HU208118B - Process for producing tetrahydropyridine derivatives and pharmaceutical compositions comprising such compounds - Google Patents

Abstract

The invention relates to novel tetrahydropyridine derivatives, a process for their preparation and pharmaceutical compositions containing such compounds as active agents. In formula (I), Ar<1> means a phenyl group optionally mono- or polysubstituted, Ar<2> means a phenyl group optionally substituted, R<1> means a hydrogen atom or an alkyl group with 1-6 carbon atoms, n can be either 0 or 1 with the proviso that if n = 0 then R<1> can only mean a hydrogen atom and Ar<2> is in any case substituted.

Description

The present invention relates to novel tetrahydropyridine derivatives of formula (I): wherein:

Ar ¹ is phenyl substituted with (C 1 -C 4) alkyl, hydroxy, 1 to 2 halogens, or 1 to 3 (C 1 -C 4) alkoxy,

Ar is phenyl, which may be monosubstituted with halogen or trifluoromethyl,

R ¹ is hydrogen or (C 1 -C 4) alkyl, n is 0 or 1 with the proviso that when n is 0 then R ¹ is hydrogen and Ar ^{2 is} always substituted and the acid addition salts thereof are prepared.

The compounds of formula I according to the invention are biologically active and have a significant nootropic effect.

The invention further relates to a process for the preparation of a novel pharmaceutical composition comprising a tetrahydropyridine derivative of the Formula I and a pharmaceutically acceptable acid addition salt thereof.

Suitable halogen substituents include fluorine, chlorine, bromine or iodine.

Alkyl groups, alone or as part of other groups, may be straight or branched chain saturated hydrocarbon groups having carbon numbers which may be, e.g. .

Depending on the n value of the compounds of formula (I), they are considered to be α- or β-amino ketones having a nitrogen atom as the heteroatom of the substituted tetrahydropyridine ring.

The β-amino ketones, also known as Mannich ketones, are well known. Their chemical properties include E E Blicke: Organic Ractions Vol. 303- 341. J. Wiley, New York, London (1942); B. Reichert, Die Mannich-Reaction, Springer Verlag, Berlin Göttingen-Heidelberg (1959); H. Hellmann-G. Opitz: aAminoalkylierung, Verlag Chemie, Weinheim / Bergstr. (1960).

Within this circle, the types of compounds described so far are very diverse, with a large number of specific compounds. Examples of major therapeutically important β-ketones are Nos. 9330 and 9565. Propipocaine Hydrochloride [3- (1-piperidinyl) -1- (4-propoxyphenyl) -1-propanone] having local anesthetic activity, as described in GDR Patent No. 6,194, or U.S. Pat. a vasodilator and toperisone hydrochloride [2-methyl- (4-methylphenyl) -3- (1-piperidinyl) -1-propanone] having central muscle relaxant activity. Also included is oxyfedrine hydrochloride (R (R *, S *) 3- (2-hydroxy-1-methyl-2-phenylethyl) amino-1- (3-methoxyphenyl) -1-) acting on the coronary artery. propanone] disclosed in German Patent No. 1 439574 and 6- [3- (3-phenylpyrrolidinyl) propionyl] -benzodioxane described in German Patent Publication No. 2252344 with α-receptor blocking action.

Among other compounds, β-aminoketones containing nitrogen as a member of the tetrahydropyridine ring are disclosed in U.S. Patent No. 3,426,036. U.S. Pat. The compounds have a muscle relaxant effect.

Also tetrahydropyridine derivatives, which may be understood as α-amino ketones, are described by M. Rajsner, E. Adlerova and M. Protiva Collection Czechoslov. Chem. Communs. 28, 1031-43 (1963), although the analgesic effect mentioned in this article for compounds containing a tetrahydropyridine ring is not demonstrated.

M. Celadnik, K. Palát, A. Sehere, C. Vrba: Arch. Pharm. 291: 3 (1958) disclose two β-aminoketones substituted with thiomorpholinyl. These two compounds are mentioned in the cited literature as a local anesthetic.

Among the γ-aminoketones which are considered to be structurally related to the compounds of formula (I) are the 4- [4- (4-chlorophenyl) -4-hydroxy-1-piperidinyl] -1- (4) with neuroleptic properties known as haloperidol. -fluorophenyl) -1-butanone having a large number of structural analogues. The same group includes the antihypertensive pitenodil, whose chemical name is 2- [4- [3- (tenoyl) propyl] -1-piperazinyl] ethyl dimethylcarbamate. Nos. 865,314 and 870,700. German patents also disclose a compound of the γ-aminoketone type, an analgesic known as methadone, which is chemically 6- (dimethylamino) -4,4-diphenyl-3-heptanone.

In contrast, it has been found that the compounds of formula I, wherein Ar ¹ , Ar ² , R ¹ and n are as defined above, have significant nootropic activity. In particular, these substances protect brain function from the damaging effects of various cognitive factors, such as hypoxia, on cognitive function.

This effect is demonstrated by measuring memory damage caused by hypoxia.

Male spontaneous hypertensive rats weighing 190-220 grams (mean blood pressure 180-220 mmHg) are trained in automated, two-space shuttle boxes to elicit a two-way active response. The animals complete 30 cycles daily consisting of 15 seconds of intersignal rest time, 15 seconds of light stimulus time (conditional stimulus: flashing light at 1 Hz), and 10 seconds of shock (unconditioned stimulus: 0.8 mA across the trachea). Animals can avoid electric shocks by switching to space during the light stimulus, thus exhibiting conditional response responses. The experimental animals were conditioned for 3 days.

On day 4, the animals were treated with an oral dose of 10.0 mg / kg (5 ml / kg) of test compound (n = 6). Two solvent-treated control groups (n = 6) were used for the measurement, one of which performs 30 daily cycles (mormoxic and hypoxic controls) under normoxic conditions and the other under hypoxic conditions. After 60 minutes of pretreatment with the solvent or test compound, the animals are placed in a shuttle box where the oxygen content of the inhaled air is reduced to 6% by 10 minutes by flow of compressed air enriched in nitrogen (200 rpm / box). After the equilibrium is reached, the chin2

HU 208 118 Β cases perform 30 cycles under hypoxic conditions.

The number of conditional reactions is automatically recorded by the microprocessor-controlled system. Group averages are calculated from the number of conditional reactions displayed by each animal. The percentage of antihypoxic activity of the test compounds is calculated using the following formula:

where

A = average of conditional response responses in the normoxic control group at day 4

B = mean of the hypoxic control group conditional response at day 4

C = mean value of conditional response at day 4 for the group treated with 10.0 mg / kg oral dose of the test compound.

The effects of some of the compounds of formula (I) of the present invention on hypoxia-induced memory damage and acute toxicity data are summarized in Table I below.

Table 1

Example number of active ingredient Dose in mg / kg p.o. Memory Damage Protection (%) LD ₅ o (mg / kg) First 10.0 60 > 2000 27th 10.0 54 > 1000 11th 10.0 51 1150 14th 10.0 83 1200 16th 10.0 50 > 1000 17th 10.0 54 850 10th 10.0 67 > 2000 21st 10.0 64 > 2000 vincamine (comparative) 10.0 24 760 naftidrofuryl (comparative) 100.0 0 - piracetam (comparative) 100.0 71 > 2000 10.0 0 -

The so-called. A common feature of cognitive stimulants is their ability to protect upper nervous system functions from the action of various damaging agents. The normobaric hypoxia used in our study is intended to model human conditions in which cognitive function is impaired as a result of circulatory or metabolic disorders (e.g., elderly supply disorders).

The reference materials used in the experiment are widely used in the therapy of old age or other memory impairment. Vincamine and naphthydrofuril exert their beneficial effects by dilating cerebral blood vessels and stimulating cerebral metabolism, with piracetam acting primarily through cerebral metabolism. These materials also provide protection against effects in memory that damage memory.

In our normobaric hypoxic model used for comparison, vincamine showed a limited effect at a dose of 10.0 mg / kg, naphthydrofuril was not effective at 100.0 mg / kg, piracetam at 10.0 mg / kg was ineffective and only 100 At 0 mg / kg.

In contrast, the compounds of the present invention provided significant protection against memory damage at an oral dose of 10.0 mg / kg and thus were more effective than compounds widely used in human therapy.

Toxicity studies were performed on mice weighing 19-21 grams. Test substances were administered via a gastric tube at a volume of 0.1 ml / 10 g body weight. LD ₅₀ values were calculated according to Litchfield-Wilcoxon.

From the data in Table I it can be seen that the compounds according to the invention have a suitable therapeutic width when administered orally.

According to the invention, the novel tetrahydropyridine derivatives of the formula (I) are represented by the formula

Ar ¹ is phenyl substituted with (C 1 -C 4) alkyl, hydroxy, 1 to 2 halogens or (C 1 -C 4) alkoxy,

AR ² is phenyl, which may be monosubstituted by halogen or trifluoromethylene,

R ¹ is hydrogen or (C 1 -C 4) alkyl, n is 0 or 1, with the proviso that when n is 0, R 'can only be hydrogen and Ar ^{2 is} always substituted and their acid addition salts can be prepared by

a) a ketone of formula II in the formula

Ar ¹ , R ¹ and n are as defined above and X is halogen, with a substituted tetrahydropyridine derivative of formula (III) wherein Ar ² is as defined above, or

b) for the preparation of compounds of formula I wherein n is 1, Ar ¹ , Ar ² and R ¹ are as defined above for a ketone of formula IV wherein Ar ¹ , R ¹ is as defined above, With a tetrahydropyridine derivative (III) or a salt thereof, wherein Ar ² is formaldehyde or formaldehyde releasing agent as defined above and optionally converting a compound of formula (I) obtained by a) or b) into an acid addition salt.

The process (a) of the present invention is preferably carried out by reacting a tetrahydropyridine derivative (III) in the form of a base with a halogen derivative (II) in a polar solvent, e.g. acetone, ethanol or acetonitrile3

EN 208 118 Β or a mixture thereof, using an acid acceptor which binds the HX acid formed during the reaction. The acid acceptor may be a lower tertiary amine, preferably triethylamine or 1-methylpiperidine, or a salt of a weaker acid than HX, preferably an organic acid, preferably sodium acetate. If starting from a compound of formula II wherein n is 0, it is convenient to cool the reaction mixture.

The compounds of formula (I) obtained in the form of a base may be converted, if desired, into salts.

Pharmaceutically acceptable mineral acids are most suitable for the salt formation of both compounds of formula (I) and (III). Thus, hydrochloric acid, hydrobromic acid, sulfuric acid and others are preferred. In the case of the compounds of the formula I, the salt-forming agent may also be pharmaceutically acceptable organic acids, preferably methanesulfonic acid, fumaric acid and the like, in particular to increase the water solubility of the compound.

The crude product can be purified by recrystallization.

Process b) of the present invention is preferably carried out by condensing an aromatic ketone of formula IV wherein Ar ¹ and R ¹ are as defined above in a polar solvent with paraformaldehyde and a salt of a tetrahydropyridine derivative of formula III reaction. Preferably the solvent is ethanol or 2-propanol. It is preferable to use paraformaldehyde in excess of 2.5 times the molar ratio of ketone to the reaction rather than at one dose. Depolymerization of paraformaldehyde to formaldehyde may be catalyzed by an acid, preferably an acid used to form a salt of a tetrahydropyridine compound of formula (III).

Formaldehyde may also be used in place of paraformaldehyde, preferably in aqueous solution. The reaction is then carried out in the presence of a water-miscible organic solvent, preferably ethanol or methanol, to provide a homogeneous reaction medium. Instead of paraformaldehyde, it is also possible to use compounds which are converted during the reaction to formaldehyde and to a compound which does not interfere with the desired reaction. Acetals of formaldehyde with lower aliphatic alcohols, preferably dimethoxy or diethoxyethane, meet this requirement. It is also advisable to react the acetals in several portions.

The progress of the reaction can be monitored by thin layer chromatography and can also be used to determine the optimum reaction time. In most cases, the compound of formula (I) precipitates upon cooling upon completion of the reaction. Otherwise, other miscible solvents, e.g. addition of acetone to promote crystallization. The base of the difficult to crystallize salt of the final product of formula (I) is liberated in an aqueous medium with an alkali metal carbonate, for example potassium carbonate, which is extracted with an apolar solvent and then converted to the desired salt after conventional isolation.

Recrystallization of the crude compound of formula (I) is carried out in the usual manner. For this purpose, it is preferable to use methanol alone or a mixture of methanol and ethanol in order to release the crude product from the salt of the heterocyclic compound of formula (III). Of course, other polar solvents, e.g. acetone, acetonitrile may also be used. The homogeneity of the final product can also be checked by thin layer chromatography.

The starting compounds of formulas II and IV are generally known and can be prepared by conventional methods for this type of compound. However, the tetrahydropyridine derivatives of formula (III) are barely known. These are disclosed in U.S. Patent No. 2973,363. It is prepared according to U.S. Pat. No. 5,197 and can be prepared from α-methylstyrene or phenyl substituted derivatives thereof.

The compounds of the invention may be formulated into pharmaceutical compositions. The pharmaceutical composition may be administered orally, rectally and / or parenterally. For oral administration, the composition may be in the form of, for example, tablets, dragees or capsules. For the preparation of oral preparations, for example, lactose or starch may be used as fillers. Gelatin, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or starch gelling agents may be used as binders or granulating agents. The disintegrants are preferably potato starch or microcrystalline cellulose, but ultra-amylopectin or formaldehyde casein and the like can be used. too. Talc, colloidal silica, stearin, calcium and magnesium stearate, etc. as antiadhesive and lubricating agents. It can be used. Liquid oral preparations include, for example, suspensions, syrups, elixirs, and may include water, glycols, oils, alcohols, coloring and flavoring agents.

For example, the tablet may be prepared by wet granulation followed by compression. The blended excipients, and optionally a part of the disintegrant, are granulated with an aqueous, alcoholic, or aqueous-alcoholic solution of the binders in a suitable apparatus, and the granulate is dried. Thereafter, other disintegrants, lubricants and anti-adhesives are mixed with the dried granulate and compressed into tablets. Optionally, the tablet may be provided with a score line for ease of administration. Tablets may also be prepared directly from the mixture of the active ingredient and suitable excipients by direct compression. If desired, the tablets may be formulated with protective, flavoring or coloring agents commonly used in pharmaceutical formulations such as sugar, cellulose derivatives (methyl or ethyl cellulose, sodium salt of carboxymethyl cellulose, etc.), polyvinylpyrrolidone, calcium phosphate, calcium carbonate. , food colorings, food colorants, flavorings, iron oxide pigments, etc. using pellets. When preparing a capsule, the mixture of active ingredients and excipients is filled into a capsule.

For rectal administration, the composition is prepared in the form of a suppository. In addition to the active ingredient, the suppository contains a carrier mass, called adeps pro suppositor.

HU 208 118 Β

Suitable carriers include vegetable fats, such as hardened vegetable oils, triglycerides of C12-C18 fatty acids (preferably carriers known as Witepsol). The active ingredient is homogeneously distributed in the molten carrier mass and suppositories are prepared by molding.

For parenteral administration, the composition is prepared by injection. In preparing a solution for injection, the active compounds are optionally dissolved in distilled water and / or in various organic solvents, such as glycol ethers, in the presence of solution mediators such as polyoxyethylene sorbitan monolaurate, monooleate, or monostearate (Tween 20, Tween 60, Tween 80). The solution for injection may also contain various excipients, such as preservatives, such as ethylenediaminetetraacetate, as well as pH-adjusting and buffering agents, and optionally a local anesthetic such as lidocaine. The solution for injection containing the pharmaceutical composition of the invention is filtered before filling into the ampoule and then sterilized after filling.

Further details of the invention are illustrated by the following non-limiting examples. The yields given refer to compounds purified to a constant melting point.

Example 1

4- (4-chlorophenyl) -l - [(4-chlorophenyl) carbonylamino etilj1,2,3,6-tetrahydropyridine hydrochloride

To 4.28 g (0.022 mol) of 4- [4- (chlorophenyl)] - 1,2,3,6-tetrahydropyridine hydrochloride was added 25 cm ^{3 of} ethanol followed by 3.6 g (0.044 mol) of sodium acetate. Under stirring, 3-chloro-1- (4-chlorophenyl) propan-1-one (4.9 g, 0.024 mol) was added in small portions to the suspension. After the addition, the reaction mixture was stirred for an additional 3 hours. It is then evaporated to dryness and 50 cm ^{3 of} water are added to the residue. The mixture was neutralized with sodium bicarbonate and extracted with chloroform. The chloroform solution was evaporated after drying. The residue was dissolved in a small amount of ethanol and acidified with ethereal hydrogen chloride. The precipitated crystalline material weighed 6.0 g. Yield 68.7% based on crude product. Recrystallized twice from ethanol, m.p. 204-205 ° C.

AII. Table I below summarizes the compounds of formula I, prepared as described in Example 1, wherein R ¹ is hydrogen and, unless otherwise stated, n is 1.

Table 11

example Number With ¹ With ² Salt Melting point (° C) Recrystallization. solvent Second 4-fluorophenyl 4-chlorophenyl HC1 200 EtOH-i-PrOH, 1: 1 Third phenyl phenyl HC1 162 i-PrOH 4th ethylphenyl phenyl HC1 170 i-PrOH 5th phenyl 4-fluorophenyl HC1 178 i-PrOH 6th 4-ethylphenyl 4-fluorophenyl HC1 185 i-PrOH 7th 4-chlorophenyl phenyl HC1 186-187 EtOH 8th 4-fluorophenyl phenyl HC1 185-186 EtOH 9th 4-fluorophenyl 4-fluorophenyl HCI 191-192 EtOH 10th 4-chlorophenyl 4-fluorophenyl HC1 194-195 EtOH 11th 4-ethylphenyl 3- (trifluoromethyl) phenyl HBr 191 EtOH-i-PrOH, 1: 1 12th phenyl 3- (trifluoromethyl) phenyl HBr 187-187.5 MeOH-EtOH, 1: 1 13th 4-chlorophenyl 3- (trifluoromethyl) phenyl HBr 206-207 MeOH 14th 4-fluorophenyl 3- (trifluoromethyl) phenyl) HBr 200 MeOH-EtOH, 2: 3 15th 4-fluorophenyl 4-methylphenyl HBr 200-201 MeOH 16th phenyl 4-methylphenyl HBr 186 EtOH 17th 4-ethylphenyl 4-methylphenyl HBr 186 i-PrOH 18th phenyl 3-methylphenyl HCI 174-175 EtOH 19th 4-fluorophenyl 3-methylphenyl HCI 199-201 EtOH 20th 4-chlorophenyl 3-methylphenyl HCI 193-195 EtOH 21. * phenyl 4-chlorophenyl HCI 220-221 EtOH 22. * phenyl 3- (trifluoromethyl) phenyl HCI 200-202 i-PrOH

* n is 0.

Abbreviations: MeOH means methanol, EtOH means ethanol, i-PrOH isopropanol.

HU 208 118 B

Example 23

4-phenyl-l- [3,4,5-trimethoxyphenyl) carbonyl-ethyl] 1,2,3,6-tetrahydropyridin

To a mixture of 2.93 g (0.015 mol) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride, 3.58 g (0.017 mol) of 3,4,5-trimethoxyacetophenone and 30 cm ^{3 of} ethanol was added 0.8 g (0.027 mol) of mole) of paraformaldehyde was added and the reaction mixture was refluxed. After 1 hour, another 0.4 g (0.013 mol) of paraformaldehyde was added and refluxed for another 5 hours. The solution was concentrated, added to 25 cm ³ of water to the residue was neutralized with sodium bicarbonate and extracted with chloroform. After drying the chloroform solution, the residue was dissolved in a small amount of ethanol and converted to the hydrochloride as in Example 1, and the crystalline precipitate was filtered off to give 2.9 g of product.

Yield: 2.9 g.

Recrystallized twice from ethanol, m.p. 188-189 ° C.

Yield: 46.3%.

In III. Table II summarizes the compounds of formula (I) prepared as described in Example 1, Example 10, wherein n is 1 and, unless otherwise stated, R ¹ is hydrogen.

Table 111

example Number With ¹ With ² Salt melting point (° C) Recrystallization. solvent 24th 4-hydroxyphenyl 4-chlorophenyl HC1 i98-199 MeOH 25th 3,4,5-trimethoxyphenyl 4-chlorophenyl HC1 194-195 EtOH 26th 4-methylphenyl 4-chlorophenyl HC1 186-187 EtOH 27th 3,4,5-trimethoxyphenyl 4-fluorophenyl HC1 185 i-PrOH 28th phenyl 3- (trifluoromethyl) phenyl HBr 187-187.5 MeOH-EtOH, 1: 1 29th 2-fluorophenyl 3- (trifluoromethyl) phenyl HBr 167 MeOH 30. * 3-ethyl-4-fluoro-phenyl 3- (trifluoromethyl) phenyl HBr 187 EtOH 31st 3,4-dichlorophenyl 4-chlorophenyl HC1 192-194 EtOH 32nd 3-methoxyphenyl 4-chlorophenyl HC1 181-182 EtOH 33rd 3,4-dimethoxyphenyl 4-chlorophenyl HC1 190-191 EtOH

'R ¹ ' is methyl.

Abbreviations: MeOH means methanol, EtOH means ethanol, i-PrOH means isopropanol.

Claims (7)

A process for the preparation of a novel tetrahydropyridine derivative of formula (I) wherein: Ar is phenyl which may be substituted by (C 1 -C 4) alkyl, hydroxy, 1 to 2 halogens or (C 1 -C 4) alkoxy. Ar is phenyl, which may be monosubstituted with halogen or trifluoromethyl, R ¹ is hydrogen or (C 1 -C 4) alkyl, n is 0 or 1 with the proviso that when n is 0, R ¹ is hydrogen only and Ar ^{2 is} always substituted to form their acid addition salts, (a) a ketone of formula (II): Ar ¹ , R ² , and n are reacted with a substituted tetrahydropyridine derivative of formula (III) as defined herein, wherein Ar ² is as defined in Reference 55, or b) for the preparation of compounds of formula I wherein n is 1, Ar ¹ , Ar ² and R ¹ are as defined herein, a ketone of formula IV wherein Ar ¹ , R ¹ is 60; 35) with a tetrahydropyridine derivative represented by the general formula (III), in which Ar is as defined in the prior art, or a salt, formaldehyde or formaldehyde-releasing agent thereof, And optionally converting a compound of formula (I) obtained by process (a) or (b) into an acid addition salt. Processes a) and b) according to claim 1, characterized in that the reaction is carried out in a polar solvent, Preferably, it is carried out in a C 1 -C 6 alkanol or ketone. Process (a) according to claim 1, characterized in that the acid acceptor is a lower tertiary amine, preferably trimethylamine, or sodium acetate. Process b) according to claim 1, characterized in that the formaldehyde release agent is paraformaldehyde or dimethoxymethane. 5. A process for the preparation of a pharmaceutical composition, wherein a novel tetrahydropyridine derivative of formula (I), wherein Ar is phenyl, which is (C1-C4) -alkyl, hydroxy, 1-2 halo, or 1-3 (1). (C4-C4) alkoxy, HU 208 118 Β Ar ² is phenyl, which may be monosubstituted with halogen or trifluoromethylene, R ¹ is hydrogen or (C 1 -C 4) alkyl, n is 0 or 1, with the proviso that when n is 0, R ¹ is hydrogen only and Ar ^{2 is} always substituted or a pharmaceutically acceptable acid addition salt thereof. and / or adjuvant. 6. A process for the preparation of a pharmaceutical composition according to claim 5, characterized in that 4- (4-chlorophenyl) -1- [4-chlorophenyl) carbonyl ethyl] -1,2,3,6-tetrahydropyridine, 4- (4-fluorophenyl) -1 - [(3,4,5-trimethoxyphenyl) carbonyl ethyl] -1,2,3,6-tetrahydropyridine, 4- [3- (trifluoromethyl) phenyl] -l - [(4-ethylphenyl) carbonylethyl] -l, 2,3,6-tetrahydropyridine, 4- [3- (trifluoromethyl) phenyl] -1 - [(4-fluorophenyl) carbonyl] ethyl] -1,2,3,6-tetrahydropyridine, 4- [3- (trifluoromethyl) phenyl] -l- (phenyl-carbonyl-ethyl) -1,2,3,6-tetrahydropyridine, 4- (4-methylphenyl) -l - [(4-ethylphenyl) ethyl-carbonyl] -l, 2,3,6tetrahidropiridin, 10 4- (4-fluorophenyl) -1 - [(4-chlorophenyl) carbonyl ethyl] 1,2,3,6-tetrahydropyridine, 4- (4-chlorophenyl) -1- (phenyl) -carbonylmethyl) -1,2,3,6-tetrahydropyridine, or a pharmaceutically acceptable acid addition salt thereof, with a pharmaceutically acceptable carrier and / or excipient.