MXPA99001500A - Ether muscarinic antagonists - Google Patents

Abstract

1,4 Di-substituted piperidine muscarinic antagonists of formula (I) or an isomer, pharmaceutically acceptable salt, ester or solvate thereof, wherein X is a bond, -O-, -S-, -SO-, -SO2-, -CO-, -C(OR7)2-, -CH2-O-, -O-CH2-, -CH=CH-, -CH2-, -CH(C1-C6 alkyl)-, -C(C1-C6 alkyl)2-, -CONR17-, -NR17CO-, -O-C(O)NR17-, -NR17C(O)-O-, -SO2NR17- or -NR17SO2-;R is cycloalkyl, optionally substituted phenyl or optionally substituted pyridyl;R2 is H, alkyl, optionally substituted cycloalkyl, cycloalkenyl, t-butoxycarbonyl or optionally substituted piperidinyl;and the remaining variables are as defined in the specification, are disclosed. Compounds of formula (I) are useful for treating cognitive disorders such as Alzheimer's disease. Also disclosed are pharmaceutical compositions, methods of preparation and combinations of compounds of formula (I) with ACh'ase inhibitors.

Description

MUSCARINIC ETHER ANTAGONISTS BACKGROUND PE THE INVENTION The present invention relates to 1,4-di-substituted piperidines, wherein the substituent of the 4-position is connected via an ether bond, these compounds are useful in the treatment of cognitive disorders , to pharmaceutical compositions containing the compounds, to a method of treatment using the compounds and to the use of the compounds in combination with acetylcholinesterase inhibitors. Alzheimer's disease and other cognitive disorders have received much attention recently, however the treatments for these diseases have not been very successful. According to Melchiorre et al. (J. Med. Chem. (1993), 36, 3734-3737), compounds that selectively antagonize M2 muscarinic receptors, especially in relation to muscarinic MI receptors, must possess activity against cognitive disorders. Baumgold et al. (Eur. J. of Pharmacol., 251, (1994) 315-317) describe 3-alpha-chloroimperialine as a highly selective muscarinic m2 antagonist. The present invention relates to a class of 1,4-di-substituted piperidines, some of which have M2 selectivity even higher than those of 3-alpha-chloroimperialine. Logemann et al. (Brit. JJ Pharmacol. (1961), 17, 286-296) discloses certain di-N-substituted piperazines, but these are not different from the compounds of the present invention. In addition, the compounds of Logemann et al. Are not described as having activity against cognitive disorders. COMPENDIUM OF THE INVENTION The present refers to compounds according to the structural formula: Or an isomer, salt, ester or pharmaceutically acceptable solvate thereof, wherein X is a bond, -O-, -S-, -SO-, -S02-, -CO-, -C (OR7) 2-, -CH2 -0-, -0-CH2-, -CH = CH-, -CH2-, -CH (alkyl with 1 to 6 carbon atoms) -, -C (alkyl with 1 to 6 carbon atoms) 2-, -CONR17-, -NR17CO-, -0-C (O) NR17-, -NR17C (O) -O- , -S02NR17-? -NR17S02-; R is cycloalkyl with 3 to 6 carbon atoms, n is 1, 2 or 3; R2 is H, alkyl having 2 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms substituted by 1 to 4 groups independently selected from R18, cycloalkenyl with 3 to 6 carbon atoms, t-butoxycarbonyl or R19 / -A 16 R3 and R4 independently are selected from the group consisting of H, halo, -CF3 / alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, and -OH; R5 and R6 independently are selected from the group consisting of H, alkyl having 1 to 6 carbon atoms, -CF3, alkoxy with 1 to 6 carbon atoms, -OH, alkylcarbonyl with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, R13CONH-, (R13) 2NCO-, R130CONH-, R13NHCONH- and NH2CONR13-; R7 is independently selected from the group consisting of alkyl with 1 to 6 carbon atoms; or the two R7 groups can be joined to form - (C (R14) 2) p- wherein p is an integer from 2 to 4; R8, R9, R10, R and R12 are independently selected from the group consisting of H, halo, alkyl having 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, benzyloxy, benzyloxy substituted by -N02 or -N ( R14), alkyl halo with 1 to 6 carbon atoms, polyhalo alkyl with 1 to 6 carbon atoms, -N02, -CN, -S02, -OH, -NH2, -N (R1) 2, -CHO, polyhalo alkoxy with 1 to 6 carbon atoms, acyloxy, (alkyl with 1 to 4 carbon atoms) 3Si-, (alkyl with 1 to 6 carbon atoms) SO0_2, arylsulfonyl, heteroarylsulfonyl, acyl, (C1-C6 alkoxy) ) CO-, -OCON (R14) 2 / -NHCOO-alkyl (1 to 6 carbon atoms), -NHCO- (alkyl with 1 to 6 carbon atoms), phenyl, hydroxy (C1-C6 alkyl) ) or morpholino; R13 is independently selected from the group consisting of H, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, - (alkyl having 1 to 6 carbon atoms) COOR15, aryl, heteroaryl, -aryl (alkyl) with 1 to 6 carbon atoms), -heteroaryl (C 1-6 -alkyl) and adamantyl; R14 is independently selected from the group consisting of H, and alkyl having 1 to 6 carbon atoms; R15 is independently selected from the group consisting of H, alkyl having 1 to 20 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, aryl substituted with 1 to 3 groups independently selected from R3 and heteroaryl substituted with 1 to 3 independently selected groups of R3; R16 is H, alkyl having 1 to 6 carbon atoms, -COR20, alkoxycarbonyl having 1 to 6 carbon atoms, -CON (R14) 2, -CONH (R3-aryl), -S0x_2-R15, -SOx_2- (CH2 ) m-R21, -SON (R14) 2 / -COSR14 or R17 is H, alkyl having 1 to 6 carbon atoms, aryl or heteroaryl; R18 is independently selected from the group consisting of halo, -CF3, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, -OH, = 0, -CON (R14) 2 and -N (R14) COR15; R19 is H, -OH, alkyl having 1 to 20 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, aryl substituted with 1 to 3 groups independently selected from R3 or heteroaryl substituted with 1 to 3 groups independently selected from R3; R20 is H, alkyl with 1 to 20 carbon atoms, alkoxy with 1 to 20 carbon atoms-alkyl (1 to 6 carbon atoms), cycloalkyl with 3 to 6 carbon atoms, aryl, aryl (alkyl with 1 to 6) carbon atoms) -, aryloxy, aryloxy (C1-C6 alkyl) -, tetrahydrofuranyl or heteroaryl, wherein the aryl or heteroaryl group is substituted by 1 to 3 groups independently selected from R3; m is 0 to 3; and R21 is cycloalkyl with bridge of 7 to 10 carbon atoms or cycloalkyl with bridge of 7 to 10 carbon atoms wherein the cycloalkyl portion is substituted by 1 or 2 substituents selected from the group consisting of alkyl with 1 to 6 carbon atoms o = 0 Preferred compounds of the formula I are those wherein X is -S-, -SO-, -S02- or -CH2-, with -S02- and -CH2- more preferred. They are also preferred compounds of the formula I wherein R is phenyl substituted with R8, R9, R10, R11, R12, preferably alkoxyphenyl, or 3,4-methylenedioxyphenyl, especially 3,4-methylenedioxyphenyl being preferred. R3 and R4 are preferably each hydrogen. R2 is preferably cycloalkyl or wherein R16 is preferably -COR20, alkoxycarbonyl having 1 to 6 carbon atoms or -S02R21 especially -COR20 wherein R20 is R3-substituted aryl. When R20 is R3-substituted aryl, it is preferably R3-substituted phenyl, especially 2-substituted phenyl, wherein the substituent is methyl or halo. R5 and R6 are preferably independently hydrogen and -CH3. Another aspect of the invention is a pharmaceutical composition comprising a compound having the structural formula I in combination with a pharmaceutically acceptable carrier. Another aspect of the invention is the use of a compound of the formula I for the preparation of a pharmaceutical composition useful in the treatment of cognitive disorders and neurodegenerative diseases such as Alzheimer's disease. Another aspect of the invention is a method for treating a cognitive or neurodegenerative disease comprising administering to a patient suffering from the disease, an effective amount of a compound of the formula I.

Another aspect of this invention is a method for treating cognitive or neurodegenerative diseases, comprising administering to a patient suffering from the disease, an effective amount of a compound of the formula I. Another aspect of the invention is a method for treating cognitive and neurodegenerative diseases such as Alzheimer's disease with a compound of the formula I in combination with an acetyl coliesterase inhibitor. Another aspect of the invention is a method for treating a cognitive or neurodegenerative disease comprising administering to a patient suffering from the disease, an effective amount of a combination of a compound of the formula I as defined above, including stereoisomers, salts and pharmaceutically acceptable solvates thereof, the compound is able to improve release of acetylcholine (ACh) (again preferably a muscarinic antagonist m2 or m4 selective) with an acetylcholinesterase inhibitor (ACh'asa). Another aspect of this invention is a kit comprising separate containers in a single package, pharmaceutical compounds for use in combination to treat cognitive disorders in a container, a compound of formula I capable of improving acetylcholine release (preferably a muscarinic antagonist, or selective m4)) in a pharmaceutically acceptable carrier and in a second vessel an acetylcholinesterase inhibitor in a pharmaceutically acceptable carrier, the combined amounts are an effective amount. DETAILED DESCRIPTION Except when otherwise stated, the following definitions apply through the specification and claims. These definitions apply whether a term is used by itself or in combination with other terms. Alkenyl represents a straight or branched hydrocarbon chain having 2 to 6 carbon atoms having at least one carbon-to-carbon double bond. Cycloalkyl represents a saturated carbocyclic ring having 3 to 6 carbon atoms. Bridged cycloalkyl represents a carbocyclic ring saturated with 7 to 11 carbon atoms, consisting of a cycloalkyl ring with 3 to 6 carbon atoms, and an alkylene chain with 1 to 6 carbon atoms attached at each end to non-adjacent carbon atoms of the carbon atom. ring; when substituted, the cycloalkyl ring may have 1 to 2 substituents selected from the group consisting of alkyl having 1 to 6 carbon atoms y = 0. Examples of optionally substituted bridged cycloalkyl groups are 7,7-dimethyl-5-oxo-bicyclo [2.2.1] hept-4 (R) -yl (which, when the group R16 is-S02- (CH2) m-R21 and m is 1 , forms a camforsulfonyl group), adamantyl, mirtanil, noradamantyl, norbornyl, bicyclo [2. 2 . 1] heptyl, 6,6-dimethylbicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl and bicyclo [2.2.2] octyl. Cycloalkenyl represents a carbocyclic ring having from 3 to 6 carbon atoms and at least one carbon-to-carbon double bond in the ring. Halo represents fluorine, chlorine, bromine or iodine. Aryl represents optionally substituted naphthyl phenyl optionally substituted, wherein the substituents are 1 to 3 groups as defined in R8. Heteroaryl represents optionally substituted heteroaryl groups, wherein the substituents are 1 to 3 groups as defined in R 8, and the heteroaryl group is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiophenyl, furanyl or pyrolyl. Polihalo represents substitution of at least 2 halogen atoms to the group modified by the term "polyhalo". Sulfonyl represents a group of the formula -S02-. Sulfinyl represents a group of the formula -SO-.

When a variable appears more than once in the structural formula, for example R7 when X is -C (OR7) 2-, the identity of each variable that appears more than once can be selected independently of the definition for that variable. The variables R5 and R6 can independently be connected to substitutable carbon atoms in the piperidinyl ring, or both variables can be connected to the same ring carbon atom. Similarly, when R2 is R18-substituted cycloalkyl, and R18 is alkyl, two substituents or a group = 0 can be connected to any of the methylene ring members. In the definition of R20, any of the substituents having an aryl or heteroaryl moiety may be substituted by 1 to 3 R3 groups on substitutable ring carbon atoms of the aryl or heteroaryl groups. Compounds of this invention can exist in at least two stereo configurations, at the carbon to which R5 and / or R6 are connected, except when R5 and R6 are connected to the same carbon atom and are identical. Additional stereisomerism is present when X is SO, or C (OR7) 2 (when two R7 groups are not the same). Also within formula I there are numerous other possibilities stereoisomerism. All possible stereoisomers of formula I are within the scope of the invention. The compound of formula I can exist in unsolvated as well as solvated forms, including hydrated forms. In general, solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to unsolvated forms for purposes of this invention. A compound of the formula I can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of acids suitable for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other minerals and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base forms with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms can be regenerated by treating the salt with a convenient diluted aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, sodium bicarbonate or ammonia. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts otherwise are equivalent to their respective free base forms for purposes of the invention. Compounds of the formula I are prepared by methods known to those skilled in the art as exemplified by the following reaction procedures: METHOD A: R5 ° Y ^ NaBH4 H0 Y ^ »? i ^ r -N A substituted 4-piperidinone 1 is reduced with NaBH4 and the resulting 4-piperidinol 2 is reacted with a 4-iodophenol derivative, 3a, in the presence of an activator such as diethyl azodicarboxylate (DEAD) and a phosphine such as triphenylphosphine (PPh3), to give a phenyl ether 4. The phenyl ether is reacted with a compound RXH, wherein R and X are as defined above, in the presence of a catalyst such as copper iodide to give a compound of formula 1. Alternatively, the following procedure may be employed: A compound of formula 2 is reacted with a phenol, 3b, in the presence of an activator such as DEAD and a phosphine PPh3 to give a compound of formula I. This alternate route is preferred when X is not S, O, or N. METHOD B; Compounds of the formula 1-A, wherein X is S, can be converted to the compound of the formula 1-B, wherein X is S (0) 1_2, by treatment with an oxidant such as m-chloroperbenzoic acid (MCPBA) in the presence of an organic acid such as methanesulfonic acid. METHOD C: Compounds of the formula 1-C (prepared by method A and / or B), wherein Y is a suitable nitrogen protecting group, can be transformed into compounds of formula I by removal of the protecting group under standard conditions, followed by reaction of the resulting piperidine with an acetone 5, wherein RA and RB together with the atom carbon atoms form R2. The preferred reaction is carried out in the presence of a Lewis acid such as titanium tetraisopropoxide. The resulting iminium ion is treated with a reducing agent such as NaCNBH3 to give a compound of formula 1. METHOD D: Compounds of the formula 1-D, wherein Y is a protecting group, are prepared according to methods A, B, and / or C. The compounds of the formula 1-D are converted into compounds of the formula 1- E upon deprotection under standard conditions, followed by treatment with a reagent G, wherein G is R16aL wherein R16a is as defined above for R16, except that it is not H, and L is a leaving group such as Cl or Br; or G is R15aNCO, wherein R15a is as defined above for R15, except that it is not H. METHOD E: Compounds of formula 1-F are prepared, wherein Q is -CO- or-S02-, by first preparing a compound of formula 5 under the procedures described in steps 1 and 2 of method A. The compound of Formula 5 is then hydrolyzed to an aniline with strong acid such as 6N HCl. The aniline derivative is acylated or sulfone with an activated reagent (RCO) or RQ-L, where R is as previously defined, Q is as defined above and L is a leaving group such as halogen or imidazolyl. Examples of activated reagents include RCO-halogen, RCOOCOCH3, ROCO-halogen and RS02-halogen. As indicated, in the previous processes, it is sometimes convenient and / or necessary to protect certain groups during the reactions. Conventional family protective groups for those with skill in the specialty, are operable. The above reactions can be followed if necessary or convenient by one or more of the following steps: (a) removing any protective groups from the compound thus produced; (b) converting the compound thus produced to a pharmaceutically acceptable salt, ester and / or solvate; (c) converting a compound according to formula I thus produced into another compound according to formula I, and (d) isolating a compound in formula I, including separating stereoisomers of formula I. Based on the sequence of In the above reaction, those skilled in the art will be able to select starting materials required to produce any compound according to formula I. The compounds of the formula I exhibit muscarinic antagonism activity m2 and / or tn4 selective, which has been correlated with pharmaceutical activity to treat cognitive disorders such as the disease of Alzheimer's and senile dementia. The compounds of the formula I exhibit pharmacological activity in test runs designated to indicate muscarinic antagonist activity ml, m2 and m4. The compounds are non-toxic at pharmaceutical therapeutic doses. To prepare pharmaceutical compositions of the compounds of the formula I capable of improving the release of ACh, and ACh'ase inhibitors, the inert pharmaceutically acceptable carriers are mixed with the active compounds. The pharmaceutically acceptable carriers can be either solid or liquid. Preparations in solid form include powders, tablets, dispersible granules, capsules, dragees and suppositories. A solid carrier may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; They can also be an encapsulating material.

Preparations in liquid form include solutions, suspensions and emulsions. As an example, water or water-propylene glycol solutions for parenteral injection may be mentioned. Also included are preparations in solid form that are intended to be converted, briefly before use, without liquid form preparations, either for oral or parenteral administration. These liquid forms include solutions, suspensions and emulsions. These particular solid form preparations are more conveniently provided in unit dose forms and as such are used to provide a simple liquid dose unit. The invention also contemplates alternative delivery systems, including but not necessarily limited to transdermal delivery. Transdermal compositions can take the form of creates, lotions and / or emulsions and may be included in a transdermal patch of the matrix or reservoir type as is conventional in the art for this purpose. Preferably, the pharmaceutical preparation is in unit dosage form. In this form, the preparation is sub-divided into unit doses containing appropriate amounts of the active components. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation such as tablets, capsules and powders in ampoules or packaged vials. The unit dosage form can also be a capsule, dragee or tablet itself, or it can be the appropriate number of any of these in packaged form. The amount of active compound in a unit dose preparation can be varied or adjusted from 1 mg to 100 mg according to the particular application and potency of the active ingredient and the intended treatment. This will correspond to an approximate dose of 0.001 to about 20 mg / kg which can be divided into three administrations per day. The composition can if desired also contain other therapeutic agents. The doses may be varied depending on the patient's requirement, the severity of the condition to be treated and the particular compound employed. The determination of the appropriate dose for a particular situation is within the skill of those in the medical specialty. For convenience, the total daily doses can be divided and administered in portions throughout the day or by means of continuous delivery. When a compound of formula I capable of improving ACh release is used in combination with an ACh'ase inhibitor to treat cognitive disorders, these two active compounds can be co-administered simultaneously or sequentially, or a simple pharmaceutical composition comprising a A compound of the formula I capable of improving the release of ACh and an ACh'ase inhibitor in a pharmaceutically acceptable carrier can be delivered. The components of the combination can be administered individually or together in any conventional oral or parenteral dosage form such as a capsule, tablet, powder, dragee, suspension, solution, suppository, nasal spray, etc. The dose of the ACh'ase inhibitor can be in the range of 0.001 to 100 mg / kg of body weight. The invention described herein is exemplified by the following preparations and examples which are not to be considered as limiting the scope of the description. In alternate mechanistic trajectories and analogous structures they may be apparent to those with skill in the specialty. Example 1 NaBH 4 (1.2 g) is added in portions to an ice-cooled solution of N-cyclohexylpiperidine-4-one (1) (10.5 g) in ethanol (EtOH) (200 mL). After the addition is complete, the cooling bath is removed and the mixture is stirred for 24 hours at room temperature. Removal of the solvent and separation of the residue between water and ethyl acetate (EtOAc) (125 mL each). Dry the organic layer over MgSO 4 and evaporate to give 9.0 g of crude product 2 which is used directly in the next step. STAGE 2 : To a solution of 2 in THF (150 mL), add 4-iodophenol (3) (11.08 g) followed by PPh3 (13.1 g). The mixture is cooled in an ice bath and slowly, with stirring, a solution of diethylazodicarboxylate (8.75 g) in THF (10 mL) is added. The resulting mixture is stirred overnight, while allowing it to warm to room temperature. The mixture is evaporated to dryness and the residue is taken up in EtOAc (250 mL). Wash the EtOAc with IN HCl (150 mL), dry over MgSO 4 and evaporate. Chromatograph the residue in 400 g of flash dried silica gel, eluting with EtOAc followed by CH2Cl2: EtOH: aqueous NH3 (100: 3: 1) to give 1.5 g of product. Stage 3: A solution of 4 (0.58 g) is heated, 4-methoxybenzentiol (0.42 g), Cul (47.6 mg), and K2C03 (1.0 g) in DMPU (9 mL) under N2 in an oil bath at 140-145 ° C for 4.5 hours. After cooling to room temperature, the mixture is poured into ice-water (700 mL) and filtered. The wet solid is dissolved in EtOAc (70 mL), dried over MgSO4 and evaporated. The resulting material is purified on 25 g of flash dried grade silica gel eluting with EtOAc to give 0.45 gram of oily product. It is converted to its hydrochloride to give a solid, mp = 223-224 ° C. In a similar manner, using appropriate starting materials, the following compounds are prepared: ÍC Prepare by adding NaH (0.005 g) to a solution of IB (0.05 g) at room temperature and stir for 20 minutes. CH31 (0.017 g) is added and the reaction mixture is stirred for two hours. The reaction mixture is diluted with water and extracted with EtOAc. The EtOAc layer is separated and concentrated and the crude material is purified by prep of silica gel. TLC, eluting with acetone / CH2Cl2 (1/4) to obtain IC (0.027 g). ID is prepared from IC by debenzylation, followed by reductive amination with the cyclohexanone derivative.

Example 2 The product of example 1 (200 mg) in acetic acid (6 mL) is treated with NaB03.4 HzO (155 mg) and the resulting mixture is stirred overnight at room temperature. The mixture is diluted with water and basified with K2C03. The solution is extracted with CH2C12 (2 x 30 mL). The combined organic layers are dried over MgSO4 and evaporated to give 200 mg of an oily residue which is predominantly sulfoxone A, with a minor amount of sulfoxide B. (using 82 mg of NaB03.4 H20 results predominantly in sulfoxide B). The sulfoxide and sulphone are separated by flash chromatography on silica gel, eluting with CH2C12: EtOH: aqueous NH3 (100: 3: 1) to give: A: p.f = 250-252 ° C (HCl salt); and B: gummy solid. EXAMPLE 3 Stage 1 : tri luoroacetic acid CH2CI2 Treat a solution of compound 5 prepared by method A in CH2C12 (15 mL) with trifluoroacetic acid (3 mL) and stir the resulting mixture for 30 minutes at room temperature. After evaporation and drying, the residue is added to IN NaOH, which is extracted with CH2C12. After drying over Na 2 SO 4, the solvent is evaporated to yield 1.0 gram of compound 6.

Step 2: To a mixture of product from step 1 and N-B0C-4-piperidinone in CH2C12 (10 mL), titanium tetraisopropoxide (3.4 mL) is added and the mixture is stirred overnight at room temperature. To this mixture, add NaCNBH3 (0.74 g) in CH30H (4 mL) and stir the reaction under N2 for 5 h. The reaction is neutralized by adding a mixture of IN NaOH (50 mL) and EtOAc (100 mL) and stirring for 1 hour. The reaction is stirred and the filtrate extracted with EtOAc. After drying over NaHCO 3, the solvent is removed and the residue purified by chromatography to give 1.32 g of the title compound. HRMS: calculated: 500.2471; found 500.2465. In a similar manner, using appropriate starting materials, the following compound is prepared: HRMS: calculated: 500.2471; found 500.2465. Example 4 Step 1: Dissolve the product of Example 3 (0.55 g) in CH2C12 (8 mL) and add CH3S03H (0.2 mL). After stirring for 20 minutes, MCPBA (0.93 g of 50-60%) is added and the reaction is stirred for 4 hours at room temperature. The reaction mixture is added to IN NaOH (50 mL), stirred for 30 minutes and extracted with CH2C12. Dry the organic layer over NaHCO 3 and evaporate to obtain 0.45 grams of the desired 1,4-bipiperidine derivative. Step 2: To the product from step 1 (65 mg) in CH2C12 (2 mL), triethylamine (Et3N) (0.5 mL) is added followed by o-toluoyl chloride (35 mg). A reaction mixture is stirred at room temperature for 1.5 hours under N2, then applied directly to a preparative silica gel TLC plate, eluting with 5% CH30H in CH2C12 to obtain 60 mg of the title compound. HRMS: calculated: 563.2216; found: 563.2211. In a similar manner, using appropriate starting materials, compounds of the following structural formula are prepared, wherein the variables are as defined in the table: Example 5 Compound 7 (0.57 g) (again prepared by method A) is dissolved in 6N HCl and heated at 100 ° C for 5 hours. The reaction mixture is cooled to room temperature and diluted with ice / water. Basify the reaction mixture with 3N NaOH and extract with EtOAc. Separate the organic layer and concentrate to give 0.41 g of product 8. Step 2: Add 4-methoxybenzenesulfonyl chloride (75 mg) to a solution of 100 mg of product 8 in THF (3 mL) containing Et3N (74 mg). ) to 0 ° C. The reaction mixture is stirred overnight while heating to room temperature. The reaction mixture is poured into semi-saturated NaHCO 3 solution and extracted with EtOAc. Concentrate the organic layer and purify on silica gel, eluting with Et2O.Et3N (96: 4) to give 50 mg of the title compound. MP = 112-118 ° C (HCl salt). In a similar manner, using appropriate starting materials, the following compound is prepared: Following are descriptions of the pharmacological test procedures. MUSCARLINAL UNION ACTIVITY The compound of interest test for its ability to inhibit binding to subtypes of cloned human muscarinic ml, m2, m3 and m4 receptors. The sources of receptors in these studies were membranes of stably transfected CHO cell lines that expressed each of the sub-types of receptors. Following growth, the cells were pelleted and subsequently homogenized using a polytron in 50 volumes of cold 100 mM Na / K phosphate buffer, pH 7.4 (Buffer B). The homogenized fractions were centrifuged at 40,000 x g for 20 minutes at 4 ° C. The resulting supernatants were discarded and the nodules were suspended in buffer B at a final concentration of 20 mg wet tissue / ml. These membranes were stored at -80 ° C until they are used in the binding assays described below. The binding to the cloned human muscarinic receptors is carried out using 3 H-quinuclidinyl benzilate (QNB) (Atson et al., 1986). Briefly, membranes (approximately 8, 20, and 14 μg of protein assay for membranes containing ml, m2, and m4, respectively) were incubated with 3H-QNB (final concentration of 100-200 pM) and increased concentrations of drug without labeling in a final volume of 2 ml at 25 ° C for 90 minutes. Non-specific binding is assayed in the presence of 1 μM atropine. Incubations were terminated by vacuum filtration on GF / B glass fiber filters using a Skatron filtration apparatus and the filters were washed with cold Na / K lOmM phosphate buffer, pH 7.4. Scintillation cocktail is added to the filters and the ampules were incubated overnight. The bound radioligand is quantified in a liquid scintillation counter (50% efficiency). The resulting data were analyzed for 1C50 values (ie the concentration of the compound required to inhibit binding by 50%) using the EBDA computer program (McPherson, 1985). Affinity values (Ki) were then determined using the following formula (Cheng and Prusoff, 1973); IC 50 K¡ = 1 + concentration of radioligand affinity (KQ) of radioligand Therefore, a lower value of Ki indicates higher binding affinity.

The following publications, all the contents of which are hereby incorporated by reference, explain the procedure in more detail. Cheng, Y.-C. and Prusoff, W.H. , Relationship between the inhibitory constant (K ±) and the concentration of inhibitor which causes 50 per cent inhibition (1C50) of an enzymatic reaction (Relationship between the inhibition constant (Kx) and the concentration of inhibitor that causes 50% inhibition ( IC50) of an enzymatic reaction). Biochem. Pharmacol. 22: 3099-3108, 1973. McPherson, G.A. Kinetic, EBDA, Ligand, Lowry: A Collection of Radioligand Binding Analysis Programs (A collection of programs for radioligand binding analysis). Elsevier Science Publishers BV, Amsterdam, 1985. Watson, M.J, Roeske, W.R. and Yamamura, H.I. [3H] Pirenzepine and (-) [3H] quinuclidinyl benzilate binding to rat cerebral cortical and cardiac muscarinic choligernic sites. Characterization and regulation of antagonistic binding to putative muscarinic subtypes [3H] (Pirenzepine and (-) [3H] quinuclidinyl benzilate that binds rat muscarinic cardiac and cortical cholinergic sites in the rat Characterization and regulation of antagonist binding to muscarinic subtypes putative). J. Pharmacol. Exp. Ther. 237: 411-418, 1986. To determine the degree of selectivity of a compound to bind the m2 receptor, the Kt value for the ml receptors is divided by the K ± value for m2 receptors. A higher ratio influences a greater selectivity to bind the m2 muscarinic receptor. A similar calculation is made to determine the m4 selectivity. METHODOLOGY OF MICRODIALYSIS The following procedure is used to show that a compound functions as a m2 antagonist. Surgery: For these studies, male Sprague-Dawley rats (250-350 g) were anesthetized with sodium pentobarbital (54 mg / kg, ip) and placed in a Kopf stereotaxic apparatus. The skull is exposed and drilled through the dura at a point 0.2 mm anterior and 3.0 mm lateral to the bregma. At these coordinates, a guide cannula is placed at the outer edge of the dura through the drilled opening, lowered perpendicularly to a depth of 2.5 mm, and permanently attached with dental cement to bone screws. After the surgery, the rats are given ampicillin (40 mg / kg, ip) and individually housed in modified cages. A recovery period of approximately 3 to 7 days is allowed before the microdialysis procedure is carried out. Microdialysis: All equipment and instrumentation used to conduct microdialysis in vivo is obtained from Bioanalytical Systems, Inc. (BAS). The microdialysis procedure involves the insertion through the guide cannula of a thin needle-type infusion probe (CMA / 12.3 mm x 0.5 mm) at a depth of 3 mm into the striatum beyond the end of the guidewire. The probe is connected in advance with tubing to a micro injection pump (CMA- / 100). Collars and leashes were placed on the rats, following probe insertion they were placed in a large transparent plexiglass bowl with mat material and with access to food and water. The probe is perfused at 2 μl / min with Ringer's buffer (147 mM NaCl, 3.0 mM KCl, 1.2 mM CaCl2, 1.0 mM MgCl2) containing 5.5 mM glucose, 0.2 mM L-ascorbate, 1 μM neostigmine bromide. pH 7.4). To achieve stable baseline readings, microdialysis is allowed to proceed for 90 minutes before fractional collection. The fractions (20 μl) were obtained at 10 minute intervals over a period of 3 hours using a refrigerated collector (CMA / 170 or 200). Four to five fractions of baseline were collected, after which the drug or combination of drugs to be tested was administered to the animal. At the end of the collection, each rat is autopsied to determine the accuracy of the placement of the probe. Acetylcholine Analysis (ACh): The concentration of ACh in the samples collected from microdialysis is determined using HPLC / electrochemical detection. The samples were self-injected (Waters 712 Refrigerated Sample Processor) onto an analytical polymeric HPLC column (BAS, MF-6150) and elute with 50 mM Na2HP04, pH 8.5. T To avoid bacterial growth, Kathon CG reagent (0.005%) (BAS) is included in the mobile phase. Eluent of the analytical column, which contains separate ACh and choline, then is immediately passed through an immobilized enzyme reactor cartridge (BAS, MF-6151) coupled to the column outlet. The reactor contains both acetyl cholinesterase and choline oxidase covalently linked to a polymeric backbone. The action of these enzymes on ACh and choline results in stoichiometric yield of hydrogen peroxide, which is detected electrochemically using a Waters 460 detector equipped with a platinum electrode at an operating potential of 500 mvolts. Data acquisition is carried out using an IBM Model 70 computer equipped with an IEEE microchannel card. The integration and quantification of peaks is achieved using the "Máxima" chromatography program (Waters Corporation). Total operating time per sample was 11 minutes at a flow rate of 1 ml / minute. Retention times for acetylcholine and choline were 6.5 and 7.8 minutes, respectively. To verify and correct possible changes in detector sensitivity during chromatography, ACh standards were included at the beginning, middle and end of each sample waiting list. Increases in ACh levels are consistent with presynaptic m2 receptor antagonism. In general, compounds according to formula I were tested with the following ranges of results: Ki receptor binding ml, nM: 7.29 to 999.20. K- junction to receiver m2, nM: 0.23 to 167.90. i binding to m3 receiver, nM: 8 to 607.50. Ki binding to m4 receptor, nM: 1.78 to 353.66. Compounds of formula I in combination with ACh 'asa inhibitor have an effect on ACh release. The present invention therefore also relates to administering a compound of formula I in combination with any ACh'ase inhibitor including but not limited to E-2020 (available from Eisai Pharmaceutical) and heptylphisostigmine.

Claims (12)

CLAIMS 1. - A compound that has the structural formula: or an isomer, salt, ester or pharmaceutically acceptable solvate thereof, wherein X is a bond, -O-, -S-, -SO-, -S02-, -CO-, -C (OR7) 2-, -CH2 -0-, -O-CH2-, -CH = CH-, -CH2-, -CH (alkyl having 1 to 6 carbon atoms) -, -C (alkyl with 1 to 6 carbon atoms) 2-, - CONR17-, -NR17C0-, -0-C (0) NR17-, -NR17C (0) -0-, -S02NR17- or -NR17S02-; R is cycloalkyl with 3 to 6 carbon atoms, n is 1, 2 or 3; R2 is H, alkyl having 2 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl having 3 to 7 carbon atoms substituted with 1 to 4 groups independently selected from R18, cycloalkenyl having 3 to 6 carbon atoms, t-butoxycarbonyl or
1. R3 and R4 independently are selected from the group consisting of H, halo, -CF3, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, and -OH; R5 and R6 are independently selected from the group consisting of H, alkyl having 1 to 6 carbon atoms, -CF3, alkoxy with 1 to 6 carbon atoms, -OH, alkylcarbonyl with 1 to 6 carbon atoms, alkoxycarbonyl with 1 to 6 carbon atoms, R13CONH-, (R13) 2NCO-, R130CONH-, R13NHCONH- and NH2CONR13-; R7 is independently selected from the group consisting of alkyl with 1 to 6 carbon atoms; or the two R7 groups can be joined to form - (C (R14) 2) p- wherein p is an integer from 2 to 4; R8, R9, R10, R11 and R12 are independently selected from the group consisting of H, halo, alkyl having 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, benzyloxy, benzyloxy substituted by -N02 or -N ( R14), alkyl halo with 1 to 6 carbon atoms, polyhalo alkyl with 1 to 6 carbon atoms, -N02, -CN, -S02, -OH, -NH2, -N (R14) 2, -CHO, polyhalo alkoxy with 1 to 6 carbon atoms, acyloxy, (alkyl with 1 to 4 carbon atoms) 3Si-, (alkyl with 1 to 6 carbon atoms) SO0_2, arylsulfonyl, heteroarylsulfonyl, acyl, (C 1 -C 6 alkoxy) ) CO-, -OCON (R14) 2, -NHCOO-alkyl (1 to 6 carbon atoms), -NHCO- (alkyl with 1 to 6 carbon atoms), phenyl, hydroxy (C1-C6 alkyl) ) or morpholino; R13 is independently selected from the group consisting of H, alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, - (alkyl having 1 to 6 carbon atoms) COOR15, aryl, heteroaryl, -aryl (alkyl) with 1 to 6 carbon atoms), -heteroaryl (C 1-6 -alkyl) and adamantyl; R14 is independently selected from the group consisting of H, and alkyl having 1 to 6 carbon atoms; R15 is independently selected from the group consisting of H, alkyl having 1 to 20 carbon atoms, cycloalkyl having 3 to 6 carbon atoms, aryl substituted with 1 to 3 groups independently selected from R3 and heteroaryl substituted with 1 to 3 independently selected groups of R3; R16 is H, alkyl having 1 to 6 carbon atoms, -COR20, alkoxycarbonyl having 1 to 6 carbon atoms, -CON (R14) 2, -CONH (R3-aryl), -S01_2-R15, -S0Í_2- (CH2 ) m-R21, -SON (R14) 2, -COSR14 or R17 is H, alkyl having 1 to 6 carbon atoms, aryl or heteroaryl; R18 is independently selected from the group consisting of halo, -CF3, alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 carbon atoms, -OH, = 0, -CON (R14) 2 and -N (R1) COR15; R19 is H, -OH, alkyl having 1 to 20 carbon atoms, cycloalkyl with 3 to 6 carbon atoms, aryl substituted with 1 to 3 groups independently selected from R3 or heteroaryl substituted with 1 to 3 groups independently selected from R3; R20 is H, alkyl with 1 to 20 carbon atoms, alkoxy with 1 to 20 carbon atoms-alkyl (1 to 6 carbon atoms), cycloalkyl with 3 to 6 carbon atoms, aryl, aryl (alkyl with 1 to 6) carbon atoms) -, aryloxy, aryloxy (C1-C6 alkyl) -, tetrahydrofuranyl or heteroaryl, wherein the aryl or heteroaryl group is substituted by 1 to 3 groups independently selected from R3; m is 0 to 3; and R21 is cycloalkyl with bridge of 7 to 10 carbon atoms or cycloalkyl with bridge of 7 to 10 carbon atoms wherein the cycloalkyl portion is substituted by 1 or 2 substituents selected from the group consisting of alkyl with 1 to 6 carbon atoms o = 0
2. 2. - A compound of claim 1, characterized in that X is -S-, -SO-, -S02- or -CH2-.
3. 3. - A compound of claim 1 or 2, characterized in that R is
4. 4. - A compound of any of claims 1, 2 or 3, characterized in that R2 is cyclohexyl or wherein R16 is-C (0) -R20, alkoxycarbonyl with 1 to 6 carbon atoms or -S02R 15. - A compound of any of claims 1, 2, 3 or 4, characterized in that R2 is
5. R16 is-C (0) -R20 and R20 is phenyl substituted with R3.
6. 6. - A compound according to any of claims 1, 2, 3, 4 or 5, characterized in that R3, R4, R5 and R6 are independently hydrogen or methyl.
7. 7. A compound according to claim 1, characterized in that it is chosen from the group consisting of compounds represented by the formula where R, X, R2, R3 and R5 are as defined in the following table
8. 8. - A pharmaceutical composition comprising a compound as defined in any of claims 1 to 7, alone or in combination with an acetylcholinesterase inhibitor, in combination with a pharmaceutically acceptable carrier.
9. 9. The use of a compound of any of claims 1 to 7, alone or in combination with an acetylcholinesterase inhibitor, for the preparation of a medicament for treating a cognitive or neurodegenerative disease.
10. 10. A method for preparing a pharmaceutical composition as defined in claim 9, characterized in that it comprises mixing a compound of any of claims 1 to 7, alone or in combination with an acetylcholinesterase inhibitor, with a pharmaceutically acceptable carrier.
11. 11. - A device for treating a cognitive or neurodegenerative disease characterized in that it comprises in separate containers in a single package, pharmaceutical compounds for use in combination, in a container a compound according to any of claims 1 to 7, and in a container separate, an acetylcholinesterase inhibitor, the compound and inhibitor are each in a pharmaceutically acceptable carrier and their combined amounts are an effective amount.
12. 12. - A method for treating a cognitive or neurodegenerative disease, characterized in that it comprises administering to a patient suffering from the disease, an effective amount of a compound of any of claims 1 to 7, alone or in combination with an acetylcholinesterase inhibitor. . SUMMARY OF THE INVENTION Disodium 1,4-piperidine muscarinic antagonists of the formula (I) are described: or an isomer, its pharmaceutically acceptable salt, ester or solvate, wherein X is a bond, -O-, -S-, -SO-, -S02-, -CO-, -C (OR7) 2-, -CH2 -0-, -0-CH2-, -CH = CH-, -CH2-, -CH (alkyl having 1 to 6 carbon atoms) -, -C (alkyl with 1 to 6 carbon atoms) 2-, - CONR17-, -NR17CO-, -O- C (0) NR17-, -NR17C (0) -O-, -S02NR17- or -NR17S02-; R is cycloalkyl, optionally substituted phenyl or optionally substituted pyridyl; R 2 is H, alkyl, optionally substituted cycloalkyl, cycloalkyl, cycloalkenyl, t-butoxycarbonyl or optionally substituted piperidinyl; and the remaining variables are as defined in the specification. Compounds of the formula (I) are useful for treating cognitive disorders such as Alzheimer's disease. Also disclosed are pharmaceutical compositions, methods for preparation and combinations of compounds of the formula (I) with ACh'ase inhibitors.