CS248044B2 - Production method of (+)-enentiomer or (+-)racemic 4a,9b-trans-hexahydro-1h-pyridoindol derivatives - Google Patents

Description

The invention relates to a process for the production of novel hexahydro-trans derivatives which are useful as neuroleptic agents.

Successful treatment of schizophrenic behavior using antipsychotic tranquilizing agents, such as chlorpromazine, has stimulated research to find new neuroleptic agents with improved biological properties. One group of such compounds is 2,3,4,4a, 5,9b-hexahydro-1H-pyrido [4,3-b] indoles and 2,3,4,5-tetrahydro-1H-pyrido [4,3- bj indoles. The basic ring structures of these compounds correspond to the formulas

The stereochemistry at positions 4a and 9b of the hexahydro derivatives may be cis or trans, each of which may exist in racemic (+) or in one of the enantiomeric (+ or -) forms). Examples of hexahydro- and tetrahydropyridoindoles useful as tranquilizing agents, neuroleptic agents, analgesics, sedatives, muscle relaxants, and hypotensive agents are disclosed in U.S. Patent Nos. 3,687,961, 3,983,239, 3,991,199, 4,001,263, 4,141,980 and 4,224 329.

Now, strong neuroleptic activity has been discovered in the novel 2,3,4,4a, 5,9b-hexahydro-4a, 9b-trans-1H-pyrido [4,3-b] indoles and 2,3,4,5-tetrahydro- 1H-pyrido [4,3-b] indoles substituted in the 5-position with an aryl group and in the 2-position with an aminoalkyl or carbonylaminoalkyl group whose carbonyl group is either further substituted by a radical such as hydrogen, alkyl, aryl, aralkyl or alkoxy, or is linked to an amino group with a divalent radical such as an alkano group [radical - (CH 2) j - where i is 3 to 5?] or a chain of 3 to 6 atoms containing different combinations of carbonyl groups, alkane groups, alkene groups, o - benzogroups,

The present invention provides a process for the preparation of (+) -enantiomeric or (+) -racemic 4a, 9b-trans-hexahydro-1H-pyridoindole derivatives of the general formula:

R '- (CH 2) _n -G' imino, sulfur and oxygen.

The neuroleptic agents produced by the process of the invention are (+ j-enantiomeric, mixed (+) - and (-) - enantiomeric or (+ j -racemic 2,3,4,4a, 5,9b-hexahydro-4a, 9b-trans- 1H-pyrido [4,3-b] indole derivatives of the general formula wherein:

R ‘represents the remainder of the formula

Nm _k

where k is a number of 1 or 2, n is a number of 2 to 6,

X and Y are each independently hydrogen, fluorine, chlorine or bromine, methoxy, methyl or ethyl; and

R ' ¹ represents a hydrogen atom, a C 1 -C 5 alkyl group, a phenyl group, a benzyl group, a C 1 -C 8 alkanoyl group, a C 1 -C 8 alkoxycarbonyl group, a benzoyl group, a phenylacetyl group, an alkylsulfonyl group C 1 -C 8 -phenyl, phenylsulfonyl or a mono- or disubstituted phenyl, benzyl, benzoyl, phenylacetyl or phenylsulfonyl group, wherein the substituents are independently selected from the group consisting of fluoro, chloro, bromo, methoxy, methyl or ethyl group.

The invention also provides pharmaceutically acceptable salts of the compounds as defined above, pharmaceutical compositions containing these compounds as active ingredients, and a method of treating psychoses and neuroses in patients requiring substantial tranquilization by oral or parenteral (intravenous, intramuscular or subcutaneous administration of an effective amount). either alone or as components of a pharmaceutical composition.

The individual general symbols in the preferred compounds have the following meanings:

k is a number of 1 or 2, n is a number of 2 to 6, each of X and Y represents a hydrogen, fluorine, chlorine or bromine atom, a methoxy group, a methyl group or an ethyl group, and

G is a radical of formula

OF \ .

- N ~ R H where

R ' ¹ represents a hydrogen atom, a C 1 -C 5 alkyl group, a phenyl group, a benzyl group, a C 1 -C 8 alkanoyl group, a C 1 -C 8 alkoxycarbonyl group, a benzoyl group, a phenylacetyl group, an alkylsulfonyl group C 1 -C 8 -phenyl, phenylsulfonyl or a mono- or disubstituted phenyl, benzyl, benzoyl, phenylacetyl or phenylsulfonyl group, wherein the substituents are independently selected from the group consisting of fluoro, chloro, bromo, methoxy, methyl or ethyl and pharmaceutically acceptable salts thereof, characterized in that the compound of formula (I) is selected from the group consisting of:

O, i; r ~~ \

Rc- (CH 2) _r . 4 ~ NN ~ Rp ^{Λ n 7} \ ._ y

Z is fluorine, k is 1,

Y is fluorine (bonded to the para-semi-product, and n has a value of 3 to 6.

i, o o 1

R-C248044

S in which

R 1 and R ⁴ are as defined above, reduced with hydride to form a compound of formula

R '- (CH 2) _n -G' in which

R ‘and n are as defined above and G‘ represents a radical of formula

If the terminal residue does not contain a carbonyl group, the compounds of the invention can also be prepared by reducing the corresponding starting amide with a hydride, for example according to the following schemes:

O, R-C

 'where

R ⁸ represents a C 1 -C 5 alkyl group, a phenyl group, a benzyl group, a C 1 -C 8 alkylsulfonyl group, a phenylsulfonyl group or a mono- or disubstituted phenyl, benzyl or phenylsulfonyl group wherein the substituents are independently of one another selected from fluorine, chlorine or bromine, methoxy, methyl or ethyl, the resulting compound wherein R ⁸ is benzyl is optionally debenzylated and the resulting compound wherein R ⁴ is hydrogen is optionally acylated with to form the corresponding product wherein R ⁴ is C 1 -C 8 alkanoyl, C 1 -C 8 alkoxycarbonyl, benzoyl or phenylacetyl, and the resulting compound is optionally converted to a pharmaceutically acceptable addition salt thereof with acid.

The process of the invention: allows the synthesis of the desired compounds of the invention, provided that the terminal moiety does not contain groups subject to hydrogenation to a significant degree under the conditions used to hydrogenate the multiple bond. If benzyl protecting groups are used, these groups can generally be cleaved off by the same reaction as the reduction: multiple bonds, for example according to the following scheme:

O .11

 if

R - C, _r c ~ N f 'Γ * —Ά' ⁿ -V_./ ⁵

A further variation consists in the alternative or simultaneous reduction of the various amidiol groups in the terminal residue, for example according to the following schemes:

 , r ~ \

R CH 2 CS C C CH 2 H?

O

R @ f CH, N @ 1 -

Λ R * M z

· /? ICH _Z )

Conveniently, these hydride reductions are carried out using an excess of lithium aluminum hydride (two equivalents required for each amide function) in an ether solvent (e.g. diethyl ether, tetrahydrofuran or dioxane) at a temperature of from 0 to 50 ° C. Alternatively, these amides are reduced with diborane or aluminum hydride in the same type of solvent, or reacted with triethyloxonium fluoroborate (e.g., methylene chloride at 20-30%) and then reduced with sodium borohydride in a lower alkanol (e.g., ethanol) at 0-25 ° C. .

Pharmaceutically acceptable salts of the compounds of the invention may be prepared by treating with either about 1 mol equivalents or about 2 mol equivalents of an organic or mineral acid in either an aqueous or non-aqueous solution. Since the compounds of the invention contain three basic functions, it is possible, depending on the number of acid equivalents used, to prepare mono-salts, bis-salts or tris-salts. Suitable salt-forming acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, methanesifonic acid, p-toluenesulfonic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid and gluconic acid.

The resulting salt can be isolated by evaporating the solvent under vacuum or, where possible and appropriate, by precipitation.

The compounds of the invention are useful as neuroleptic agents in the treatment of mental disorders and diseases, including schizophrenia, psychoses and neuroses. Symptoms requiring such treatment include anxiety, aggression, agitation, depression, hallucination, tension, and emotional or social alienation.

In general, the disclosed derivatives exhibit significant tranvilizing activity with a lower incidence of side effects than currently used drugs.

The compounds of the present invention can be formulated into a variety of pharmaceutical compositions containing the derivatives either alone or in combination with pharmaceutical carriers such as inert solid diluents, aqueous solutions or various non-toxic organic solvents. These compositions may be in unit dosage forms such as gelatin capsules, tablets, powders, lozenges, syrups, injectable solutions and the like. The above carriers include water, ethanol, gelatin, lactose, starches, vegetable oils, natural petrolatum, acacia, glycols, talc, benzoyl alcohols and other known carriers for the preparation of dosage forms. If desired, these compositions may contain other materials, such as preservatives, wetting agents, stabilizing agents, glidants, absorbents, buffering agents, and isotonic agents.

The compounds of the invention are administered to patients by a variety of conventional routes of administration, such as orally, intravenously, intramuscularly, or subcutaneously. In general, small dosages are begun with administration and gradually increased to the optimum dose. The choice of the active ingredient and its dosage, dosage form and route of administration for each individual patient is a matter for the treating physician.

In the usual course of treatment in human medicine, an effective dose of a compound of the invention ranges from about 0.1 mg per day to 100 mg per day. If the active substance has a protracted effect, it may be administered less frequently, as every other day or in one or two divided doses each week.

The tranquilizing activity of the compounds of the invention can be determined using a standard known assay of antagonizing amphetamine-induced symptoms in rats. This method is in excellent correlation with efficacy in human medicine as described by A. Weissman et al., J. Pharmacol. Exp. Ther. 151, p. 339 (1966) and Quinton et al., Nature 200, p. 178 (1963), and in particular Harbert et al., Molecular Pharmacology 17, 38-41 (1980). In this test, the neuroleptic effects of the test substances are determined in vivo by blocking the amphetamine-induced behavior.

Groups of 5 rats are placed in covered plastic cages. After brief cage acclimatization, rats are intraperitoneally administered test compound in log-graded doses (i.e. ... 1, 3.2, 10, 32, ... mg / kg) and then intraperitoneally 5 mg after 1, 5 and 24 hours. / kg d-amphetamine sulfate. Every 1 hour after amphetamine administration, each rat is characterized by amphetamine administration, exhibiting a cage movement of the rat, which is evaluated using a six-point scale [See Weissman et al., J. Pharmacol. Exp. Ther. 151, pp. 339-352 (1966)]. The aforementioned classification represents increasing degrees of action of the test substance (see Quinton and H, alliwell, Nature (London) 200, pp. 178-179 (1963)) and the time chosen for evaluation falls within the time of peak amphetamine effect [Weissman, Psychopharmacologia 12, p. 142-157 (1968)]. Results are dichotomized (see Weissman et al. Ibid.) And approximate ED 50 values are determined based on quantum data. Doses for hydrochlorides are given.

As can be seen from the results summarized in Table I below, this test demonstrates the excellent tranquilizing activity of the compounds of the invention as compared to a standard comparator, chlorpromazine.

The so-called "intrinsic" tranquilizing neuroleptic activity of the compounds of the invention is determined using the ³ H-spiroperidol binding to the dopamine receptor according to the method of Leysen et al., Bio248044 Chem. Pharmacol. 27, p. 307 (1978) and adapted by Burt et al., Mol. Pharmacol. 12 ,. pp. 800-812 (1976).

Male rats (Sprague-Dawley CD, 250-300 g.) Charles River Laboratories, Wilmington, Mass., Are decapitated and their brains immediately removed for corpus striatum isolation. This tissue is homogenized in 40 volumes of ice cold tris buffer, pH 7 The homogenate is centrifuged twice at 50,000 g for 10 minutes at 0-4 ° C, the intermediate precipitate rehomogenized in the same volume of the above buffer. The final precipitate is carefully suspended. in 90 volumes of cold 50 mM Tris buffer, pH 7.6, containing 120 millimoles of sodium chloride, 5 mmol of potassium chloride, 2 mmol of calcium chloride, 1 mmol of magnesium chloride, 0.1% ascorbic acid and 10 mole of pargylin. The mixture was placed in a 37 ° C water bath for 5 minutes and then cooled with ice until use. The incubation mixture consisted of 0.02 ml solution, inhibitor or vehicle, 1.0 ml t of a cannula preparation and 0.10 ml of ³ H-spiroperidol (New England Nuclear, 23.6 Ci / mmol) prepared to a final concentration of 0.5 nM.

Incubate the tubes successively for 10 minutes at 37 ° C in groups of three, then 0.9 ml of the mixture from each incubation tube and vacuum filter through a Whatman GF / B filter. After washing twice with 5 ml of cold Tris-buffer, pH 7.7, each filter is transferred to a 10 ml Aquasol-2 scintillation vial (New England Nuclearj) and the contents of each vial are vortexed vigorously. and then on a scintillation counter to determine their radioactivity. the amount of bound substance is expressed in fentamol ³ H-spiroperidol bound per milligram of protein. triplicate are carried out as well as control experiments (vehicle or 10 ^{_ /} M 1 butaclamolj, the blank (10 ⁷ (d-butaclamol) and inhibitor solution experiments (four concentrations), using 50% semi-logarithmic paper (IC50). IC50 values shown in Table I represent the average of two or three experiments. the test substances are dissolved in ethanol (ethanol concentration in the final incubation mixture 1 to 2%).

The data in Table I show that the compounds of the invention exhibit excellent neuroleptic activity.

Table I neuroleptic activity of 1H-pyrido [4,3-b] indoles

structure 'activity against amphetamine min ^b) (approximate inhibition of ED50 value in mg) in intraperitoneal binding''

R ¹ n administration of H ³ -spircperidol h 5 h 24 h IC 50 (nmol)

/ \ 4 > 10 1 - 3,2 > 10 -N. NH \__F 2 0.18 0 06 0.57 • π-ς nccch ₃ 4 2 (3) 1 - 3.2 0.04 0.32 - 1.0 0 02 0.32 - 1.0 0.23 4 3,2 - 10 -3.2 3,2 - 10 chlorpromazine 5.3 8.5 > 32

Legend:

(a) unless otherwise indicated by means of (+) or (-) signs, the test compounds are racemic (+) mixtures

(b) the ranges within which ED50 values for blocking amphetamine-induced hyperactivity and behavior are reported (details are given in the text)

c) IC 50 values were determined graphically, usually using four concentrations of the test substance in the above logarithmic scaling. Generally, values representing the average of two or three determinations are given (details are given in the text)

The invention is illustrated by the following non-limiting examples.

Example 1 1-Benzyl-4- (4-chloro-butyryl) -piperazine

1.0 g (5.7 mmol) of N-benzylpiperazine and 1.17 ml (8.5 mmol) of triethylamine are added in 20 ml of methylene chloride, 0.945 ml (8.5 mmol) of 4-chlorvaleryl chloride in 10 ml are added dropwise over 20 minutes. ml of methylene chloride and the resulting mixture was stirred at room temperature for 16 hours. After addition of 20 ml of water, the organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo to a gummy residue which was chromatographed on silica gel using ethyl acetate as eluent. The progress of column chromatography was monitored by thin layer chromatography. Fractions containing pure product were combined and evaporated to give 920 mg of the title compound as a gummy material having Rf ₌ 0.5 (ethyl acetate).

Example 2 (+) -8-Fluoro-5- (4-fluoro-phenyl) -2- (3- (4-benzyl-piperazinocarbonyl) -1-propyl) -2,3,4,4a, 5,9b- hexahydro-4a, 9b-trans-β-pyrido [4,3-b] indole-bis-hydride chloride

625 mg (2.2mmol) of (+) -8-fluoro-5- (4-fluorophenyl) -2,3,4,4a, 5,9b-hexahydro-4a, 9b-trans-1H-pyrido [4.3] -b] indole is reacted with 1-benzyl-4- (4-chlorobutyryl) piperazine. Chromatography yields the title compound as the free base. This free base was taken up in acetone and converted into bis-hydrochloride by addition of excess ethereal hydrogen chloride. The title compound is isolated by evaporating the mixture to dryness and triturating with ether. Yield 0.485 g.

Mass spectrum: m / e - S30.

Analysis:

Calcd for C32H36ON4F2.2HCl.2.25 H2O:

% C, 59.67;% H, 6.52;% N, 8.69; ňfllQZQinQ '*

H, 6.53; N, 8.68.

EXAMPLE 3 [+] -8-Fluoro-5- (4-fluorophenyl) -2- (4- (4-benzylpiperazin-1-butyl) -2,3,4 / 4a, 5) 9b-hexahydro-4a, 9b-trans-1H-pyrido [4,3-b] indole-tris hydrochloride g (+) -8-fluoro-5- (4-fluorophenyl) -2- [3] % 4-benzylpiperazinocarbonyl) -1-propyl] -2,3,4,4a, 5,9b-hexahydro-4a, 9b-trans-1H-pyrido [4,3-b] indole-bis-hydrochloride was taken up in 30 ml. tetrahydrofuran and lithium aluminum hydride (about 9 equivalents) were added portionwise to the solution, and hydrogen was evolved throughout almost all the addition, and the reaction mixture was stirred at room temperature for 30 minutes, then excess Glauber's salt (sodium sulfate decahydrate) was added. After stirring for a further 10 minutes, the resulting mixture was filtered, the filter residue was washed with tetrahydrofuran, the filtrate was combined with the washings and evaporated to dryness, the resin residue was taken up in acetone and converted to the hydrochloride by addition of ethereal hydrogen chloride. The residue was triturated with a mixture of 30 ml of acetone and 10 ml of methanol. Filtration gave 120 mg of the title compound Rf = 0.2 (methanol).

Mass spectrum: m / e = 516.

Analysis:

for C32H38N4F2. 3 HCl calculated:

% C, 61.39;% H, 6.59;% N, 8.95; found:

61.26% C, 6.68% II, 8.78% N.

Example 4 (+) -8-fluoro-5- (4-fluorophenyl) -2- (4-piperazino-1-butyl) -2,3,4,4a, 5,9b-hexahydro-4a, 9b trans-1H-pyrido [4,3-b] indole-tris hydrochloride

All (+) -8-fluoro-5- (4-fluorophenyl) -2- [4- (4-benzylpiperazino) -1-butyl] -2,3,4,4a, 5,9b-hexahydro- 4a, 9b-trans-1H-pyrido [4,3-b] indole-tris hydrochloride from the previous example is taken up with 10 ml of ethanol containing 3 drops of concentrated hydrochloric acid, 250 mg of 10% palladium on carbon catalyst are added and the mixture is It is hydrogenated at 40 ° C for 6 hours. The catalyst was filtered off and washed with ethanol, the filtrate combined with the washings and evaporated to a gummy residue. This resinous residue was dissolved in a minimum amount of methanol and brought to crystallization by addition of 100 ml of acetone and stirring for 30 minutes.

The yield of the title compound, as the trihydrate, is 0.3 g. The product melts at 229-232 ° C.

Example 5 (i) -8-Fluoro-5- (4-fluorophenyl) -2- (4- (4-acetylpiperazino) -1-butyl) -2,3,4,4a, 5,9b-hexahydro -4a, 9b-trans-1H-pyrido [4,3-b] indole-bis-hydrochloride

377 ml (0.64 mmol) of (+) -8-fluoro-5- (4-fluorophenyl) -2- (4-piperazino-1-butyl) -2,3,4,4a are dissolved in 8 ml of methylene chloride. 5,9b-hexahydro-4a, 9b-trans-1 H-pyrido [4,3-b] indole-tris hydrochloride trihydrate and 0.68 ml (4.92 mmol) of triethylamine, dropwise over 20 minutes 0.055 mL (0.77 mmol) of acetyl chloride in 4 mL of methylene chloride was stirred at room temperature overnight. Water (12 ml) was added to the reaction mixture, the organic layer was dried over anhydrous magnesium sulfate and evaporated to a gummy residue. This resinous material was taken up in ether and converted to the hydrochloride by addition of ethereal hydrogen chloride. The mixture was evaporated to dryness and the residue triturated with acetone to give 150 mg of the title compound as a hygroscopic solid.

Analysis;

for C27H34N4OF2. 2 HCl. 2 H 2 O calculated;

% C, 56.15;% H, 6.92;% N / 9.69; found:

% H, 7.24;% N, 9.75.

EXAMPLE 6 (i) -8-Fluoro-5- (4-fluorophenyl) -2- (3-piperazinocarbonyl-1-propyl) -2,3,4,4a _/ 5,9b-hexahydro -4a, 9b-trans-1H-pyrido [4,3-b] indole-bis-hydrochloride

S (+) -8-fluoro-5- (4-fluorophenyl) -2- [3- (4-benzylpiperazinocarbonyl) -1-propyl] -2,3,4,4a, 5,9b-hexahydro-4a, 9b The trans-1H, -pyrido [4,5-bindole-bis-hydrochloride of Example 2 was hydrogenated in 20 ml of ethanol containing 6 drops of concentrated hydrochloric acid, in the presence of 300 mg of 10% palladium on carbon catalyst. The catalyst is filtered off and the filtrate is evaporated to a gummy residue which crystallizes after trituration with acetone to give 0.640 g of the desired product.

IR (KBr):

470, 1508, 1639, 1733, 3390 ^cm-first Mass spectrum: m / e = 440.

Analysis:

for • C25H30N4OF2.2 HCl. 3 H2O calculated:

% C, 52.91;% H, 6.69;% N, 9.87; found:

H, 6.53; N, 9.93.

Example 7 (i) -8-Fluoro-5- (4-fluorophenyl) -2- (3- (4-acetylpiperazinocarbonyl) -1-propyl) -2,3,4,4a, 5,9b-hexahydro- 4a, 9b-trans-1H-pyrido [4,3-b] indole hydrochloride

50 (1 mg piperazinocarbonyl derivative from the previous example (1.14 mmol), 0.089 ml (1.25 mmol) acetyl chloride and 0.628 ml (4.5 mmol) triethylamine were reacted in a total of 15 ml methylene chloride as described in Example 5. Crude product isolated from the methylene chloride layer after mixing with water, was chromatographed on silica gel using a mixture of equal parts of methanol and ethyl acetate as eluant, the column was monitored by thin layer chromatography [R _f is equal to 0.2 (methanol-ethyl acetate 1: 1) The pure product fractions were combined and evaporated to dryness, the resin residue was taken up in ether and converted to the hydrochloride by addition of ethereal hydrogen chloride, and the mixture was evaporated to a solid which triturated with acetone (10 ml) and filtered to give 50 mg of the title compound. 220 DEG-223 DEG.

Analysis:

for C27H32N4O2F. HCl. 0.75 H2O calculated:

% C, 60.90;% H, 6.54;% N, 10.52; found:

% C, 60.96;% H, 6.44;% N / 10.32.

Claims (1)

Process for the preparation of [+) -enantiomeric or (+) - racemic 4a, 9b-trans-hexahydro-1H-pyridoindole derivatives of general formula R ‘- (CH 2) n - G kterém in which R ‘represents the remainder of the formula OF THE INVENTION NR ⁴ - fk is a number of 1 or 2, n is a number of 2 to 6, each of X and Y being a hydrogen, fluorine, chlorine or bromine atom, a methoxy group, a methyl group or an ethyl group, and G is a radical of formula V_y kde R ⁴ represents a hydrogen atom, a C 1 -C 5 alkyl group, a phenyl group, a benzyl group, a C 1 -C 8 alkanoyl group, a C 1 -C 8 alkoxycarbonyl group, a benzoyl group, a phenylacetyl group, an alkylsulfonyl group C 1 -C 8 -phenylsulfonyl or a mono- or disubstituted phenyl, benzyl benzoyl, phenylacetyl or phenylsulfonyl group wherein the substituents are independently selected from the group consisting of fluoro, chloro, bromo, methoxy, methyl or ethyl, and pharmaceutically acceptable salts thereof, characterized in that the compound is of the formula O RC- (' ^N ~ ^RI ') in which R 'and R ⁴ are as defined above, reduced with hydride to form a compound of formula R '- (CH 2) _n -G' in which R ‘and n are as defined above and G ‘represents the remainder of the formula I kde R ⁸ represents a C 1 -C 5 alkyl group, a phenyl group, a benzyl group, a C 1 -C 8 alkylsulfonyl group, a phenylsulfonyl group or a mono- or disubstituted phenyl, benzyl or phenylsulfonyl group wherein the substituents are independently of one another selected from the group consisting of fluorine, chlorine or bromine, methoxy, methyl or ethyl, the resulting compound wherein R ⁸ is benzyl is optionally debenzylated and the resulting compound wherein R ⁴ is hydrogen is optionally acylated to form of the corresponding product wherein R ⁴ is C 1 -C 8 alkanoyl, C 1 -C 8 alkoxycarbonyl, benzoyl or phenylacetyl, and the resulting compound is optionally converted to its pharmaceutically acceptable acid addition salt.