MXPA00010454A - Indolyl derivatives as serotonergic agents - Google Patents

Abstract

The present invention provides compounds represented by general formula (1) wherein R1 is selected from H, OH, OR2 or halogen (F, Cl, Br, I);R2 is lower alkyl (C1 to C6);n is selected from 0, 1 or 2;X is CH or CH2;m is selected from 2, 3 or 4;Y is N or CH;Ar is aryl or heteroaryl, both optionally substituted;or pharmaceutically acceptable salts thereof, as well as methods and pharmaceutical compositions utilizing these compounds for the inhibition of serotonin uptake and the treatment of CNS disorders, particularly depression.

Description

DERIVATIVES OF INDOLYLL AS SEROTONERGIC AGENTS Field of the Invention The present invention relates to the novel compounds useful as serotonergic agents. More particularly, this invention relates to indolyl compounds that are useful as serotonergic agents, particularly as inhibitors of serotonin reuptake.

Background of the Invention Depression is a psychiatric condition that is thought to be associated with • the decreased release of serotonin. Most antidepressant agents potentiate the effects of serotonin by blocking the termination of its activity through reuptake within the nerve terminals. United States Patent No. 5.3 2.8 5 (Cho ai et al.) Teaches the indolecarboxamide derivatives of the general formula: Ref: 124167 wherein R1 is lower alkyl and R2 is selected from hydrogen, halogen, lower alkyl or lower alkoxy, useful for the regulation of gastrointestinal motor activity, such as antimigraine, antipsychotic or anti-anxiety drugs. U.S. Patent No. 5,61, 523 (Audia et al.) Teaches hetero-oxy-alkanamines which are effective in treatments for conditions related to or affected by the reuptake of serotonin and by the serotonin 1A receptor. United States Patent No. ,693,655 (Bottcher et al.) Describes the 3-m-diolylpiperidines showing action on the central nervous system, particularly dopamine agonist actions or dopamine antagonists.

U.S. Patent No. 5,670,511 (Marz et al.) Claims the indolpiperidine derivatives which also have dopamine agonist or antagonist action, the compounds having the following general formula, wherein R2 is selected from -NH-CO- Ar, -NH-S0 -Ar, or D, where D is also shown below: U.S. Patent Nos. 5,541,794 and 5,654,324 (both to Booher et al.) Claim the 6-heterocyclic-4-amino-1, 2, 2a, 3, 4, 5-hexahydrobenz- [cd] indoles useful in the modification of serotonin function in mammals. United States Patent No. ,654,320 (Catlo et al.) Also describes the indazolcarboxamides useful as antagonists and - "- • partial agonists of the 5-HT serotonin receptor and treatments for its dysfunctions. This invention relates to the novel indolyl derivatives, to the processes for their preparation, to the pharmaceutical compositions containing them and to their use in therapy. The novel compounds are useful for the treatment of disorders of the central nervous system, particularly depression, by virtue of their ability to inhibit serotonin uptake.

Brief Description of the Invention The compounds of the present invention are represented by the general formula (1) (1) wherein: Ri is selected from H, OH, 0R2, F, Cl, Br, or I; R2 is lower alkyl of 1 to 6 carbon atoms; n is selected from 0, 1 or 2; X is CH or CH2; m is an integer selected from 2, 3 or 4; And it is N or CH; Ar is aryl or heteroaryl, both optionally substituted with one to three groups selected from fluorine, bromine, chlorine, iodine, -OH, -CN, lower alkoxy of 1 to 6 carbon atoms or lower alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.

A preferred subgroup of compounds of this invention are those in which Y is nitrogen and Ri, R2, n, X, m, Y and Ar are as defined above. The aplo or heterarilo groups that comprise Ar in the above groups are phenyl, benzodioxane, indole bound to the Y portion in the 4 or 7 position of the indole, pyridine, 2-pyrimidine, thiophene, furan or pyrrole. The most preferred of these groups are phenyl, benzodioxol-5-yl, and 2-pyridine. The pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable inorganic or organic acid, such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, fumaric, acetic, lactic or methanesulfonic.

Detailed description of the invention The compounds of the present invention can be prepared using conventional methods. For example, the appropriately substituted indole (A) can be coupled with an arylpiperazine or arylpiperidine (B) substituted with chloroalkyl using a base such as diisopropylethylase. The product can then be used to form a pharmaceutically acceptable salt.

The preparation of the 3- (-piperidinyl) -Indoles and 3- (4-tetrahydropipdinyl) appropriately substituted ones can be achieved by known and conventional methods. For example, the reaction of an indole (D) optionally substituted with 4-piperidone (E) gives the 3- (4-tetrahydropyridinyl) indole (F). This can be reduced using the standard catalytic hydrogenation methodology to provide a 3- (4-piperidinyl) indole (G).

The preparation of the appropriately substituted 3- (4-piperidylmethyl) (H) s and the 3-β4-tetrahydropyridylmethyl) (I) can also be carried out by known and conventional methods. Such methodology is described in C. Gueremy et al., J. Med. Chem., 1980, 23, 1306-1310, J-L. Malleron et al., J. Med. Chem., 1993, 36, 1194-1202 and J. Bergman, J. Heterocyclic. Chem., 1970, 1071-1076.

The compounds of the present invention inhibit with very high affinity the binding of paroxetine to the serotonin transporter and, consequently, are useful as antidepressant and anxiolytic agents for the treatment of disorders of the central nervous system such as depression, sleep disorders, sexual dysfunction, addiction to alcohol and cocaine, improvement of cognition and related problems. In addition, the compounds of the present invention can be used in conjunction with an agonist or antagonist of the serotonin 1 (5-HT1) receptor to aid or enhance the biological properties of the compounds. Such compositions may be useful for the aforementioned disorders in addition to the treatment of Alzheimer's disease, Parkinson's disease, schizophrenia, obesity and migraine. It is understood that the therapeutically effective dose that is going to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician. The variables involved include the specific psychosis or state of anxiety and the patient's size, age and response pattern. The novel method of the invention for the treatment of conditions related to or that are affected by the reuptake of serotonin, comprises the administration to warm-blooded animals, including humans, of an effective amount of at least one compound of this invention or a pharmaceutically acceptable, non-toxic addition salt thereof. The compounds can be administered orally, rectally, parenterally, or topically to the skin and mucous membranes. The usual daily dose is dependent on the specific compound, the method of treatment and the condition treated. An effective dose of 0.01-1000 mg / kg may be used for oral application, preferably 0.5-500 mg / kg, and an effective amount of 0.1-100 mg / kg may be used for parenteral application, preferably 0.5-50. mg / kg. The present invention also includes pharmaceutical compositions containing a compound of this invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. Applicable solid carriers or excipients may include one or more substances that they may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid, which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions, and compacted in the desired 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, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidine, low melting point waxes, and ion exchange resins. . Liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically liquid carrier acceptable, such as water, an organic solvent, 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, colorants, viscosity regulating agents, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (containing particularly additives as mentioned above for example cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and its derivatives, and oils (for example fractionated coconut oil and peanut oil). For parenteral administration, the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in compositions of sterile liquid form for parenteral administration. Liquid pharmaceutical compositions that are sterile solutions or suspensions can be use for example by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The oral administration can be either in the form of a liquid or solid composition. Preferably, the pharmaceutical composition is in unit dosage form, for example as tablets or capsules. In such form, the composition is subdivided into unit doses containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packaged powders, flasks, ampoules, pre-filled syringes or sacks containing liquids. The unit dosage form may be, for example, a capsule or tablet itself, or this may be the appropriate number of any such compositions in packaged form. The affinity of the drugs for the serotonin transporter was determined by evaluating the ability of the agents to displace the specifically bound 3H-paroxetine, which binds from rat cortical membranes. A protocol similar to that used by Cheetham and colleagues (Neuropharmacol., 32: 737, 1993) was used to determine the affinity of the compounds for the serotonin transporter. In summary, the frontal cortical membranes prepared from rats S.D. Male were incubated with 3H-paroxetine (0.1 nM) for 60 minutes at 25 ° C. All tubes also contained either the vehicle, the test compound (one to eight concentrations), or a saturation concentration of fluoxetine (10 μM) to define the specific binding. All reactions are terminated by the addition of ice-cooled Tris buffer, followed by rapid filtration using the To Tech filtration device to separate bound 3H-paroxetine from free. The bound radioactivity was quantified using the Wallac 1205 Beta Píate® counter. Non-linear regression analysis was used to determine the IC50 values that were converted to Ki values using the Cheng and Prusoff method (Biochem Pharmacol, 22: 3099, 1973); Ki = IC 50 / ((radioligand concentration) / (1 + KD)). The non-specific binding was determined using fluoxetine. Using this assay, the following Ki's were determined for a series of standard inhibitors of serotonin uptake.

Compound Inhibition of the linkage of [3H] -paroxetma Ki (nM) Clomipramine 0.18 Fluoxetine 4.42 Imipramine 17.6 Zimelidine 76.7 The results for a number of examples of compounds of formula 1 in this standard experimental test procedure were as follows: Compound Inhibition of [3 H] -paramethine Kl (nM) linkage Example 1 4.8 Example 3 1.2 Example 6 10.0 Example 7 19.0 The following specific non-limiting examples are included to illustrate the synthetic procedures that can be used to prepare the compounds of formula 1. In these examples, all chemicals and intermediates are either commercially available or can be prepared by methods standards found in the literature or are known to those skilled in the art of organic synthesis.

Example 1 -fluoro-3- (l- { 2- [4- (2-methoxyphenyl) piperazin-1-yl] ethyl} piperidin-4-ylmethyl) -lH-indole Powdered potassium carbonate (0.76 g, . 5 mmol) and potassium iodide (0.97 g, 5.5 mmol) was added to a mixture of 4- (5-fluoro-lH-indol-3-ylmethyl) piperidine (1.16 g, 5.0 mmol) and l- (2-chloroethyl) ) -4- (2-methoxyphenyl) piperazine (1.27 g, 5.0 mmol) in 25 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen atmosphere for 5 hours. After cooling, this was diluted with 150 ml of water and the product was extracted into 50 ml of ethyl acetate. The organic layer was washed with 50 ml of water, with 50 ml of brine, and after drying over sodium sulfate, filtration and concentration in vacuo, gave the required product as a white solid (1.8 g, 80%). Treatment with an excess of 1 M ethereal hydrochloric acid gave the salt addition of acid, which was recrystallized from methanol. p.f. 253-254 ° C. Elemental analysis for: C27H35FNaO .2HC1 Calculated: C, 61.95; H, 7.13; N, 10.68 Found: C, 61.84; H, 7.18; N, 10.61 Example 2 -fluoro-3- (l- { 2- [4- (2-methoxy phenyl) piperazin-1-yl] ethyl.}. Pipepdin-4-yl) -lH-mdol Powdered potassium carbonate (0.35 g, 2.5 mmol) and potassium iodide (0.44 g, 2.5 mmol) was added to a mixture of 4- (5-fluoro-lH-indol-3-yl) piperidine (0.5 g, 2.3 mmol). ) and 1- (2-chloroethyl) -4- (2-methoxyphenyl) piperazine (0.58 g, 2.3 mmol) in 20 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. After cooling, this was diluted with 150 ml of water and the product was extracted into 50 ml of ethyl acetate. The organic layer was washed with 50 ml of water, with 50 ml of brine, and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a solid white (0.83 g, 83%). Treatment with an excess of 1 M ethereal hydrochloric acid gave the salt by the addition of acid, which was recrystallized from methanol. p.f. 251-252 ° C. Elemental analysis for: C26H33FN40.2HC1.0.25H20 Calculated: C, 60.76; H, 6.96; N, 10.90 Found: C, 60.79; H, 7.09; N, 10.85 Example 3 -fluoro-3- (1- { 3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl}. Piperidin-4-ylmethyl) -lH-indole Powdered potassium carbonate (0.33 g, 2. 4 mmol) and potassium iodide (0.40 g, 2.4 mmol) was added to a mixture of 4- (5-fluoro-lH-indol-3-yl) methylpiperidine (0.5 g, 2.3 mmol) and l- (2-chloroethyl) ) -4- (2-methoxyphenyl) piperazine (0.58 g, 2.3 mmol) in 20 ml of acetonitrile. The resulting mixture was heated to reflux under nitrogen atmosphere for 3 hours. After cooling, this was diluted with 150 ml of water and the product was extracted into 50 ml of ethyl acetate. The organic layer was washed with 50 ml of water, with 50 ml of brine, and after drying over sodium sulfate, filtration and concentration in vacuo afforded the required product as a white solid (0.78 g, 76%). Treatment with an excess of 0.25 M ethanolic fumaric acid in solution gave the salt by acid addition, which was recrystallized from ethanol / diethyl ether to give the title compound as white needles, m.p. 156-157 ° C. Elemental analysis for: C28H31FN40.2C4H40 Calculated: C, 62.06; H, 6.51; N, 8.04 Found: C, 61.76; H, 6.68; N, 7.87 Example 4 -fluoro-3- (l- { 3- [4- (2-methoxy phenyl) piperazin-1-yl] propyl}. Piperidin-4-yl) -lH-indole The title compound was prepared using the procedure described in the above examples 1-3. The product was purified by chromatography on silica gel, and isolated in 68% yield. Its fumaric acid salt was obtained as a fine white powder. p.f. 200 ° C Elemental analysis for: C27H35FN40.2C H404 Calculated: C, 61.57; H, 6.35; N, 8.21 Found: C, 61.59; H, 6.53; N, 8.12 Example 5 3- (L-. {2- 2- [4- (2-methoxyphenyl) piperazin-1-yl-ethyl}. Piperidin-4-yl) -lH-indole The title compound was prepared using the procedure described in the above examples 1-3. The product was purified by column chromatography on silica gel, and isolated in 96% yield as a white solid. Their fumaric acid salt was prepared as reported in Example 3 and obtained as a fine white powder, m.p. 212-213 ° C Elemental analysis for: C26H34N40.2C4H40 Calculated: C, 62.76; H, 6.51; N, 8.61 Found: C, 62.82; H, 6.48; N, 8.63 Example 6 3- (L- { 2- [4- (2-methoxyphenyl) piperazin-1-yl] ethyl] l, 2,3,6-tetrahydropyridin-4-yl) -lH-indole The title compound was prepared using the procedure described in the above examples 1-3. The product was purified by column chromatography on silica gel, and isolated in 64% yield as a light yellow solid. Their fumaric acid salt was prepared as reported in Example 3. p.f. 189 ° C Elemental analysis for: C26H32N40.0.5C4H 04 Calculated: C, 70.82; H, 7.26; N, 11.73 Found: C, 70.50; H, 7.27; N, 11.68 Example 7 -fluoro-3- (l-. {2- 2- [4- (2-methoxy phenyl) piperazin-1? L] et? L.] L, 2, 3, 6-tetra idropyrid? N-4 -? l) -IH- indole The title compound was prepared using the procedure described in the above examples 1-3. The product was purified by column chromatography on silica gel, and isolated in 69% yield as a yellow solid. Their fumaric acid salt was prepared as reported in Example 3 and obtained as a fine white powder. p.f. 198-199 ° C Elemental analysis for: C26H3? F 0.2C4H404 Calculated: C, 61.25; H, 5.90; N, 8.40 Found: C, 61.37; H, 5.87; N, 8.46 Example 8 - fluoro-3- (l- { 3- [4- (2-methoxyphenyl) 1,2,3,6-tetrahydropyridin-1-yl] propyl}. Piperidin-4-ylmethyl) -lH-indole The title compound was prepared using the procedure described in the above examples 1-3. The product can be purified by column of silica gel. Its fumaric acid salt can be prepared as reported in Example 3.

Example 9 -fluoro-3- (l- { 2- [4- (2-fluorophenyl)? Perazin-1-yl] ethyl} 1, 2, 3, 6-tetrahydropyridin-4-yl) -lH- mdol The title compound was prepared using the procedure described in the above examples 1-3. The product can be purified by column of silica gel. Its fumaric acid salt can be prepared as reported in example 3.

Example 10 -fluoro-3- (l- { 2- [4- (indol-4-yl) piperazin-1-yl] ethyl]} l, 2,3,6-tetrah? Dropiridi -4-il ) -ÍH- indole The title compound was prepared using the procedure described in the above examples 1-3. The product can be purified by column chromatography on silica gel. Its fumaric acid salt can be prepared as reported in example 3.

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.

Claims (12)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound according to the formula 1: (1) characterized in that; Ri is selected from H, OH, OR2, or halogen (F, Cl, Br, I); R2 is lower alkyl of 1 to 6 carbon atoms; n is selected from 0, 1 or 2; X is CH or CH2; m is selected from 2, 3 or 4; And it is N or CH; Ar is phenyl, benzodioxane, mdol linked to the Y portion in the 4 or 7 position of the indole, pyridine, 2-pyrimidine, thiophene, furan or pyrrole, each optionally substituted with one to three groups selected from fluorine, chlorine, bromine, iodine, -OH, -CN, lower alkoxy of 1 to 6 carbon atoms or lower alkyl of 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, characterized in that it is 5-fluoro-3- (l-. {2- 2- [4- (2-methoxy phenyl) piperazin-1-yl] ethyl.}. -piperidin-4- ilmethyl) -lH-mdol or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1, characterized in that it is 5-fluoro-3- (l-. {2- 2- [4- (2-ethoxyphenyl) piperazin-1-yl] ethyl) -p? Peridin-4-yl ) -IH-indole or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1, characterized in that it is 5-fluoro-3- (l-. {3- [4- (2-methoxyphenyl) piperazin-1-yl] propyl.} - piperidin-4-ylmethyl. ) -IH-indole or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 1, characterized in that it is 5-fluoro-3- (l-. {3- [4- (2-ethoxy phenyl) piperazin-1-yl] propyl.} - piperidin-4- ilmethyl) -lH-indole or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1, characterized in that it is 3- (L-. {2- 2- [4- (2-methoxyphenyl) piperazin-1-yl] ethyl.}. Piperidin-4-yl) -lH-indole or a pharmaceutically acceptable salt thereof.

7. A compound according to claim 1, characterized in that it is 3- (l-. {2- 2- [4- (2-methoxyphenyl) piperazin-1-yl] ethyl) l, 2,3,6-tetrahydropyridin-4- il) -lH-indole or a pharmaceutically acceptable salt thereof.

8. A compound according to claim 1, characterized in that it is 5-fluoro-3- (1 -. {2- [4- (2-methoxy-phenyl-1-piperazin-1-yl] -ethyl}, 2,3,6-tetrahydropyridin-4-yl) -lH-indole or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier or excipient and a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

10. A method for inhibiting the reuptake of serotonin in a mammal, the method is characterized in that it comprises administering to a mammal in need therefor, a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. A method for the treatment of depression in a mammal, the method is characterized in that it comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of according to claim 1, or a pharmaceutically acceptable salt thereof.

12. A method for the treatment of anxiety in a mammal, the method is characterized in that it comprises administering to a mammal in need thereof a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof.