IE43528B1 - Pyrido / 3,4-b / indole derivatives - Google Patents

Abstract

1502038 Pyrido[3,4 - b]indole derivatives ENDO LABORATORIES Inc 20 Aug 1976 [22 Aug 1975 22 June 1976] 34864/76 Heading C2C The invention comprises compounds of formula and their pharmaceutically suitable salts, wherein one of R 1 and R 3 is Me or Et and the other is H, Me or Et; and R 2 is H, C 1-3 alkyl, allyl or propargyl, provided that the total no. of C atoms in R 1 +R 2 +R 3 is #4. In examples, these compounds are prepared by reducing with BH 3 or NaBH 4 , followed by acid treatment, of the 4a,9a-dehydro analogues in which the 2- substituent is R 2 , MeCO or EtCO, or by hydrolysis of the corresponding 2-cyano compounds (for R 2 =H). Starting materials otherwise prepared are the corresponding 3,4 - dihydropyrido[3,4-b)indoles and their quaternary salts, 2-acyl analogues of the compounds of the invention, and compounds of formulae QCH:CRNO 2 , QCH 2 CHRNH 2 and QCH 2 CHRNHCOR1, where R is H, Me or Et, and R1 is Me or Et. Therapeutic compositions having antidepressant activity comprise compounds of the above formula and may be administered orally, parenterally or rectally.

Description

This invention relates to substituted pyridoindole anti-depressants.

Cl in-Midy, in PateaE Specification No. 37162 and Canas-Rodriquez & Leeming in British Patent 1,220,628 disclose various intermediates.used in the preparation of compounds of this invention.

Duschinsky, in U.S. Patent 2,642,438 discloses 9-aryl-2substituted-1,2,3,4-tetrahydro-9H-pyrido [3,4-bJ indoles useful as spasmolytics and adrenolytics, and 1-phenyl -33 (β-aminoethyl) indole and its derivatives which are intermediates in the preparation of compounds of this invention. These intermediates are also disclosed in J. Pharm. Sci. 57: 1364-69 (1968).

Mental illness encompasses both psychoses and neuroses. Symptoms requiring treatment include depression, anxiety, agitation, and hallucinations. Among the drugs used particularly for treatment of both reactive and endogenous depressions are monoamine oxidase (MAO) inhibitors, such as iproniazide, tranylcypromine, nialamide, phenelzine, and pargyline, and the non-MAO-inhibiting tricyclic aromatic dibenzazepines, such as imipramine, and dibenzocycloheptenes such as amitriptyline.

All of these drugs have adverse side effects that limit -243528 their usefulness, MAO inhibitors may benefit milder forms of depression, but the risk of serious toxic effects is a strong argument against their use. They can cause liver damage and acute hypertension, especially if given in conjunction with cheese, bananas or other amine-containing foods. The MAO inhibitors can also cause tremors, insomnia, hyperhydrosis, agitation, hypermanic behavior, confusion, hallucinations, convulsions and orthostatic hypotension. They frequently cause dizziness, vertigo, headache, inhibition of ejaculation, difficulty in urination, weakness, fatigue, dry mouth, constipation and blurred vision.

Imipramine can cause blurred vision, dryness of mouth, constipation, urinary retention, orthostatic hypotension, respiration depression, myocardial infarction, and congestive heart failure. Similar difficulties are experienced with amitriptyline.

There is a continuing need for psychotherapeutic agents that have fewer side effects than the drugs in use today; also for psychotherapeutic agents that have different modes of action than presently used agents, since none of these is completely effective.

The present invention results from efforts to develop new, safe, and effective psychotherapeutic compounds -3v/ith minimal side effects.

SUMMARY OF THE INVENTION According to this invention, there is provided novel compounds of formula I and their pharmaceutically suitable salts, compositions containing them, and methods of using them to alleviate depression in mammals. where R1 = H, CHg, or C2H5; 10 R2 = H, C-j - Cg alkyl or allyl Rg = H, CHg, or C2 Hg·, provided that the total number of carbon atoms in R-j + R2 + R3 is not more than four, and provided further that one of R^ or Rg must be other than H.

The compounds of formula I where Rg = H and either R^ -44 3 3 2 8 or Rg = CHg, while the other = H are also useful as intermediates in the preparation of the other compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION Preferred Embodiment A compound of formula I most preferred because of its high degree of activity is the compound where Rj is CHg Rg is Cg Hg and Rg is H.

Pharmaceutical Salts Pharmaceutically suitable acid addition salts of these compounds include those made with physiologically acceptable acids that are known in the art; such salts include hydrochloride, sulfate, phosphate, nitrate, citrate and maleate.

Stereoisomers All compounds of formula I have at least two asymmetric centers, resulting from the reduction of the &4a θ3 to the trans-fused system. This invention includes the optically active enantiomers, as well as the racemic mixtures. In addition, any substituents at the 1 and/or the 3 position can exist as either cis or trans to the 53§S§ 4a H giving rise to further stereoisomeric forms; all the resulting diastereoisomers are also included in this invention.

Synthesi s The compounds of formula I wherein Rg is C-| - C3 alkyl or allyl may e.g. be made by contacting a compound of II where R = -CH, II C 0 CH3)-C CgHg, alkyl or allyl and R^ and R3 are as defined above; or alternatively, contacting an acid addition salt of a compound of the above formula with Na BH^, then treating with acid, where R = C-j - Cg alkyl; and and R3 are as defined above.

In more detail, the compounds of formula I can be -6obtained by methods outlined below in reaction schemes 1 and 2. In the reaction schemes, Tables and Examples which follow, all temperatures are in degrees Centigrade -73528 Reaction Scheme 1 H I -84 3 5 2 3 -9Reaction Scheme 2 X R^K) H 3 S 2 8 Reaction Scheme 3 II -10formula I R1R2R3 m.p. (Salt) la. ch3C2H5 H 131 - 133° b. ch3 ch3 H 122 - 125° c. ch3 n-C3H7 H 244 - 246° (-HC1) d. ch3H3H7 H 290° (•HCl) e. ch3 ch3 H 134 - 136° f.C2H5C2H5 H 120 - 123° g. ch3 H H 95 - 97.5° h. ch3 CHgCaCH H 144 - 146° 1 . ch3 CH2CH=CH2 H 104. 5 - 105.5° j· H CH2CH=CH2 ch3 k. HC2H5 ch3 192 - 195° (.HCl) 1. ch3C2H5 ch3 m.C2H5 H H n. H ch3C2H5 0 . ch3 ch3C2H5 P· ch3 H ch3 q.C2K5 H ch3 r. ch3 HC2H5 s. H i-C3H7 ch3 -11Formula I continued.

R-j Rg Rg m.p.(salt) It. H CHgCsCH CHg u. CHg ch3 CHg V. CgHg ch3 CHg w. H H CH3 formula II M CX,-..-.,, R 3 m.p. (Salt) Ila. H 232 - 233° (.HCl) lib. CHg 210 -212°C. (.HCl) IIC. CgHg -1243538 -13formula IV continued. 43538 R1R3 IVc. ch3 ch3 d.C2H5 ch3 e. ch3C2H! f.C2H5C2H! m.p. formula V R1R3 m.p Va. ch3 H 85 b.C2H5 H 118 c. ch3 ch3 185 d. H ch3 200 e. H CgHg f.C2H5 CHg 9· ch3 _C2H5 208° (dec. 185 - 190°J(dec.

(.HCl) -1443528 R-] Rg m.p.

Via. CHg CHg H 136 - 142°C b. CHg CgHg H 114 - 117°C c. CgHg CHg H 117 - 120°C d. CHg H CHg e. CHg CHg CHg f. H CHgC2H5 g. H CHg H h. H CHgCH3 i. H CnH,- H -15formula VII R1 r2R3 m.p. . (Salt). Vila. CH3 ch3 H 235 -240° (.HCl) b. ch3C2H5 H 237 - 240° (.HCl) c. CgHg ch3 H 245 - 251° (.HCl) d. CH3 i-c3H7 H 224 - 235° (.HCl)C2H5 ch3 ch3 f. ch3 ch3C2H5 g. H c2h5 C2Hg h. ch3 n-C3H7 H i. H H ch3 200 - 208° (dec.) j. HC2H5 ch3 k. H1-^3R7 ch3 1. ch3 ch3 ch3 -16formula VIII -1743528 formula IXB Formula X Xa. ch3 ch3 H 136 - 142 b. ch3 H ch3 81 - 86° c.C2H5 ch3 H d.CH3C2H5 H e. ch3 ch3 ch3 f. H ch3 H g. H ch3 ch3 h. HC2H5 H XI Ia. Η 153 - 155°C b. ch3 104 - 105°C 5 c. CgHg A general procedure for preparation of compounds of formula I as follows: Compounds of formula II are acylated with an anhydride, mixed anhydride, or an appropriate acyl halide in a basic solvent system to give the amides of formula III. These are converted to a dihydropyridoindole (formula IV) by the Bischler-Napieralski reaction using reagents such as phosphorus oxychloride, phosphorus pentoxide or polyphosphoric acid in a suitable solvent, such as benzene, xylene, toluene, or chloroform followed by reduction with lithium aluminium hydride or sodium bis(2 - raechoxyethoxy) aluminum hydride (Red-al) to the tetrahydropyridoindoles of formula V. These may also have be obtained directly from formula II by the Pictet-Spengler reaction using an aldehyde of the type R^20 CHO in an acidic medium. -194 3 5 2 S Acylation of formula V with an anhydride or an acid chloride or alkylation v/ith a suitable alkyl halide or alkyl sulfate or sulfonate gives the compounds of formulas VI and VII respectively. Subsequent reaction of these with BHg or of an acid addition salt of VII with NaBH^ followed by treatment with acid of the amine borane intermediates gives the hexahydropyridoindoles of Formula I.

Alternatively, compounds of formula IV can be quaternized 10 with methyl iodide to formula VIII, then reduced with lithium aluminum hydride to formula VII, where R2=CHg. Treatment with borane or of an acid addition salt with NaBH^ followed by acid gives the compounds of formula I where R2=CHg. To convert the latter to compounds of formula I where R2 is not H, two routes can be used.

Reaction of the compound with ci — coc2h5 in benzene gives carbamates of formula IXA, which, upon hydrolysis with KOH in n-butanol gives the compounds of !0 formula I where R2=H. In the preferred route, compounds of formula I where R2=CHg are treated with cyanogen bromide in chloroform to give the N-cyano compounds of formula IXB, which, without further purification, are -20 43538 converted to compounds of formula I where Rg=H by means of frydralysis with dilute «ydrocsif'k arid, or acylation and subsequent reduction of the amides (formula X) yields compounds of formula I where R2 is not H.

Compounds of formula II can be prepared by the methods outlined in reaction scheme 3. Treatment of 1-phenylindole-3-carboxaldehyde (formula XI) with nitroalkanes gives the nitrovinyl indoles of formula XII. The amines of formula II can be obtained by the reduction of compounds of formula XII.

The following Examples further illustrate the preparation of these compounds.

Example 1 -21S3S3S To a stirred solution of 30.2 g. of N-phenyltryptamine (Ila) in 500 ml. methylene chloride is added 21.0 g. triethylamine, followed by dropwise addition of a solution of 15.6 g. propionyl chloride in 75 ml. methylene chloride The reaction mixture is stirred at room temperature overnight, poured into 600 ml. water, with stirring, the organic layer separated, dried over Na2S0^ and the solvent evaporated in vacuo. The dark orange oily residue is treated with a small amount of ether and petroleum ether (30°), the precipitated product chilled in an ice bath, filtered and 33.4 g. of light orange solids collected. Recrystallization from ethyl acetate-ether gives 30 g. of IIIb, m.p. 110 - 112°C.

Compounds of formula Illa-f exemplify those that can be j prepared by the general acylation procedure described in Examplel.

Example 2. -2243 A mixture of 40.8 g. N-acetyl-1-phenyltryptamine (Ilia), 800 ml. dry benzene and 220 g. phosphorus oxychloride is refluxed for one hour. After cooling, the reaction mixture is poured into two liters of cold water with continued stirring and cooling for 1.5 hours. The organic layer is separated, washed twice with water and the aqueous fractions combined and backwashed once with ethyl acetate. The aqueous extract (total volume 3 1 iters) is treated with one liter of 10% NaOH, followed by one liter of 50% NaOH while stirring and cooling in an ice bath. The product precipitates from the cooled solution and is filtered and washed well with water to remove any co-precipitated inorganic material Upon drying, 34 g. of 4,9-dihydro-l-methyl-9-phenyl15 3H-pyrido {3,4-bJ indole, (IVa), m.p. 110 - 112°C. is obtained. An analytical sample had an m.p. 110 - 112°C (benzene-petroleum ether).

Anal. Calc'd for c-|gHigN2· Calc'd: C:83.04; H:6.19; N:10,76 Found: C:83.21; H:6.12; N:10.74 Compounds of formula IVa-f exemplify those that can be prepared by the Bischler-Napieralski reaction described in Example 2. -2343528 Example 3.

In an Ng atmosphere a solution of 18,8 g. of IVa in 550 ml. anhydrous ether is added dropwise to a stirred suspension of 11.1 g. LiAlH^ in 500 ml. anhydrous ether over a one-hour period. The reaction mixture is refluxed for 5 hours, cooled in an ice bath and the excess LiAlH^ is decomposed by the dropwise addition of 105 ml. water.

The ether solution is decanted, dried over NagSO^ and evaporated in vacuo to give a yellow solid. Cyrstallization from ether-petroleum ether gives 17.2 g. of Va. An analytical sample had a m.p. 85 - 87°C.

Anal. Calc'd for C-igH-jgNg.

Calc'd: C:82.40; H:6.92; N.10.68 Found: C:82.34; H;6.84; N:10.71 -2443528 Example 4.

To a suspension of 5.2 g. of N-phenyltryptamine 5 hydrochloride (Ila) in 150 ml. water is added a total of 14.1 g. propionaldehyde (in 3 portions), 5 ml. ethanol and 21. ml. concentrated HCl (in 2 portions), while reaction mixture refluxes a total of one hour. After cooling, the mixture is washed with ether, the ether layer separated and backwashed with dilute HCl and the aqueous fractions combined. Upon shaking the aqueous fraction with fresh ether, the product precipitates as light gray solids that are filtered and collected to give 5.1 g. of Vb hydrochloride An analytical sample recrystallized from methanol-acetone had a m.p. 185 - 190°C.(dec.) Anal. Calc'd for NgCl · Calc'd: 0:72.95; H:6.77; N:8.95; 01:11.33 Found: 0.72.82; H:6.73; N:8.74; Cl:11.38 -25Compounds of formula Va-g exemplify those that can be prepared by the methods described in Examples 3 and 4. -ch3 A mixture of 13.6 g. of Va in 50 ml. dry pyridine and 40 ml. acetic anhydride is allowed to stand at least 16 hours at room temperature, then poured into one liter of cold water with stirring. The mixture is extracted into ether and the ether extract washed with saturated NaCl solution, dried over NagSO^ and evaporated in vacuo to a clear yellow oil. The product is crystallized from etherpetroleum ether to give 13.6 g. of Via as granular cream white solids, m.p. 136-142°C.

Compounds of formula Via- iexemplify those that can be prepared by the general method of acylation of compounds of formula V as described in Example 5. N-formyl derivatives can be made using a mixed anhydride of formic acid and another carboxylic acid as acylating agent. -2643528 Example 4.

To a suspension of 5.2 g. of N-phenyltryptamine 5 hydrochloride (Ila) in 150 ml. water is added a total of 14.1 g. propionaldehyde (in 3 portions), 5 ml. ethanol and 21. ml. concentrated HCl (in 2 portions), while reaction mixture refluxes a total of one hour. After cooling, the mixture is washed with ether, the ether layer separated and backwashed with dilute HCl and the aqueous fractions combined. Upon shaking the aqueous fraction with fresh ether, the product precipitates as light gray solids that are filtered and collected to give 5.1 g, of Vb hydrochloride. An analytical sample recrystallized from methanol-acetone had a m.p. 185 - 190°C.(dec.) Anal. Calc'd for C^gH^^ N,,C1.

Calc'd: C:72.95; H:6.77; N:8.95; Cl:11.33 Found: C.72.82; H-.6.73; N: 8.74; Cl-.11.38 -255 £ 8 Compounds of formula Va-g exemplify those that can be prepared by the methods described in Examples 3 and 4.

A mixture of 13.6 g. of Va in 50 ml. dry pyridine and 40 ml. acetic anhydride is allowed to stand at least 16 hours at room temperature, then poured into one liter of cold water with stirring. The mixture is extracted into ether and the ether extract washed with saturated NaCl solution, dried over NagSO^ and evaporated in vacuo to a clear yellow oil. The product is crystallized from etherpetroleum ether to give 13.6 g. of Via as granular cream white solids, m.p. 136-142°C.

Compounds of formula Via- iexemplify those that can be prepared by the general method of acylation of compounds of formula V as described in Example 5. N-formyl derivatives can be made using a mixed anhydride of formic acid and another carboxylic acid as acylating agent. -2643538 In a similar manner, but using compounds of formula I where Rg = H as starting materials, compounds of formula Xa-n can be obtained.

Example 6.

A mixture of 5.2 g. of Va, 12 g. of triethylamine, 8.4 g. of KI and 6.2 g of 2-bromopropane in 50 ml. of dimethyl formamide is stirred at 50 - 55°C. for 65 hours. After cooling reaction mixture is poured into 800 ml. cold water, extracted into ether and the ether extract washed with saturated NaCl solution, dried over Na^O^ and concentrated in vacuo to a dark oil. Treatment with ethereal HCl and crystallization from methanol-acetone gives 6.5 g. of Vlld hydrochloride, m.p. 224 - 235°C.

Compounds Vlld and Vllh exemplify those that can be obtained by the method described in Example 6. By utilizing compound Ig as the starting material, compounds Id, Ih, and Ii can be prepared by this same method, using the -2743528 appropriate organic halide. When compound Ip is the starting material, compound 11 can be obtained in the same manner. Similarly, compounds lj, k, s and t can be obtained from the compound Iw.

Example 7 In a N2 atmosphere, a solution of 1.9 g. of Via in 100 ml. anhydrous ether is added dropwise to a stirred suspension of 850 mg. of LiAlH^. The reaction mixture is refluxed for 2.5 hours, cooled in an ice bath and the excess LiAlH^ destroyed by the dropwise addition of 10 ml. water, The ether solution is filtered, dried over Na-jSO^ and concentrated in vacuo to a pale yellow oil.

Treatment with ethereal HCl and crystallization from acetone gives 1.7 g of Vllb hydrochloride, m.p. 233-236°C. An analytical sample had a m.p. 237-240°C. -28Anal. Calc'd for C2OH23N2C1.

Calc'd: C:73.49; H:7.09; N:8.57; Cl.-10.85 Found: C:73.22; H:7.40; N:8.49; 01:10.79 Compounds Vila, b.c.e.f,g,h,j and 1 exemplify those 5 that can be prepared by the method described in Example 7. By utilization of the compounds of formula Xa-h as starting materials, the corresponding compounds of formula I can be obtained in a similar manner.

Example 8 Via ia In a Ng atmosphere, a solution of 33.0 g. of Via in 800 ml. tetrahydrofuran is added dropwise to a stirred solution of 650 ml. 1 molar borane in tetrahydrofuran.

The reaction mixture is refluxed for 18 hours and the solvent removed by distillation to give an almost colorless oily residue that solidifies upon cooling.

Ten ml. of water is added dropwise, followed by 1200 ml of 5N HCl, added slowly at first. After refluxing 3.5 -2943SS8 hours the reaction mixture is cooled and treated with 375 ml. of 50% NaOH. without further cooling until the pH is>12. After cooling to room temperature, it is extracted into ether. The ether extract is washed with saturated NaCl solution, dried over Na2S0^ and the solvent removed in vacuo to give a pale yellow oil. Crystallization from ether-petroleum ether gives 17.3 g. of Ia, m.p. 131-133°C. An analytical sample had a m.p. 128-129°C.

Anal. Calc'd for ^20^24^2’ Calc'd: C:82.15; H:8.27; N:9.58 Found: C:82.13; H:8.25; N:9.55 Compounds la, c,f,k, 1 exemplify those that can be prepared as illustrated in Example 8.

Example 9. -3043SS8 A mixture of 12.5 g. of IVb and 32 g. of iodomethane in 500 ml. of ethanol is refluxed for 4 hours. The product that precipitates upon concentration of the solution to 1/4 volume in vacuo is filtered, washed with ethanol and ether, dried, and 14.9 g. of crude VUIb is collected.

Crystallization from acetone and small amounts of methanolethyl acetate affords 9.3 g. of pure VUIb, m.p. 209 - 211°C Compounds of formula VUIa-e exemplify those that can be prepared by the method illustrated in Example 9.

Example 10 VUIb Vile To a stirred suspension of 3.5 g. of LiAlH^ in 500 ml. of anhydrous ether in a >12 atmosphere, is added 9.3 g. of VUIb in small portions while maintaining the temperature of the reaction mixture between 17-20°C. After the -3143528 addition is complete, the reaction mixture is stirred at room temperature for one hour, cooled, and the excess LiAlH^ decomposed by the dropwise addition of 35 ml. of water over a 45 - minute period. The ether solution is filtered, dried and concentrated in vacuo to a cloudy oil. Treatment with ethereal HCl gives 7.3 g. of Vile hydrochloride. After two recrystallizations from acetone methanol, the analytical sample had a m.p. 245 - 251°C. (dec).

Anal Calc'd for ^20^23^2^· Calc'd: C:73.49; H:7.09; N:8.57- Cl:10.85 Found: C:73.30; H:7.33; N:8.58; Cl:10.83 Compounds Vila, c,e,f and 1 exemplify those that can be prepared by the method described in Example 10. -32A solution of 4.4 g. of NaBH^ in 50 ml diglyme (ethylene glycol dimethyl ether) is added dropwise to a stirred suspension of 32 g. of Vila hydrochloride in 75 ml. diglyme in a N2 atmosphere. After stirring one hour at room temperature, the reaction mixture is poured into one liter of water with stirring. The precipitated white solids are filtered and washed with water. The moist filter-cake is suspended in 150 ml. dioxane and 85 ml of concentrated HCl is added. The mixture foams considerably and is slowly brought to reflux over a period of one hour. After refluxing 15 minutes, the solution is cooled in an ice bath and treated with 10% NaOH until pH>10.

Dilution with an equal volume of water to a total volume of 1400 ml. and cooling in an ice bath precipitates the product as white solids which are filtered, washed with water and collected to give 27.2 g. of Ib. An analytical sample recrystallized from acetone-methanol had a m.p. 122 - 125°C.

Anal. Calc'd for C^gH22N2· Calc'd: C:81.97; H:7.96; N: 10.06 Found: C:81.91; H:7.96; N:1O.O8 Compounds of formula Ia, b,c,d,e,f,k,l,n,o,s,u and v can be prepared by the method described in Example 11, however, they can also be prepared using the BHg method illustrated in Example 8. -3335S8 Example 12.

Ia - R2=CH2CH3 Ib - R2=CH3 In a well ventilated hood, a solution of 8.0 g. of cyanogen bromide in 35 ml. chloroform is added to a solution of 7.5 g. of Ia in 35 ml. chloroform. The resulting clear solution is heated to reflux for six hours. The reaction mixture is then evaporated to dryness to yield a blue oil which is washed with n-pentane. On digestion with ethanol, a solid, m.p. 145 - 147°, is obtained.

Using the same procedure,· but starting with Ib instead of Ia, the identical material is obtained. 435S8 Example 13.

IXB Ig Without further purification, 5.0g, of the cyanamide IXB 5 from Example 12 is suspended in 60 ml. of 5N aqueous hydrogen chloride, and the resulting suspension is refluxed for six hours. On cooling, the lilac precipitate is filtered and triturated with ethyl acetate to give Ig hydrochloride, m.p. 242 - 246°C.

A solution of Ig hydrochloride is dissolved in water, the solution is basified with 50% NaOH, and Ig as the free base is obtained, m.p. 95 - 97.5°.

Anal. Calc'd for C^gHggHg.

Calc'd: C:81.78; H:7.63; N:10.60 Found: C:81.84; H:7.66; N:10.52 -354 3 5 2 3 Compounds of formula Ig, m,p,q,r and w exemplify those that can be prepared by the method described in Example 13..

Example 14 A mixture of 6.88 g. of phenylindole-3-carboxaldehyde XI, 11.6 g. of-nitroethane and 0.7 g. of ammonium acetate in 25 ml. of glacial acetic acid is refluxed for 5 hours. Evaporation of the solvent in vacuo gives a dark yellow oil. Crystallization from ethanol-water and ethanol gives 2.8 g. of Xllb as a yellow solid, m.p. 104 - 105°C, Compounds of formula Xlla-c can be obtained by this method. -36Example 15 To a stirred suspension of 2.8 g. of LiAlK^ in 100 ml. anhydrous ether in a N., atmosphere is added dropwise a solution of 2.8 g. of Xllb in 100 ml. of anhydrous ether and 30 ml. of dry benzene. The reaction mixture is refluxed one hour, cooled, and the excess LiAlH^ decomposed by the dropwise addition of 28 ml. of water. The ether solution is filtered, dried over Na2S0(| and concentrated in vacuo to a pale yellow oil. Treatment with ethereal HCl precipitates the product which is filtered and dried to give 2.5 g. of lib hydrochloride. Crystallization from ethanol gives 1.4 g., m.p. 210 - 212°C.

Compounds of formula Ila-c can be prepared as illustrated by the method described in Example 15. -374 3 5 28 Dosage Forms and Use.

The antidepressant agents of this invention can be administered as treatment for psychiatric depressions of the reactive and endogenous types by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. In addition to their antidepressant activity they also have a beneficial sedative action. They can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a daily dosage of active ingredient can be θ-g, o.2 to 100 milligrams per kilogram of body weight. Ordinarily 1 to 20 and preferably 2 to -3843528 milligrams per kilogram per day given in divided doses 2 to 4 times a day or in sustained release form is effective to obtain desired results.

Dosage forms (compositions) suitable for internal administration e.g. contain from 50 milligrams to 100 milligrams of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of e.g. 0.01-90% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions; it can also be administered parenterally, in sterile liquid dosage forms; or rectally in the form of suppositories.

Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate or stearic acid. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration -394 3 5 S 8 in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration contain preferably a water soluble salt of the active ingredient, suitable stablizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisfulite, sodium sulfite, or ascorbic acid either alone or combined are suitable stablizing agents Also used are citric acid and its salts and sodium EDTA (ethylenediaminetetraacetic acid). In addition parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propylparaben, and chlorobutanol.

Suppositories contain the active ingredient in a suitable oleaginous or water-soluble base. The oleaginous class includes cocoa butter and fats with similar properties; I the water-soluble class includes polyethylene glycols.

Suitable pharmaceutical carriers are described in -40Remington's Pharmaceutical Sciences, E.W.Martin, a standard reference text in this field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows: Capsules Capsules can be prepared by filling standard two-piece hard gelatin capsules with the following mixture using conventional encapsulating equipment: Active ingredient 75 mg 10 Lactose 225 mg Talc 25 mg Magnesium stearate 8 mg Capsules A mixture of active drug in soy bean oil is prepared and 15 injected by means of a positive displacement pump in gelatin to form soft gelatin capsules containing 75 mg. of the active ingredient. The capsules are washed in petroleum ether and dried.

Tablets Tablets can be prepared by conventional precedures so that -4143528 each unit will contain: Active ingredient 75 mg. Spray dried lactose 100 mg. Microcrystalline cellulose 50 mg. Magnesium stearate 3 mg.

Parenteral Parenteral composition suitable for intra muscular administration is prepared so that each ml. contains: Active ingredient 75 mg Sodium carboxy methyl cellulose 0.75% Polysorbate 80 0.04% Benzyl alcohol 0.9% Sodium chloride 0.9% Water for injection Q.S. 1 ml.

Suspension An aqueous suspension is prepared for oral administration so that each 5 mis. contain: Active ingredient mg. -4243S28 Methyl cellulose 5% Carboxy methyl cellulose 5% Syrup 30% Polysorbate 80 0.2% Sodium saccharin 2 mg. Cherry flavor 0.1% Sodium benzoate 5 mg. Water Q.S. 5 ml.

A standard procedure for detecting and comparing the antidepressant activity of compounds in this series for which there is good correlation with human efficacy is the prevention of tetrabenazine-induced sedation and depression in mice. (Everett, The Dopa Response Potentiation Test and Its Use in Screening for Antidepressant Drugs, pp. 164167 in Antidepressant Drugs (Proceedings of the Frist International Symposium), S.Garattini and M.N.G. Dukes, eds., 1967).

Groups of 10 Carworth CF-jS female mice, 18-21 g. each, were fasted 1.5 hours and were incubated with antagonist compounds at oral doses of 0>5,25, and 125 mg/kg or 0, 1,3,9,27 and 81 mg-kg in 0.20 ml. of 1% Methocel (registered Trade Mark for methylcellulose). The mice were challenged 30 minutes later with tetrabenazine (as the methane-sulfonate), 32 mg/kg intraperitoneally (dissolved in 0.20 ml. 0.56M KC1 at pH.2.0). One hour after antagonist (30 minutes after tetrabenazine,) -4343528 the mice were examined for signs of exploratory activity and ptosis (eyelid closure). Normal exploatory activity (relief from sedation) was recorded when a mouse lifted by the tail from a group of 10 in a testing box and placed on a stainless steel testing box lid (12.5 x 8 with 0.33" mesh) either turned its head horizontally 30° in both directions or moved to the edge of the screen within 10 seconds after being placed on the screen. Relief from ptosis was recorded when exactly two seconds after placing the mouse facing the observer, lid closure was less than 50% in both eyes. The following table gives results.

ANTAGONISM OF TETRABENAZINE-INDUCED DEPRESSION IN MICE ORALLY AT 1 HOUR POST-DRUG -4443528 COMPOUND EDg0 (mg/kg) for PREVENTION OF EXPLORATORY R1R3R3 LOSS PTOSIS ch3C2H5 H 4.2 3.0 5 ch3 ch3 H 38 16 ch3n_C3H7 H 38 14 ch3 i-CgH? H 19 11.2C2H5 ch3 H 11.2 9.1C2H5C2H5 H 38 27 10 ch3 H H 31 25 HC2H5 ch3 <5 <5 Amitriptyline 4.7 1.7 CLAIMS

Claims (16)

1. A compound of the formula -45528 where R-|=H,CHg, or C^Hg·, Rg=H,C-j-Cg alkyl or allyl, Rg=H, CHg or CgHg; 5 provided that the total number of carbon atoms in R^+Rg+ Rg is not more than four, and provided further that one of R^ or Rg must be other than H; and its pharmaceutically suitable salts.

2. (+) - trans - 2 - Ethyl - 2,3,4,4a,9,9a - hexahydro ι 1 - methyl - 9 - phenyl - IH - pyrido [3,4 - b] indole and its pharamceutically suitable salts.

3. (+) - trans - 2 - Ethyl - 2,3,4,4a,9,9a - hexahyd.ro 3 - methyl - 9 - phenyl - IH - pyrido [3,4 - bj indole and its pharmaceutically suitable salts.

4. Compounds of claim 1 as hereinbefore specifically disclosed and their pharmaceutically suitable salts excepting the compounds of claims 2 and 3.

5. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective antidepressant amount of a compound of claim 1 or 4.

6. A pharmaceutical composition comprising a suitable -46pharmaceutical carrier and an effective antidepressant amount of a compound of claim 2.

7. A pharmaceutical composition comprising a suitable pharmaceutical carrier and an effective antidepressant 5 amount of a compound of claim 3.

8. A pharmaceutical composition according to any of claims 5 - 7 in unit dosage form.

9. A pharmaceutical composition according to claim 8 wherein each unit dose contains 50-100 mg of said compound.

10. 10. A method of alleviating depression in a non-human mammal which comprises administering to the mammal an effective antidepressant amount of a compound of any of claims 1 - 4.

11. A process for preparing a compound of claim 1 wherein 15 Rg is C 1 - C 3 alkyl or allyl which comprises: contacting a compound of the following formula with BHg then treating with acid: -47Ο Ο II Ί where R = - CH, -C - CHg Ο -C-CgHg, (C-j-Chalky! or allyl; and R-j and Rg are as defined in claim 1; or, alternatively, contacting an acid addition salt of 5 a compound of the above formula with NaBH^, then treating with acid, where R=C 1 -Cg alkyl; and R-j and Rg are as defined in claim 1; provided that the total number of carbon atoms in R^+Rg+Rg is not more than four, and provided further that one of R^ and Rg must be other than H. 0

12. A process for preparing a compound of claim 1 wherein Rg is hydrogen and R^ and Rg are as defined in claim 1 which comprises preparing a compound of claim 1 wherein Rg is methyl or ethyl by the process of claim 11, reacting said compound with cyanogen bromide, and hydrolysing κ it to a corresponding product wherein Rg is hydrogen.

13. A process for preparing a compound of claim 1 wherein Rg is hydrogen and R-j and Rg are as defined in claim 1 which comprises preparing a compound of claim 1 wherein Rg is methyl or ethyl by the process of claim 11, reacting 1 said compound with ethyl chloroformate, and hydrolysing it under alkaline conditions to a corresponding product wherein Rg is hydrogen.

14. A process according to claim 11 in which the final product is (+) - trans - 2 - ethyl -2,3,4,4a,9,9a -4843528 hexahydro - 1 - methyl - 9 - phenyl - IH-pyrido - [3,4 bj indole.

15. A process according to any of claims 12 - 14 including the step of converting the resulting product to 5 a pharmaceutically suitable acid addition salt.

16. A process according to any of claims 11-12, substantially as hereinbefore described with reference to the Examples.