FI74005C - Process for Preparing Therapeutically Useful 2-Substituted E-8-Fluoro-5- (4-Fluorophenyl) -2,3,4,5-Tetrahydro-1 H -pyrido / 4,5-b / indolder ivate - Google Patents

Description

74005

Process for the preparation of therapeutically useful 2-substituted 8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,5-b] indole derivatives 5 Partitioned from application 820138

The invention relates to a process for the preparation of therapeutically useful 2-substituted 8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,5-b] indole derivative-10 having the formula (I). ) (CH2) n-NR5R6 (I)

15 JL

Φ

F

Wherein n is 2-6; R 5 is hydrogen and R 6 is C 1-4 alkanoyl or. (C ~ _2 ^ alkoxy) carbonyl; or R and R together are - (CH9) C-, wherein r is 3-5; and their pharmaceutically. 4 ΓΝ 0 to prepare acceptable salts.

25 Successful appendix behavior: treatment with antipsychotic sedatives such as chlorpromazine has encouraged researchers to look for other stress-relieving agents with even better biological profiles. One such class of compounds is 2,3,4,4a, 5,9a-hexahydro-1H-pyrido [4,3-b] indoles and 2,3,4,5-tetrahydro-1H-pyrido [2,3 -b7-. indoles.

The basic structures are:; ** ·; 35 2 74005 9 1 9 1 • xs—

33 7 V ^ N

5 4 6 5 5

Stereochemically, positions 4a and 9b of the hexahydro series may exist in cis or trans forms, both of which may be racemic (+) or enantiomeric (+ or -) forms. Examples of hexahydro- and tetrahydro-pyridoindo-10s which are useful as sedative, tension-triggering, analgesic, sedative, muscle relaxant, and antihypertensive agents are disclosed in the following U.S. Patents 3,687,961, 3,983,239. 001 263, 4 141 980 and 4 224 329.

Effective stress-releasing activity has now been found with the novel 2-substituted-8-fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyridoZ4,3-fc7 of formula (I). indoleilla.

Preferred are compounds wherein n is 3-6. The first 20 substituents are derivatives of either the racemic or, more particularly, the (+) enantiomeric form.

The process according to the invention for the preparation of compounds of formula (I) is characterized in that a) a compound of formula 'ΌαΟ' "

30 I

Φ

F

35 3 74005 is reacted with a compound of formula D- (CH-) NR 5 R 6 in 5 wherein n and R® are as defined above and D is a nucleophilic displaceable group which is Cl, Br, I or CH 2 SC 2. O; or b) acylating a compound of formula 10 F / v o

F

20 to give a compound of formula: * '-NR5R6 XXXj 25 | a Φ

F

30: * - wherein n is as defined above, R 5 is hydrogen: · and R 6 is C 2-4 alkanoyl or (C 1-4 alkoxy) carbonyl; and, if desired, converting the resulting compound into a pharmaceutically acceptable acid addition salt.

35 4 74005

In method a) the nucleophilic displacement reaction is carried out in a reaction-neutral solvent such as a lower afiphatic ketone (e.g. acetone, 2-butanone, 3-methyl-2-butanone, 3-methyl-2-Penta-5-non, lower alkanol (e.g. ethanol, 2-propanol), or a lower aliphatic amide (e.g., dimethylformamide, dimethylacetamide) Pyridoindole (RH) is preferably maintained in the form of a much more reactive free base by adding at least one equivalent of a base such as sodium carbonate to the reaction mixture. iodide ion can be added, if desired, to increase the reaction rate, but temperature is not critical, the temperature is usually raised (e.g. between 50-150 ° C) to increase the reaction rate, but not so high as to cause undesirable excessive thermal decomposition of products and / or reactants.

The pyrido [3,3-h] indoles required in the process of the invention are obtained by the methods of U.S. Patents 3,687,961, 3,983,239, 20,991,199, 4,001,263, 4,141,980 and 4,224,329.

Piperidone derivatives are readily obtained by reacting the anion of 2-piperidone with a disubstituted alkane, * D (CH2> nD, where D and n are as defined above and the D groups may be the same or different. in excess of D (CH2) nD and / or with one group being more easily replaced by Zesim Cl (CH2) nB £ 7.

The reaction conditions (solvent and temperature) are otherwise generally as described above, but the use of protic solvents (e.g. alcohols) which are more acidic than 2-piperidone is avoided.

In process b) the acylation is carried out under mild conditions (e.g. -25 to + 35 ° C), usually in a reaction-neutral solvent in the presence of at least one equivalent of an inorganic base or a tertiary amine (e.g. triethylamine). , N-methylmorpholine).

Pharmaceutically acceptable salts of the derivatives can be prepared by reacting them with either about one molar equivalent or about two molar equivalents of an organic or inorganic acid in either an aqueous solution or an anhydrous solution. Since the compounds of this invention are generally dibasic, either mono-salts or bis-salts are formed depending on the amount of 10 molar equivalents of acid. The compounds which are tribasic can, of course, form a trisalve, in which case three molar equivalents of acid may be used. Suitable salt-forming acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, lactic acid, citric acid, tartaric acid, succinic acid and maleic acid. The salt may be isolated by removal of the solvent in vacuo or, where appropriate, by precipitation.

Derivatives are useful as stress-relieving agents in the treatment of mental illnesses and diseases, including jaundice, psychoses and neuroses. Symptoms that require such treatment include anxiety, assault, arousal, depression, hallucinations, tension, emotional or social isolation. In general, derivatives have a main: Y: essential sedative effect, but they have fewer side effects than currently used drugs.

30 6 74005

The derivatives can be formulated into various pharmaceutical preparations containing the derivative alone or a combination thereof with pharmaceutical carriers such as neutral solid diluents, aqueous solutions or various non-toxic organic solvents, and dosage forms such as gelatin capsules, tablets, powders, powders, pastes, pastes similar preparations. Such carriers include water, ethanol, gelatins, lactose, starches, vegetable oils, petrolatum, resins, glycols, talc, benzoyl alcohols, and other known pharmaceutical carriers. If desired, these pharmaceutical preparations may contain an additive such as preservatives, wetting agents, stabilizers, glidants, absorbents, buffers and isotonic agents.

The derivatives are administered to a patient in need of treatment by various conventional routes of administration such as orally, intravenously, intramuscularly or subcutaneously. Usually, small doses are initially given by increasing the dose gradually until the optimum amount is determined. However, as with any drug, the particular dose, formulation, and route of administration will vary with the age, weight, and response of a particular patient and will be at the discretion of the attending physician.

In the context of a standard regimen, treatment of a human patient is effective at a dosage of the derivative of approximately 0.1 mg / day to 100 mg / day. When the effect of the derivative is long-lasting, the dose may be administered less frequently, such as every other day or in one or two divided doses per week.

The sedative effect of the derivatives can be determined using a well-known standard method - the amphetamine-induced symptom-induced effect assay in rats. This method has a good correlation with efficacy in humans and has been described by 5 A. Weissman, et al., J. Pharmacol. Exp. Ther. 151, pp. 339 (1966) and Quinton, et al., Nature 200, pp. 178 (1963) and in more detail Harbert et al., Molecular Pharmacology 17, pp. 38-41 (1980). In detail, the stress-triggering effects in vivo were evaluated based on amphetamine-induced repetitive obstruction blockade.

Rats were each housed in individually covered plastic compartments; after a short acclimation period to the compartments, groups of five rats were given intraperitoneally the test compound at 0.5 log dose differences. units (i.e. 1, 3.2, 10, 32 15. · mg / kg). They were then administered d-amphetamine sulphate, 5 mg / kg ip, at 1, 5 and 24 hours. One hour after each exposure, for each rat, its most typical movement behavior in the cage was assessed using a 6-point rating scale / Weissman et al., J.

20 Pharmacol. Exp. Ther. 151, pp. 339-352 (1966) J7. These estimates correspond to the rates of increase in drug effect, / Quinton and Halliwell, Nature (London) 200, pp. 178-179 (1963) 7 and: γ; the selected assessment time is consistent with the peak effect of amphetamine / Weissman, Psychopharmacologia 12, pp. 142-: 25 157 (196817. Scores were halved (cf. Weissman et al., supra), and approximate ED 1 g values were determined. As can be seen from the results tabulated in Table I, this method demonstrates that the compounds of this invention have an excellent sedative effect over the standard test drug, chlorpromazine.

The so-called "internally" calming stress-triggering effect of the derivatives was determined using *; 35 binding of 1 H-spiroperidol to the dopamine receptor δ 74005

According to the method of Leysen et al., Biochem. Pharmacol.

27, p. 307 (1978) and applied by the method of Burt et al., Mol. Pharmacol. 12, 800-812 (1976). Rats (Spraque-Dawley CD males, 250-300 g, Charles River Laboratories, 5 Wilmington, Mass.) Were decapitated and the brain was immediately dissected to recover the stroke. This was homogenized in 40 volumes of ice-cold 50 mM Tris (tris / hydroxymethyl / aminomethane). HCl buffer, pH 7.7 with Brinkmann Polytron PT-10. The homogenate was centrifuged twice for 10 minutes / 50,000 g at 0-4 ° C, rehomogenizing the resulting pill again in fresh Tris buffer (equal volume) in a Polytron. The final pill was gently resuspended in 90 volumes of cold 50 mM Tris-HCl buffer, pH 7.6 with 120 mM NaCl, 5 mM KCl, 2 mM CaCl 2, 1 mM MgCl 2, 0.1% ascorbic acid and 10 .mu.mol of pargyline. The tissue suspension was placed in a 37 ° C water bath for 5 minutes and kept ice cold until use. The incubation mixture contained 0.02 ml of inhibitor solution 3 or medium, 1.0 ml of tissue preparation, and 0.10 ml of H-spiroperidol (New England Nuclera, 23.6 Ci / mmol), prepared to give a final concentration of 0.5 nmol. . The tubes were incubated in series for 10 minutes at 37 ° C in groups of three, after which a 0.9 ml aliquot of each of the 25 incubation tubes was filtered under vacuum through Whatman GF / B filters. After washing twice with 5 ml of cold Tris-HCl buffer, pH 7.7, each filter was placed in a scintillation vial with 10 ml of Aquasol-2 (New England Nuclear) and each vial was spun. Samples were kept at room temperature overnight before determining radioactivity in a liquid scintillation counter. Binding was calculated as fmoles of H-spiroperidol bound per milligram of protein. Control experiments -7 * -7 (medium or 10 molar 1-butaclamol), Q experiments (10 35 molar d-butaclamol), and inhibitor solution experiments (four 9 74005 concentrations) were performed in triplicate. The concentration that reduced binding by 50% (IC 2 q) was estimated from semi-logarithmic paper. The IC 50 values in Table I are the averages of two or three experiments. Insoluble fractions were dissolved in ethanol (1-2% ethanol in the final incubation mixture). As shown in Table I, this internal method demonstrates that the compounds of this invention have excellent stress-triggering activity.

Table I

10 1H-pyrido [4,3-b] indole residue-triggering effect —rj ^ r <cn2> nRl 15 0 20 v 3

Compound Structure Amphetamine H-spiroperidol; activity (b) inhibition of binding (approx. ED ((c) mg / kg ip) 25 R * _n 1 h_5_h_24 h ICqn (nM) -I «XXB3 6 0.32-1.0 0.32-1, 0> 10 8.8 4 wl ~ 3.2> 10 4.0

3Q

-NHOOOC ^ 6 1-3.2 ~ 3.2> 10 6.8 chloropranazine 573 875> 32 51 10 74005 b) Labels are areas where amphetamine-induced hyperactivity and repetitive obstructive ED5Q values are present. Details are provided in the text.

5 c) IC, jQ values were evaluated graphically using four herbal concentrations with dose differences of 0.5 log. units. Entries are usually the means of two or three determinations. See text for details.

The following examples illustrate the invention.

Example 1 1- (4-Chloro-1-butyl) -2-piperidone Sodium hydride (3.87 g of a 50% oil dispersion, 0.0808 mol) was suspended and stirred in 80 ml of dry dimethylformamide. Within 1 hour, a solution of 1,4-dichlorobutane (44 mL, Q, 4Q4 moles) and 2-piperidone (8 g, 0.0807 moles) in 100 mL of dimethylformamide was added dropwise, maintaining the temperature between 25-30 ° C using a water bath. ° C. The reaction mixture was stirred for 16 hours at room temperature, then the salt by-product was removed by filtration and the mother liquor was evaporated in vacuo to one tenth by volume. The resulting concentrate was partitioned between 100 ml of water and 100 ml of hexane. The lower, three-phase oily phase was separated, diluted with 50 ml of methylene chloride, dried over magnesium sulfate, filtered and evaporated to dryness to give 1- (4-chloro-1-butyl) -2-piperidone as an oil / Ϊ4.3 g; pnmr (CDCl 3, 1.4-1.83 (4H, m), 3.03-3.72 (6H, m), 4.10-4.43 (2H, t, J = 7)).

Example 2 8-Fluoro-5- (4-fluorophenyl) -2- [4- (2-piperidon-1-yl) -1-butyl] -2,3,4,5-tetrahydro-1H-pyrido] 4,3-b7-Indole hydrochloride 1- (4-chloro-1-butyl) -2-piperidone (1.98 g, 10.5 mmol), 8-fluoro-5- (4-fluorophenyl) -2, 3,4,5-Tetrahydro-35H-pyrido [4,3-b] indole (2 g, 7.0 mmol), anhydrous sodium carbonate (4.4 g, 41.6 mmol) and potassium iodide (20 mg ) was combined in 3-methyl-2-butanone (80 ml) and the slurry was boiled for 16 hours. The reaction mixture was evaporated in vacuo to a solid and the residue partitioned between 50 ml of methylene chloride and 50 ml of water. The aqueous phase was washed with 50 ml of fresh methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to a gum. The resin was chromatographed on silica gel 10 using ethyl acetate as eluent and using flash chromatography for monitoring. The pure product fractions were evaporated to dryness, dissolved in acetone and the title product precipitated by the addition of ethereal hydrogen chloride solution (1.2 g, mp 202-205 ° C).

15 Analysis for ^ 26 ^ 29 ^ 21 ^ 011 ^ 1 ^ 0:

Calculated: C 64.65, H 6.21, N 8.70%

Found: C 64.75, H 6.37, N 8.58%

Example 3 8-Fluoro-5- (4-fluorophenyl) -2- (5-cyano-1-pentyl-20) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole 8- fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (10.8 g, 0.034 mol), 6-bromo-hexanenitrile (6.5 g, 0.037 mol), anhydrous sodium carbonate (21.6 g, 0.204 mol), potassium iodide (100 mg) and 3-methyl-2-butanone (250 ml) were combined and the mixture was boiled for 24 hours. The reaction mixture was cooled, diluted with 250 mL of water and stirred to dissolve excess sodium carbonate. The layers were separated and the aqueous layer was extracted with 200 mL of methylene chloride. The organic layers were combined, dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. Addition of hexane gave the title product as crystals / 11.3 g, mp 90-98 ° C, Rf 0.5 (ethyl acetate / methanol 9: 1) 7-7405

Example 4 8-Fluoro-5- (4-fluorophenyl) -2- (6-amino-1-hexyl-11) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole the title compound of the example (11.3 g, 0.03 mol) was stirred at room temperature in 500 ml of ether for 15 minutes, as a result of which dissolution had taken place almost completely during this time. Lithium aluminum hydride (3.0 g) was added portionwise with vigorous stirring. After stirring for an additional 1.5 h-10 h, about 5 g of Glauber salt was added in five 1 g portions and stirring was continued for 15 minutes. The solid was removed by filtration, washing with tetrahydrofuran. The combined filtrate and washings were evaporated to dryness to give the title product as an oil (10.7 g, Rf 0.1 (ethyl acetate / methanol 9: 1), 0.1 (methanol / acetic acid 9: 1).

Example 5 8-Fluoro-5- (4-fluorophenyl) -2- (6-acetamido-1-hexyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole 20 The title of the previous example the amino compound (10.7 g, 0.028 mol) was dissolved in 80 ml of methylene chloride at room temperature. Triethylamine (15.6 mL, 0.112 mol) was added followed by dropwise addition of acetyl chloride (2.35 g, 0.030 mol) in 20 mL of methylene chloride. Slight exotherm was observed. The mixture was stirred for an additional 30 minutes and then concentrated to an oil (14 g). the oil was chromatographed on silica gel using 1: 1 methanol / ethyl acetate as eluent and monitored by thin layer chromatography. The pure product fractions were combined, evaporated to dryness and the residue crystallized from ether to give the pure title product / 6.33 g; mp 114-116 ° C; Rf 0.6 (methanol / ethyl acetate 1: 1) 7. Analysis for C25H29ON3F2:

Calculated: C 70.56, H 6.87, N 9.88% 35 Found: C 70.34, H 6.96, N 9.66% 74005 13

Example 6 8-Fluoro-5- (4-fluorophenyl) -2- (6-ethoxycarbonylamino-1-hexyl) -2,3,4,5-tetrahydro-1H-pyrido [4,5-b] indole the procedure of the previous example 8-fluoro-5- (4-fluorophenyl) -2- (6-amino-1-hexyl) -2,3,4,5-tetrahydro-1H-pyrido [2,3-f] 7indole (1.6 g, 4.2 mmol) was reacted with ethyl chloroformate (0.45 mL, 4.6 mmol) in methylene chloride (5 mL) in the presence of triethylamine (2.3 mL, 16.7 mmol) and the title product was isolated. and purified, however, using silica gel chromatography as eluent, ethyl acetate (365 mg, mp 159-162 ° C).

Analysis for C 26 H 31 O 2 N 3 F 2 * HCl · 0.75 H 2 <D: 15 Calculated: C 61.77, H 6.33, N 8.31%

Found: C 61.84, H 6.47, N 8.33%

Example 7 8-Fluoro-5- (4-fluorophenyl) -2- [4- (2-piperidon-1-yl) -1-butyl] -2,3,4,5-tetrahydro-1H-pyrido [4] 1,3-b7indole hydrochloride 8-Fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [1,3-b] indole (2 g, 7.0 mmol) was reacted by the method of Example 2 with 1- (4-chloro-1-butyl) -2- [4] piperidone (1.98 g, 10.5 mmol) to give the crude free base as a resin. The crude base was chromatographed on silica gel with ethyl acetate as eluent. The pure product fractions were evaporated to dryness, dissolved in acetone and the title product precipitated by the addition of ethereal hydrogen chloride solution (1.2 g, mp 202-205 ° C). Analysis for ^ -26 ^ 9 ^ ^ 30.11 ^ I ^ O:

Calculated: C 64.65, H 6.21, N 8.70

Found: C 64.75, H 6.37, N 8.58.

35

Claims (2)

A process for the preparation of therapeutically useful 2-substituted 8-fluoro-5- (4-fluorophenyl) -2,3,5,5-tetrahydro-1H-pyrido [4,5-b] indole derivative of formula (I) F -rr ^^ N-iCH ,,) -NR5R6 l | j n 2 n 10 (I) V F C g where n is 2-6; R 1 is hydrogen and R is C 2 - alkanoyl or (C 2 - 2 alkoxy) carbonyl or R 5 and R 6 taken together are - (CH-) C-, where r is 3-5; and pharmaceutically acceptable salts thereof, characterized in that one a) reacts with a compound of formula:. xxxy island \ F with a compound of formula D- (CH-) NR5R6 2 n where n, R4 and R4 are the same as above and D is a nucleophilically substituted group which is Cl, Br, I or CH3SO20-; or