MXPA97000418A - (1h-indol-4-il) -piperidine or tetrahydropyridine ethylamines etilcarboxami - Google Patents

Abstract

This invention provides a compound having the structure wherein R and R4 are each, independently, hydrogen, -CN, -OR2, -COR2, -COOR2, -CONR2R3, alkyl, alkenyl, alkynyl, perhaloalkyl, or halogen; interrupted indicate an optional double bond, R1 is hydrogen, -OH, -OR2, or is absent when the double bond occurs, R2 and R3 are each, independently, alkyl, alkenyl, alkynyl, phenyl, or phenylalkyl; R5 is hydrogen, alkyl of 1-6 carbon atoms, or -COR6. R6 is alkyl, alkenyl, alkynyl, cycloalkyl, phenylalkyl, or Ar, and Ar is an aryl or heteroaryl radical which may be optionally substituted or a pharmaceutically acceptable salt thereof which are used as antipsychotic, antidepressant and anxiolytic agents in the treatment and relief of the symptoms of those states of enfermed

Description

(1H-IND0L-4-ID-PIPERIDINE OR TETRAHYDROPYRIDINE ETHYLAMINS AND ETILCARBOXAMIDES This invention provides a compound that has selective activity for the serotonergic 5-HT, 1A receptor, useful in the treatment of disorders of the central nervous system, which has the structure wherein AR and R are each, independently, hydrogen, -CN, -OR2, -COR2, -COOR2, 2 3 -CONR R, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, or halogen; interrupted lines indicate an optional double link; 1 2 R is hydrogen, -OH, OR, or is REF; 23845 absent when the double bond is presented; 2 3 R and R are each, independently, alkyl of 1-7 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, phenyl, or phenylalkyl of 7-10 carbon atoms; R is hydrogen, alkyl of 1-6 carbon atoms, or -COR, 6 Ru is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-10 carbon atoms, phenylalkyl of 7-10 carbon atoms, or Ar; and Ar is an aryl or heteroaryl radical which may be optionally mono-, di-, or tri-, substituted with a group selected from alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6 carbon atoms per group alkyl, dialkyl, 3-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms, -SOgH, and -C02H; or a pharmaceutically acceptable salt thereof.

The pharmaceutically acceptable salts are those derived from such inorganic and organic acids as: acetic, lactic, citric, tartaric, succinic, maleic, maldonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids .

The terms alkyl of 1-6 carbon atoms, alkenyl, of 2-7 carbon atoms, and alkynyl of 2-7 carbon atoms, both include straight chain, also as branched carbon chains. The term "halogen" refers to fluoro, chloro, bromo, or iodo. It is preferred that the cycloalkyl ring is 4-7 carbon atoms. It is preferred that the aryl and heteroaryl radicals of Ar be phenyl, pyridyl, furyl, pyrrolyl, thiophenyl, imidazolyl, oxazoyl, or thiazoyl, which may be optionally mono-, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbon atoms carbon, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6 carbon atoms per alkyl group, dialkylaminoalkyl of 3-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms, -S03H, and -C02H.

The compounds within the purpose of the invention, by the value of their configuration, exhibit this-reoisomerism. Such centers may contain either the R or S configuration or may be racemic with respect to such center or centers.

Of these compounds, the preferred miarriers are those in which R is hydrogen; those in which r e c c c R is COR; and those in which R is COR and R is cycloalkyl of 7-10 carbon atoms.

The compounds of this invention can be prepared by conventional methods, from raw materials that are either commercially available or can be made by methods disclosed in the literature. For example, as shown below, an appropriately protected 4-bromo-indole N is lithiated and reacted with 4-piperidone benzylcarbamate. Deprotection can be completed using selective hydrogenation to provide the desired 4-hydroxy-4-indol-4-yl-1-piperidine (1).

The substituted piperidine 4 can then be condensed with an appropriately substituted cyclic sulfamate to produce the compound 2.

The desired compound (3) can be obtained by dehydration and subsequent acylation with an appropriately substituted acid chloride.

Other compounds of this invention can be prepared using the methodology described above using appropriately substituted reagents and raw materials.

The representative compounds of this invention were evaluated and determined to have high affinity for the serotonin 5-HT receptor by evaluating the ability of the compound to displace [Hjd-OHDPTA (dipropi laminotetral in) from the serotonin 5-HT receptor. ,. following the procedure of Hall et al., J. Neurochem.44, 1685 (1985). This standard pharmacological test procedure was employed to analogize this property of the claimed compounds, with those of buspirone, which is a standard for anxiolytic activity and, like the same compounds of this invention, show potential affinity for the serotonin receptor subtype. of 5-HT .. "The anxiolytic activity of buspirone is believed to be, partially lower, due to its affinity for the 5-HT receptor, (Vander Maclen et al., Eur. J Pharmacol., 1986, 129 ( 1-2) 133-130). In this standard pharmacological test procedure, buspirone has an IC50 of approximately 10 nM.

The results obtained by the representative compounds of this invention, in the standard pharmacological test procedure described above, are as follows: Compound (I C5Q) 5-HT linker Example 1 11.6 n M Example 2 1.7 nM The results obtained in the standard pharmacological test procedure demonstrate that the compounds of this invention possess high affinities for the 5-HT .. serotonin receptor, and consequently, they are useful in the treatment of CNS receptive multi-orders. by treatment with antipsychotic, antidepressant and anxiolytic agents. As such, the compounds of this invention can be administered to a mammal in need of medical antisychotic, antidepressant and / or anxiolytic treatment, in an amount sufficient to alleviate the symptoms of the disease state, such as depression, paranoia, schizophrenia, anxiety. , sleep disorders, eating disorders, cognitive disorders, social panic, phobia, obsessive compulsive disorders, sexual dysfunction, addiction and relative problems. When administered for the treatment of the above disease states, the compounds of this invention can be administered to a mammal, orally, parenterally, intranasally, intrabronchially, transdermally, intravaginally, or rectally.

The compounds of this invention can be formulated alone or with a pharmaceutical carrier to a mammal in need thereof. The pharmaceutical carrier can be solid or liquid. A solid carrier may include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending, fillers, glidants, compression aids, pastes or tablet disintegrating agents; they can also be an encapsulating material. In powders, the carriers are a divided solid which is a mixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in convenient proportions and compacted in desirable shape and size. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes, and exchange resins. of ions.

Liquid carriers are used in prepared solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo regulators. Suitable examples of liquid carriers by oral and parenteral administration include water (containing additives partially as above, eg, preferably sodium carboxymethylcellulose solution), alcohols (including hydrocarbon alcohols, hydrocarbon alcohols, eg, glycols) and their derivatives and oils ( for example, coconut oil and fractionated peanut oil). For parenteral administration, the carrier can also be an ester oil such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions of sterile liquid forms for parenteral administration. The liquid carrier for presoaked compositions may be a halogenated hydrocarbon or other pharmaceutically acceptable propellant. The liquid pharmaceutical compositions which are sterile solutions or suspensions may be used for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compound can also be administered orally either in solid or liquid form composition. The compounds of this invention can be administered rectally in the form of a conventional suppository. Upon administration by intrabronchial or intranasal inactivation or insufflation, the compounds of this invention can be formulated into an aqueous or partially aqueous solution, which can then be used in the form of an aerosol. The compounds of this invention can also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inserted into the active compound, is not toxic to the skin, and of course allows the agent to systemic absorption within the bloodstream via the skin. The carrier can take any number of forms such as creams and ointments or ointments, pastes, gels, and occluding devices. The creams and ointments or ointments can be viscous liquids or semi-solid emulsions of the types either oil in water or oil in oil. The pastes comprise of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient which may be convenient. A variety of occlusive apparatuses can be used to release the active ingredient into the bloodstream such as a semipermeable membrane that covers a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in the literature. The dosage to be used in the treatment of a specific psychosis can be determined subjectively by medical attention. Complicated variables include the specific psychosis or state of anxiety or depression and the size, age, and model response of the patient. Based on the results obtained in the standard pharmacological test procedures, the suggested oral daily dosages of the active compound will be 1-100 mg / kg preferably between 1-30 mg / kg and more preferably between 1-iO mg / kg. The suggested intravenous daily dosages will be 0.2-20 mg / kg, preferably between 0.2-6 mg / kg, and more preferably between 0.2-2 mg /? G. Ki treatment may generally be initiated with small dosages, less than the optimum dose of the compound. Thereafter, the dosage is increased to the optimum effect under the circumstances reached; Precise dosages for oral, parenteral, nasal or intrabronchial administration may be determined by medical administration based on experience with the subject subject to treatment. Preferably, the pharmaceutical composition is a single dosage from, for example, tablets or capsules. In such forms, the composition is subdivided into unit doses containing appropriate amounts of the active ingredient; the unit dosage forms can be packaged compositions, for example, packaged powders, vials, ampoules, syringes or pads containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or they can be the appropriate number of any such compositions in the form of packings.

The following examples illustrate the production of the representative compounds of this invention.

EXAMPLE 1 (R) -2 [4- (1H-Indol-4-yl) - (1,2> 3,6-tetrahydropyridin-1-yl) J-1-methi 1 o- et i 1 or} - (pyridine-2-y1) amine A commercially available solution of 4-bromoindole (10 mmol, 2.084 g) in dry N, N-dimethylformamide (DFM, 5 ml) was added dropwise to a stirred suspension of sodium hydride (60%, 12 mmol). , 0.48 g) in dry DMF (15 ml) at 10 ° C. The reaction mixture was stirred for 30 minutes at 10 ° C after which t-butylidene chloride was added in a manner proportionally. The reaction mixture was left at room temperature, at which point it was placed between ice water (70 ml) and the crude product extracted with methylene chloride (3 x 60 ml). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness in vacuo. The flash chromatography column of the residue in 200 g of silica gel with chloroform / hexane as eluant afforded 2.2 g of protected 4-bromoindole N which was dissolved in dry tetrahydrofuran (THF, 100 ml). At -78 ° C under a nitrogen atmosphere, n-butyllithium (2.5 M, 13.4 mmol, 5.4 mL) was added to the solution via syringe and was stirred continuously for 30 minutes at -78 ° C. A solution of 1- (N-benzyloxycarboni 1) -4-piperidone (6.8 mmol, 1586 g) in dry THF (40 ml) were added at -30 ° C and continuously stirring at room temperature for 12 hours. The reaction mixture was then placed in ice water (150 L) and the crude product extracted with ether (3 x 100 L). The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed instantaneously on 160 g of silica gel using 2% methanol / chloroform as eluent to obtain 1.15 g of the desired intermediate * piperidine which was then hydrogenated for three hours under atmospheric pressure in ethanol (80 mL) in the presence of 10% palladium or carbon (120 mg). The reaction mixture was purged with nitrogen, the catalyst separated by filtration and the filtrate evaporated in vacuo to yield the deprotected hydroxypiperidine derivative as a colorless oil. A solution of the hydroxypiperidine (2.87 pmol, 950 mg) in acetonitrile (20 mL) was treated with (R) -4-methyl-3-piperidine-2-l- [1,2,3] oxathiacinnan-2,2- dioxide (3 mmol, 631 mg) at room temperature for 2 hours. The mixture was evaporated in vacuo and the residue dissolved in THF (10 mL) and water (10 mL). Concentrated sulfuric acid (0.15 mL) was added as a drop for 1 minute after which the mixture was stirred for another 30 minutes at room temperature. Thereafter the pH was adjusted to 7 with the addition of sodium acid carbonate powder. He continued shaking for another hour. The reaction mixture was then diluted with ethyl acetate and water. The separated organic layers, washed with brine, dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue was refluxed in acetic acid (60 mL) for 3 hours, evaporated in vacuo and the residue partitioned between the aqueous sodium carbonate acid solution (50 mL) and chloroform (80 mL). The organic layers were separated, dried over magnesium sulfate and evaporated. The residue was subjected to flash column chromatography on silica gel (50 g). Elution with 3% methanol / chloroform gave 300 mg of an oil, some of which was converted to chloroform with the addition of ethereal HCl of the main compound, obtaining as reddish-brown microcrystals, mp 102-4 ° C. Elemental Analysis for: C21H24N4 2.8 HCl 1 H20. Calculated: C, 55.73; H, 6.41; N, 12.38. Found: C, 56.10; H, 6.73; N, 11.92.

EXAMPLE 2 (R) -N- (f2- [4- (1H-indol-4-yl) 1,2,3,6-tetrahydro-2H-pi ri di na- 1 - i 11 -1-met i lo -eti lojr-pyridine-2-i 1) - cyclohexanecarboxamide A solution of cyclohexanecarbonyl chloride (0.6 mmol, 88 mg) in methylene chloride (10 L) were added as drops at 0 ° C to a solution of the compound of Example 1 (0.54 mmol, 180 mg) in methylene chloride (10 mL). The reaction mixture was allowed to reach it at room temperature and was stirred continuously for 16 hours. The obtained solution was washed with 2N sodium hydroxide (15 mL), the separated organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated to dryness. The residue obtained was subjected to flash column chromatography on silica gel (10 g). Elution with 5% ethanol in chloroform gave a white foam which was dissolved in ethanol (3 mL) and treated once more with a solution of maleic acid (0.338 mmol, 39 mg) in ethanol (2 mL). The obtained solution was concentrated in vacuo and triturated with ether procedure 120 mg of the main compound as light amber microcrystals, mp 70-3 ° C.

Elemental Analysis for: 2QH34N40 1.7 C4H404 o.1 CHCl 3 * Calculated: C, 64.12; H, 6.31; N, 8.59. Found: C, 64.50; H, 6.64; N, 8.00 It is noted that in relation to this date, the best method known by 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 above, the content of the following is claimed as property.

Claims (8)

Claims

1. A compound that has the structure characterized in that R and R are each, independently, hydrogen, -CN, -OR2, -COR2, -COOR2, 2 -CONR R, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl from 2-7 carbon atoms, Perhaloalqui 1-6 carbon atoms, or halogen; interrupted lines indicate an optional double link; 1 2 R is hydrogen, -OH, OR, or is absent when the double bond occurs; 2 3 R and R are each, independently, alkyl of 1-7 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, phenyl, or phenylalkyl of 7-10 carbon atoms; R is hydrogen, alkyl of 1-6 carbon atoms, or -COR R is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3- 10 carbon atoms, phenylalkyl of 7-10 carbon atoms, or Ar; and Ar is an aryl or heteroaryl radical which may be optionally mono-, di-, or tri-, substituted with a group selected from alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6 carbon atoms per alkyl group, dialkyl, 3-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms, alkylthio of 1-6 carbon atoms, -S03H, and -C02H; a pharmaceutically acceptable salt thereof.

2. The compound according to claim 5, wherein R is hydrogen or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 6, characterized in that R is -COR or a pharmaceutically acceptable salt thereof,

4. The compound according to claim 2, characterized in that R is cycloalkyl of 3-10 carbon atoms or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1, characterized in that it is. { (R) -2- [4- (1H-indol-4-yl) - (1,2,3,6-tetrahydro-pyridin-1-y1)] meti lo-eti 1 oJ - (pi ri dina- 2-i 1) -amine or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, characterized in that it is (R) - N - ([2- [4- (1H-indol-4-yl) 1,2,3,6-tetrahydro-2H-pyridine-1-i) 1] -1-methylo-eti loj-pyridin-2-yl) -cyclohexanecarboxamide or a pharmaceutically acceptable salt thereof.

7. A method of treatment of anxiety, psychosis, or depression in a mammal in need thereof, characterized in that it comprises administering to said mammal, an effective amount of a compound of the structure wherein 4 R and R are each, independently, hydrogen, -CN, -OR2, -COR2, -COOR2, 2 -CONR R, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, perhaloalkyl of 1-6 carbon atoms, or halogen; the lines in parentheses indicate an optional double bond; 1 2 R is hydrogen, -OH, OR, or absent when the double bond occurs; 2 3 R and R are each, independently, alkyl of 1-7 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, phenyl, or phenylalkyl of 7-10 carbon atoms; R is hydrogen, alkyl of 1-6 carbon atoms, or -COR, Rb is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3 -10 carbon atoms, phenylalkyl of 7-10 carbon atoms, or Ar, and Ar is a heteroaryl radical which may be optionally mono-, di, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, and hydroxy, nitro, carbalkoxy of 2-7 atoms, carbon, trif luoro eti l? j trif luoromethoxy, amino, dialkylamino of 1-6 carbon atoms per alkyl group, dialkylaminoalkyl of 3-12 carbon atoms, hydroxyalkyl of 1-6 carbon atoms, alkoxyalkyl of 2-12 carbon atoms carbon, alkylthio of 1-6 carbon atoms, -S03H, and -C02H; a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition which comprises a compound of the structure characterized in that 4 R and R are each, independently, hydrogen, -CN, -OR2, -COR2, -COOR2, 2-CONR R, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms , alkynyl of 2-7 carbon atoms, erhaloalqui what of 1-6 carbon atoms, or halogen; interrupted lines indicate an optional double link; 1 2 R is hydrogen, -OH, -0R, or is absent when the double bond occurs; 2 3 R and R are each, independently, alkyl of 1-7 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, phenyl or phenylalkyl of 7-10 carbon atoms; R is hydrogen, alkyl of 1-6 carbon atoms, or -COR; Rb is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-10 carbon atoms, phenylalkyl of 7-10 carbon atoms, or Ar, and Ar is an aryl or heteroaryl radical which may be optionally mono, di-, or tri-substituted with a group selected from alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2 -7 carbon atoms, alkoxy of 1-6 carbon atoms, cyano, halo, hydroxy, nitro, carbalkoxy of 2-7 carbon atoms, trifluoromethyl, trifluoromethoxy, amino, dialkylamino of 1-6 carbon atoms per alkyl group, dialqui laminoalkyl, 3-12 carbon atoms, hydroxyalkyl, 1-6 carbon atoms, alkoxyalkyl, 2-12 carbon atoms, alkylthio, 1-6 carbon atoms, -S03H, and -C02H; or a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier. SUMMARY OF THE INVENTION This invention provides a compound that has the structure wherein R and R are each, independently, hydrogen, -CN, -OR2, -COR2, -COOR2, 2 -CONR R, alkyl, alkenyl, alkynyl, perhaloalkyl, or halogen; interrupted lines indicate an optional double link; 1 2 'R is hydrogen, -OH, -OR, or is absent when the double bond occurs; 2 3 R and R are each, independently, alkyl, alkenyl, alkynyl, phenyl, or phenylalkyl; R5 is hydrogen, alkyl of 1-6 carbon atoms, or -COR. R is alkyl, alkenyl, alkynyl, cycloalkyl, phenylalkyl, or Ar, and Ar is an aryl or heteroaryl radical which may be optionally substituted or a pharmaceutically acceptable sai thereof which are used as antipsychotic, antidepressant and anxiolytic agents useful in the art. treatment and relief of the symptoms of those disease states.