CS207671B2 - Method of making the piperazinylchinazoline derivatives - Google Patents

Abstract

The invention relates to new quinazoline derivatives of the formula (I) wherein (R)n represents 6,7-di(lower alkoxy) or 6,7,8-tri(lower alkoxy); m is 1 or 2; X represents -CHR1- or -CH2CH2-; each R1, which may be the same or different, represents hydrogen or lower alkyl; and R2 and R3, which may be the same or different, each represent hydrogen, lower alkyl, lower alkoxy, halogen, lower alkanoyl, lower alkoxycarbonyl or a group of the formula-CONR4R5 or -SO2NR4R5 wherein R4 and R5, which may be the same or different, each represent hydrogen or lower alkyl; and the pharmaceutically acceptable acid addition salts thereof. Two processes for preparing these derivatives are also described. The new quinazolines are useful as regulators of the cardiovascular system, in particular for the treatment of hypertension.

Description

The present invention relates to a process for the preparation of therapeutically effective novel 4-amino-1- (1-piperazinyl- or 1-homopipprazinequinazoline) derivatives, said compounds being useful as regulators of the cardiovascular system and in particular for the treatment of hypertension.

The novel compounds of the invention correspond to the general formula I,

nh ₂ in which (R) n represents a 6,7-diilkoxy group in which each alkoxy group contains 1 to 6 carbon atoms, or a 6,7,8-trioxy group in which each alkoxy group contains 1 to 6 carbon atoms, m has 1 or 2, ^X represents a radical -CH no ^{b R} a -C? CIL -, each of R ', R', R 11, which may be identical or different, represents a hydrogen atom or an alkyl group having 1-6 carbon carbon and

3 each of R and R-, which may be the same or different, represents a hydrogen atom, a C1-C6 alkyl group, a C1-C6 alkoxy group, a halogen atom, a C2-C6 alkanoyl group, an alkoxycarbonyl group - a group with 1 to 6 atoms in uhfku ^alk ox ^y ^ hunting ^E time no ^b oz ^{thee the} formula -S ^ N ^ R wherein each of R ^{4 and} sable ^- which may be the same or different, represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

The invention also includes pharmaceutically acceptable acid addition salts. ·. Salts of these compounds

Halogen atoms are fluorine, chlorine, bromine and iodine atoms. All alkyl, alkoxy and alkanoyl groups may be straight or branched and preferably contain up to 4 carbon atoms.

The pharmaceutically acceptable acid addition salts of the compounds of this invention are those derived from non-toxic acid addition salts containing pharmaceutically acceptable anions such as hydrochlorides, hydrobromides, sulfates or bisulfates, phosphates or acid phosphates, acetates, maleates, fumigates, succinates. , lactates, tartrates, citrates, gluconates, saccharates and p-toluenesulfonates.

One preferred group of compounds of the present invention are compounds of formula IA,

(IA) in which (R) n is a 6,7-di-a-6-di-6-group, wherein each of the (C 1 -C 6) -carbonyl group contains from 1 to 6 carbon atoms, or 6, 7,8-traaiooxyseskupeni wherein each llktχyskuρina contains 1 to 6 carbon atoms, ^R1 is not voďi ^b ^ alts of Vou quick match with ^1-6 atom and ^y coal.

ka ^moves ý from ^Y MboI ^{of R} and ^{R, the} liquor can ^b YT same no ^b of different ^A is H, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, halogen, · alkanoyl having 2 to 6 carbon atoms, or a radical of formula -SCLNR ⁴ R ⁵ , wherein

5 ^{to d} ý from ^Y MboI ^{of R 4} and ^{R kt} ns may be ^ be of the same not ^b o · rtzdílaé ^represents in ^ZDY hydrogen or alkyl having 1 to 6 carbon atoms, '' and their pharmaceutically upoořehitelné street salt with acids.

A further preferred group of compounds of the invention are those compounds of formula (I) wherein (R > n is 6,7-dimethoxy-6,7-diethethoxy- or 6,7,8-trimethoxy), m is 1 or 2p, respectively. MboI ^{y y r1, r1} and ^r · ⁿ nezávíle znammnaaí ^runs with hydrogen in ^ZDY not walk on ^b mettylovou group and

1 each of R 6 and R 6, which may be the same or different, represents a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group, a halogen atom, a C 2 -C 6 alkanoyl group , an alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkoxy moiety or the radical -SO ₂ N (CHh) ₂ .

the compounds of the invention having the general formula IB,

_NH2 wherein ^R1 zalmna ^and atoms as ^d Cart no ^b a methyl group and each of R ² and R ^ is hydrogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, halogen or alkanoyl C 2 -C 6. '

The most preferred individual compound of the invention is 4-amino-2- [4- (1,4-benzodioxane-2-carbonyl) -1-piperazinyl] -6,7-dimethoxyquinazoline.

Compounds of the invention containing one or more centers of asymmetry may exist in one or more pairs of enantiomers and these pairs as well as individual isomers may be separated by physical methods, for example, fractional crystallization of suitable salts. The invention includes separate pairs as well as mixtures thereof, racemic mixtures and resolved optically active d- and 1-isomeric forms.

J ^ X represents a tliže ^b yte ^to -CRR ¹¹ -, wherein R ¹¹ represents a ^{plurality of projections} with ^the nominal UPIN s is ^{from 1 to} 6 carbon atoms and is possibly cis-traás isomerit, while the present invention encompasses both isomeric forms as well as their mixtures.

In accordance with the invention, the compounds of formula (I) and their salts are prepared by quinazin (II) of formula (II),

(II) nh ₂ in which

Q is chlorine, bromine or iodine and (R) n is as defined above, reacted with piperazine or homooiperazine of formula III,

(III) wherein the individual symbols are as defined above, and the product of formula (I) obtained is optionally converted by treatment with a non-acidic acid into a pharmaceutically acceptable acid addition salt.

In this reaction, the hydrogen halide of the corresponding HQ is cleaved. Q is preferably chlorine or bromine.

The reaction is usually carried out by heating the reactants, for example to a temperature of from 80 to 150 ° C, for example to reflux, in an inert organic solvent, for example n-butanol. Upon completion of the reaction, the product can be isolated and purified by conventional means. In accordance with a typical embodiment, for example, the reaction mixture is cooled, the precipitated crude solid product is collected, washed, for example, with cold n-butanol and dried. The raw product is possible _? in accordance with a conventional embodiment, resolved by dissolving in hot aqueous dimethylformamide, filtering, and concentrating the swept solution, for example under vacuum. The solution is then cooled, and the addition of ether precipitates the pure product which can be filtered off and washed with ether.

The starting materials of formulas II and III are either known compounds or can be prepared by methods analogous to those known in the art. Thus, for example, the starting materials of formula III can be prepared according to the following reaction scheme:

(IN)

The intermediates of formulas IV and V are either known or can be prepared by conventional methods. When X is -CH 2 -, where r 1 'is C 1 -C 6 alkyl, the cis- and trans- isomers of the compound of formula (V) may exist. A mixture of these isomers may be used for the reaction, if to produce the product predominantly in the form of cis or trisulfonyl, then the corresponding cis or trans starting material can generally be prepared by substituting the corresponding methyl ester or ethyl ester followed by conversion to the acid chloride.

The pharmaceutically acceptable acid addition salts of the compounds of the invention may be prepared in a conventional manner, for example by reacting the free base with the appropriate acid in an inert organic solvent, and thereby precipitating the salt. If necessary, the obtained product can be resolved by reinstalling it. The products prepared according to the process of the invention often result in the form of acid-solders.

The invention also relates to pharmaceutically acceptable biocompounds of the compounds of formula I and their salts.

The term pharmaceutically acceptable bispteturist requires some light. To overcome a certain undesirable physical or chemical property of a drug, it is common practice in pharmaceutical chemistry to convert the drug to a chemical derivative that does not have the undesirable property, but which is converted back to the parent drug after administration to the animal or human. For example, if the drug is not well absorbed after oral administration to humans or humans, it is possible to convert it into a chemical derivative that absorbs well and from which the original drug is recovered in serum or tissue. Alternatively, if the drug is unstable in solution, it can be converted to a stable chemical derivative that can be applied in solution, but is again converted into the parent drug in the patient. Those of ordinary skill in pharmaceutical chemistry are well known in the art of overcoming the characteristic deficiencies of drugs by their chemical moieties, which are only transient and administered to an animal or human.

In the present invention, a pharmaceutically acceptable biopsy compound of formula (I) refers to a compound of a structural formula different from that of formula (I), which, however, is converted into a compound of formula (I) after application to an animal or human.

The antihypoetensive activity of the compounds of the invention demonstrates their ability to reduce the blood pressure of awake, spontaneously rats and awake, renally hypertensive dogs when administered orally at doses of 5 mg / kg.

The following is a summary of the results of tests on various compounds of the invention.

In these tests, the compounds of the invention were administered orally (usually in a mixture of methyl ethyl acetate and water) at a dose of 5 mg / kg to spontaneously hypertensive rats. Blood pressure was sensed and measured using an incision on the animal's tail. The results were calculated using the following formula:

the actual decrease in blood pressure (mm Hg) x 100 ^{of ES} okl Ualm in% = ^ y _{p νηί before apllicaeí te3to} _ Vane material (Pa) - 17392. The results are summarized in the following table.

compound maximum decrease time to k up to example no. blood pressure getting maximum decrease (%) (h)

1 77 6 2 . No. 6 3 44 4 4 72 2 5 81 6 6 22nd 1 7 67 6 8 1 16 2 9 58 1 10 100 ALIGN! 1 1 1 33 6 12 83 6 13  109 2 14 102 6 15 Dec 72 1 16 90 6 17 40 4 18 92 1 19 Dec 85 4 20 May ⁴⁰ 1 21 79 1 22nd 56 1 23 47 6

The compounds produced by the process of the invention may be administered alone, but are generally administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing, for example, starch or lactose as carriers, or in the form of capsules containing the active substances either alone or in admixture with carriers and / or excipients, or in the form of elixirs or suspensions containing flavors. additives or dyes. The compounds produced by the method of the invention may further be administered parenterally in the form of injections, for example, intramuscular, intravenous or subcutaneous injections. For parenteral administration, the disclosed compounds are best used in the form of sterile aqueous solutions which may contain other soluble substances, for example, an appropriate amount of sodium chloride or glucose to ensure the isotonic nature of the solution.

Accordingly, the present invention also provides pharmaceutical compositions comprising a compound of Formula I or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable diluent or carrier.

The compounds of the present invention may be administered to humans either orally or parenterally to treat hypertension. For oral administration, an average adult patient (70 kg) is administered a dose ranging from about 1 to 20 mg / day, in a single dose or divided into three divided doses. The intravenous dose is expected to be about 1/5 to 1/10 of the daily oral dose. Thus, for an average adult patient, an individual oral dosage in the form of a tablet or capsule will range from about 1 to 50 mg of the active ingredient. Of course, variations will necessarily occur in the present case depending on the weight and condition of the person being treated and the route of administration chosen, as is common in the art.

The invention further describes a method of treating ^ER Hyp tensivních animals, including humans, wherein at ≤ že'se sUšnnému administered to the animal an effective antihypertensive 'moOsSví compound of formula I or a pharmaceutically upoořebitelné acid addition salt thereof, or the above defined pharmaceutical composition. .

The invention is illustrated by the following examples, which are not to be construed as limiting the scope of the invention in any way. .

Example 1

4- [4- (1,4-benzodioxane-2-carbonyl) -1-etherazioyl] -6,7-dimethoxyquinazoline

140 g of 4-Amii ^ c ^ o- ^ _c ^ i _1] ^ (^]? - 6,7- ^ C ^: = methoxy; ^ C ^ C ^ i ^ i ^ i ^ ^ c ^ o 150 g of N- (1,4-benzodioxane-2-carbononyl) etherazone in 2 liters of o-butanol was refluxed for 3.5 hours, cooled to 80 ° C, the solid product was filtered off, washed The crude product is dissolved in a mixture of 530 ml of dimethylformamide and 130 ml of water heated to -80 DEG C., the solution is filtered, and the mixture is concentrated in vacuo to a volume of about 300 ml. After cooling down, 1.8 liters of ether are added, and the resulting solid is filtered off and washed with ether to give 215 g of 4-arinoo2- [4 '((1,4-benzo-oxo-oxo-kaaboonl) - (- peperazinyl) - 289 DEG-290 DEG C. 6,7-direthoxychioazoline hydrochloride.

For C23H25N5O5.HCl calculated: C 56.6%, H 5.4%, N 14.4%; found: C 56.9%, H 5.4%, N 14.4%.

Example 2

4- (minoo-- [4- (1,4-benzodioxane-2-carbonyl) -1-piperazin-6-one) -6,7,8-trirethoxyquinazoline 4-aminoo - ((hhoo-6, 7,8-trimethoxquinquinazoline and 1.168 g of N- (1,4-benzodioxane-2-carbonol) eiperazine in 67 ml of n-butanol together with 1.87 g of triehlycaria are refluxed for 24 hours. g of N - (1,4-beosodioxane-2-carborone) piperazine and the mixture was refluxed for an additional 30 hours, butanol was evaporated in vacuo and the residue was partitioned between aqueous sodium carbonate solution and chloroform. water, dried over sodium sulfate and evaporated in vacuo. 3.4 g of solid residue which is taken up in a minimal mnnostvím dimethylfomaamldu and allowed to stand overnight p ^{s t} EPLO 0 ° C. After BC ^IFA O ^{I H} et ERO alný ^{to d,} but the solution cooled to yield ^F is obtained 0.58 g of 4-aminoo2 - [[4- _(1> 4 benzoOfooxao - carbonyl) - (- eperaaZnyl; | -6,7,8-trirethюxychioazoliou a ^t e Lot ^{of p th} n ^e and ^{269 f} 271 C.

Andýza for ^{С 24Н27 М} 5 ° 6 Calculated: C 59.9,% H 5.7%, N 14.6%;

Found: C 59.3%, H 5.6, N 14.1, 1%.

Example 3

4-Amino-2- [4- (1H-benzodioxanecarboofi-1-piperazinyl) -6-diethoxyquinazoline

0.33 g of 4-nitro-2-cChox-6,7-diethoxichiorooleate 0.32 g of N- (1'-benzodioxane-4-carbororl) pebenoate was refluxed in 30 ml of o-butrool overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between sodium carbonate solution and chloroform. The combined chloroform extracts were washed; The residue is chromatographed on a 70 g silica gel column using chloroform / 0-5% mmol / n as the eluent. Similar fractions were combined and evaporated in vacuo, and the residue was taken up in chloroform / methanol and ethereal hydrogen chloride was added. The solution was evaporated in an external residue, and the residue was redissolved in isoxeroerole to give 0.19 g of 4-nitro-2- [4- (1,4-benzodioxane-2-carbonynyl) -1-piperazoyl] -7- (7-carboxylic acid). diethoxlchiorzx100 (hexylchloride-2 1/2-hydrate, quenching on rooklnd at 180 µl 184 ° C).

Anal. Calcd for C 25 H 29 N 5 Cl 5 .HCl.2 1/2 H 8 O: C 53.5%, H 6.3%, N 12.5%; orlezeox: C 53.3%, H 5.6%, N 12.2%.

Example 1 4

4-Amino-2- (4- (1,4-benzoddoxyl- · 2-carbonol) -1 · (β-β-piperidin) -6,7-diethoxyxazinazole

1.58 g of 4-amino-C-chloro-7,7-dimethoxy-quinazoline or 2,0 N-1,4-oeosodixan-2-carboxylic acid) homo-generazine in 114 ml of n-Outrool are boiled under reflux for 60 hours. The reaction mixture was cooled, butrool was evaporated in vacuo, the solid residue was triturated with ether, taken up in hot methanol, filtered and the filtrate cooled. The solid product is filtered off, and the residual root is evaporated in an oven, and the residue is taken up in a hot solution. The solution was cooled after filtration and re-evaporated in vacuo. The residue was combined with the initially treated solid product, and the product was washed with cold methanol and extracted with ethanol. To give 0.57 g of 4-rminoχC2C44 (1,4-OenzoXdoxxэoC kkrboxoll "1 cixmooepeebzZin'll 6,7-diie tho xy ihinazo linhydrochlor te ^ CS ^ o ^ t ^and n ^I 25 ^n? 25 ° C ^one .

Calcd for C 24 ^H 27 ^N 5 O 5 · HCl: C 57.4 H 5.6 Ni 14 0%;

orleoene: C 57.2 ´H 5.4%, N 13.8%.

The following compounds can be prepared in an analogous manner to the foregoing examples:

example. Z nh ₂ ^r1 m.p. (° C) mn ^ n (%) orleoeno (calculated) CH · N

H hydrochhoridc

-Hemihydrate

238 to 240 °

56.2 5.4 13.9 (56.4 5.7 13.7) (8- n 5-isomer mixture)

example number OF R 6 í _o X © ^ch ' ^ch '' ^{! U} 8 (mixture of 8- and 5-isomers) H 7 H 8 OCH-1X H 9 xX OCH ₃ H 10 XX> (mixture of 6- and 7-isomers) H 1 1 Όοχ at 12 H 13 £ O _W H 14 XO mixture of cis, trans H 15 Dec Ί0Ο H

melting point (° C) analysis (%) found (calculated) C H N hydrochloride- 58.0 6.2 '3,3 -Hemihydrate (57.9 6.2 13.0) 225-230 ° hydrochloride- 57.5 5.8 '3,3 -Hemihydrate (57.2 6.0 13.3) 286 DEG-288 DEG hydrochloride- 54.1 5.5 13.9 -Hemihydrate (54.7 5.5 13.3) 268-270 hydrochloride- 53.4 5.3 12.8 -hydrate (53.8 5.6 13.1) 230 ° (decomposition) hydrochloride- 52.3 4.8 12.8 -hydrate (52.0 4.9 13.2) 280 DEG-281 DEG heaihydrate 52.5 4.3 '3,2 242 to 243 (52.2 4.6 13.2) hydrochloride - 279-280 ° 56.5 5.6 '4,1 = -.3 [deg.] (56.6 5.4 14.4) (0.4% in dimethyl- formamide) hydrochloride 284-286 ° 56.2 5.4 4,5 Λ = + 95 ° (56.6 5.4 14.4) (0.4% in dimethyl- f orjnamidu) hydrochloride- 55.0 5.5 '3,6 -hydrate (55.4 5.8 '3,5) 237 DEG-240 DEG hydrochloride- 55.8 5.7 '3,1 -hydrate (55.4 5.8 13.5) · 242 DEG-243 DEG

trance

example OF R ¹ melting point analysis (%) number (° C) iron (calculated) C Η N

hydrochloride- 54.0 5.5 12.7 -dihydrate (53.6 6.0 13.0)

214 to 215

hydrochloride- -hydrate 234-237 ° 55.6 (55.4 5.4 5.8 13.3 13,5) hydrochloride- 55.6 5.2 13.0 -Hemihydrate (55.7 5.4 13.0) 272 ° hydrochloride- 54.4 5.2 12.8 -hydrate (54.8 5.5 12.8) 230 °

hydrochloride-

-hydrate 232-234 ° (decomposition) 48.6 (49.0 5i 3 5.4 13.5 13.7) hydrochloride- 55.3 6.1 12.9 -sesquimethanolate (55.7 6.2 12.7) 205-207 ° oxalate-seskvi- 53.8 5.4 11.6 hydrate (53.6 5.5 12.0) 176-179 ° hy dro cHLorid- -dihydrate 52.2 5.2 114 08 to 210 ° (52.4 5.8 11, 8)

(hygroscopic) (mixture of 6- and 7-isomers)

The following preparations illustrate the production of starting materials.

Preparation 1 (A) of N- (1,4-Benzooxoxa-cocaine) piperazine

The tone suspension is stirred

11.88 g of piperazine and 20.30 g of sodium acetate in a mixture of 70 ml of water and 95 ml at a temperature of 10-15 ° C are added, and concentrated hydrochloric acid is added until pH 1.5 (approx. 35 ml).

· While maintaining the temperature at ^10-15 ° C while maintaining the pH by adding NaOH to a value from 1.7 to 2.2 (5N NaOH, about 45 ml) was then added portionwise 31.0 g benzodioxan-2-karbonyychloridu. After the addition was complete, the pH was adjusted to 2.0 by addition of sodium hydroxide and the resulting suspension was stirred for 30 minutes. Water was added to the slurry until a homogeneous solution was formed, then the acetone was evaporated in vacuo and the aqueous residue was extracted three times with 200 ml of chloroform each. The aqueous phase is basified to pH 8-9 with 5N sodium hydroxide solution, extracted three times with 200 ml of chloroform each, the extracts are washed with water, dried over magnesium sulphate and evaporated in vacuo.

The oily residue was dissolved in ethyl acetate, ethereal hydrogen chloride was added to the solution, the mixture was evaporated in vacuo and the solid residue was first triturated with ether and then recrystallized from methanol. There were obtained 3.85 g of N- (1,4-benzodioxan-2-carbonyl) piperazinhydrochlori-du o ^ ^th the fence ²⁶⁵ and ^from 26 ⁷ ° ^C.

Analysis for C; HCl.

calculated: C 54, β%, H ¢, 0%, N9.8 found: C 54.6%, H 5.0%, N 9.7%.

Preparation 2

N- (1H-Benzodioxane-4-carbonyl) homooppprazine

This compound was obtained in an analogous manner to Preparation 1, using homopiperazine instead of piperazine. A sample of the hyro-chloride of the product obtained melts after recrystallization from methanol at 189 ° C.

H, 6.4%; N, 9.4 Found: C, 56.2%; H, 6.2 $., N, 9.3. .

Claims (2)

SUBJECT OF THE INVENTION A process for the preparation of pipeoazinylquinazoline derivatives of the general formula I. wherein (R) o represents a 6,7-rialkoxy group in which each alkoxy group contains 1 to 6 carbon atoms, or a 6,7,8-traacoxy group in which each alkoxy group contains 1 to 6 carbon atoms, m is 1 or 2 , * ' X is ^and Z ^b yte ^to C ^HR '- or - ^CKD .- Each of R, R and R, which may be the same or different, represents a hydrogen atom or a C 1 -C 6 alkyl group, and each of the R and R 6, which may be the same or different, represents is hydrogen, alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, a halogen atom, an alkanoyl group having 2-6 carbon atoms, alkoxycarbonyl having 1 to 6 carbon ulhYku in the alkoxy ^Y moieties of or ^b yte ^to -S ^^ ^ ⁴ with the toe of Kama ^y mbo! L ^{of R4} and R ^ 11, which may be the same or different, represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and pharmaceutically acceptable acid addition salts thereof, characterized in that the quinazoline of the formula II, (II) nh ₂ in which: Q is chlorine, bromine or iodine and (R) _n is as defined above, reacted with piperazane or homopiperazine of formula (III), (III) wherein the individual symbols are as defined above, and the product of formula (I) is optionally converted by reaction with a non-toxic acid to a pharmaceutically acceptable acid addition salt. 2. The process of item 1 for producing compounds of formula IA, wherein:. (R) _n represents a 6,7-dialkoxy group in which each alkyloxy group contains 1 to 6 carbon atoms, or a 6,7,8-trioxinoxy group in which each alkyloxy group contains 1 to 6 carbon atoms, r 'represents a hydrogen atom or an alkyl group (1-6C) atoms and each of R ⁶ and R ⁶ which may be the same or different is hydrogen, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, halogen, (C 2 -C 6) -alkanyl up to 6 carbon atoms or a radical of formula -SOogRRR, wherein each of R ⁴ and R 6, which may be the same or different, each represent a hydrogen atom or a C 1 -C 6 alkyl group, and their pharmaceutically acceptable acid addition salts, characterized by reacting the quinazoline of the above-mentioned general formula (II), in which (R) _R and Q have the meaning as in 1, with a piperazine of the general formula (IIIA), (IIIA) in which 16 7 R @ ¹ , R @ ¹ and R @ 1 are as defined herein, and the product of formula (I) obtained is optionally converted by treatment with a nontoxic acid into a pharmaceutically acceptable acid addition salt.