HK1010102B - 4-indolylpiperazinyl derivatives - Google Patents

Description

This invention relates to 4-indolylpiperazinyl derivatives, processes for their preparation and the use of these compounds in the treatment of certain diseases or disorders.

US Patent 4,988,814 discloses a group of compounds in which the tertiary alkyl carboxylic acid acyl moiety appears. GB 2230781, GB 2218988, EP 372,657 and WO 95/33743 disclose 5-HT_1A antagonists which contain a heteroarylpiperazine moiety. USP 3641029 discloses benzoxazole and benzothiazole carboxamides useful for their CNS activity as tranquilizers and depressants. USP 3646048 discloses N-(tert.aminoalkyl) derivatives of substituted or unsubstituted 2-indenecarboxamides, useful for depressant and analgesic activity.

In accordance with this invention there is provided a group of novel compounds which exhibit serotonin 5HT_1A activity which characterizes them as compounds capable of regulating various physiological functions and behaviour including anxiety and affective states. In addition, 5-HT₁-like antagonists, like those involved in the present disclosure have been shown to be useful in inhibiting the growth of certain cancers, such as human prostatic carcinoma. Hence, the compounds of this invention are also useful in the treatment of cancer.

Therefore, according to the present invention there is provided a compound of the formula: in which the compound is of the (R) configuration and R¹ is alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, aryl of 6 to 10 carbon atoms or arylalkyl of 7 to 12 carbon atoms; R² is hydrogen or alkyl of 1 to 6 carbon atoms; R³ is phenyl, benzyl, substituted phenyl, or substituted benzyl in which the substituents are hydroxy, halogen, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, nitro, cyano, alkoxycarbonyl of 2 to 7 carbon atoms, amino or dialkylamino in which each alkyl group contains 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.

The halogen substituent referred to above may be chlorine, bromine, fluorine or iodine, fluorine being preferred.

When R¹ is alkyl it is preferably methyl. When R¹ is cycloalkyl it is preferably cyclohexane. When R¹ is aryl it is preferably phenyl and when R¹ is aralkyl it is preferably benzyl.

When R² is alkyl it is preferably methyl. R² is preferably hydrogen.

R³ is preferably phenyl or benzyl.

The pharmaceutically acceptable salts are derived from known inorganic or organic acids such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, toluene sulfonic, naphthalenesulfonic, formic, acetic, propionic, oxalic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic, para-amino benzoic, para-hydroxybenzoic, salicylic, sulfanilic acids, and the like.

The compounds of formula (A) contain a chiral center, providing for various stereoisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers, which isomers can be either prepared directly by asymmetric or stereospecific synthesis or by conventional separation of epimers or optical isomers from the racemic mixture.

The present compounds are those of the (R) configuration. Particularly preferred are the compounds of the (R) configuration in which R¹ is phenyl or cyclohexyl, R² is hydrogen and R³ is phenyl or benzyl, or a pharmaceutically acceptable salt thereof.

Specifically preferred compounds are :

• (R)-cyclohexanecarboxylic acid-(2-[4-indolyl]-1-piperazin-1-yl]-1-phenyl-ethyl)-amide or a pharmaceutically acceptable salt thereof.
• (R)-acetic acid (2-[4-indolyl]-1-piperazin-1-yl]-1-phenyl-ethyl)-amide or a pharmaceutically acceptable salt thereof.
• (R)-benzoic acid-(2-[4-indolyl]-1-piperazin-1-yl]-1-phenyl-ethyl)-amide or a pharmaceutically acceptable salt thereof.
• (R)-cyclohexane carboxylic acid 1-phenylmethyl -2-[1-[4-(4-indolyl)piperazinyl]]ethylamide or a pharmaceutically acceptable salt thereof.

The compounds of this invention (A) are prepared by a sequence beginning with the reaction of 4-indolyl-piperazine (B) with an N-protected aminoacid (C) in the presence of a coupling reagent such as 1,1'-carbonyldiimidazole, isobutylchloroformate, diethylcyanophosphonate or a carbodiimide, to give the N-protected aminoacid amide (D). The protecting group R⁴ for the aminoacid is of the urethane type, particularly useful are those in which R⁴ is tertiarybutyloxycarbonyl (removable by acid) or benzyloxycarbonyl (removable by hydrogenation or by HBr).

After deprotection of (D) the aminoacid amide may be reduced to (F) using a reducing agent such as diborane or LiAlH₄.

Acylation with a carboxylic acid (G) affords the compounds (A) of the invention.

Examples of acylating reactants include the acid halides (e.g. acid chlorides), azides, anhydrides, imidazolides (e.g. obtained from carbonyldiimidazole) or o-acylureas (e.g. obtained from a carbodiimide).

In a further aspect of the present invention there is provided a process for the preparation of a compound of formula (A) which comprises the steps described above.

The compounds of this invention possess high affinity for the serotonin 5-HT_1A receptor, and consequently, they are useful as antidepressant and anxiolytic agents for the treatment of a variety of central nervous system disorders such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and cocaine addiction, cognition enhancement and related problems. In addition, the compounds of this invention show marked selectivity for the 5-HT_1A receptors as opposed to the α₁ receptors.

High affinity for the serotonin 5-HT_1A receptor was established by testing the claimed compound's ability to displace [³H] 8-OHDPAT (dipropylaminotetralin) from the 5-HT_1A serotonin receptors in rat hippocampal membrane homogenate following the procedure of B. S. Alexander and M. D. Wood, J. Pharm. Pharmacol. 1988, 40, 888-891. The compound of Example 1 exhibited an IC₅₀ of 2 nM; the compound of Example 2 exhibited an IC₅₀ binding potency of 35.5 nM; the product of Example 3 exhibited an IC₅₀ of 5 nM and the product of Example 4 exhibited an IC₅₀ of 8.3 nM. These compounds are highly selective for the 5-HT_1A receptors in comparison with their affinity for other receptors such as the alpha 1, alpha 2, D1, etc. receptors.

Based upon this receptor binding data, the compounds of this invention are characterized as anxiolytic and/or antidepressant agents useful in the treatment of depression and in alleviating anxiety . Thus, in a further aspect of the present invention there is provided a compound of the formula A or a pharmaceutically acceptable salt thereof, for use in the treatment of a human or animal.

The compounds of formula A may be administered neat i.e. unformulated, or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid.

Applicable solid carriers can 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 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 shape and size desired. 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 ion exchange resins.

Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient 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 fat. The liquid carrier can 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 above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis 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 sterile liquid form compositions for parenteral administration.

Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form. Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.

The dosage to be used in the treatment of a specific patient suffering from depression or anxiety must be subjectively determined by the attending physician. The variables involved include the specific state of anxiety or depression, and the size, age and response pattern of the patient.

Therefore as a further aspect of the present invention there is provided a pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.

The following examples are presented, to illustrate the preparation of representative members of the compounds of the invention.

Example 1 (R)-Cyclohexanecarboxylic acid-(2-[4-indolyl]-1-piperazin-1-yl]-1-phenyl-ethyl)-amide

Benzyloxycarbonyl-D-phenylglycine (2.36 g, 0.0083 mol), and N-methylmorpholine (0.84 g, 0.0083 mol) were stirred in 100 mL of methylene chloride at -15 °C under a nitrogen atmosphere as isobutylchloroformate (1.13 g, 0.0083 mol) was added. After 15 minutes, 4-piperazinylindole (1.33 g, 0.0075 mol) was added and the mixture was stirred as it reached room temperature over 20 hours. The solution was washed with water (2 x), saturated NaHCO₃ (2 x) and dried over anhydrous Na₂SO₄. Evaporation of solvent left 3.6 g of product as a gum which was stirred in 30% HBr in acetic acid (100 mL) at room temperature for 30 minutes. Diethyl ether (300 mL) was added and the hydrobromide salt was filtered, washed with diethyl ether, and dried in vacuo overnight. The salt was shaken in 1 N NaOH and the amine was extracted with methylene chloride (3 x). The extracts were washed with water, dried over anhydrous Na₂SO₄, and evaporated to a gum, yield 1.6 g (57.6% from cbz-D-phenylglycine).

(R)(1-Phenylglycyl)-4-(4-indolyl)piperazine (1.6g, 4.92 mmol) and lithium aluminum hydride (0.81 g, 21.7 mmol) were refluxed in THF (500 mL) overnight under nitrogen. The cooled reaction was quenched with IN NaOH (4.92 mL), stirred for 30 minutes, filtered, and the filtrate was evaporated. The residue was dissolved in ethyl acetate, washed with water, then brine, and dried (Na₂SO₄). Evaporation of the solvent left (R)-2-(4-indolyl)-piperazin-1-yl-1-phenyl-ethylamine (1.39 g). Yield 88%. The IR spectrum was devoid of carbonyl peaks. Mass spectrum, EI M⁺.M/H 320.

(R)-2-[4-(1H-Indol-4-yl)-piperazin-1-yl]-1-phenyl-ethylamine (1.8 g, 5.5 mmol), cyclohexanecarbonyl chloride (0.8 g, 5.5 mmol) and diisopropyl ethylamine (1 mL, 5.5 mmol) were stirred in THF (50 mL) in an ice bath and allowed to reach room temperature overnight. The solvent was evaporated and the residue was shaken with ethyl acetate and water. The organic layer was washed with saturated NaHCO₃, then brine and dried (Na₂SO₄). After removal of solvent the product was purified on a silica dry column (400 mL) and eluted with 1:1 ethyl acetate/hexane. Yield 1.4 g (59%). The product was dissolved in ethyl acetate containing 10% ethanol, acidified with 3.6N HCI in ethyl acetate, diluted with two volumes of diethyl ether and filtered.

The salt was washed with diethyl ether and dried in vacuo overnight at room temperature to provide the title compound as the hydrochloride, 2.5 hydrate. Yield 1.3 g (46.2%). MP 210-215 °C; IR 1650 cm^-1. Mass spectrum EI M⁺ 430. ¹H NMR (DMSO-d₆): δ 1.2-1.4 (m, 6H), 1.58-1.62 (d, 1H), 1.62-1.8 (m, 4H), 1.8-1.88 (d, 1H), 2.28-2.38 (m, 1H), 3.65-3.75 (t, 2H), 3.85-4.05 (s, 1H), 6.45 (s, 1H), 6.55-6.58 (d, 1H), 6.95-7.0 (t, 1H), 7.05-7.14 (d, 1H), 7.25-7.3 (t, 2H), 6.35-7.24 (m, 5H). [α]_D ²⁵ -28.8 c=1.00 EtOH.

Calc'd	C, 63.53;	H, 7.87;	N, 10.94
Found	C, 63.46;	H, 7.43;	N, 10.87

Example 2 (R)-Acetic acid (2-[4-indolyl]-1-piperazin-1-yl]-1-phenyl-ethyl)-amide

(R)-2-[4-(1H-Indol-4-yl)-piperazin-1-yl]-1-phenyl-ethylamine (0.5 g, 1.5 mmol), acetic anhydride (0.237 g, 2.35 mmol) and triethylamine (0.24 g, 2.35 mmol) were stirred in methanol (50 mL) overnight. The methanol was evaporated and the residue was shaken with dichloromethane and water, then saturated NaHCO₃. The organic solution was dried (Na₂SO₄) and evaporated. Yield 0.5 g (92%). The amine was dissolved in dichloromethane (15 mL), acidified with 3.6N HCl in ethyl acetate, filtered, and dried in vacuo at room temperature to provide the title compound as the hydrochloride, sesquihydrate. Yield 0.42 g (72%). MP 188-190 °C; IR 1650 cm^-1. Mass spectrum EI M⁺362. ¹H NMR (DMSO-d₆): δ 1.97 (s, 3H), 3.2-3.8 (m, 10H), 5.38-5.42 (m, 1H), 6.45 (S, 1H), 6.55-6.7 (d, 1H), 6.97-7.02 (t, 1H), 7.1-7.13 (d, 1H), 7.18-7.25 (m, 2H), 7.35-7.42 (6, 2H), 7.43-7.46 (d, 2H), 8.78-8.90 (d, 1H), 10.56-10.67 (s, 1H), 11.17 (s, 1H), [α]_D ²⁵ 36.8, c=1.01 ethanol.

Calc'd	C, 57.15;	H, 6.76;	N, 12.11
Found	C, 57.44;	H, 6.77;	N, 11.82

Example 3 (R)-Benzoic acid-(2-[4-indolyl]-1-piperazin-1-yl]-1-phenyl-ethyl)-amide

(R)-2-[4-(1H-Indol-4-yl)-piperazin-1-yl]-1-phenyl-ethylamine (0.5 g, 1.5 mmol), diisopropylethylamine (0.22 g, 1.7 mmol) and benzoylchloride (0.239 g, 1.7 mmol) were stirred in dichloromethane (50 mL) overnight at room temperature. The solution was washed with water, saturated NaHCO₃, dried (Na₂SO₄) and evaporated. Yield 0.625 g (98.2%). The hydrochloride salt was prepared in ethyl acetate with 3.6 N HCl in ethyl acetate and dilution with diethyl ether. The product was filtered, washed with diethyl ether and dried in vacuo overnight. Yield 0.26 g (34.3%); MP 178-180°C, IR 1650 cm^-1. Mass spectrum EI M⁺ 424. ¹H NMR (DMSO-d₆): δ 3.14-3.25 (m, 2H), 3.4-3.58 (m, 2H), 3.59-3.65 (t, 2H), 3.65-3.85 (m, 4H), 5.62-5.7 (t, 1H), 6.45 (s, 1H), 6.5-6.55 (d, 1H), 6.95-7.0 (t, 1H), 7.06-7.10 (d, 1H), 7.26-7.3 (t, 1H), 7.3-7.35 (d, 1H), 7.35-7.4 (t, 2H), 7.45-7.6 (m, 5H), 8.0-8.06 (d, 2H), 9.3-9.38 (d, 1H), 10.48-10.6 (s, 1H), 11.12-11.16 (s, 1H). [α]_D ²⁵-19.99, c=1.00 ethanol.

Calc'd	C, 64.02;	H, 6.17;	N, 11.06
Found	C, 63.99;	H, 6.37;	N, 10.63

Example 4 (R)-Cyclohexane Carboxylic Acid 1-Phenylmethyl -2-[1-[4-(4-indolyl)piperazinyl]]ethylamide

A tetrahydrofuran solution (40 mL) of N-t-Boc-D-Phe (4.9g) was stirred under argon and treated portionwise with carbonyldiimidazole (CDI )(1.1 equivalents, 3.3g). After stirring for 15 minutes at ambient temperature, the indolylpiperazine (3.7g, 1 equivalent) was added and the reaction mixture stirred for 16 hours. The solvent was removed in vacuo, water (100 mL) added and the product extracted into ethyl acetate (3x 100mL). The organics were dried (Na₂SO₄) and concentrated in vacuo to give 8.9g of (R)-4-[4-(1H-indolyl)]-1-[2-N-(tertiary-butoxycarbonyl)amino-3-phenyl]propionyl piperazine. The product was purified by chromatography on neutral alumina to give a white solid. (5.2g, 63 % yield) mp=102°C.

Calc'd	C, 68.93;	H, 7.23;	N, 12.37
Found	C, 69.01;	H, 7.39;	N, 12.18

A dichloromethane solution (20 mL) of the amide (3.4g) produced in the previous paragraph was treated with trifluoroacetic acid (10mL) under argon. After stirring for one hour, the solvent was removed in vacuo. Water (100 mL) was added and the solution was neutralized to pH 7 with aqueous NaHCO₃ solution. The product was extracted into ethyl acetate (3 x 100 mL). The organics were dried (Na₂SO₄) and concentrated to give 2.56g of (R)-4-[4-(1H-indolyl)]-1-[2-amino-3-phenyl]propionyl piperazine as the trifluoroacetate salt. (97% yield) mp=91°C.

Calc'd	C, 59.73;	H, 5.45;	N, 12.11
Found	C, 60.53;	H, 5.95;	N, 11.63

Lithium aluminum hydride (0.78g) was added portionwise to a stirred solution of the amide (2.4g) in tetrahydrofuran (30 mL) at ambient temperature. The mixture was refluxed for 15 minutes to complete the reaction. Upon cooling to ambient temperature, the excess hydride was destroyed by adding saturated ammonium chloride solution cautiously. The product was extracted into ethyl acetate (3x 100 mL), dried over sodium sulphate, and concentrated in vacuo to give 2.13g of crude (R)-4-[4-(1H-indolyl)]-1-[2-amino-3-phenyl]propyl piperazine, which was used directly in the next step.

Triethylamine (1.29g, 2 equivalents) was added to a dichloromethane solution (20 mL) of the crude amine (2.13g, 1 equivalent) at 0°C. under argon and the stirred solution was treated with cyclohexanoyl chloride (1.03g, 1.1 equivalents). After 3 hours, the solvent was removed in vacuo, water (100 mL) was added and the pH was made basic with aqueous 1N NaOH. The product was extracted into ethyl acetate (3 x 100 mL), dried over sodium sulphate and concentrated to give 3g of crude product. The crude product was purified by chromatography over silica gel to afford pure (R)-cyclohexane carboxylic acid 1-phenylmethyl -2-[1-[4-(4-indolyl)piperazinyl]]ethylamide as a white solid. The monohydrochloride was obtained as a cream colored solid. mp=142°C.

Calc'd	C, 67.38;	H, 7.88;	N, 11.23
Found	C, 67.67;	H, 7.71;	N, 11.09

Claims (14)

1. A compound of the formula: in which the compound is of the (R) configuration and R¹ is alkyl of 1 to 6 carbon atoms, cycloalkyl of 5 to 7 carbon atoms, aryl of 6 to 10 carbon atoms or arylalkyl of 7 to 12 carbon atoms; R² is hydrogen or alkyl of 1 to 6 carbon atoms; R³ is phenyl, benzyl, substituted phenyl, or substituted benzyl in which the substituents are hydroxy, halo, alkoxy of 1 to 6 carbon atoms, trifluoromethyl, nitro, cyano, alkoxycarbonyl of 2 to 7 carbon atoms, amino or dialkylamino in which each alkyl group contains 1 to 6 carbon atoms; or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1, in which R¹ is phenyl or cyclohexyl, R² is hydrogen and R³ is phenyl or benzyl, or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 which is (R)-cyclohexanecarboxylic acid-(2-[4-indolyl]-1-piperazin-1-yl]-1-phenyl-ethyl)-amide or a pharmaceutically acceptable salt thereof.
4. A compound according to claim I which is (R)-acetic acid (2-[4-indolyl]-1-piperazin-1-yl]-1-phenyl-ethyl)-amide or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 which is (R)-benzoic acid-(2-[4-indolyl]-1-piperazin-l-yl]-1-phenyl-ethyl)-amide or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1 which is (R)-cyclohexane carboxylic acid 1-phenylmethyl -2-[1-[4-(4-indolyl)piperazinyl]]ethylamide or a pharmaceutically acceptable salt thereof.
7. A compound of the formula: in which the compound is of the (R) configuration and R¹ R² and R³ are as defined in any of claims 1 to 6 or a pharmaceutically acceptable salt thereof for use as antagonists of serotonin 5HT_1A activity.
8. A compound of the formula: in which the compound is of the (R) configuration and R¹ R² and R³ are as defined in any of claims 1 to 6 or a pharmaceutically acceptable salt thereof, for use as a medicament.
9. A pharmaceutical composition comprising a compound of the formula: as defined in any of claims 1 to 6 or a pharmaceutically acceptable salt thereof and a pharmaceutical carrier.
10. Process for the preparation of compounds of formula: as defined in any of claims 1 to 6 which comprises

    (a) reacting a compound of formula (B) with a compound of formula (C) in which R² and R³ are as previously defined and R⁴ is a protecting group, in the presence of a coupling reagent to give a compound of formula (D):

    (b) the compound of formula (D) is deprotected to give a compound of formula (E):

    (c) the compound of formula (E) is reduced with a reducing agent to a compound of formula (F):

    (d) the compound of formula (F) is acylated with a carboxylic acid of formula (G): to provide the compound of formula (A), either directly by asymmetric or stereospecific synthesis or by conventional separation of epimers or optical isomers from the racemic mixture.
11. Compound of formula : in which R² and R³ are as defined in any of claims 1 to 6 and R⁴ is a protecting group of the urethane type.
12. Compound of formula: in which R² and R³ are as defined in any of claims 1 to 6.
13. Compound of formula : in which R² and R³ are as defined in any of claims 1 to 6.
14. Process for the preparation of a compound of Formula (F) as defined in claim 13, comprising:

    a) reacting a 4-indolyl-piperazine of Formula (B) with an N-protected aminoacid of Formula (C) in the presence of a coupling reagent to give an N-protected aminoacid amide of Formula (D)

    b) deprotecting the compound of Formula (D) to produce the corresponding aminoacid amide of Formula (E) and c) reducing the aminoacid amide of formula (E) to produce the compound of Formula (F)