MXPA01006855A - New 1,4-disubstituted cyclohexane derivatives for the treatment of depression - Google Patents

Abstract

Compounds useful for the treatment of disorders of the serotonin-affected neurological systems are provided which have formula (I) wherein:X is carbon or nitrogen;the dotted line represents an optional bond which is absent when X=N;R1 and R2 are each, independently, hydrogen, halogen, CF3, alkyl, alkoxy, or MeSO2;R3 is hydrogen, halogen, or alkyl;R4 is hydrogen, alkyl, alkylaryl, or aryl;and R5 is hydrogen, halogen, CF3, CN, carbamide, or alkoxy;or a pharmaceutically acceptable salt thereof.

Description

NEW DERIVATIVES OF CYCLOHEXAN 1, -DISUBSTITUIDOS FOR THE TREATMENT OF DEPRESSION FIELD OF THE INVENTION This invention relates to compounds useful for the treatment of diseases affected by disorders of neurological systems affected with serotonin, such as depression and anxiety. More specifically, the present invention is directed to 1,4-dissociated cyclohexane derivatives for the treatment of such disorders, processes for preparing them and pharmaceutical compositions containing them.

BACKGROUND OF THE INVENTION Pharmacists who increase the neurotransmission of serotonin (5-HT) are useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective drugs that affect serotonin are made to work through a variety of physiological means that cause them to possess numerous unwanted side effects. The most recently prescribed drugs, Selective Serotonin Reuptake Inhibitors (SSRIs), act REF: 130897 predominantly by inhibiting 5-HT, which is released at the synapse, since it is actively removed from the synaptic cleft via a transporter carrier of presynaptic serotonin. Since SSRIs require several weeks before they exert their full therapeutic effect, this mechanism of blocking 5-HT can not fully explain its therapeutic activity. It is speculated that these two weeks of induction that occur before an antidepressant effect is observed, is due to the commitment of the 5-HT1A autoreceptors that suppress the detonating activity of the 5-HT neurons, causing a decrease in the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of 5-HT autoreceptors occurs that allows an anti-depressant effect in most patients. (See, for example, Le Poul et al., Arch. Pharmacol., 352: 141 (1995)). Therefore, it is believed that this negative feedback predominates using antagonists of 5HT1A increase and potentially accelerate the clinical antidepressant reaction. Recent studies by Artigas et al., Trends Neurosci., 19: 378-383 (1996), suggest a combination of 5-HT1A activity and inhibition of 5HT uptake within a single molecular entity can achieve a stronger antidepressant effect and act faster. The present invention relates to a novel class of molecules that have the ability to act on the autoreceptors of 5-HT1A and concomitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders. U.S. Patent No. 5,468,767 reports a series of substituted characters of the following formula for the treatment of disorders associated with dysfunction in serotonergic neurotransmission, including depression wherein Ri is hydrogen or alkyl of 1 to 4 carbon atoms; R2 is alkyl of 1 to 4 carbon atoms or (CH2) pAr; m is zero or 1; n is an integer from 1 to 3; and p is zero or an integer from 1 to 4.

U.S. Patent No. 5,622,951 describes a series of piperazine derivatives of the following formula for the treatment of CNS disorders, including depression wherein R is hydrogen or one or two lower alkyl groups Ri and R2 are each the same or different mono- or bicyclic aryl or heteroaryl radicals; R3 is hydrogen, one or two of the same or different lower alkyl groups or a spiro-cycloalkyl group; and n is 1 or 2 and m is from 1 to 3 and the total of n + m is 2, 3 or 4. PCT Publication No. WO 93/10092. describes a series of 1,3-cycloalkenes or substituted cycloalkanes useful in the treatment of dopaminergic disorders.

BRIEF DESCRIPTION OF THE INVENTION The compounds of this invention are arylpiperazinyl-cyclohexyl derivatives represented by Formula I: X is carbon or nitrogen; dotted lines represent an optional link that is absent if X is N; Ri and R are each, independently, hydrogen, halogen, CF3, alkyl, alkoxy, or MeS02; R3 is hydrogen, halogen or alkyl; R 4 is hydrogen, alkyl, alkylaryl, or aryl; and R5 is hydrogen, halogen, CF3, CN, carbamide, or alkoxy; or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION Preferably, the compounds of the present invention are those of Formula I, wherein: X is carbon; and / or Ri and R2 are each, independently, hydrogen or alkoxy; and / or R3 is hydrogen; and / or R is hydrogen; and / or R5 is halogen; or a pharmaceutically acceptable salt thereof.

More preferably, the compounds of the present invention are selected from: 5-Fluoro-3-. { (1, 4-cis) -4- [4- (3-methoxy-iofen-2-yl) -3,6-dihydro-2H-pyridin-1-yl] -cyclohexyl} -lH-indole; and 5-Fluoro-3-. { (1,4-trans) -4- [4- (3-methoxy-thiophen-2-yl) -3,6-dihydro-2H-pyridin-1-yl] -cyclohexyl} -lH-indole As used herein, the terms "alkyl" and "alkoxy" as a group or part of a group, for example arylalkyl, are intended to include both linear and branched carbon chains containing 1-6 carbon atoms. The term "aryl" is intended to include aromatic radicals of 6-12 carbon atoms. The term "halogen" is intended to include fluorine, chlorine, bromine and iodine. The compounds of this Formula I can also be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well known in the art, are formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylene-salicylic, methanesulfonic, ethanesulfonic, acetic, oxalic, propionic, tartaric acids , salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric. The compounds of the present invention can be prepared by any conventional method that will be recognized by those skilled in the art. Accordingly, this invention provides a process for the preparation of compounds of formula I: (I) where: X is carbon or nitrogen; dotted lines represent an optional link that is absent if X is N; Ri and R2 are each, independently, hydrogen, halogen, CF3, alkyl, alkoxy, or MeS02; R3 is hydrogen, halogen or alkyl; R is hydrogen, alkyl, alkylaryl, or aryl; and R5 is hydrogen, halogen, CF3, CN, carbamide, or alkoxy; or a pharmaceutically acceptable salt thereof, comprising one of the following: a) dehydrating a compound of the formula II wherein Ri, R2, R3, R and R5 are as defined above, to give a compound of formula I where X is carbon and the optional bond is present; or b) reacting a compound of the formula (neither) with a compound of the formula (IV) (IV) wherein formulas X, dotted lines, Ri, R2, R3, R4 and R5 are as defined above, to give a compound of formula I where X is carbon and the bond is optionally present; or c) acidifying a basic compound of formula I with a pharmaceutically acceptable acid to a pharmaceutically acceptable salt; or d) separating a mixture of cis and trans isomers of a compound of the formula (I) to isolate an isomer substantially free of the other isomer. With respect to process a) the dehydration can be carried out using an acid, for example acetic acid and optionally heating, for example at about 70 ° C. Process b) can be carried out by reductive alkylation, for example, using a reducing agent such as sodium triacetoxyborohydride in a suitable solvent, for example acetic acid. On the compound of the formula (III) can be prepared by the reaction of an aminothiophene with nitrogen mustard (R = H) or an N-protected derivative, for example R = benzyl: followed by the deprotection. The reaction is conveniently carried out using a high boiling point solvent, for example xylene, toluene or butanol, optionally with base, for example K2C03. The compounds of formula I can be isolated in the form of a salt of a pharmaceutically acceptable acid, for example an organic or inorganic acid by treatment with an acid as described above. Geometric isomers (cis and trans) are possible and such isomers can be separated by standard techniques for example, chromatography. The initial / reagent materials used in the above process are known or can be made by methods known in the art from materials readily available by processes known or readily apparent to those skilled in the art. However, the present compounds can be advantageously prepared according to Reaction Scheme I set forth below.

Reaction Scheme I The specific exemplification of the production of representative compounds of this invention is given in the following procedures.

INTERMEDIARY 1 4- (5-Fluoro-lH-3-indolyl) -cyclohex-3-ßn-β-β-β-β-β-5-fluoroindole (4.96 g, 0.036 mole), 1,4-cyclohexanedione monoethylene (7.17 g, 0.046) were heated to reflux. moles) and potassium hydroxide (6 g, 0.043 moles) in 70 ml of methanol for 6 hours. The reaction was cooled and the product was isolated by filtration and washed with water to give 8.59 g (86%) of product as a white solid: m.p. 153-155 ° C.

INTERMEDIARY 2 4- (5-Fluoro-lH-3-indolyl) -cyclohexanone-ethylene ketal A mixture of 4- (5-fluoro-lB-3-indolyl) -cyclohex-3-en-ethylene ketal is hydrized for 5 hours (8.5 g) and 10% palladium on carbon (2.72 g) in ethanol (200 ml). The catalyst was removed by filtration and the solvent was removed under vacuum. Chromatography (methanol-methylene chloride) produced 7.55 g (82%) of product as a white solid: m.p. 183-185 ° C.

INTERMEDIARY 3 4- (5-Fluoro-lH-3-indolyl) -c-clohexanone A solution of 4- (5-fluoro-lH-3-indolyl) -cyclohexanone-ethylene ketal (2.8 g, 10 mmol) in 2 1, tetrahydrofuran-hydrochloric acid (1: 1) (IN) was allowed to stir at room temperature for 16 hours. The solvent was evaporated under vacuum. The crude product was dissolved in ethyl acetate, and washed with IN sodium hydroxide (3 x 150 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (40% ethyl acetate-hexanes) yielded 2.1 g (91%) of product as a yellow solid: m.p. 112-114 ° C.

INTERMEDIARY 4 5-Fluoro-3-. { (1,4-cis) -4-hydroxy-4- [4- (3-methoxy-thiophen-2-yl) -3,6-dihydro-2H-pyridin-1-yl] -cycloalxyl} -lH-indole A solution of 4- (5-fluoro-lH-3-indolyl) -cyclohexanone (1.32 g, 5.7 mmol), 4-hydroxy-4- (3-ethoxy-thiophen-2-yl) -piperidine, produced according to the procedures set forth in U.S. Patent No. 5,525,600 (0.5 g, 2.5 mmol), sodium triacetoxyborohydride (1.82 g, 8.6 mmol) and acetic acid (0.65 mL, 11 mmol) in 1, 2- Dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with IN sodium hydroxide (10 ml), extracted with methylene chloride (3 x 60 ml) and washed with brine (3 x 60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) yielded (0.52 g (22%) of product as a white foam: MS m / e 428 (M +).

INTERMEDIARY 5 5-Fluoro-3-. { (1,4-trans) -4-hydroxx-4- [4- (3-methox ± -thiophen-2-yl) -3,6-dihydro-2H-pyridin-1-yl] -cyclohexyl} -lH-indole The trans compound was isolated at the same time as the cis isomer in 2.5% yield (0.06 g) as a clear oil; MS M / e 428 (M +).

EXAMPLE 1 5-Fluoro-3-. { (1, 4-cis) -4- [4- [3-methoxy-thiophen-2-yl) -3,6-dihydro-2H-pyridin-1-yl] -cyclohexyl} -lH-indole A solution of (0.42 g) of Intermediate 4 was heated in 20 ml of acetic acid at 70 ° C for 0.5 hours. The reaction mixture was poured into 100 ml of 2.5 N sodium hydroxide, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% ethyl acetate-hexanes) yielded 0.32 g of product as a yellow oil, MS m / e 410 (M +). The HCl salt was prepared in ethyl acetate: m.p. 64-167 ° C. Elemental analysis for C24H27F0SN2 * HC1 «1.25H2O» 0.07C4H8O2 Calculated: C, 61.39; H, 6.55; N, 5.97 Found: C, 61.50; H, 6.19; N, 6.02 EXAMPLE 2 5-Fluoro-3-. { (1, -trans) -4- [4- [3-methoxy-thiophen-2-yl] -3,6-dihydro-2H-pyridin-1-yl] -cyclohexyl} -lH-indole This compound was prepared in the manner described above by Example 1 with the exception that Intermediate 5 (0.48 g) in 20 ml of acetic acid was heated to give a yield of 70% (0.32 g). ) of product as a white solid: pf, 190. 5-191.5 ° C. The HCl salt was prepared in ethyl acetate m.p. 253.5-255.5 ° C. Elemental analysis for C2 H27FOSN2 »HCl * Calculated: C, 64.49; H, 6.31; N, 6.27 Found: C, 64.07; H, 6.22; N, 6.01 The activity of the present compounds was demonstrated by the following standard pharmacological test procedures. The cloning of the human 5-HT1A receptor subtype from a genomic library has been previously described by Chanda et al., Mol. Pharmacol., 43: 516 (1993). A stable Chinese hamster ovary cell line expressing the human 5-HT? A receptor subtype (5-HT? A. CHO cells) was employed throughout this study. Cells were maintained in DMEM supplemented with 10% fetal bovine serum, non-essential amino acids and penicillin / streptomycin. The cells were growing at confluence of 95-100% as a monolayer before the membranes were harvested for binding studies. The cells were gently scraped from the culture plates, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 minutes, 4 ° C) in buffer (50 mM Tris, pH 7.5). The resulting pellets are aliquoted and maintained at -80 ° C. On the day of the test, the cells were melted on ice, and resuspended in buffer. The studies were conducted using [3 H] 8-OH-DPAT as the radioligand. The binding assay was performed in 96-well microtiter plates in a final total volume of 250 μl of buffer. The comparison experiments were performed using 7 unclassified drug concentrations and a final ligand concentration of 1.5 nM. No specific binding was determined in the presence of 10 μM 5HT. The saturation analysis was conducted by driving [3 H] 8-OH-DPAT at concentrations ranging from 0.3-30 nM. After an incubation of 30 minutes at room temperature, the reaction was terminated by the addition of ice-cooled buffer and rapid filtration using a Brandel M-96 Cell Harvester (Gaithersburg, MD) through a GF / B filter pre-moistened with 30 ml. minutes in 0.5% polyethyleneimine. A protocol similar to that used by Cheetham et al., Neuropharmacol. , 32: 737 (1993) to determine the affinity of the compounds for the serotonin transporter. Briefly, the frontal cortical membranes prepared from male Sprague-Dawley rats were incubated with 3H-paroxetine (0.1 nM) per. 60 minutes at 25 ° C. All tubes also contained any vehicle, test compounds (one to eight concentrations), or a saturating concentration of fluoxetine (10 μM) to define the specific binding. All reactions were terminated by the addition of ice-cooled Tris buffer followed by rapid filtration using a Tom Tech filtration device to separate the free H3-paroxetine linkage. Linkage radioactivity was quantified using a Wallac 1205 Beta Piate® counter. The non-linear regression analysis was used to determine the IC50 values that were converted to Ki values using the method established in Cheng and Prusoff, Biochem. Pharmacol., 22: 3099 (1973) (Ki = IC50 / ((Radioligand concentrate) / (1 + KD)). The [35S] -GTP? S binding assay was similar to that used by Lazareno and Birdsall, Br. J Pharmacol.109: 1120 (1993): Briefly, membrane fragments of the cloned 5-HT? (as used by the binding assays of the 5-HT? A receptor) at -70 ° C. When needed, the membranes were rapidly thawed, centrifuged at 40, 000 x g for 10 minutes in a test buffer (25 M HEPES, 3 M MgCl, 100 M NaCl, 1 M EDTA, 10 uM GDP, 500 M DTT, pH 8.0). These membranes were then incubated for 30 minutes at 30 ° C with [35S] GTPgS (1 nM) in the presence of a vehicle, a test compound (one to eight concentrations), or an excess of 8-OH-DPAT to define the Maximal agonist response. All reactions were terminated by the addition of an ice-cooled Tris buffer followed by rapid filtration using a Tom Tech® filtration device to separate the binding of free [35S] GTPgS. The agonists produced an increase in the binding amount of [35S] GTPgS while the antagonists produced no increase in the binding. The binding radioactivity was counted and analyzed as in the above. The following assays were performed by incubating the cells with DMEM containing 25 mM HEPES, 5 M theophylline and 10 μM pargyline for a period of 20 minutes at 37 ° C. Functional activity was assessed by treating the cells with forskolin (final concentration of 1 uM) followed immediately by the test compounds (6 concentrations) for an additional 10 minutes at 37 ° C. In separate experiments, 6 concentrations of the antagonist were preincubated for 20 minutes before the addition of 10 nM 8-OH-DPAT and forskolin. The reaction was terminated by removing the medium and adding 0.5 ml of ice-cold assay buffer. The plates were stored at -20 ° C before the evaluation of cAMP formation by a cAMP SPA assay (Amersham). The compounds tested correspond to those prepared in Examples 1 and 2 above. The results of the procedures are set forth in Table 1.

Example 5-HTXA ST No. (Ki, nM) (Ki, nM,) 1 48% @ 1000 nM 2.5 2 20.4 18% @ 100 nM As demonstrated by the results set forth above, the compounds of the present invention are active with respect to 5HT1A receptors and generally elevate serotonin levels by inhibiting 5-HT transport. Accordingly, the present compounds should be useful in the treatment of disorders related to defects in serotonin concentration.

The compounds of this invention can be prepared orally or parenterally, either pure or in combination with conventional pharmaceutical carriers. Applicable solid carriers may include one or more substances which 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 that 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. Any of the solid carriers known to those skilled in the art can be used with the compounds of this invention. Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, low melting waxes, and ion exchange resins.

The liquid carriers can be used in the preparation of solutions, suspensions, emulsions, syrups and elixirs of the compounds of this invention. The compounds of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier 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, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as in the above, for example, cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, for example glycols) and their 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 for parenteral administration. Liquid pharmaceutical compositions which are sterile solutions or suspensions may be used for example, by intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. The compositions for oral administration can be either in the form of liquid or solid composition. Preferably, the pharmaceutical compositions containing the compounds of this invention are in unit dosage form, for example, tablets or capsules. Thus, the compositions can be sub-divided into unit doses containing appropriate amounts of the present compounds. The unit dosage forms may be packaged compositions, for example, packaged powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dose form can be, for example, a capsule or tablet itself, or it may be the appropriate number of any such compositions in package form. The therapeutically effective amount of the compounds of this invention that are administered and the dosage regimen depends on a variety of factors, including the subject's weight, age, sex and medical condition, the severity of the disease, the route and frequency of administration , and the specific compound employed, and thus can vary widely. However, it is believed that the pharmaceutical compositions may contain the compounds of this invention in the range of about 0.1 to about 2000 mg, preferably in the range of about 0.5 to about 500 mg and more preferably between about 1 and about 100 mg . The projected daily doses of the active compound are from about 0.01 to about 100 mg / kg of body weight. Daily doses can be conveniently administered two to four times per day. The present invention may be expressed in other specific forms without departing from the spirit and essential attributes thereof and accordingly, reference is made to the appended claims, rather than to the preceding specification, as it indicates the scope of the invention. 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 (11)

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

1. A compound of the formula: characterized in that: X is carbon or nitrogen; dotted lines represent an optional link that is absent if X is N; Ri and R2 are each, independently, hydrogen, halogen, CF3, alkyl, alkoxy, or MeS02; R3 is hydrogen, halogen or alkyl; R is hydrogen, alkyl, alkylaryl, or aryl; and R5 is hydrogen, halogen, CF3, CN, carbamide, or alkoxy; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1, characterized in that X is carbon.

3. A compound according to claim 1 or claim 2, characterized in that Ri and R2 are each, independently, hydrogen or alkoxy.

4. A compound according to any of claims 1 to 3, characterized in that R3 is hydrogen.

5. A compound according to any of claims 1 to 4, characterized in that R is hydrogen.

6. A compound according to any of claims 1 to 5, characterized in that R5 is halogen.

7. The compound according to claim 1, characterized in that it is 5-Fluoro-3-. { (1, 4-cis) -4- [4- (3-methoxy-thiophen-2-yl) -3,6-dihydro-2H-pyridin-1-yl] -cyclohexyl} -IH-indole or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1, characterized in that it is 5-Fluoro-3-. { (1, 4-trans) -4- [4- (3-methoxy-iiophen-2-yl) -3,6-dihydro-2H-pyridin-1-yl] -cyclohexyl} -IH-indole or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition, characterized in that it comprises a compound of the formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

10. The use of a compound of the formula (I) or its pharmaceutically acceptable salts according to any of claims 1 to 8 for the manufacture of a medicament for treating a patient suffering from depression.

11. A process for the preparation of a compound of the formula (I) according to any of claims 1 to 8 or a pharmaceutically acceptable salt thereof, characterized in that it comprises one of the following: a) dehydrating a compound of the formula II wherein Ri, R2, R3, R and R5 are as defined in claim 1, to give a compound of formula I as defined in claim 1, wherein X is carbon and the optional bond is present; or b) reacting a compound of the formula (I heard) with a compound of the formula (IV) wherein formulas X, dotted lines, Ri, R2, R3, R4 and R5 are as defined in claim 1, to give a compound of formula I as defined in claim 1, wherein X is carbon and the bond optionally present; or c) acidifying a basic compound of formula I with a pharmaceutically acceptable acid to a pharmaceutically acceptable salt; or d) separating a mixture of cis and trans isomers of a compound of the formula (I) to isolate an isomer substantially free of the other isomer.