KR870000440B1 - Process for preparing tetrahydro pyrido indole derivatives - Google Patents

Abstract

Tetrahydro pyrido indole derivs. of formula(I) and their pharmaceutically acceptable salts are produced from an acylation of (II). R5 is H; R6 is acetyl or ethoxycarbonyl; n is 4-6 integer. (I) are useful as nervine. Thus, the rxn. comprise e.g. (A) reacting 8- fluoro-5-(4-fluoro phenyl)-2,3,4,5-tetrahydro-1Hpyrido-, 3-b! indole with 1-(4-chloro-1-butyl)-2-piperidone, (B) chromatograph on silica gel by ethylacetate as developing, (C) drying and dissolving in acetone, (D) addn. of ethereal hydrogen chloride for eduction of title compds.

Description

Method for preparing tetrahydropyridoindole derivative

Successful treatment of schizophrenia using anti-psychotic stabilizers of antipsychotic diseases such as chloropromazine has encouraged research to find other neurological inhibitors with improved biological characteristics. One such class of compounds is the 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indoles. The basic ring structure is as follows.

Tetrahydroindoles useful as mental stabilizers, neurosuppressants, analgesics, sedatives, muscle relaxants and hypertension agents are described in US Pat. Nos. 3,687,961, 3,983,239, 3,991,199, 4,001,263, 4,141,980 and 4,224,329. .

), 아미노, 황 또는 산소의 여러 가지 조합을 포함하는 3-6개의 원자쇄에 의하여 아민에 결합됨)로 치환된 신규의 2,3,4,5-테트라히드로-1H-피리도[4,3-b] 인돌류에 대한 유효한 신경 억제 작용이 이제 밝혀지기에 이르렀다.In the fifth position is substituted with an allyl group, in the second position an amino alkyl group or a carbonyl amino alkyl group, wherein the carbonyl group is further substituted by a radical such as hydrogen, alkyl, aryl, aralkyl or alkoxy, or alkino [-( CH ₂ ) _i -wherein i is 3 to 5; or by two radicals, such as carbonyl, alkano, alkeno (-

2,3,4,5-tetrahydro-1H-pyrido [4, substituted with amines by 3-6 atom chains containing various combinations of amino, sulfur or oxygen) 3-b] Effective neurosuppressive action on indoles has now been found.

Neural inhibitors of the present invention are 2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole derivatives of the formula (V), ie 2,3,4,5-tetrahydro-1H -Pyrido [4,3-b] indole.

In each expression above,

X and Y are each independently H, F, Cl, OCH ₃ , CH ₃ or CH ₂ CH ₃

k is an integer of 1 or 2,

n is an integer from 2 to 9,

P is 0 or 1,

R ⁵ is hydrogen when taken separately,

(여기서, r는 3 내지 5의 정수)이다.R ⁶ is acetyl or ethoxy carbonyl when taken separately, and R ⁵ and R ⁶ when bonded together

(Where r is an integer of 3 to 5).

Also within the scope of the present invention is an pharmaceutically acceptable salt of the compounds defined above, the pharmacological composition of these compounds and one kind of these compounds alone or as a component of the pharmacological composition, an effective amount of oral or parenteral (intravenous) It is a method for treating mental and neurological diseases of patients in need of stabilization by administering to the patient by the route of (muscular or subcutaneous).

In all cases, preferred compounds are when X is F, k is 1, Y is F (substituted in the para position), n is 3 to 6 or n is 2 to 4.

The compounds of the present invention can be easily prepared by the method described in detail in the following section. In the present specification, for purposes of discussion, the following nuclei of 2,3,4-tetrahydro-1H-pyrido [4,3-b] indole are each referred to as R "or generally referred to as R '. will be.

In each of the above equations, k, X and Y are as defined above.

It is conceivable that the compounds of the present invention can be synthesized from the following three synthetic starting materials of (a)-(c). In other words,

(a) R "H.

(b) alpha, omega-disubstituted straight chain alkanes (or alkane precursors).

(c) end groups, or end group precursors of the side chains.

The synthesis of 2-piperidone-1-yl derivatives ((CH ₂ ) ₃ CO, when the general formula (V), R ⁵ and R ⁶ binds) illustrates the basic approach applied.

Method A: (a) + (b) (c) (a) (b) (c)

In each formula, n and R 'are as defined above and D represents a substitutable group (Cl, Br, I, CH ₃ SO ₂ O, etc.). Such nucleophilic substitution reactions include lower aliphatic ketones (eg, acetone, 2-butanone, 3-methyl-2-butanone, 3-methyl-2-pentanone, 3-methyl-2-pentanone), lower alkanols (E.g., ethanol, 2-propanol), or lower fatty acid amides (e.g., dimethyl-formamide, dimethyl acetamide). It is preferable to add pyridoindoles (RH, R " H) to the reaction mixture by adding at least one equivalent of a base such as sodium carbonate to maintain a more reactive free base. When D is other than I, If desired, the reaction rate can be increased by adding iodine ions Temperature is not critical, but is usually raised to speed up the reaction (eg, 50-150 ° C.) However, the product and / or reactants are pyrolyzed. It is not necessary to raise the temperature unnecessarily.

The pyrido [4,3-b] indoles required for the synthesis of these materials and the synthesis described in further detail below are described in US Pat. Nos. 3,687,961, 3,983,239, 3,991,199

Piperidone derivatives can be easily obtained by reacting a di-substituted alkane, D (CH ₂ ) _n D (where D and n are as defined above and the D groups are the same or different) and anion of 2-piperidone. Bis-substitution is minimized by using excess D (CH ₂ ) _n D or by using a group that is easier to substitute (eg Cl (CH ₂ ) _n Br).

Reaction conditions (solvent and temperature) are generally as described above, except to avoid protein solvents that are more acidic than 2-piperidone.

The same method can be widely used to synthesize various other compounds of the present invention. Examples are compounds in which the end groups of the side chains are alkanoylamino, alkoxycarbonylamino, or N-substituted species thereof.

Method B: (a) (b) + (c) (a) (b) (c)

In the above formula, R 'and n are as defined above. This nucleophilic substitution reaction is carried out using substantially the same equivalents of the reactants, or under the conditions described above to synthesize materials of the following general formula.

Substituted pyrido [4,3-b] indole can be obtained by various processes, but the following reaction process is preferred.

Piperidone anions are generally formed immediately upon reaction of sodium hydride with piperidone.

Method C: (a) (b ') (c) (a) (b) (c)

-90℃, 편리하게는 20-50℃의 온도 범위에서 실시한다. 적당한 적용 압력은 2-3 기압이다.In each of the above formulas, R and n are as defined above, x and y are each 1 or 2 or more, and x + y-2 = n. These reactions are hydrogenation reactions and proceed in an inert solvent under a hydrogen atmosphere in the presence of a hydrogenation catalyst. As the hydrogenation catalyst, noble metal catalysts including platinum, palladium, rhodium, and ruthenium, preferably supported or unsupported, and known catalyst compounds such as oxides, chlorides and the like are preferable. Specific examples of suitable catalysts include 5% palladium on carbon, 5% palladium on barium carbonate, 5% rhodium on carbon, rhodium chloride, platinum oxide and 5% ruthenium on carbon.

It is carried out at a temperature range of -90 ° C, conveniently 20-50 ° C. Suitable pressure is 2-3 atm.

Materials required for these synthesis methods can generally be obtained according to Method A, but in order to obtain D (CH ₂ ) _n D, unsaturated compounds are substituted. In other words,

As an alternative, the following synthetic route can be used.

The first stage nucleophilic substitution reaction is carried out under the conditions described above. The second stage formaldehyde bond of acetylene to RH is a reaction inert solvent (lower alkanol is preferred) using RH and formaldehyde (30% aqueous solution is preferred) and an equivalent of acetylene in the free base form in the presence of cuprous chloride as a catalyst. To be done within). The temperature doesn't matter, but (

The process of the method described in detail above synthesizes hexahydropyrido [4,3-b] indoles, designated RH, since the tetrahydro compounds (R "H) have double bonds which can complicate the hydrogenation of olefins. It will be appreciated that the end group of the tetrahydro compound is a precursor amine, but the reduction reaction of lithium hydride of amide or nitrile fits well.

Of course, diborane is not used unless it is necessary to simultaneously convert tetrahydro to hexahydropyrido [4,3-b] indole.

Method D: (a) (b) (c ') (a) (b) (c)

In each formula, n, R 'and D are the same as defined above, and R ⁷ is a (C ₁ -C ₅ ) alkyl group. The nucleophilic substitution reaction of D proceeds under the conditions described above. The anion may originally be formed or formed with a strong base such as sodium hydride. Intermediates are conveniently derived by acylation of amines. In other words,

This intermediate need not be separated, but can be formed originally and then converted to an anion. The acylation reaction usually proceeds under mild conditions (eg -25 to 35 ° C.) in a reaction inert solvent in the presence of at least one equivalent of an inorganic base or tertiary amine (eg, triethylamine, N-methylmorpholine).

Alternative cyclization of amino ester precursors proceeds by simply heating the free base form of the amino ester in a reaction inert solvent of an aromatic hydrocarbon such as benzene, toluene or xylene. The temperature is not critical (eg 80-150 ° C., preferably 100-125 ° C.), but is heated to a temperature where pyrolysis is minimized so that the reaction proceeds at a moderate rate. Since the cyclization reaction occurs most rapidly at the lowest possible temperature, the preferred methyl group is R ⁷ . Amino esters are conveniently prepared by alkylation of amines or reduction of aldehydes. In other words,

In a modified method, the reactions just described can be applied to the preparation of other compounds of the invention. In other words,

In each of the above formula, n, R ", R ⁴ and R ⁶ are as defined above.

As described above, various paths related to the method of the present invention have been described, but the method of the present invention, in more detail, in the preparation of the compound of the following structural formula (V ′), R ⁵ is a hydrogen atom When R ⁶ is alkanoyl or alkoxy carbonyl, acylate the compound of formula (E), or when R ⁵ and R ⁶ are bonded together to form 2-piperidone-1-yl, A method for the preparation of tetrahydropyridoindoles of the following formula (V ′) and pharmaceutically acceptable salts thereof characterized by alkylating the compound of (F) with a compound of formula (G).

In each expression above,

R ⁵ is a hydrogen atom,

R ⁶ is acetyl or ethoxycarbonyl or 2-piperidone-1-yl when R ⁵ and R ⁶ are bonded together,

n is an integer of 2 to 6, preferably 4 to 6,

D is a nucleophilic substituent such as Cl, Br, I, CH ₃ SO ₂ O-.

Pharmacologically acceptable salts of these derivatives can be prepared by reacting about 1 molar equivalent or about 2 molar equivalents of organic or inorganic acid in an aqueous or non-aqueous solution. In general, the compounds of the present invention are dibasic so that mono or diacid salts are formed according to the molar equivalents of the acid. Of course, triacids of these compounds which are tribasic can be formed, in which case 2 molar equivalents of acid are used. Acids which form preferred salts include hydrochloric acid, bromic acid, iodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, lactic acid, citric acid, tartaric acid, succinic acid, malic acid and gluconic acid. Salt is dissolved in vacuum

Derivatives of the compounds of the present invention are useful as neurosuppressive agents for treating psychotic disorders and psychosis, including schizophrenia, psychosis and neurosis. Indications that require such treatment are anxiety, aggression, excitement, oppression, hallucinations, tension, and emotional or social withdrawal. In general, these derivatives show major mental stabilizing effects but have fewer side effects than currently used drugs.

These derivatives may be derived from a variety of formulations, including derivatives alone or in combination with pharmacological carriers such as inert solid diluents, aqueous solutions or various non-toxic organic solvents, including dosage forms of genlatin capsules, tablets, powders, pills, syrups, injectable solutions, and the like. It can be formulated as follows. Carriers mentioned above include water, ethanol, genlatin, lactose, starch, rapeseed oil, petroleum jelly, gums, glycols, talc, benzoyl alcohol, and other carriers known in the pharmaceutical art. If necessary, these formulations may contain preservatives, wetting agents, stabilizers, lubricants, absorbents, buffers, isotonic agents, and the like.

These derivatives are administered to patients in need by various convenient routes of administration, such as oral, parenteral, intramuscular or subcutaneous. In general, a small dose is initially administered and the dose is gradually increased until an optimal amount is established. However, as with other drugs, the particular dosage, formulation and administration will depend on the age, weight and symptoms of the specified patient and depend on the judgment of the attending physician.

In the general course of treatment, the dosage of any derivative of about 0.1 mg to 100 mg daily is an effective treatment for the patient. Each derivative is continuous

The psychostable activity of this derivative can be measured using the well-known standard method antagonism of alfetamine-induced syndrome in rats (rats). This method has a very good correlation with the efficacy for a person. The paper by A. Weissman and his collaborators, Pharmacol. Exp. Ther. 151, p. 339 (1966) and the papers of Quinton and his co-investigators, Nature 200, p. 178 (1963), in particular the papers of Herbert and his co-investigators, Molecular Pharmacology 17, pp. 38-41 (1980). In detail, the neurosuppression effect in vivo was evaluated by the blocking of amphetamine homology. Each rat was confined in a plastic compartment covered with a lid and acclimated to the rat cage in a short period of time, then divided into 5 groups and divided into 0.5 log units (ie, 1, 3.2, 10, 32,… mg / kg). The compound was administered intraperitoneally. They were then intraperitoneally administered 5 mg / kg of d-alphetamine sulfate after 1,5 and 24 hours. One hour after each amphetamine administration, each rat was placed on a six-point scale (Waysman and his collaborators, J. Pharmacol. Exp. Ther. 151, pp. 339-352 (1966)], the most characteristic of our movement behavior in rats was evaluated. Their assessments indicate an elevated level of drug effects and are presented in Quinton and Holliwell's paper, Nature (London) 200, pp. 178-179 (1963), and the selected evaluation time is consistent with the maximum effect of amphetamine [Waysman. Psychopharmacologia 12, pp. 142-157 (1968)]. Scores are bisected (see Weissman and his collaborators, above), and quantity data ₅₀

The so-called "unique" mental stabilizing neurosuppressive action of these derivatives has been described in the journal Biochem. Pharmacol. 27, p. 307 (1978), measured using ³ H-spiroperidol that binds to the dopamine receptor, and published by Burt and his collaborators, Mol. Pharmacol. 12, pp. 800 Modifications were made from the method described in -812 (1976).

Rats (Spraker-Dolly CD species males, 250-300 g, Charles River Labradoris, Wilmington, Mass.) Were single-headed and brains were dissected immediately to recover autopsies. The autopsies were ice-cooled (Tris [hydroxymethyl] amino methane) HCl buffer 40 for homogenization by adjusting to pH 7.7 with Brinkmann Polyton PT-10. Homogenates were centrifuged twice in an amount of 50,000 g for 10 minutes at 0-4 ° C. while re-homogenizing the intermediate granules in fresh Tris buffer in polytron (equal dose). The final granules were cold 50 mM Tris at pH 7.6 containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ , 1 mM MgCl ₂ , 0.1% ascorbic acid and 10 μM pargiline. Resuspend gently in HCl buffer 90. The tissue suspension is immersed in a water bath at 37 ° C. for 5 minutes and then in an ice cold bath until use ^{3 3 -7 -7} ₅₀

Examples of the present invention are as follows. However, it should be understood that the present invention is not limited by these examples.

TABLE 1

Inhibitory Activity of 1H-pyrido [4,3-b] Indole

(a) Unless otherwise expressed as (+) or (-), the test compound is a racemic (±) variant.

(b) Dosage ranges from lower ED ₅₀ values to block hyperactivity and homology induced by amphetamines. Details are described in the specification.

(c) IC ₅₀ values were usually assessed on graphs using four drug concentrations separated by 0.5 log units. Dosage is generally the average of two or three measurements. See the specification for details.

Example 1

8-fluoro-5- (4-fluorophenyl) -2- [4- (2-piperidone-1-yl) -1-butyl) -2,3,4,5-te

8-Fluoro-5- (4-fluorophenyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (2 g, 7.0 mmol) 1- (4- Reaction with chloro-1-butyl) -2-piperidone (1.98 g, 10.5 mmol) gave a rubbery free base. This crude base was chromatographed on silica gel using ethyl acetate as a developing agent. The clear product fractions were evaporated to dryness to dissolve in acetone and the title compound precipitated by addition of ethereal hydrogen chloride (1.2 g, melting point 202-205 ° C.).

Elemental Analysis Value: C ₂₆ H ₂₉ F ₂ N ₃ OHClO.0.55H ₂ O

Calculated Value: C, 64.65; H, 6. 21; N, 8.70

Found: C, 64.75; H, 6. 37; N, 8.58

Example 2

8-fluoro-5- (4-fluorophenyl) -2- (5-cyano-1-pentyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] Indole.

8-fluoro-5- (4-fluorophenyl-2- (5-cyano-1-pentyl) -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 mole), anhydrous sodium carbonate (21.6 g, 0.204 mole), potassium iodide (100 mg) and 3-methyl-2-butanone (250 mL) were mixed and the mixture was refluxed for 24 hours. . Cool the reaction mixture, dilute with 250 ml of water and stir

Example 3

8-fluoro-5- (4-fluorophenyl) -2- (6-amino-1-hexyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole .

At room temperature, the title compound (11.3 g, 0.03 mol) of the previous example was stirred in 500 ml of ether for 15 minutes. By this time almost complete solution was produced. Lithium aluminum hydride (3.0 g) was added with vigorous stirring and further stirred for 1.5 hours, then about 5 g of glover salt was added 5 times in 1 g portions and stirring continued for 15 minutes. The solid was removed by filtration, washing with tetrahydrofuran. The filtrates were combined and evaporated to afford the title compound as an oil [10.7 g; Rf 0.1 (9: 1 ethyl acetate: ethanol), 0.1 (9: 1 methanol: acetic acid).

Example 4

8-fluoro-5- (4-fluorophenyl) -2- (6-acetamido-1-hexyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b ] Indole.

At room temperature, the title amino compound (10.7 g 0.028 mol) of the previous example was dissolved in 80 ml of methylene chloride. Triethylamine (15.ml, 0.112mol) was added followed by the dropwise addition of acetyl chloride (.235g, 0.030mol) in 20ml of methylene chloride. Weak exothermic reaction

Elemental Analysis Value: C ₂₅ H ₂₉ ON ₃ F ₂

Calc .: C, 70.56; H, 6.98; N, 9.88

Found: C, 70.34; H, 6.96; N, 9.66

Example 5

8-fluoro-5- (4-fluorophenyl) -2- (6-ethoxycarbonylamino-1-hexyl) -2,3,4,5-tetrahydro-1H-pyrido [4,3 -b] indole.

8-Fluoro-5- (4-fluorophenyl) -2- (6-amino-1-hexyl) according to the method of the previous embodiment, except that ethyl acetate was used as the developer in silica gel chromatography. ) -2,3,4,5-tetrahydro-1H-pyrido [4,3-b] indole (1.6 g, 4.2 mmol) was charged with methylene chloride in the presence of triethylamine (2.3 mL, 16.7 mmol). ML) and ethylchloroformate (0.45 mL, 4.6 moles) and the title product was isolated and purified (365 mg, melting point 159-162 ° C.).

Elemental Analysis Value: C ₂₆ H _3l O ₂ N ₃ F ₂ HCl0.75H ₂ O

Calc .: C, 61.77; H, 6. 33; N, 8.31

Found: C, 61.84; H, 6. 47; N, 8.33

Claims (2)

A process for preparing a tetrahydropyridoindole derivative of the following formula (V ′) and a pharmaceutically acceptable salt thereof, characterized by acylating the compound of the following formula (E).

In each expression above, R ⁵ is hydrogen, R ⁶ is acetyl or ethoxycarmonyl, n is an integer of 4-6. A process for the preparation of tetrahydropydoraindole derivatives of formula (V ′) and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (F) is alkylated with the compound of formula (G).

In each expression above, R ⁵ and R ⁶ join together to form 2-piperidone-1-yl, n is 4 and D is a halogen atom.