Title of Invention

A METHOD FOR PREPARING A DEUTERATED N-AND a-SUBSTITUTED DIPHENYL ALKOXY ACETIC ACID AMINOALKYL ESTERS

Abstract

A method for preparing a deuterated N-and a-substituted diphenyl alkoxy acetic acid aminoalkyl esters of the general formula I wherein Rl represents hydrogen, deuterium, an n-propyl group, or a singly deuterated. multiply deuterated, or perdeuterated n-propyl group, R2 is oxygen, a methyl group, or a mono-, di-, or trideuteromethyl group, and R3 independently of one another, indicates H or deuterium, wherein at least one of the groups Rl, R2 or R3, independently of one another, is deuterium or contains deuterium; comprising the steps : (i) heating methyl benzilate with sodium dissolved in methanol and N-methvl-4-piperidinoI in a solvent mixture of toluene and benzene at 110°C for 4 housrs; 13 maximally distilling out methanol azeotrope and replacing separated solvent by pure toluene; (iii) adding dimethyl formamide and thionyl chloride under heating at temperature range from 100 to 105°C for 1 hour thereby evolving SO2 and HC1, resulting in temperature drop from 90 to 85°C; (iv) crystalising out crystals of l-methyIpiperidyl-4-hydrochIoride ester of a, a-diphenyl-a-chloro acetic acid and removing excess of thionyl chloride and said solvents by heating upto 110°C temperature under water-jet-vaccum; (v) adding d9-n-propanol and distilling out remaining toluene in azeotropically unit still the temperature reaches to 100(IC; (vi) refluxing the above reaction batch for 10 hours resulting in temperature drop to 93°C and removing hydrogen chloride and water containing n-propanol filtering the solution still hot after adding activated charcoal; and (vii) cooling, filtering and washing the product obtained with small amount of n-propanol and thereafter drying the product. 14 Dated this on 18th December, 2003.

Full Text

FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (See Section 10RULE 13) TURICUM DRUG DEVELOPMENT AG of SJODALA GARD, SJODALAVAGEN 85, S-23335 SVEDALA, SWITZERLAND, SWISS Company The following specification particularly describes the nature of the invention and the manner in which it is to be performed : - The invention concernsldeuterated N- and a-substituted diphenyl alkoxy acetic acid aminoalkyl esters as well as pharmaceutical drugs containing these compounds. A known representative of the N- and a-substituted diphenyl alkoxy acetic acid aminoalkyl esters is propiverine (DD 106,643, DD 139,212, and DE 2,937,489). This compound is employed for the treatment of detrusor hyperactivity. The problem of the present invention is to make available N- and a-substituted diphenyl alkoxy acetic acid aminoalkyl esters that, in comparison to the already known compounds, have improved pharmacokinetic and / or pharmacodynamic properties. Surprisingly, it has now been found that the deuterated N- and a-substituted diphenyl alkoxy acetic acid aminoalkyl esters in accordance with the invention have appreciably better pharmacokinetic and / or pharmacodynamic properties than the non-deuterated compounds. Thus, in accordance with the invention, the problem is solved by making avaiiabie deuterated N- and a-substituted diphenyl alkoxy acetic acid aminoalkyl esters of the general formula I, 2 wherein R1 represents hydrogen, deuterium, an n-propyl group, or a singly deuterated, multiply deuterated, or perdeuterated n-propyl group, R2 is oxygen, a methyl group, or a mono-, di-, or trideuteromethyl group, and R3, independently of one another, indicates H or deuterium, wherein at least one of the groups R1 R2 or R3, independently of one another, is deuterium or contains deuterium, as well as the physiologically tolerated salts thereof. Especially preferred here are deuterated N- and 9(-substituted diphenyl alkoxy acetic acid aminoalkyl esters in accordance with the invention wherein R1 represents an n-propyl group or a singly deuterated, multiply deuterated, or perdeuterated n-propyl group, R2 is a methyl group or a mono-, di-, or trideuteromethyl group, and R3, independently of one another, indicates H or deuterium, wherein at least one of the groups Ri, R2, or R3, independently of one another, is deuterium or contains deuterium, as well as the physiologically tolerated salts thereof. 3 Furthermore, especially preferred are deuterated N-and a-substituted diphenyl alkoxy acetic acid aminoalkyl esters in accordance with the invention wherein Ri represents an n-propyl group or a singly deuterated, multiply deuterated, or perdeuterated n-propyl group, R2 is oxygen, and R3, independently of one another, indicates H or deuterium, wherein at least one of the groups R1, R2 or R3, independently of one another, is deuterium or contains deuterium, as well as the physiologically tolerated salts thereof. Especially preferred in accordance with the invention are the following N and u-substituted diphenyl alkoxy acetic acid aminoalkyl esters deuterated in accordance with the invention: 2,2-diphenyl-2-(d-hydroxy)acetic acid N-methyl-4-piperidinyl ester, 2,2,-diphenyl-2-hydroxyacetic acid N-thdeteuromethyl-4-piperidinyl ester, 2,2-diphenyl-2-(d-hydroxy)acetic acid N-oxido-4-piperidinyl ester, 2,2-bis(pentadeuterophenyl)-2-(d-hydroxy)aceticacid N-trideutetomeihyl-4-perdeuteropiperidinyl ester, 2,2-bis(pentadeuterophenyl)-2-hydroxyacetic acid N-trideuteromethyl-4-perdeuteropiperidiny! ester, 2,2-bis(pentadeuterophenyl)-2-(perdeuteropropy!oxy)acetic acid N-oxido-4-perdeuteropiperidinyl ester, 2>2-diphenyl-2-(perdeuteropropyloxy)acetic acid N-methyl-4-piperidinyl ester, ^ 2,2-dipheny!-2-(perdeuteropropyloxy)acetic acid N-trideuteromethyl-4-piperidinyl ester, 2,2-diphenyl-2-(perdeuteropropyloxy)acetic acid N-monodeuteromethyI-4-piperidinyl ester, 2,2-diphenyl-2-(perdeuteropropyloxy)acetic acid N-dideuteromethyl-4-piperidinyl ester, 2,2-diphenyl-2-(perdeuteropropyloxy)acetic acid N-oxido-4-piperidinyl ester. 2,2-diphenyl-2-(3,3,3trideuteropropyloxy)acetic acid N-methyl-4-piperidinyl ester, 2,2-diphenyl-2-(3,3,3-trideuteropropyloxy)acetic acid N-trideuteromethyl-4-piperidinyl ester, 2,2-dipheny!-2-(3,3,34rideutefopropyloxy)acetic acid N-monodeuteromethyl-4-piperidinyl ester, 2,2-diphenyi-2-(3(3,3-trideuteropropyioxy)acetic acid N-dideuteromethyl-4-piperidinyl ester, 2,2-diphenyl-2-(3,3,3-trideuteropropyloxy)acetic acid N-oxido-4-piperidinyl ester, 2,2-diphenyl-2-(perdeuteropropyloxy)acetic acid N-methyl-4-perdeuteropiperidinyl ester, 2,2-diphenyl-2-(perdeuteropropyloxy)acetio acid N-liideuteromethyl-4-perdeuteropiperidinyl ester, I 5 2,2-diphenyl-2-(perdeuteropropy[oxy)acettcacid N-monodeuteromethyl-4-perdeuteropiperidinyl ester, 2,2-diphenyl-2-(perdeuteropropyloxy)acetic acid N-dideuteromcthyl-4-perdeuteropiperidiny! ester, 2,2-diphenyl-2-(perdeuteropropyloxy)acetic acid N-oxido-4-perdeuteropiperidinyl ester, 2,2-bis(pentadeuterophenyl)-2-(perdeuteropropyloxy)acetic acid N-trideuteromethyl-4-perdeuteropiperidinyl ester, 2,2-bjs(pentadeuterophenyl)-2-(perdeuteropropyloxy)acetic acid N-oxido-4-perdeuteropiperidinyl ester, 2,2-bis(pentadeuterophenyl)-2-(perdeuleropropyloxy)acetic acid N-methyl-4-piperidinyl ester, and 2,2-bis(pentadeuterophenyi)-2--(perdeulteropropyloxy)acetic acid N oxido 4-piperidinyl ester, Preferred is the use of the deuterated N- and a-substituted diphenyj alkoxy acetic acid aminoalkyi esters in accordance with the invention as well as the physiologically tolerated salts thereof for'the treatment of hypertonic functional states in the region of the urinary bladder. Especially preferred is the use of the deuterated N- and a-substituted diphenyl alkoxy acetic acid aminoalkyi esters in accordance with the invention as well as the physiologically tolerated salts thereof for the preparation of pharmaceutical 6 drugs for the treatment of hypertonic functional states in the region of the urinary bladder. Especially preferred are pharmaceutical formulations that contain the deuterated N- and a-substituted diphenyl alkoxy acetic acid aminoalkyi esters in accoidance with the invention as well as the physiologically tolerated salts thereof for the treatment of hypertonic functional states of the urinary bladder in addition to containing pharmaceutical tolerated adjuvants and / or additives. Another subject of the present invention is comprised of pharmaceutical formulations for the percutaneous and / or transdermal application of the deuterated N- and a-substituted diphenyl alkoxy acetic acid aminoalkyi esters in accordance wfth the invention as well as \he physiologically tolerated salts thereof. The preparation of the N- and a-substituted diphenyl alkoxy acetic acid aminoalkyi esters in accordance with the invention is in itself known and can take place as described in DD 106,643. To this end, the methyl ester of benzilic acid is transesterified with an N substituted amino alcohol in the presence of a catalytically acting, strong base with simultaneous azeotropic removal of methanol and converted into the a-chloro compound by reaction with thionyl chloride. The halogen compound is brought to reaction with an alcohol, water, or D20 and affords, after a reaction time of up to 10 hours, the desired N- and a-substituted diphenyl a!koxy acetic acid amino alkyl ester in the form of its acid chloride. The preparation of the deuterated compounds tluts takes place by reaction of the corresponding deuterated starting materials, such as d-benzilic acid methyl ester or deuterated N-substituted amino alcohols, or, as described in Embodiment Example 1, by reaction of the a-chloro compound with deuterated alcohol. 7 Conventional physiologically tolerated inorganic and organic acids are, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, malic acid, citric acid, salicylic acid, adipic acid, and benzoic acid. Further salts that can be used are described, for example, in Fortschritte der Arzneimittelforschung [progress in Drug Research], Vol. 10, pages 224-225, Birkhauser Publishing Co., Basel and Stuttgart, 1966, and Journal of Pharmaceutical Sciences, Vol. 66, pages 1-5 (1977). The acid addition salts are obtained, as a rule, in a way that is in itself known by mixing the free base or solutions thereof with the corresponding and or solutions thereof in an organic solvent, such as, for example, in a lower alcohol, like methanol, ethanol, n-propanol, or isopropanol, or in a lower ketone, like acetone, methyl ethyl ketone, or methyl isobutyl kelone, or in an ether, like diethyl ether, tetrahydrofuran, or dioxane. In order to achieve better separation of the crystals, it is also possible to use mixtures of the solvents mentioned. Beyond this, it is possible to prepare physiologically tolerated aqueous solutions of acid addition salts of the compounds used in accordance with the invention in an aqueous acid solution. The acid addition salts of the compounds in accordance with the invention can be transformed into the free base in ways that are in themselves known - for example, with alkalies or ion exchangers. Further salts can be obtained from the free base by reaction with inorganic or organic acids, in particular with those suitable for the formation of salts that can be used therapeutically. These or else other salts of the new compound, such as, for example, the picrate, can also serve for the purification of the free base by transforming the free base into a salt, separating the latter, and liberating the base once again from the salt. 8 The subject of the present invention is also comprised of pharmaceutical drugs for oral, rectal, subcutaneous, intravenous, or intramuscular application that, in addition to conventional carriers and diluents, contain a compound of the general formula I or its acid addition salt as the active ingredient. The pharmaceutical drugs of the invention are prepared in a known way in a suitable dosage with the conventional solid or liquid carriers or diluents and the conventionally used technical pharmaceutical adjuvants depending on the desired kind of application. The preferred formulations consist in a form of administration that is suitable for oral application. Such forms of administration are, for example, tablets, film tablets, dragees, capsules, pills, powders, solutions, or suspensions or depot forms. Obviously, parenteral formulations, such as injection solutions, also come into consideration. Furthermore, suppositories are also mentioned as formulations by way of example. Corresponding tablets can, for example, be obtained by mixing the active ingredient with known adjuvants, such as, for example, inert diluents, (ike dextrose, sugar, sorbitol, mannitol, polyvinyl pyrrolidone, disintegrators, such as cornstarch or alginic acid, binders, such as starches or gelatins, lubricants, such as magnesium stearate or talc, and / or means for achieving a depot effect, such as carboxylpolymethylene, carboxymethylcellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets can also consist of several layers. In a corresponding manner, dragees can be prepared by coating cores, prepared in analogy to the tablets, with substances usually used in dragee coats, such as, for example, polyvinyl pyrrolidone or shellac, gum arabic, talc, titanium dioxide, or sugar. Here, the dragee shell can also consist of several layers, wherein the adjuvants mentioned above for the tablets can be used. ° Solutions or suspensions containing the active ingredient used in accordance with the invention can contain, in addition, substances that improve taste, such as saccharin, cyclamate, or sugar, as well as, for example, flavoring substances, such as vanilla or orange extract. In addition,thoy can contain suspending agents, such as sodium carboxymethylceliulose, or preservatives, such as p-hydroxybenzoates. For example, capsules that contain active ingredients can be prepared by mixing the active ingredient with an inert carrier, such as lactose or sorbitol, followed by encapsulation in gelatin capsules. Suitable suppositories can be prepared, for example, by admixture with carriers, such as neutral fats or polyethylene glycol or their derivatives, that are provided for this purpose. The preparation of the pharmaceutical drugs in accordance with the invention for percutaneous application is known to the person skilled in the art. In the preparation of the pharmaceutical drugs in accordance with the invention for transdermal application, the adjuvants and enhancers that are in themselves known are used. The preparation of the pharmaceutical formulations in accordance with the invention is in itself known and is described in handbooks known to the person skilled in the art, such as, for example Hager's Handbuch [Hager's Handbook] (5th) 2, 622-1045; List et al, Arzneiforrnenlehre [Drug Forms], Stuttgart: Wiss. Publishing Co. 1985; Sucker et al, Pharrnazeutische Technologie [Pharmaceutical Technology], Stuttgart: Thieme 1991; Ullmann's Enzyklopadie [Ullmann's Encyclopedia] (5th) A 19, 241-271; Voigt, Pharrnazeutische Technologie [Pharmaceutical Technology], Berlin: Ullstein Mosby 1995. The pharmaceutical drugs prepared in this way can be used for the treatment of hypertonic functional states in the region of the urinary bladder. Included in the symptoms here are involuntary discharge of utine (enuresis), pathologically 10 frequent urination (urge incontinence), and painful urinary bladder ciamps (tenesmus). The compounds in accordance with the invention have a number of advantages over compounds known in the prior art, which do not bear any deuterium. The deuteration brings about a change in metabolism in the organism, in particular, the hydroxylation on the phenyl group is impeded, this leading to a reduced first-pass effect. In this way it is possible to change the dosage and to create longer-acting formulations, which, in the form of depot formulations, can also improve compliance. In addition, the pharmacodynamics are also changed, because the deuterated compounds form completely different hydrate shells, so that the distribution in the organism differs markedly from that of the non-deuterated compounds. (t is possible in this way to develop completely new forms of formulation. The following example illustrates the invention: Example 1 Preparation of the 1-methylpiperidyl hydrochloride ester of a-a-diplienyi-d7- propyloxyacetic acid 24.2 g of the methyl benzilate, 0.05 g of sodium (dissolved in 3 mL of methanol), and 11.75 g of N-methyl-4-piperidinol are healed in a stirred solvent mixture consisting of 80 mL of toluene and 200 mL of benzene for 4 hours at 110 °C. During this time, approximately 32 mL of methanol azeotrope are distilled off. Subsequently, an additional 65 to 70 mL of methanol azeotrope are distilled off and the separated solvent is [replaced] by pure toluene. Then, 0.1 mL of dimethylformamide is added and, after heating the solution to 100 to 105 C, 13.2 g of thionyl chloride are added under stirring within one hour. SO2 / HC! evolution commences and the reaction temperature drops to 90 to 85 °C. Once the 1-methylpiperidy! 4-hydrochloride ester of a,a-diphenyl-a-chloroacetic acid begins to crystallize out, heating up to 110 °C is carried out carefully, as a function of the gas evolution, and excess thionyl chloride and solvent are removed as much as possible with an increasing water-jet vacuum. Under stirring, 15 mL of d9-n-propanol are added and the remaining toluene is distilled off azeotropically until the internal temperature has reached 100 °C. The reaction batch is heated for 10 hours at reflux, this resulting in the occurrence of a temperature drop to approximately 93 °C. After removal of 50 to 60 mL of hydrogen chloride and water-containing n-piopanol, activated carbon is added and the solution is filtered while still hot. Subsequently, the solution is cooled and the product is filtered off, washed with a small amount of n-propanol, and dried. Addition of n-hexane to the mother liquor affords additional product, which is recrystallized with a small amount of activated carbon from a small amount of n-propanol. Yield: 34.52 g; 84% Melting point: 212-217 °C N: 3.41 % N: 3.42% Calculated C: 67.22%, H: 9.07%, Found C: 67.24%, H: 9.04%, WE CLAIM : 1. A method for preparing a deuterated N-and a-substituted diphenyl alkoxy acetic acid aminoalkyl esters of the general formula I wherein Rl represents hydrogen, deuterium, an n-propyl group, or a singly deuterated. multiply deuterated, or perdeuterated n-propyl group, R2 is oxygen, a methyl group, or a mono-, di-, or trideuteromethyl group, and R3 independently of one another, indicates H or deuterium, wherein at least one of the groups Rl, R2 or R3, independently of one another, is deuterium or contains deuterium; comprising the steps : (i) heating methyl benzilate with sodium dissolved in methanol and N-methvl-4-piperidinoI in a solvent mixture of toluene and benzene at 110°C for 4 housrs; 13 maximally distilling out methanol azeotrope and replacing separated solvent by pure toluene; (iii) adding dimethyl formamide and thionyl chloride under heating at temperature range from 100 to 105°C for 1 hour thereby evolving SO2 and HC1, resulting in temperature drop from 90 to 85°C; (iv) crystalising out crystals of l-methyIpiperidyl-4-hydrochIoride ester of a, a-diphenyl-a-chloro acetic acid and removing excess of thionyl chloride and said solvents by heating upto 110°C temperature under water-jet-vaccum; (v) adding d9-n-propanol and distilling out remaining toluene in azeotropically unit still the temperature reaches to 100(IC; (vi) refluxing the above reaction batch for 10 hours resulting in temperature drop to 93°C and removing hydrogen chloride and water containing n-propanol filtering the solution still hot after adding activated charcoal; and (vii) cooling, filtering and washing the product obtained with small amount of n-propanol and thereafter drying the product. 14 Dated this on 18th December, 2003.

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