture of 4-bromophenylacetic acid (172 g, 0.800 mol), 2-amino-2-methyl- l-propanol (115 ml, 1.20 mol) and 900 ml of xylenes were refluxed for 24 hours in an apparatus equipped with a Dean-Stark trap. The mixture was then cooled, filtered and concentrated to obtain a crystalline solid. The solid was dispersed in hexanes and filtered to obtain 147 g of a white solid. The hexane filtrate was concentrated, dispersed with hexanes and filtered to obtain another 13 g of 4-bromo-α- (4,4-dimethylisoxazolin-2-yl) -toluene as a white solid. The combined yield was 160 g (75%). Example 2 - Preparation of 4-bromo-a, a-dimethyl-a- (4,4-dimethylisoxazolin-2-yl) -toluene A 250 ml three-neck balloon flask was charged with 5.0 g (0.0186 mol) of 4 -bromo-α- (4,4-dimethylisoxazolin-2-yl) -toluene, prepared according to Example 1, and 50 ml of anhydrous THF under an atmosphere of N 2. Then KHMDS, 27 ml (0.0279 mol, 1.5 eq) was slowly added over a period of 10 minutes. A change in color to intense orange was observed. After stirring the mixture for 15 minutes at room temperature, 1.16 ml (0.0186 mol, 1 eq) of methyl iodide were added in a single portion. The reaction exhibited an exotherm to 46 ° C and a white solid precipitated while the solution retained a pale yellow dye. After stirring for 1 hour, another 27 ml (0.0279 mol, 1.5 eq) of KHMDS was added, causing the reaction temperature to rise from 27 to 30 ° C and the color to change to orange. The reaction mixture was stirred for another 20 minutes and then a second equivalent of CH3I was added. An aliquot was withdrawn, it was cooled with water and subjected to extraction with ethyl acetate. TLC analysis (thin layer chromatography) (4: 1, hexane / ethyl acetate) demonstrated the presence of the more polar product 4-bromo-a-methyl-a- (4,4-dimethylisoxazolin-2-yl) -toluene ("monoadduct"). An additional 0.2 ml of CH3I was added, whereupon the pale yellow solution turned white. Then to the reaction mixture was added 100 ml of 10% acetic acid / water together with 250 ml of methylene chloride. The organic phase was washed twice with 50 ml of brine and dried over sodium sulfate. After concentrating and dehydrating at room temperature and at a pressure of 0.1 mm Hg overnight, 5.65 g (103%) of a yellowish solid was obtained. The solid was dissolved in 30 ml of isopropanol and 20 ml of water was slowly added until an oil formed. To the mixture was added 5 ml of isopropanol with heating to dissolve all the oil. The oil crystallized on cooling in an ice bath to obtain 4.61 g (0.0156 mmol, 84%) of pure 4-bromo-a, a-dimethyl-a- (4,4-dimethylisoxazolin-2-yl) -toluene, without traces of the monoadduct. Example 3 - Preparation of 4- (cyclopropyl-oxo-methyl) -a, a-dimethyl-a- (4,4-dimethyloxozolin-2-yl) -toluene A solution of 4-bromo-a, a-dimethyl-a - (4, -dimethylisoxazolin-2-yl) -toluene prepared according to Example 2 (10.0 g, 0.0338 mol) in 400 ml of THF, cooled to -78 ° C, n-butyllithium (16 ml, 0.042 mol) with a syringe and the mixture was stirred at -78 ° C for 30 minutes. Maintaining the temperature below -75 ° C, N, N-dimethylamide of cyclopropylcarboxylic acid (11.5 g, 0.102 mol) in 30 ml of THF was added dropwise and the mixture was stirred at -78 ° C for 30 minutes. The reaction mixture was allowed to warm to -15 ° C and the reaction was stopped with water. The product was extracted with methylene chloride, washed with a saturated solution of NaCl, dried over Na 2 SO 4 and concentrated. The residue was cooled to 0 ° C, treated with minimal acetonitrile and filtered, to obtain 6.95 g of 4- (cyclopropyl-oxo-methyl) -a, α-dimethyl-α- (4,4-dimethyl-oxozolin- 2-yl) -toluene in the form of a white solid (72%).

Example 4 - Preparation of 4- (4-chloro-1-oxobutyl) -a, a-dimethyl-1-acetic acid A mixture of 4- (cyclopropyl-oxo-methyl) -a, a-dimethyl-a- (4,4-dimethyloxozolin) -2-il) -toluene, prepared in accordance with Example 3 (42 g, 0.15 mol), 150 ml of concentrated hydrochloric acid and 150 ml of 1,4-dioxane was brought to reflux temperature for 18 hours. The mixture was extracted 3 times with ethyl acetate. The organic phases were washed with a saturated NaCl solution, dried over MgSO4 and concentrated. The crude product was purified by column chromatography using 240 g of silica gel and eluting with hexanes / ethyl acetate / acetic acid, 81: 14: 5. The cleanest fractions were combined and recrystallized from methylene chloride / hexanes to obtain 27 g of 4- (4-chloro-l-oxobutyl) -a, a-dimethylphenylacetic acid as a white solid (68%). Example 5 - Preparation of Methyl 4- (4-chloro-l-oxobutyl) -a, a-di and il-enylacetate A solution of 4- (4-chloro-l-oxobutyl-a, -dimethylphenylacetic acid prepared in accordance with Example 4 (15 g, 0.056 mol) in 450 ml of methanol saturated with HCl was refluxed for 1 hour.The mixture was concentrated to dryness and partitioned into ethyl acetate and water. twice more with ethyl acetate.The organic phases were combined and the combined was dried over MgSO4 and concentrated to an oil.The oil was purified by column chromatography using 150 g of silica gel and eluting with hexanes / ethyl acetate. ethyl, 11: 1. The clean fractions were combined and concentrated to obtain 13 g of methyl 4- (4-chloro-l-oxobutyl) -a, a-dimethylphenylacetate in the form of a clear and colorless oil (82%). Example 6 - Preparation of 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -a, a-dimethylphenylacetate Methyl To a solution of 12.6 g of methyl 4- (4-chloro-l-oxobutyl) -a, a-dimethylphenylacetate in 500 ml of toluene, in a one-liter three-neck flask with mechanical stirring, was added 8.8 g of 4- (a, a-diphenyl) -piperidinemethanol and 23 g of K2CO3 and the mixture was refluxed for 7 hours. Then, the cold reaction reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in Et20 and treated with an excess ethereal HCl. The mixture was then concentrated to a solid. The solid was treated with EtOAc and collected by filtration. Subsequently the product was extracted by partition in EtOAc and Na 2 C 3 3 N. The organic phases were dried over MgSO 4, filtered and concentrated in vacuo to obtain methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -a, a-dimethylphenylacetate. Example 7 - Preparation of 4- [4- [4- (hydroxydiphenylmethyl) -1-pxperidinyl] -1-hxdroxxbu xl] -a, methyl α-dxmethyl enylacetate A solution of 13.5 g of 4- [4- [4- (hydroxydiphenimethyl) -1-piperidinyl] -1-oxobutyl] -a, methyl-methyl-dimethylphenylacetate in 250 ml of CH 3 OH was cooled in an ice bath with CH 3 OH and 1.8 g of NaBH 4 were added portionwise. After 1 hour the reaction mixture was concentrated to a solid. The residue was extracted by partition in EtOAc and saturated aqueous NaHCOß. The aqueous portion was extracted with EtOAc. The organic phases were combined and the combined was washed with a saturated aqueous solution of NaCl, dried over MgS? , filtered and concentrated in vacuo to obtain methyl 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylphenylacetate as a foam. Example 8 - Preparation of Asido 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dxmetxlfenxlacéico To a solution of 9.5 g of 4- [4- [4- ( methyl hydroxydiphenylmethyl) -1-piperidyl] -1-hydroxybutyl] -a, a-dimethylphenylacetate in 300 ml of CH 3 OH and 150 ml of H 2 O were added with 10 g of NaOH. The mixture was refluxed for 1 hour and then cooled. The CH3OH was removed in vacuo. The concentrate was diluted with H2O and CHCl3 and the pH adjusted to approximately 5.5-6.0. The phases were separated and the aqueous phase was extracted with CHCl3. The organic phases were combined and the combined was dried over MgSO4, filtered and the solvent was removed to obtain a crude product. The crude product was dissolved in CH2Cl2 and subjected to Si02 Davisil Grade 633 chromatography, eluting with a CHCl3 gradient. 10% CH3OH in CHCl3, CH3OI1 at 25% in CHCl3. The fractions containing the product were concentrated to obtain 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, α-dimethylphenylacetic acid. Example 9 - Preparation of Methyl 4- [4- [4- (bis (4-methylphenyl) -hydroxymethyl) -1-piperidinyl] -1-oxobutyl] -a, a-dimethylphenylacetate To a solution of 6.4 g (0.017 mol) ) of methyl 4- (4-chloro-1-oxbutyl) -a, a-dimethylphenylacetate in 500 ml of toluene, in a 1-liter flask equipped with a mechanical stirrer, 5.1 g (0.017 mol) of sodium hydroxide were added. - (α, α-bis (4-methylphenyl) -piperidinomethanol, followed by 11.8 g (0.086 mol) of solid potassium carbonate The solution was heated to reflux for 24 hours, after cooling, the mixture was filtered and toluene The residue was removed by partition in ethyl acetate and 2N sodium carbonate solution, the aqueous phase was extracted twice with ethyl acetate, the organic phases were combined and the combined was dried over sodium sulfate and the organic phase was extracted. the ethyl acetate was removed under vacuum, to obtain 4- [4- [4- (bis (4-methylphenyl) -hydroxymethyl) -1-piperidinyl] -1-oxobutyl] -a, a-dimethyl-phenylacetate d and methyl Example 10 - Preparation of methyl 4- [4- [4- (bis- (4-methylphenyl) -hydroxymethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylphenylacetate To a solution a - 10 ° C of 6.8 g (0.013 mol) of 4- [4- [4- (Bis- (4-methylphenyl) -hydroxymethyl) -1-piperidinyl] -1-oxobutyl] -a, methyl-methyl-dimethylphenylacetate in 150 ml of methanol, in a 500-ml flask equipped with a mechanical stirrer, 0.86 g (0.023 mol) of sodium borohydride was added slowly and the reaction mixture was stirred for 2 hours. The methanol was removed in vacuo and the residue was partitioned into ethyl acetate and aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate, the organic phases were combined and the combined was dried over sodium sulfate and the ethyl acetate was removed under vacuum, to obtain a crude product. The resulting material was purified by column chromatography (Davicil Grade 633 Silica Gel, packed in methylene chloride, material applied in chloroform, and eluted with a gradient of 2% methanol to methylene chloride at 5% methanol to chloride. methylene) to obtain methyl 4- [4- [4- (bis- (4-methylphenyl) -hydroxymethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylphenylacetate. Example 11 - Preparation of 4- [4- [4- (Bis (4-ethylphenyl) -h-droxime-yl) -1-piperxdinyl] -1-hydroxybutyl] -α-a-dimethylphenylacetate A To 350 ml of methanol in a flask 1 1 balloon equipped with mechanical agitator, 5.3 g was added (9.8 mmol) of 4- [4- [4- (bis- (4-methylphenyl) -hydroxymethyl) -l-piperidinyl] -l-hydroxybutyl] -a, methyl-dimethylphenylacetate, 5.1 g (0.13 mol) of solid sodium hydroxide and 100 ml of water. The mixture was refluxed for 3 hours. After cooling, the methanol was removed in vacuo and 6N hydrochloric acid was added dropwise until the solution was no longer alkaline (pH = 7). The solution was extracted three times with ethyl acetate. The organic phases were combined and precipitation was induced. The solid was washed with ether to obtain 4- [4- [4- (bis- (4-methylphenyl) -hydroxymethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylphenylacetic acid, in the dihydrate form. Example 12 - Preparation of 4- (1-hydroxy-4-chlorobutyl) -a, a-dimethylphenylacetic acid To a solution of 50 mg of 4- (chloro-l-oxobutyl) -a, a-dimethylphenylacetic acid in 3 ml of methanol, 50 mg of NaBH were added. The mixture was stirred for 30 minutes, acidified with 2N HCl and the methanol was removed in vacuo. The concentrate was extracted with EtOAc. The organic phases were dried over sodium sulfate, filtered and concentrated to obtain 4- (l-hydroxy-4-chlorobutyl) -a, -dimethylphenylacetic acid. Example 13 - Preparation of Asidium 4- [4- [4- (hydroxy-diphenylmethyl) -1-piperidinyl] -1-oxobutyl] -a, α-dimethyl-phenylsity A mixture of 800 mg of 4- (4-chloro) acid -l-oxobutyl) -a, a-dimethylphenylacetic acid, 800 mg of 4- (a, a-diphenyl) -piperidinemethanol and 2.4 g of K2CO3 in 25 ml of toluene was stirred for 48 hours at room temperature. The mixture was concentrated in vacuo. The residue was treated with EtOAc, filtered and concentrated to obtain 4- [4- [4- (hydroxydiphenylmethyl) -1-piperidinyl] -1-oxobutyl] -a, a-dimethylphenylacetic acid. Example 14 - Preparation of 4- [4- [4- (Hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethyl-phenylacetoic acid A mixture of 4- [4- [4- (hydroxydiphenyl- methyl) -1-piperidinyl] -1-oxobutyl] -a, a-dimethylphenylacetic acid and 300 g of NaBH 4 in 25 ml of CH 3 OH was stirred overnight at room temperature. Then the mixture was concentrated in vacuo. The residue was extracted by partition between EtOAc and H20. The aqueous portion was treated with concentrated HCl until a pH of 6 was obtained and then extracted with EtOAc. The organic phases were concentrated in vacuo. The residue was dissolved in EtOAc, filtered and concentrated in vacuo to obtain an oil. The oil was dissolved in CH3OH and concentrated to a solid. The solid was dispersed in EtOAc, filtered and rinsed with EtOAc to obtain 4- [4- [4-hydroxydiphenylmethyl) -1-piperidinyl] -1-hydroxybutyl] -a, a-dimethylphenylacetic acid. Since the present invention has been described in detail for purposes of illustration, it should be understood that these details are for that purpose only and those skilled in the art can make variations without departing from the spirit and scope of the invention, which will be defined. by the following claims. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as an antecedent, what is contained in the following is claimed as property.

Claims

CLAIMS 1. A process for the preparation of a piperidine derivative compound of the Formula: where n is 0 or 1; _ R is a hydrogen atom or a hydroxy group; 2 R is a hydrogen atom; or, when n is 0, R 1 and R 2 taken together form a second bond between the carbon atoms carrying R 1 and R, provided that when n is 1, then R and R are each a hydrogen atom; R3 is a group -COOH or -COOR4; R is an alkyl group or an aryl moiety; A, B and D are ring substituents, each of which may be the same or different, and are selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy and other substituents; characterized in that the method comprises: obtaining a regioisomer of the following Formula: where Z is -CG, 1G ^, '2G ^ "3
OR - / / / v (CRSR7) 7 m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of 0, S, and NR; G 1, G 2 and G 3 are the same or different and are selected from the group consisting of OR, SR and NR R; R and R are the same or different and are selected from the group consisting of hydrogen, an alkyl portion, an aryl portion, OR, SR and NR R; and R 5, R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion and the regioisomer is transformed into a piperidine derivative compound, with a piperidine compound. 2. A process according to claim 1, characterized in that obtaining the regioisomer comprises: acylating a disubstituted methylbenzene derivative in the a, a position of the formula: wherein X is a halogen, trialkyltin or triaryltin group, trialkylborate or triarylborate, trialkylsilicon, alkylhalosilicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions with a compound of the Formula: ? wherein 2 X is a halogen group; an alkali metal oxide; a portion of the Formula -OR 10; a portion of the Formula -SR 10; or an amine; and R is selected from the group consisting of hydrogen, an alkyl portion and an aryl portion, under conditions effective to produce the regioisomer.
3. A method according to claim 2, characterized in that it further comprises: reacting an unsubstituted methylbenzene derivative in position a, a of the formula: with a methylating agent under conditions effective to produce the disubstituted methylbenzene derivative at a, a. 4. A method according to claim 3, characterized in that Z has the Formula: and further comprises reacting a non-disubstituted benzyl acid derivative in a, a position of the Formula: with an aminoalkyl derivative of the Formula: H2N- (CR6R7) m-Q-H under conditions effective to produce the non-disubstituted methylbenzene derivative in position a, a. 5. A method according to claim 2, characterized in that Z has the Formula:
X "~ X (CR6R7) m and further comprising: reacting a disubstituted benzyl acid derivative in the a, a position of the Formula:
CH 3 with an aminoalkyl derivative of the Formula: H 2 N - (CR 6 R 7) m - Q - H Under conditions effective to produce the methylbenzene derivative disubstituted at a, a. 6. A process according to claim 1, characterized in that obtaining the regioisomer comprises: reacting a 4- (a, α-disubstituted) -tolucic acid derivative of the formula: wherein X is a hydrogen atom; a halogen group; an alkali metal oxide; a portion of the Formula
-OR; a portion of the Formula -SR; or an amine; and R 10 is selected from the group consisting of hydrogen, an alkyl portion and an aryl portion, with a compound of the Formula: x '~ < ] where X1 is a halogen group, trialkyltin or triaryltin, trialkylborate or triarylborate, trialkylsilicon, alkylhalosilicon, a substituted sulphonic ester, or substituents useful in organometallic coupling reactions under conditions effective to produce the regioisomer.
7. A process according to claim 6, characterized in that it further comprises: reacting a 4- (a, a-unsubstituted) -tolucic acid derivative of the Formula: with a methylating agent under conditions effective to produce the derivative of 4- (a, disubstituted) -tolucic acid.
8. A method according to claim 7, characterized in that Z has the Formula: ), and further comprising: reacting a 4- (α-carboxy-a, non-disubstituted) -tolucic acid derivative of the Formula: with an aminoalkyl derivative of the Formula: H2N- (CR6R7) m-Q-H under conditions effective to produce the 4- (a, a-unsubstituted) -tolucic acid derivative.
9. A method according to claim 6, characterized in that Z has the Formula: and further comprising: reacting a 4- (α-carboxy-a, disubstituted) -tolucic acid derivative of the Formula: CHj with an aminoalkyl derivative of the Formula: H2N- (CR6R7) m-Q-H under conditions effective to produce the 4- (a, α-disubstituted) -tolucic acid derivative.
10. A process according to claim 1, characterized in that obtaining the regioisomer comprises: obtaining a precursor of the non-disubstituted regioisomer in position a, a of the formula: and methylating the precursor of the non-disubstituted regioisomer in position a, under effective conditions to produce the regioisomer.
11. A process according to claim 10, characterized by obtaining the precursor of the non-disubstituted regioisomer in the a position, comprising: acylating a non-disubstituted methylbenzene derivative in the a, a position of the formula: wherein X is a halogen, trialkyltin or triaryltin group, trialkylborate or triarylborate, trialkylsilicon, alkylhalosilicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions with a compound of the Formula: X2 czzzzzzz or A where 2 X is a halogen group; an alkali metal oxide; a portion of the Formula -OR 10; a portion of the Formula -SR; or an amine; and R 10 is selected from the group consisting of hydrogen, an alkyl portion and an aryl portion, under conditions effective to produce the precursor of the disubstituted regioisomer in position a, a.
12. A process according to claim 10, characterized in that obtaining the precursor of the non-disubstituted regioisomer in position a, comprises: reacting a 4- (a, a-unsubstituted) -tolucic acid derivative of the formula: wherein X is a hydrogen atom; a halogen group; an alkali metal oxide; a portion of the Formula -OR; a portion of the Formula -SR; or an amine; and R is selected from the group consisting of hydrogen, an alkyl portion and an aryl portion, with a compound of the Formula: wherein X is a halogen, trialkyltin or triaryltin group, trialkylborate or triarylborate, trialkylsilicon, alkylhalosilicon, a substituted sulphonic ester, or substituents useful in organometallic coupling reactions under conditions effective to produce the precursor of the disubstituted regioisomer in a, a position.
13. A process according to claim 1, characterized in that it further comprises: reducing the piperidine derivative compound under effective conditions to form a hydroxylated piperidine derivative compound of the Formula:
14. A process according to claim 13, characterized in that the hydroxylated piperidine derivative compound has the Formula:
15. A process according to claim 13, characterized in that the hydroxylated piperidine derivative compound has the Formula:
16. A process according to claim 1, characterized in that the piperidine derivative compound has the Formula:
17. A process according to claim 1, characterized in that the piperidine derivative compound has the Formula:
18. A process according to claim 1, characterized in that the transformation comprises: halogenating the regioisomer of the Formula: under effective conditions to form a first intermediate compound of the Formula: wherein X is a halogen or hydroxy group, alkoxy or an aryloxy moiety.
19. A process according to claim 18, characterized in that the halogenation comprises, sequentially: deciclizing (opening) the regioisomer to produce an oxobutyl derivative of the Formula: and then transform the oxobutyl derivative into the first intermediate compound.
20. A process according to claim 18, characterized in that the transformation further comprises: reacting the first intermediate compound with a piperidine compound of the Formula: under effective conditions to form the piperidine derivative compound of the Formula:
21. A process according to claim 18, characterized in that the transformation further comprises: esterifying the first intermediate compound to obtain an ester thereof, of the Formula: reacting the ester with a piperidine compound of the Formula: under effective conditions to form the piperidine derivative compound of the Formula:
22. In addition, it comprises: hydrolyzing the piperidine derivative compound of the Formula: to obtain a piperidine derivative compound of the Formula:
23. A process according to claim 18, characterized in that n is 1 and wherein the transformation further comprises: reacting the first intermediate compound with 4-hydroxypiperidine under effective conditions to produce an N-substituted hydroxypiperidine of the Formula: reacting the N-substituted hydroxypiperidine with a diarylhalomethane of the Formula: wherein X is a halogen under conditions effective to form the piperidine derivative compound of the Formula:
24. A method according to claim 1, characterized in that the transformation comprises: deciclizing (opening) the regioisomer of the Formula: under effective conditions to form an oxobutyl derivative of the Formula: wherein X is a halogen or a hydroxy, alkoxy, or an aryloxy moiety.
25. A process according to claim 24, characterized in that the transformation further comprises: reacting the oxobutyl derivative with a piperidine compound of the Formula: under effective conditions to form the precursor of the piperidine derivative of the Formula:
26. A method according to claim 25, characterized in that it further comprises: transforming the precursor of the piperidine derivative into a piperidine derivative compound of the Formula:
27. A method according to claim 25, characterized in that it further comprises reducing the precursor of the piperidine derivative under effective conditions to form a precursor of the hydroxylated piperidine derivative of the Formula:
28. A method according to claim 27, characterized in that it further comprises transforming the precursor of the hydroxylated piperidine derivative into a hydroxylated piperidine derivative compound of the Formula:
29. A process according to claim 24, characterized in that n is 1 and wherein the transformation further comprises: reacting the oxobutyl derivative with 4-hydroxypiperidine, under conditions effective to produce an N-substituted hydroxypiperidine of the Formula: reacting the N-substituted hydroxypiperidine with a diarylhalomethane of the Formula: wherein X is a halogen under conditions effective to form the precursor of the piperidine derivative of the Formula:
30. A method according to claim 29, characterized in that it further comprises transforming the precursor of the piperidine derivative into a piperidine derivative compound of the Formula:
31. A method according to claim 29, characterized in that it further comprises reducing the precursor of the piperidine derivative, under conditions effective to form a precursor of the hydroxylated piperidine derivative of the Formula:
32. A method according to claim 31, characterized in that it further comprises transforming the precursor of the hydroxylated piperidine derivative into a hydroxylated piperidine derivative compound of the Formula:
33. A regioisomer of the Formula: characterized in that Z is -CG1G2G3, / (CR6R7 > 7 m is an integer from 1 to 6; Q and Y are the same or different and 5 are selected from the group consisting of 0, S, and NR; G, G and G are the same or different and are selected from the group consisting of OR, SR and NR R; R and R are the same or different and are selected from the group consisting of hydrogen, an alkyl portion, an aryl portion, OR, SR and NR R; Y R 5, R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion; and A is a ring substituent, wherein each of which may be the same or different and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy and other substituents.
34. A regioisomer according to claim 33, characterized in that Z is R1 3 wherein R and R are each a methyl group, and R and R are each a hydrogen atom.
35. A process for the preparation of a regioisomer of the Formula: where r -Q \ (CR6R7) r - // (CRßR7), r, where m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR; G, G and G are the same or different and are selected from the group consisting of OR, SR and NR R; 6 R and R are the same or different and are selected from the group consisting of hydrogen, an alkyl portion, an aryl portion, OR, SR and NR R; R5, R and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion; and A is a ring substituent, wherein each of which may be the same or different and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy and other substituents, characterized in that the process comprises acylating a derivative of disubstituted methylbenzene in position a, a of the Formula: CH, wherein X is a halogen, trialkyltin or triaryltin group, trialkylborate or triarylborate, trialkylsilicon, alkylhalosilicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions with a compound of the Formula: X2 -C _____ 0? wherein X is a halogen; an alkali metal oxide; a portion of the Formula -OR; a portion of the 10 Formula -SR; or an amine; and R 10 is selected from the group consisting of hydrogen, an alkyl portion and an aryl portion; under effective conditions to produce the regioisomer.
36. A method according to claim 35, characterized in that it further comprises: reacting a non-disubstituted methylbenzene derivative in position a, a of the formula: with a methylating agent, under conditions effective to produce the disubstituted methyl benzene derivative at a, a.
37. A method according to claim 36, characterized in that Z has the formula: / - // \ (CR6R7), and further comprises reacting a non-disubstituted benzyl acid derivative in a, a position of the Formula: with an aminoalkyl derivative of the Formula: H2N- (CR6R7) m-Q-H under conditions effective to produce the non-disubstituted methylbenzene derivative in position a, a.
38. A method according to claim 35, characterized in that Z has the Formula: and further comprising: reacting a disubstituted benzyl acid derivative in a, a position of Formula: CH3 with an aminoalkyl derivative of the Formula: H2N- (CR6R7) m-Q-H under conditions effective to produce the methylbenzene derivative disubstituted in position a, a.
39. A process for the preparation of a regioisomer of the Formula: z where Z is -CG ^ G3, .N (CR6R7) r II o X / where m is an integer from 1 to 6; Q and Y are the same or different and 5 are selected from the group consisting of O, S, and NR; G 1, G2 and G3 are the same or different and are fi fi fi selected from the group consisting of OR, SR and NR R; R and R are the same or different and are selected from the group consisting of hydrogen, a βf 8 Q alkyl portion, an aryl portion, OR, SR and NR R; R 5, R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion; and A is a ring substituent, wherein each of which may be the same or different and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy and other substituents, characterized in that the method comprises: reacting a 4- (a, disubstituted) -tolucic acid derivative of the Formula: wherein 2 X is a hydrogen atom; a halogen group; an alkali metal oxide; a portion of the Formula -OR; a portion of the Formula -SR; or an amine; and R 10 is selected from the group consisting of hydrogen, an alkyl portion and an aryl portion with a compound of the Formula: ? j- < 3 wherein X is a halogen, trialkyltin or triaryltin group, trialkylborate or triarylborate, trialkylsilicon, alkylhalosilicon, a substituted sulphonic ester or substituents useful in organometallic coupling reactions under conditions effective to produce the regioisomer.
40. A method according to claim 39, characterized in that it further comprises: reacting a 4- (a, non-disubstituted) -tolucic acid derivative of the Formula: with a methylating agent, under conditions effective to produce the 4- (α, α-disubstituted) -tolucic acid derivative.
41. A method according to claim 40, characterized in that Z has the Formula: and further comprising: reacting a 4- (α-carboxy-a, non-disubstituted) -tolucic acid derivative of the Formula: with an aminoalkyl derivative of the Formula: H2N- (CR6R7) m-Q-H under conditions effective to produce the 4- (a, non-disubstituted) -tolucic acid derivative.
42. A method according to claim 41, wherein Z has the Formula: characterized in that the method further comprises: reacting a 4- (α-carboxy-a, disubstituted) -tolucic acid derivative of the Formula: with an aminoalkyl derivative of the Formula: H2N- (CR6R7) m-Q-H under conditions effective to produce the 4- (a, disubstituted) -tolucic acid derivative.
43. A process for the preparation of a regioisomer of the Formula: where \\ (CReR7) r X / (CRßR7), Q where m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of 0, S, and NR; G 1, G2 and G3 are the same or different and are selected from the group consisting of OR, SR and NR R; R 6 and R 7 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion, an aryl portion, OR, SR and NR R; R 5, R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion; and A is a ring substituent, wherein each of which may be the same or different and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy and other substituents, characterized in that the process comprises: obtaining a precursor of the non-disubstituted regioisomer in position a, a of the Formula: and methylating the precursor of the non-disubstituted regioisomer in position a, a, under effective conditions to produce the regioisomer.
44. A process according to claim 43, characterized in that the preparation of the precursor of the non-disubstituted regioisomer in position a, comprises: acylating a non-disubstituted methylbenzene derivative in the a, a position of the formula: wherein X is a halogen, trialkyltin or triaryltin group, trialkylborate or triarylborate, trialkylsilicon, alkylhalosilicon, a substituted sulfonic ester, or substituents useful in organometallic coupling reactions with a compound of the Formula: x2? wherein 2 X is a halogen group; an alkali metal oxide; a portion of the Formula -OR 10; a portion of the Formula -SR10; or an amine; and R is selected from the group consisting of hydrogen, an alkyl portion and an aryl portion; under conditions effective to produce the precursor of the non-disubstituted regioisomer in position a, a.
45. A method according to claim 44, characterized in that obtaining the precursor of the non-disubstituted regioisomer in position a, comprises: acylating a 4- (a, a-unsubstituted) -tolucic acid derivative of the formula: wherein 2 X is a halogen group; an alkali metal oxide; a portion of the Formula -OR; a portion of the Formula -SR 10; or an amine; and R is selected from the group consisting of hydrogen, an alkyl portion and an aryl portion, with a compound of the Formula: x > ~ < 3 wherein X is a halogen, trialkyltin or triaryltin group, trialkylborate or triarylborate, trialkylsilicon, alkylhalosilicon, a substituted sulfonic ester or substituents useful in organometallic coupling reactions under conditions effective to produce the precursor of the non-disubstituted regioisomer in a, a position.
46. A disubstituted methylbenzene derivative in the a, a position of the Formula: where Z is -CG1G2G3, O - / \ (CRSR7). where m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S, and NR; G 1, G 2 and G 3 are the same or different and are selected from the group consisting of OR, SR and NR R; R and R are the same or different and are selected from the group consisting of hydrogen, a fi x alkyl moiety, an aryl moiety, OR, SR and NR R; R 5, R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion; and A is a ring substituent, wherein each of which may be the same or different and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy and other substituents; and X is a halogen, trialkyltin or triaryltin group, trialkylborate or triarylborate, trialkylsilicon, alkylhalosilicon, a substituted sulfonic ester or substituents useful in organometallic coupling reactions.
47. A disubstituted methylbenzene derivative in a position a, according to claim 46, characterized in that Z is R and R are each a methyl group, R and R are each a hydrogen atom and X is bromine.
48. A non-disubstituted methylbenzene derivative in a, a position of Formula: A where Z is 1 2 3 -CG G G, \\ _ (CR6R7) r OR ), where m is an integer from 1 to 6; Q and Y are the same or different and 5 are selected from the group consisting of 0, S, and NR; G1, G and G are the same or different and are selected from the group consisting of OR, SR and NR R; R and R are the same or different and are selected from the group consisting of hydrogen, an alkyl portion, an aryl portion, OR, SR and NR R; R 5, R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion; A is a ring substituent, wherein each of which may be the same or different and is selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy and other substituents, and X is a halogen, trialkyltin or triaryltin group , trialkylborate or triarylborate, trialkylsilicon, alkylhalosilicon, a substituted sulphonic ester or substituents useful in organometallic coupling reactions.
49. A disubstituted methylbenzene derivative in position a, in accordance with claim 48, characterized in that Z is R and R are each a methyl group, R and R 13 they are each a hydrogen atom and X is bromine.
50. An oxobutyl derivative of the Formula: characterized in that Z is -CG1G2G3, / (CR6R7) r where m is an integer from 1 to 6; Q and Y are the same or different and 5 are selected from the group consisting of 0, S, and NR; G1, G2 and G3 are the same or different and are selected from the group consisting of OR, SR and NR R; 6 R and R are the same or different and are selected from the group consisting of hydrogen, an alkyl portion, an aryl portion, OR, SR and NR R; R 5, R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion; A is a ring substituent, each of which may be the same or different and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy and other substituents; and 3 X is a halogen or hydroxy group, alkoxy, or an aryloxy moiety.
51. A disubstituted methylbenzene derivative in a position a, according to claim 50, characterized in that Z is R13 R and R are each a methyl group, R and R13 are each a hydrogen atom and X is a halogen.
52. A precursor of piperidine derivative of a: OR characterized in that n is 0 or 1; R is a hydrogen atom or a hydroxy group; R is a hydrogen atom; or, when n is 0, R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2, provided that when n is 1, R 1 and R 2 are each a hydrogen atom; Z is -CG1G2G3, \\ \ (CRßR7) r or // (CRSR7). where m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of 0, S, and NR; G1, G2 and G3 are the same or different and are selected from the group consisting of OR, SR and NR R; R 7 R and R are the same or different and are selected from the group consisting of hydrogen, a p p Q alkyl portion, an aryl portion, OR, SR and NR R; R 5, R 8 and R 9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion; and A, B and D are the substituents of the rings, each of which may be the same or different and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxy, alkoxy and other substituents.
53. A precursor of the piperidine derivative according to claim 52, characterized in that Z is R and R are each a methyl group, and R and R are each a hydrogen atom.
54. A method for the treatment of allergic reactions in a patient, characterized in that it comprises: administering to the patient an effective amount of a precursor of the piperidine derivative according to claim 53.
55. A method for the treatment of allergic reactions in a patient. patient, characterized in that it comprises: administering to the patient an effective amount of a precursor of the piperidine derivative according to claim 52. 1 8 SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of derivative compounds or piperidine in Formulas (I, II), wherein n is 0 or 1; R1 is a hydrogen atom or a hydroxy group; R 2 is a hydrogen atom or, when n is 0, R 1 and R 2 taken together form a second bond between the carbon atoms bearing R 1 and R 2, provided that when n is 1, R 1 and R 2 are each a carbon atom. hydrogen; R3 is -COOH or -COOR4; R4 is an alkyl or aryl moiety; A, B and D are substituents of the rings, each of which may be the same or different and are selected from the group consisting of hydrogen, halogens, alkyl, hydroxyl, alkoxy and other substituents. The process comprises obtaining a regioisomer of Formula (III), wherein Z is -C 1 G 2 G 3 (VI or V), m is an integer from 1 to 6; Q and Y are the same or different and are selected from the group consisting of O, S and NR5; Gl, G2 and G3 are the same or different and are selected from the group consisting of OR8, SR8 and NR8R9; R6 and R7 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion, an aryl portion, OR8, SR8 and NR8R9; and R5, R8 and R9 are the same or different and are selected from the group consisting of hydrogen, an alkyl portion and an aryl portion and transforming the regioisomer into a piperidine derivative compound, with a piperidine compound.