WO1996012721A1 - Indole derivatives useful as serotonergic agents - Google Patents

Indole derivatives useful as serotonergic agents Download PDF

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WO1996012721A1
WO1996012721A1 PCT/US1995/013124 US9513124W WO9612721A1 WO 1996012721 A1 WO1996012721 A1 WO 1996012721A1 US 9513124 W US9513124 W US 9513124W WO 9612721 A1 WO9612721 A1 WO 9612721A1
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hydrogen
c2
compound
alkyl
c3
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PCT/US1995/013124
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French (fr)
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Thomas Joseph Commons
Christa Marie Laclair
Susan Christman
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American Home Products Corporation
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems

Abstract

The compound of formula (A), where R1 and R5 are independently hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO2H, C1-C6 alkyl, C2-C10 alkenyl, C1-C6 alkoxy, C3-C8 cycloalkyl, cycloalkylalkyl, C3-C8 cycloalkyloxy, C2-C7 alkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 alkoxycarbonyl, mono- or di-alkylaminocarbonyl, tetrazolyl, -OH, -(CH2)1-6OH, -SH, -NH2 or -(CH2)1-6NR8R9 where R8 is hydrogen, C1-C6 alkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl and R9 is hydrogen or C1-C6 alkyl; R10 and R11 together represent dimethylene whilst R2 is hydrogen or C1-C6 alkyl or R2 and R11 together represent dimethylene whilst R10 is hydrogen; R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; R6 and R7 are independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C8 cycloalkyl, cycloalkylalkyl or R6 and R7 taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 3 to 8 atoms; or a pharmaceutically acceptable salt thereof is useful as a serotonergic agent.

Description

ΪNnθl-F. DERIVATIVES USEFUL AS SEROTONERGIC AGENTS

Background of Invention

The compounds of this invention possess high affinity for the serotonin 5- HTIA receptor and as such are useful as antidepressant and anxiolytic agents for the treatment of a variety of central nervous system disorders such as depression, anxiety, eating disorders, sexual disfunction, addiction and related problems. As an example buspirone (US Patent 3,717,634 ) is known to display potent affinity for the 5-HTIA serotonin receptor. Buspirone is used extensively for the treatment of anxiety and this anxiolytic activity is believed to be due, at least partially, to its 5-HTI A receptor affinity [VanderMaelen et al., Eut. J. Pharmacol. 1986, 129 (123-130)].

WO 9,311,122-A and US 4,988,814 exemplify piperazine derivatives as compounds with affinity for the 5-HTJ receptor.

DESCRIPTION OF THE INVENTION

This invention relates to a series of novel compounds which are useful as pharmaceuticals and in particular have activity as serotonergic agents and have the general formula A,

Figure imgf000003_0001

where

R] and R5 are independently hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO2H, C\-C(, alkyl, C2-C10 alkenyl, Ci- alkoxy, C3-C8 cycloalkyl, cycloalkylalkyl where the alkyl group is of 1 to 6 carbon atoms and the cycloalkyl group has 3 to 8 carbon atoms, C3-C8 cycloalkyloxy, C2-C7 alkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 alkoxycarbonyl, mono- or di- alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, tetrazolyl, OH, -(CH2)l -όOH, -SH, -NH2 or -(CH2)i-6 R8R9 where Rg is hydrogen, Ci - alkyl, C2 - C7 alkylcarbonyl, C2- C7 alkoxycarbonyl and R9 is hydrogen or

Figure imgf000004_0001
alkyl;

RlO and Ri 1 together represent dimethylene whilst R2 is hydrogen or -C6 alkyl or R2 and R 1 ] together represent dimethylene whilst R io is Hydrogen;

R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond;

R>5 and R7 are independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C8 cycloalkyl, cycloalkylalkyl where the alkyl group is 1 to 6 carbon atoms and the cycloalkyl group is 3 to 8 carbon atoms or Rό and R7 taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 3 to 8 atoms; or a pharmaceutically acceptable salt thereof.

The compounds where Ri o and R\ \ together represent dimethylene are Pyrido[3,4-b] indole derivatives. Those where R2 and R J I together represent dimethylene are pyrazino[ l,2-a] indole derivatives. Of both these kinds of compounds, a preferred group from the viewpoint of facile production and economic considerations, are those in which R\ and R5, independently, represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C2- C4 alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, -OH, -NH2 or -(CH2)i-3NRgR9 where R8 is hydrogen or C1-C3 alkyl and R9 is hydrogen or C1-C3 alkyl; R2 is H or C1-C3 alkyl; R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; and R and R7, taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 5 to 8 atoms; or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts may be those derived from such organic and inorganic acids as: acetic, lactic, citric, tartaric, succinic, maleic, malonic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, and similarly known acceptable acids. Where the compounds of this invention contain acidic substituents such as the carboxylic acid group, salts may be formed with pharmaceutically acceptable bases to form alkali metal (such as Na, K or Li), alkaline earth metal (such as Ca or Mg), the ammonium or mono- or dialkylamine salts, the alkyl portion of said amine salts containing 1 to 6 carbon atoms.

The compounds of this invention possess one or three chiral centers depending on the identity of R3 and R4. Therefore they present diastereoisomers and enantiomers, which may be separated by conventional procedures. In naming the compounds throughout this disclosure and in the appended claims it is to be understood that it is intended to embrace the isomers as their mixtures and in their pure form.

The compounds having formula A and their pharmaceutically acceptable salts may be prepared by process which comprises reaction of a compound having formula B

Figure imgf000005_0001
2

B

where Rl, R2,R3,R4,R10 and Rl 1 are as defined above with a compound having the formula C:

Figure imgf000006_0001

where X is a leaving group, for example, chlorine, bromine or methanesulfonyloxy and R5,R6 and R7 are as defined above and, where appropriate, converting a resultant compound havineg formula A into a pharmaceutically acceptable salt thereof. In particular the compounds of this invention are conveniently prepared by the route shown in the following scheme. Specific examples are given in the Experimental Section. These examples are for illustrative purposes only and are not to be construed as limitations for the disclosed invention. Those skilled in the art will be aware of other methods of preparing compounds of this invention. The starting materials or intermediates are available commercially or can be prepared by standard literature procedures.

Figure imgf000007_0001

High affinity for the serotonin 5-HTJ A receptor for the compounds of this invention was established by testing them in accordance with the standard pharmacological test procedure in which the compound's ability to displace [3H] 8- OHDPAT (dipropylaminotetralin) from the 5-HTI A serotonin receptor was determined following the procedure of Hall et al., J. Neurochem. 44 1685 (1985). This procedure is employed to analogize the properties of the claimed compounds with that of buspirone, which is a standard for anxiolytic activity, and, like the compounds of this invention, displays potent affinity for the 5-HTIA serotonin receptor subtype. The anxiolytic activity of buspirone is believed to be, at least partially, due to its 5-HTIA receptor affinity [VanderMaelen et al., Eur. J. Pharmacol. 1986, 129 (123-130)]. The results of this experimental test procedure are given in the following table: TABLE

5-HTIA_Binding (ICSQ) Example 1 30.9 nM Example 2 33.3 nM

Example 3 37.1 nM

Example 4 67.4 nM

Example 6 85.3nM

Hence, the compounds of this invention demonstrated high affinity for the serotonin 5-HTj A receptor subtype, and are therefore useful in the treatment of multi- CNS disorders amenable to treatment with antidepressant and anxiolytic agents. The Pyride [3,4-b] indole derivatives are preferred.

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 . The compounds may be administered orally or parentally. As such , the compounds may be administered neat or with a pharmaceutical carrier to a patient in need thereof. The pharmaceutical carrier may be solid or liquid. The invention therefore also provides a pharmaceutical composition comprising a compound having formula A or a pharmaceutically acceptable salt thereof in association or combination with a pharmaceutical carrier.

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-disintergrating 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 (panicularly 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. EXAMPLE 1

1.A7eDan-1.vl-2.Dhenv[.4-ri.3.4.9-tetrahvdro-2H-nvridor3.4.h1indol.2.vn- l?utan-l- ng

A mixture of l ,2,3,4-terrahydro-9H-pyrido[3,4-b]indole (520 mg, 3.0 mmol), l -(azepan- l -yl)-4-chloro-2-phenyl-butan-l -one (840 mg, 3.0 mmol), N,N- diisopropylethylamine (520 μl, 3.0 mmol) and potassium iodide (500 mg, 3.0 mmol) in 15 ml of anhydrous dimethylformamide was heated under nitrogen at 80°C for five hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was separated and the organic layer washed five times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 1.16 g of a brown oil. Purification of the oil on 200 g of silica gel (230-400 mesh) eluting with 75% ethyl acetate-hexane gave 441 mg of a solid foam. The foam was dissolved in diethyl ether containing a small amount of methylene chloride. To this solution was added 1.1 ml of I N ethereal HC1. An oil precipitated, which after concentration of the supernatant liquid, solidified. The solid was collected by filtration and then recrystallized from isopropyl alcohol - ethanol to give 329 mg (22%) of the title compound as a light brown solid, hydrochloride, 0.375 isopropanolate, 0.375 ethanolate, mp 238-239°C.

Elemental Analysis for C27H34CIN3OO.375 C H8O»0.375 C2H6O Calc'd: C, 70.51; H, 8.04; N, 8.54 Found: C, 70.51; H, 7.86; N, 8.75

EXAMPLE 2

l-A7eπan.l.vl-4-r9.ιnethvl.l.3.4.9.tetrahvdro.2H.nvridor3.4.h1.indol.2.vn.2. phenvl-hutan-l-one

A solution of benzyl chloroformate (8.3 ml, 58 mmol) in 20 ml of anhydrous tetrahydrofuran was added dropwise under nitrogen to a warm solution of 1,2,3,4- tetrahydro-9H-pyrido[3,4-b] indole (10.0 g, 58 mmol) and triethylamine (8.1 ml, 58 mmol) in 200 ml of anhydrous tetrahydrofuran. After the addition, the reaction was stirred at room temperature for four hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and IN HCl. The organic layer was separated, extracted one time with IN HCl, dried (MgSO 4) and the solvent removed under reduced pressure to give 15.7 g of an off-white solid. Recrystallization of the solid from 100 ml of 25% hexane-ethyl acetate gave 4.23 g (24%) of the benzyloxycarbonyl derivative of the starting material as a white solid. Recrystallization of the mother liquors from ethyl acetate-diisopropyl ether gave an additional 5.84 g (33%) of material, mp 102-104°C.

Elemental Analysis for C19H 18 2O2 Calc'd: C, 74.49; H, 5.92; N, 9.14

Found: C, 74.44; H, 5.96; N, 9.30

Sodium hydride [1.5 g of a 60% oil dispersion (37 mmol)] was added in portions over fifteen minutes to a solution of the material prepared in the previous paragraph (9.5 g, 31 mmol) in 100 ml of anhydrous dimethylformamide under nitrogen at room temperature. After the addition was complete the reaction was stirred for three hours. Methyl iodide (5.8 ml, 93 mmol) was then added and the reaction stirred at room temperature overnight. The reaction was quenched by the slow addition of IN HCl. The reaction was then partitioned between IN HCl and ethyl acetate. The organic layer was separated, extracted three times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 10.4 g of a light yellow solid. Recrystallization of the solid from 100 ml of 20% ethyl acetate- diisopropyl ether gave 7.59 g (76%) of the 9-methyl derivative of the starting material as a white solid, mp 100-101°C.

Elemental Analysis for C20H20N2O2

Calc'd: C, 74.97; H, 6.29; N, 8.79 Found: C, 74.95; H, 6.30; N, 8.77

A mixture of the material prepared in the previous paragraph (4.0 g, 12 mmol) and 500 mg of 10% Pd/C in 40 ml of ethyl acetate was hydrogenated at room temperature and 40 psi for 5.5 hours. The catalyst was removed by filtration through celite and then rinsed thoroughly with ethanol and then dimethylformamide. The filtrate was concentrated under reduced pressure to give 2.39 g of an oil. The oil was dissolved in 15 ml of ethanol and 10 ml of IN ethereal HCl was added. A solid formed which was collected by filtration, rinsed with diethyl ether, and dried under high vacuum to give 2.23 g (80%) of l,2,3,4-tetrahydro-9-methyl-pyrido[3,4-b]indole as the hydrochloride salt, mp > 250°C.

Elemental Analysis for C12H15CIN2

Calc'd: C, 64.71; H, 6.79; N, 12.58 Found: C, 64.50; H, 6.73; N, 12.51

A mixture of the material prepared in the previous paragraph (1.56 g, 7.0 mmol), l-(azepan- l-yl)-4-chloro-2-phenyl-butan- l-one (2.0 g, 7.0 mmol), N,N- diisopropylethylamine (2.4 ml, 14.0 mmol) and potassium iodide (1.2 g, 7.0 mmol) in

50 ml of anhydrous dimethylformamide was heated under nitrogen at 80°C for five hours and then left at room temperature overnight. The reaction was partitioned between ethyl acetate and water. The aqueous layer was separated and the organic layer washed five times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 2.89 g of a brown foam. Purification of the foam on 400 g of silica gel (230-400 mesh) eluting with 75% ethyl acetate- hexane gave 2.34 g of an off-white foam. The foam was dissolved in diethyl ether and to this solution was added 7 ml of IN ethereal HCl. The solid formed was collected by filtration, rinsed with diethyl ether, and dried under high vacuum to give as a light yellow solid the title compound (2.00g, 58%) as a hydrochloride, hydrate,

0.08 diethyl etherate, mp 105-170°C.

Elemental Analysis for C28H38CIN3O2O.O8 C4H10O Calc'd: C, 69.41 ; H, 7.98; N, 8.87

Found: C, 69.47; H, 7.78; N, 8.64

EXAMPLE 3

l-A7enan-1.vl-4.fftrans>.9.melhvl.1., .4.4a.9-9a-hexahvdro-2H-Dvridor3.4- blindol-2-yl)-2-phenyl-butan-l-one

A mixture of l,2,3,4-tetrahydro-9-methyl-pyrido[3,4-b]indole hydrochloride, prepared in the third paragraph of Example 2 (4.50 g, 20 mmol), potassium carbonate (14.0 g, 100 mmol) and benzyl chloride (2.3 ml, 20 mmol) in 45 ml of water plus 45 ml of tetrahydrofuran was stirred at room temperature overnight. The reaction was partitioned between water and ethyl acetate. The organic layer was separated, extracted one time with saturated sodium chloride, one time with water, dried (MgSO4) and the solvent removed under reduced pressure to give 4.12 g of a yellow solid. Purification of the solid on 200 g of silica gel (230-400 mesh) eluting with hexane-ethyl acetate gave 3.67 g (66%) of the 2-benzyl derivative of the starting material as a white solid, mp 109-110°C.

Elemental Analysis for C19H20N2 Calc'd: C, 82.57; H, 7.29; N, 10.14

Found: C, 82.29; H, 7.29; N, 10.01

A solution of 1M BH3 THF (49.2 ml, 49.2 mmol) was added under nitrogen dropwise over ten minutes to a solution of the material prepared in the previous paragraph (3.63 g, 13 mmol) in 250 ml of anhydrous tetrahydrofuran at ice bath temperature. After the addition the cooling bath was removed and the reaction stirred at room temperature for thirty minutes and then refluxed for thirty minutes. After cooling to room temperature the solvent was removed under reduced pressure. To this residue 80 ml of one to one glacial acetic acid - IN HCl was added cautiously. After the evolution of gas ceased the reaction was refluxed for fifteen minutes and then stirred overnight at room temperature. The reaction was again refluxed for forty- five minutes and then cooled in an ice bath before 50% aqueous NaOH was added until the reaction was basic. The reaction was extracted with methylene chloride, dried (MgSO4) and the solvent removed under reduced pressure to give 5 g of a clear oil. Purification of the oil on 600 g of silica gel (230-400 mesh) eluting with 10% ethyl acetate - hexane gave 3.70 g of a white solid. Recrystallization of the solid from diisopropyl ether gave 2.61 g (71%) of the hexahydro derivative of the starting material as a white solid, mp 59-60°C.

Elemental Analysis for C19H22 2

Calc'd: C, 81.97; H, 7.97; N, 10.06 Found: C, 81.84; H, 7.95; N, 10.05

A mixture of the material prepared in the preceding paragraph (2.48 g, 8.9 mmol) and 1.2 g of 10% Pd/C in 250 ml of absolute ethanol was hydrogenated at room temperature and 40 psi for 24 hours. The catalyst was removed by filtration through celite and the filtrate concentrated to dryness under reduced pressure to give 1.49 g of a tan solid. Recrystallization of the solid from diisopropyl ether gave 617 mg (37%) of the debenzylated derivative of the starting material as an off-white solid, mp 68-70°C.

Elemental Analysis for C12H16N2

Calc'd: C, 76.55; H, 8.57; N, 14.88

Found: C, 76.47; H, 8.68; N, 14.77

A mixture of the material produced in the previous paragraph (1.355 g, 7.2 mmol), l-(azepan- l -yl)-4-chloro-2-phenyl-butan- l-one (2.0 g, 7.2 mmol), N,N- diisopropylethylamine (1.3 ml, 7.2 mmol) and potassium iodide (1.2 g, 7.2 mmol) in 30 ml of anhydrous dimethylformamide was heated under nitrogen at 80°C for five hours. The reaction was partitioned between ethyl acetate and water. The organic layer was separated, washed four times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2.95 g of a brown solid. Purification of the solid on 300 g of silica gel (230-400 mesh) eluting with 50% hexane - ethyl acetate gave 2.30 g of an off-white solid. Recrystallization of the solid two times from isopropyl alcohol gave 0.542 g (17%) of the title compound as a white solid. NMR analysis of this material indicated it to be a single diastereomer, mp 1 1 1-1 13°C.

Elemental Analysis for C28H37N3O

Calc'd: C, 77.92; H, 8.64; N, 9.74

Found: C, 77.52; H, 8.70; N, 9.63

The mother liquor from the above recrystallization was purified by HPLC (hexane-isopropyl alcohol) to give 169 mg of a yellow oil. The oil was dissolved in diethyl ether plus a small amount of CH2CI2- One equivalent of IN ethereal HCl was added and the solvent was concentrated to approximately half its volume. Diethyl ether was added and a solid formed. The solid was collected by filtration, rinsed with diethyl ether and dried under high vacuum to give 88.4 mg of a brown solid. NMR analysis indicated the solid to be the other diastereomer formed in the reaction, melting range 150-200 'C. Elemental Analysis for C28H37N3O»HC1«4H2O«0.1 C4H10O Calc'd: C, 62.30; H, 8.65; N, 7.67 Found: C, 62.81; H, 7.37; N, 7.60

EXAMPLE 4

l-AzeDan-1-yl-4-((cisV1.3.4.4a.9.9a-hexahvdro-2H-pyridor3.4-b1indol-2-vn-2- phenvl-butan-1-Qne

Triethylsilane (27.8 ml, 174 mmol) was added under nitrogen to a solution of 1, 2, 3, 4-tetrahydro-9H-pyrido [3,4-b]indole (10.0 g, 58 mmol) in 150 ml of trifluoroacetic acid and the reaction stirred at 50°C for approximately five days. The solvent was removed under reduced pressure to give 96.88 g of a two phase oil. Purification of the oil by HPLC eluting with 2:1 : 1 ethyl acetate:methanol:ammonium hydroxide gave 3.83 g of the hexahydro derivative (trifluroacetic acid salt) of the starting material as a white solid, mp 146-149°C.

Elemental Analysis for CnHi4N2»CF3CO2H Calc'd: C, 54.17; H, 5.24; N, 9.72.

Found: C, 54.26; H, 5.20; N, 9.70.

A mixture of the material produced in the previous paragraph (4.0 g, 14 mmol), l-(azepan- l-yl)-4-chloro-2-phenyl-butan- l-one (3.89 g, 14 mmol), N,N- diisopropylethylamine (4.85 ml, 28 mmol) and potassium iodide (2.31 g, 14 mmol) in 250 ml of anhydrous dimethylformamide was heated under nitrogen at 75°C for six hours. The reaction was partitioned between ethyl acetate and water. The organic layer was separated, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 5.33 g of a brown oil. Purification of the oil by HPLC eluting with methanol-methylene chloride gave 1.14 g of a yellow oil. The oil was dissolved in diethyl ether containing a small amount of methylene chloride. One equivalent of ethereal HCl was added and the solid formed was collected by filtration and dried under high vacuum to give the title compound as a light brown solid, hydrochloride, hydrate, 0.2 diethyl etherate. NMR analysis and chiral HPLC showed the material to be a mixture of diastereomers and their enantiomers, mp 105-130°C. Elemental Analysis for C27H35N3OΗCIΗ2OO.2 C4H10O Calc'd: C, 68.57; H, 8.28; N, 8.63. Found: C, 68.51; H, 8.19; N, 8.57.

EXAMPLE 5

l.AzeDan-l-vl-4-f(cis>-9-methvl-1.3.4.4a.9.9a-hexahvdro-2H-Dvridor3.4-hlindol-

2-vn.2-Dhenvl-hutane-1.one

A solution of benzyl chloroformate (3.80 mL, 26.6 mmol) in 100 mL of anhydrous dimethyl- formamide was added under nitrogen dropwise over two hours to a solution of the material prepared in paragraph 1 of Example 4 (7.64 g, 26.6 mmol) and triethylamine (7.42, 53.2 mmol) in 100 ml of anhydrous dimethylformamide at ice bath temperature. After the addition the reaction was stirred at ice bath temperature for two hours and at room temperature overnight. The reaction was diluted with ethyl acetate, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 5.74g of an oil. Purification of the oil on 450g of silica gel (230-400 mesh) eluting with hexane-ethyl acetate gave 2.04g of a solid. Recrystallization of the solid from isopropyl alcohol gave 1.44g (18%) of the benzyloxycarbonyl derivative of the starting material, mp 88-90 *C.

Elemental Analysis for C19H20N2O2 Calc'd: C, 74.00; H, 6.54; N, 9.08

Found: C, 73.96; H, 6.54; N, 9.03

Sodium hydride (271 mg of a 60% oil dispersion containing 6.78 mmol) was added in portions under nitrogen to a solution of the material prepared in the preceding paragraph (1.74g, 5.65 mmol) in 20 ml anhydrous dimethylformamide at room temperature. After the addition , the reaction was stirred a room temperature for two hours. Methyl iodide (1.06 ml, 16.95 mmol) was added and the reaction stirred at room temperature overnight. The reaction was diluted with ethyl acetate, washed multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give l.Og of an oil. Purification of the oil on 450g of silica gel (230-400 mesh) eluting with hexane- ethyl acetate gave 850 mg (47%) of the methyl derivative of the starting material as a clear oil, MS m/e 322 [M+].

Elemental Analysis for C20H22N2O2 Calc'd: C, 74.51 ; H, 6.88; N, 8.69

Found: C, 73.35; H, 6.85; N, 8.52

A mixture of the material prepared in the preceding paragraph (800 mg, 2.48 mmol) and 120 mg of 10% Pd/C in 80 ml of ethanol was hydrogenated at room temperature and 40 psi for 17 hours. The catalyst was removed by filtration through celite and the solvent was removed under reduced pressure to give 426 mg (91%) of a brown oil which was used in the next step without purification.

A mixture of the material prepared in the preceding paragraph (382 mg, 2.03 mmol), l-(azepan-l-yl)-4-chloro-2-phenyl-butan-l-one (568 mg, 2.03 mmol), N,N- diisopropylethylamine (353 μl, 2.03 mmol)and potassium iodide (337 mg, 2.03 mmol) in 15 ml of anhydrous dimethylformamide was stirred under nitrogen at 80*C for five hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was separated and the organic layer washed multiple times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 739 mg of a brown oil. Purification of the oil on 200 g of silica gel (230-400 mesh) eluting with ethyl acetate-methylene chloride gave 361 mg of an off- white solid. This solid was further purified by trituration with hexane to give 205 mg of a solid. The solid (195 mg, 0.45 mmol) was dissolved in diethyl ether and 452 μl (0.45 mmol) of IN ethereal HCl was added. The solid formed was collected by filtration and dried under high vacuum to give as an off-white solid the title compound (120 mg, 12%) as a hydrochloride, sesquihydrate, 0.2 diethyl etherate, MS, m/e 431 (M+ - HCl).

Elemental Analyses for C28H37N3θ«HCl' 1.5 H2θ« 0.2 C4H 10O Calc'd: C, 67.84; H, 8.30; N, 8.24 Found: C, 68.09; H, 8.43; N, 8.48 EXAMPLE fi

1.AzeDan-1.vl.4.(3. 4.dihvdro-1H.Dvrazinori. 2-alindol-2.vl 2-Dhenvl- tnιtan-1-pne

A mixture of 1, 2, 3, 4-tetrahydropyrazino [1, 2-a]indole (2.35 g, 12 mmol), 1-

(azepan- l -yl)-4-chloro-2-phenyl-butan- l-one (2.72 g, 10 mmol), N, N- diisopropylethylamine (1.7 ml, 10 mmol) and potassium iodide (1.6 g, 10 mmol) in

50 ml of anhydrous dimethylformamide was heated under nitrogen at 80°C for five hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was separated and the organic layer washed five times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to five 4.25 g of a brown oil. Purification of the oil on 400 g of silica gel (230-400 mesh) eluting with 30% ethyl acetate-hexane gave 3.70 g (92%) of a yellow foam. The foam (2.0 g) was dissolved in 30 ml of diethyl ether and 5 ml of IN ethereal HCl was added. The solid formed was collected by filtration, rinsed with diethyl ether and dried under high vacuum. Recrystallization of the solid from ethyl acetate gave the title compound as a light yellow solid, hydrochloride, hemihydrate, 0.233 ethylacetate, mp 145-150°C.

Elemental Analysis for C27H33N3O«HC1'0.5 H2O«0.233 C4H8O2 Calc'd: C, 69.66; H, 7.72; N, 8.72 Found: C, 69.91; H, 7.61; N, 8.65

EXAMPLE

1-AzeDan.l.vl-2-nhenvi-4.r3. 4. 10. lOa-te.rahvdro-IH.nvrazinori. 2-alindol-2- vl i-hntan-l-one

A mixture of 1, 2, 3, 4, 10, 10a-hexahydro-pyrazino[l, 2-a]indole (735.9 mg,

4.22 mmol), l-(azepan-l-yl)-4-chloro-2-phenyl-butan-l-one (1.18 g, 4.22 mmol), N, N-diisopropylethylamine (736 μl, 4.22 mmol) and potassium iodide (701 mg, 4.22 mmol) in 20 ml of anhydrous dimethylformamide was heated under nitrogen at 80°C for five hours. The reaction was partitioned between ethyl acetate and water. The aqueous layer was separated and the organic layer washed five times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give 1.64 g of a dark brown oil. Purification of the oil on 400 g of silica gel (230-400 mesh) eluting with ethyl acetate gave 710 mg (40%) of a brown oil. The oil (610 mg) was dissolved in 10 ml of diethyl ether and 1.44 ml of IN ethereal HCl was added. The solid formed was collected by filtration. The solid on standing turned to a foam which was dried under high vacuum to give the title compound as a light tan foam, hydrochloride, sesquihydrate, 0.1 diethyl etherate, MS m e 417 M+.

Elemental Analysis for C27H35N3OΗCM .5 H2OO.IC4H10O Calc'd: C, 67.39; H, 8.25; N, 8.60

Found: C, 67.08; H, 8.00; N, 8.35

Claims

c aimsi
(1) A compound of the formula:
Figure imgf000020_0001
where Rl and R5 are independently hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO2H, Ci-Cό alkyl, C2-C1 0 alkenyl, Cj-Cό alkoxy, C3 - C8 cycloalkyl, cycloalkylalkyl where the alkyl group is of 1 to 6 carbon atoms and the cycloalkyl group has 3 to 8 carbon atoms, C3-C8 cycloalkyloxy, C2-C7 alkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, tetrazolyl, -OH, -(CH2)i-όOH, -SH, -NH2 or -(CH2)i-6NRsR9 where R8 is hydrogen, -C6 alkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl and R9 is hydrogen or C1-C6 alkyl;
RlO and Rl 1 together represent dimethylene whilst R2 is hydrogen or C1-C6 hydrogen;
R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; R6 and R7 are independently H, C1-C10 alkyl, C2-C10 alkenyl, C3-C8 cycloalkyl, cycloalkylalkyl where the alkyl group is 1 to 6 carbon atoms and the cycloalkyl group is 3 to 8 carbon atoms or R$ and R7 taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 3 to 8 atoms; or a pharmaceutically acceptable salt thereof.
(2) A compound of Claim 1 in which Rio and Rπ together represent dimethylene whilst R2 is hydrogen or Ci-C alkyl.
(3) A compound of Claim 2 in which Ri and R5, independently, represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C2-C4 alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, -OH, -NH2 or -(CH2)i-3NR8R9 where Rs is hydrogen or C1-C3 alkyl and R9 is hydrogen or C1-C3 alkyl; R2 is H or C1-C3 alkyl; R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; and R6 and R t taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 5 to 8 atoms; or a pharmaceutically acceptable salt thereof.
(4) The compound of Claim 2 which is l -azepan- l -yl-2-phenyl-4-( 1,3,4,9- tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-butan-l-one or a pharmaceutically acceptable salt thereof.
(5) The compound of Claim 2 which is l-azepan-l -yl-4-(9-methyl- 1,3,4,9- tetrahydro-2H-pyrido[3,4-b]indol-2-yl]-2-phenyl-butan-l-one or a pharmaceutically acceptable salt thereof.
(6) The compound of Claim 2 which is l-azepan-l-yl-4-((trans)-9-methyl- l,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butan-l-one or a pharmaceutically acceptable salt thereof.
(7) The compound of Claim 2 which is l-azepan-l-yl-4-((cis)- l,3,4,4a,9,9a- hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butan-l-one or a pharmaceutically acceptable salt thereof. (8) The compound of Claim 2 which is l-azepan-l-yl-4-((cis)-9-methyl- l,3,4,4a,9,9a-hexahydro-2H-pyrido[3,4-b]indol-2-yl)-2-phenyl-butane-l-one
(9) A compound of Claim 1, in which R2 and Ri i together represent dimethylene whilst Rio is hydrogen.
(10) A compound of Claim 9 in which R\ and R5, independently, represent hydrogen, fluorine, chlorine, bromine, trifluoromethyl, CO2H, C1-C3 alkyl, C1-C3 alkoxy, C2-C4 alkoxycarbonyl, mono- or di-alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, -OH, -NH2 or -(CH2)i-3NRsR9 where Rs is hydrogen or C1-C3 alkyl and R9 is hydrogen or C1-C3 alkyl; R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; and R(, and R7 taken together are polymethylene, which, with the nitrogen atom to which they are attached, form a ring of 5 to 8 atoms; or a pharmaceutically acceptable salt thereof.
(11) The compound of Claim 9 which is l-azepan- l -yl-4-(3, 4-dihydro-lH- pyrazinof l, 2-a]indol-2-yl)-2-phenyl-butan-l-one or a pharmaceutically acceptable salt thereof.
(12) The compound of Claim 9 which is l-azepan-l-yl-2-phenyl-4-(3, 4, 10, 10a- tetrahydro-l H-pyrazino[l , 2-a]indol-2-yl)-butane- l -one or a pharmaceutically acceptable salt thereof.
(13) A pharmaceutical composition of matter comprising a compound of as claimed in any one of Claims 1 to 12 in combination or association with a pharmaceutically acceptable carrier.
(14) A process for the preparation of a compound as claimed in Claim 1, which comprises reaction of a compound having formula B:
Figure imgf000023_0001
B
where Rl, R2, R3, R4, Rl0> and Rl 1 are as defined in claim 1 with a compound having the formula C
Figure imgf000023_0002
where X is a leaving group and R5, R6 and R7 are as defined in Claim 1 and, where appropriate, converting a resultant compound having the formula A into a pharmaceutically acceptable salt thereof.
(15) A method for relieving symptoms of anxiety which comprises administering a compound as claimed in any one of Claims 1 to 12 in an anxiolytic amount to a mammal in need thereof. A ENDED CLAIMS
[received by the International Bureau on 19 February 1996 (19.02.96); original claim 1 amended; remaining claims unchanged (1 page)]
( 1 ) A compound of the formula:
Figure imgf000024_0001
where R\ and R5 are independently hydrogen, fluorine, chlorine, bromine, iodine, trifluoromethyl, cyano, nitro, CO2H, Cj-C6 alkyl, C2-C10 alkenyl, C\-C(, alkoxy, C3-C8 cycloalkyl, cycloalkylalkyl where the alkyl group is of 1 to 6 carbon atoms and the cycloalkyl group has 3 to 8 carbon atoms, C3-C8 cycloalkyloxy, C2-C7 alkylcarbonyl, C2-C7 alkylcarbonyloxy, C2-C7 alkoxycarbonyl, mono- or di- alkylaminocarbonyl in which each alkyl group, independently, contains 1 to 6 carbon atoms, tetrazolyl, -OH, -(CH2)i-6OH, -SH, -NH2 or -(CH2)i-6NRgR9 where R8 is hydrogen, Ci-Cβ alkyl, C2-C7 alkylcarbonyl, C2-C7 alkoxycarbonyl and R9 is hydrogen or Cj-Cό alkyl;
RlO and Ri 1 together represent dimethylene whilst R2 is hydrogen oτ C\-C(, alkyl or R2 and Ri 1 together represent dimethylene whilst R10 is hydrogen;
R3 and R4 are hydrogen or taken together with the carbon atoms to which they are attached form a double bond; STATEMENT UNDER ARTICLE 19
The amendment at page 18 consists in the correction of an obvious error in the definition of the symbols R2, RlO and Rll- The error resided in the omission of the words "alkyl or R2 and Rn together represent dimethylene whilst Rio is". The correction does not involve the introduction of new matter because the correct definition of the aforesaid symbols can be seen from page 2, lines 9 to 11 and claims 2 and 9 as originally filed.
PCT/US1995/013124 1994-10-20 1995-10-03 Indole derivatives useful as serotonergic agents WO1996012721A1 (en)

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US9073925B2 (en) 2009-07-01 2015-07-07 Albany Molecular Research, Inc. Azinone-substituted azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8618299B2 (en) 2009-07-01 2013-12-31 Albany Molecular Research, Inc. Azinone-substituted azapolycycle MCH-1 antagonists, methods of making, and use thereof
US8629158B2 (en) 2009-07-01 2014-01-14 Albany Molecular Research, Inc. Azabicycloalkane-indole and azabicycloalkane-pyrrolo-pyridine MCH-1 antagonists, methods of making, and use thereof
US8637501B2 (en) 2009-07-01 2014-01-28 Albany Molecular Research, Inc. Azinone-substituted azepino[b]indole and pyrido-pyrrolo-azepine MCH-1 antagonists, methods of making, and use thereof
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US8993765B2 (en) 2010-12-21 2015-03-31 Albany Molecular Research, Inc. Tetrahydro-azacarboline MCH-1 antagonists, methods of making, and uses thereof
US9006244B2 (en) 2012-03-16 2015-04-14 Vitae Pharmaceuticals, Inc. Liver X receptor modulators
US9073931B2 (en) 2012-03-16 2015-07-07 Vitae Pharmaceuticals, Inc. Liver X receptor modulators
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