CS245899B1 - 6-substituted and 2-chloro-6-substituted 10-piperazino-10,11-dihydrodibenzo(b,f)thiepines and their methanesulphonates - Google Patents

Description

The invention relates to 6-substituted and 2-chloro-6-substituted 10-piperazrazo-10,11-dihydrodibenzo (b, phthiepines of formula I,

wherein R is methyl, ethyl or inethoxy; and R ¹ is hydrogen or chlorine, and their methinesulfomates.

The compounds of the formula I, in particular in the form of their methanesulfonates, are psychotropically active substances which are of interest in that their efficacy includes both neuroleptic and anti-depressant features, with some of the compounds according to the invention being predominantly one or the other component. In all cases, they are non-catalaiptic, suggesting that patients will be free of extrapyramidal side effects. Although they still have a number of central and vegetative neurotrophic effects and, in part, some effects on the cardiovascular system, the compounds of Formula I are practically useful mild antipsychotics with a neuroleptic and / or autidepressant component of action, their main indications being schizophrenia and depressive psychoses.

The following specific data on the effects of the individual substances according to the invention were obtained either in in vitro tests or in in vivo tests in experimental animals. All of the dimethanesulfonates were used for testing, and the doses are calculated on a base basis.

6-Methyl-10-pipera, zino-10,11-dihydrodibenzo (b, phthiepine (I, R = CH ₂ , "R ¹ = H"). Incoordinating action in rotating rod test in mice; Oral dose, 25 mg / kg induces ataxia in 40% of animals It significantly potentiates the toxicity of yohimbine in mice, typical of antidepressants; ED- ₍₎ = 4.6 mg / kg po (dose that results in 50% of mice who were 1 hour after administration a non-toxic dose of 20 mg / kg of scohimbine was administered to the substance to release ( ³ H) imiipruimine from its binding sites in the rat hypothalamus, again typical of antidepressants, IC ₅₀ ~ 335.8 nM (comparable to Effect of mouse locomotor activity in the Dews beam test: 30 mg / kg dose first decreases activity to 41% of control value, but this decrease in activity is followed by an increase to 200 to 400% of control value (effect very similar to Peripheral antiadrenergic effect, PD ₅₀ = 10.5 mg / kg po (dose that protects 50% of the mice from the lethal effect of adrenaline). Overall, the substance is predominantly antidepressant.

6-Ethyl-10-piperazino-10,11-dihydrodibenzoate (b, f Jthiepine (I, R = C ₂ H ₅ , R ¹ = H) Acute toxicity in mice, LD ₅₀ = 50 mg / kg iv very mild incoordination effect in mice, dose 200 mg / kg after inducing -ataxia in 40% of animals Potentiate yohimbim toxicity in mice about ten times weaker than the previous compound, ED ₅ o = 36.1 mg / kg po

Hypothermal effect in rats; a dose of 5 to 10 mg / kg i.p. reduces the rectal temperature by 1 degree Celsius. Spasmiolytic effect in vitro - on isolated rat duodenum; concentrations of 1 to 10 µg / ml lead to a reduction in acetylcholine and barium, chloride conitrafrations by 50% (papaverine-type effect).

At the i. V. Dose of 5 mg / kg, it causes short and deep piocles of blood pressure in normotensive rats. The substance shows a general indication of the nature of an antidepressant with vegetative side effects.

6-Methoxy-10-piperazino-10,11-dihydrodibenzo- (b, phthiepine (I, R = OCH ₃ , R ¹ = H). Incoordination action in mice, ED ₅₀ = 20.3 mg / kg p.o. -. relatively strongly potentiates yohimbine toxicity in mice, ED ™ 7.8 mg / kg exhibited relatively weak affinity binding sites pHjimip tyramine in rat hypothalamus; IC _{50 to} 1 520 nm (comparable effect -antidepresiva nomifensiniu). effect on locomotor activity, mouse: dose of 30 mg / kg p.o. initially reduces activity to 30% of control, but this decrease is followed by hypermatility (200-400%) .The peripheral aintiadrenergic effect is weak; doses of 10 a (25 mig / kg p.o.-) protect only 20% of the mice from the lethal effect of adrenaline. The effect on, o-br-ait and dopamine metabolism in the striatum-rat brain- 25 mg / kg dose. p.-o. significantly increases the level of homovanilic acid, which is typical of neuroleptics Antagonism to verticalization (climbing) of mice induced by a dose of 2 m g / kg sc apomorphine PD ₅₀ 30 mg / kg po (dose blocking said response in 50% of animals); typical of neuroleptics. The substance is now predominantly a neuroteptic, whereas the thymole effect is only indicated.

2-Chloro-6-methyl-10-piperazino-10,11-dihydrodibenzo (b, phthiepine (I, R = CH ₃ , R ¹ = - Cl). Acute toxicity in mice, LD ₅₀ = 30 mg / kg iv It has a high incordinating effect in mice, ED ₅₀ = 3.6 mg / kg po It significantly sensitizes the toxicity of yo-himbin in mice; ED ₅₀ - 3.8 mg / kg po (similarly effective as It exhibits a remarkable antagnionismius against apomorphine ve-r, ticalisation in mice; PD ₅₀ = 9.7 mg / kg p.o. (comparable to the effect, thioridazine j.). in a test for the lethal effect of adrenaline in mice, PD ₅₀ = 3.8 mg / kg p.o. at an intravenous dose of 0.05 and 0.1 mg / kg reduces adrenaline pres-oric-kau-response to It has a slice effect in the test for affecting dopiarainic turnover and metabolism in rat striatum, already an oral dose of 0.5 mg / kg significantly increases the level of homovanilic acid in the striatum, has hypothermic activity in rats, ED = 1 mg / kg ip V considerably over-the-above-mend thiopental sleep in mice, intravenous doses of 0.5 to 1.0 mg / kg thiopentalového prolong the duration of sleep to 200% of control values.

It exhibits a marked lantiamphetamine effect in mice; at an intravenous dose of 2.5 mg / kg it protects 100% of the animals from the lethal effect of amphetamine. In the last three tests, the substance is equivalent to chloro-orpromazine. It has an antihistamine effect in guinea-pig, ED = - = 0.5 to 1.0 mg / kg s.-c. (a dose that protects 50% of the animals from the lethal effect of an intra -ugally administered dose of 5 mg / kg histamine). At concentrations of 1 to 10 µg / ml, it has a spasmolytic effect on the isolated rat diuoden against both acetythiol and barium chloride (contraction reduction by 50%). At an intravenous dose of 6 mg / kg, it induces short and deep reductions in blood pressure in normotensive rats. It is a mixed type of neuroleptic and antidepressant, and the neurolytic component is very prominent.

β-Chior-ε-methoxy-10-piperazinolin-10,11-dihydro-dibenzo (b, phthiepin (I, R = OCH ₃ , R ¹ = Cl) Acute toxicity in mice, LD 50 = 60 mg / kg iv Incoordination effect in mice, ED _5n 8.8 mg / kg po It shows a significant effect in the apomorphine antagonism test in mice, at a dose of 10 mg / / kg after blocking the reaction in 80% of animals. mouse, ED = 2.5 mg / kg iv It has an anitihistamine effect in guinea pigs, ED = 1 mg / kg sc The spasmoilytic effect against both aicetylcholine and barium chloride is similar to the previous compounds (concentrations 1 to 2) 10 (Ug / ml inhibits contractions by 50%) It has anti-static effect in rats, oral dose of 60 mg / kg reduces coughing activity to 39% of the control group.

At an intravenous dose of 12 m-g / kg, it induces pressure drops in the n-rm-ote, rats, and, at a dose of 0.1 to 0.5 mig / kg i.v., inhibits the adrenaline presorative reaction to 50%. Finally, it has antiarrhythmic activity in rats against aconitine; at an intravenous dose of 5 to 12 mg / kg significantly increases the 1-attitude of jakinitin-induced ventricular eixtrasystol. It appears clearly in three tests as a neuroleptic; it has a number of neurotrophic and cardiovascular side effects.

The compounds of the formula I according to the invention are accessible by hydrolysis of the carbamates of the formula II

wherein R and R * are the same as in the formula I. The hydrolysis is carried out preferably with a concentrated boiling solution of potassium hydroxide in ethanol. The carbamates of formula (II) are all novel and their preparation is therefore described in the examples below. The origin of the starting materials used for the synthesis of these carbamates is also cited in the examples. The bases of formula I obtained by hydrolysis of the carbamates of formula II are partly crystalline, partly oily.

In both cases, the bases have been converted by neutralization with methanesulfonic acid and dimethanesulfooates, which crystallize well, are excellent in water solubility and are more suitable than bases for pharmacological testing and for the manufacture of dosage forms. The following examples describing the preparation of the compounds I according to the invention are intended to illustrate some of the possibilities of the invention; it is by no means intended to describe all the possibilities of the invention. The compounds of the formula I, their dimethanesulfoates and all the intermediates described are novel substances which have not been previously described in the literature. Their identity was assured by analyzes and all common spectral methods.

Example 1

B-Methyl-10-piperazino-10,11-dihydrodibenzation (b, phthiepine (I, R = CH _; ¹ , R ¹ -H)

To a solution of 32.7 g of potassium hydroxide in 350 ml of water is added 21.3 g of 2-methylthiophenol (commercial product), and after stirring for 10 minutes, 45.1 g of (2-iodophenyl) acetic acid (Sindelář K. et. al., Collect. Czech. Chem. Commun. 37, 1734 (1972) and 2.0 g of freshly reduced copper. The mixture was then stirred and refluxed for 17 h. Filter hot while the solid on the filter was washed with hot water and the filtrate acidified with hydrochloric acid. After standing overnight at 0 ° C, the precipitated crude product is filtered, dissolved in benzene, and the acidic product is extracted into 60 ml of a 15% sodium carbonate solution, divided into three portions. The combined aqueous solutions were filtered from charcoal, the filtrate was acidified with hydrochloric acid, the precipitated product was filtered after standing overnight at 4 ° C, washed with water and dried in vacuo. 27.2 g (61%) of crude [2- (2-methylphenylthiophenyl) acetic acid, melting at 77-83 ° C, was obtained, followed by purification by crystallization from aqueous ethanol to give a melting point of 87-89 ° C.

A mixture of 37.3 g of the previous acid, 160 ml of toluene and 350 g of polyphosphoric acid is stirred vigorously and refluxed for 4.5 hours. After partial cooling, it is poured into 1 kg of ice-water and the product is extracted with benzene. The extract was washed with 5% sodium hydroxide solution and 15.2 g of the starting acid were recovered by acidifying the wash solution with hydrochloric acid. The washed benzene extract was dried (MgSO 4) and evaporated under reduced pressure. 17.6 g (86% per conversion) of crude 6-diethyldibenzo (b, f) thiepin-10 (HH) -one are obtained, which is purified by crystallization from cyclohexane, m.p. 103-106 ° C.

To a stirred solution of 20.9 g of the previous ketone in a mixture of 60 ml of benzene and 300 ml of ethianol is slowly added a solution of 6.6 g of sodium borohydride in 60 ml of water containing 1.5 ml of 10% sodium hydroxide solution.

The mixture was then refluxed for 5 h and evaporated in vacuo. The residue was partitioned by shaking between water and benzene, the benzene layer was washed with 3% sodium hydroxide solution and water, dried over magnesium sulphate and evaporated after filtration. The residue was dissolved in ethanol, the solution was filtered with charcoal and the filtrate was evaporated again. 19.2 g (91%) of crude 6-methyl-10,11-dihydro-dibenzo [b, f] thiepin-10-ol are obtained, which is purified by crystallization from cyclohexane, m.p. 88-90 ° C.

To a solution of 19.1 g of the preceding alcohol in 250 ml of benzene was added 25 g of anhydrous powdered calcium chloride, and the suspension was saturated with anhydrous hydrogen chloride at room temperature for 3 hours. After standing overnight, the calcium chloride was filtered off, washed with benzene and the filtrate was evaporated under reduced pressure. The solid residue afforded 15.8 g (77%) of 6-methyl-10-chloro-10,11-dihydrodibenzo (b, phthlepin, m.p. 75-78 ° C) from 25 ml acetone.

A mixture of 8.9 g of the preceding chloro derivative and 15 g of 1- (ethoxycarbonyl) piperazine (commercial product) was heated in a bath maintained at 100 ^DEG- 115 ^DEG C. for 6.5 h. After cooling, the mixture was partitioned by shaking between water and from the benzene phase, the base is extracted into excess 1: 1 dilute hydrochloric acid, the aqueous hydrochloride solution is liberated again by alkalization with aqueous ammonia and isolated by extraction with benzene. The extract was washed several times with water, dried over anhydrous potassium carbonate and evaporated under reduced pressure. 9.75 g (75%) of crystalline 6-methyl-10- (4-ethoxycarbonylpiporazino) -10,11-dibydrodibenzo (b, phthiepine (II, R = = CH j, R ¹ -H) are obtained, The residue was purified by crystallization from 15 ml of ethanol, mp 106-109 ^° C

To a solution of 6.4 g of potassium hydroxide in 15 ml of ethanol was added 9.5 g of the preceding carbamate and the mixture was heated under reflux (bath 120-130 degrees Celsius) for 6 hours. The ethanol was evaporated under reduced pressure, the residue was partitioned by shaking between water and benzene, and the base was extracted from the benzene phase into excess 3M HCl.

Most of the hydrochloride precipitates in solid form, aspirated and added to the aqueous phase of the filtrate. Alkalization with aqueous ammonia liberates the base, which is isolated by extraction with benzene. Drying and evaporation of the extract gave 7.3 g (95%) of a crude, oily base which did not crystallize even on standing. It is the desired 6-methyl-10-piiperazmo-10,11-dihydrodi, benzo (b, f) thiepine. Neutralization with methanesulfoic acid in ethanol and addition of ether s-e affords the dimethanesulfonate, which crystallizes from ethanol and melts at 206-209 ° C in pure state.

Example 2

6-Etbyl-10-ipiperazinol-1,11-dihydrodibenzo (b, phenylene (I, R = C ₂ H ₅ , R ¹ = H)

34.2 g of 2-ethylthiophenol (Hansch C. et al., J. Qrg. Chem. 21, 265, 1936) are dissolved in a stirred solution of 47.5 g of potassium hydroxide in 500 ml of water at 50 DEG C. 7 g of (2-iodophenyl) acetic acid (cited) and 2.5 g of copper are added and the mixture is refluxed for 14 h. Work-up is similar to that described in the analogous step in Example 1, and 65.5 g of an oily product are obtained which slowly crystallizes from a mixture of benzene and pelroilether. Filtration gave 44.8 g (67%) of [2- (2-ethyl-phenylthio) -phenyl] -acetic acid melting at 56-58 ° C pure.

A mixture of 13.2 g of the previous acid and 68 g of polyphosphoric acid is stirred and heated for 5 hours ir; 100-120 ° C (bath temperature). After cooling, it is quenched with 250 ml of ice-water and the product is extracted with benzene. The extract was washed with 5% sodium hydroxide solution and passed through, dried over magnesium sulphate and evaporated under reduced pressure. The crude product obtained was crystallized from 20 ml of ethanol to give 9.4 g (76%) of 6-ethyldi-benzo (b, phthiepin-10 (11H) -oin, m.p. 76-78 ° C).

A solution of 27.2 g of the preceding ketone in 110 ml of benzene and 220 ml of ethanol is reduced with 2.5 g of sodium borohydride in 20 ml of water containing 0.5 ml of 10% sodium hydroxide solution, in a similar manner as described in the corresponding. step in Example 1,

21.8 g (80%) of 6-ethyl-10,11-dihydrodibenzo [b] phthiepin-10-ol is obtained, which crystallizes from ethanol and melts at 108-110 ° C.

A solution of 18.2 g of the preceding alcohol in 200 ml of benzene was saturated with hydrogen chloride at room temperature in the presence of anhydrous calcium chloride, as described in the appropriate step of Example 1. A similar treatment yielded 17.1 g (88%) of 6-8. ethyl 10-chloro-10,11-dihydrodibenzo (b, phthiepine), which crystallizes from acetone and melts at 93-95 ° C.

The substitution reaction of 7.8 g of the preceding chloro derivative with 11 g of 1- (ethoxycarbonyl) plperazine was carried out in the presence of 10 ml of chloroform at the reflux temperature of the mixture (8.5 h). After evaporation of the chloroform under reduced pressure, the mixture was worked up analogously to Example 1. 9.0 g of crude product were obtained, which was crystallized from ethanol to give

7.8 g (69%) of 6-ethyl-10- (4-ethoxycarbonylpiperazino) - 10,11-dlodium, mp (b, phthiepiin, mp 83-86 ° C).

Hydrolysis of the preceding carbamate (3.7 g) by boiling with a solution of 2.5 g of potassium hydroxide in 6 ml of ethanol under reflux for 6 h. Analogous treatment as described at the end of Example 1 afforded 2.9 g (96 g). %) of an oily base ^{1-ethyl-6-LO-LO} -piperazin-l-dihydródibenzoiíb, jthiepinu f (I, R = G ₂ | H _5, R ^l = H). Neutralization with methainsulfonic acid in ethanol and addition of ether gives the dimethanesulfcinate, which crystallizes from a mixture of ethanol and ether and melts at 207-210 ° C.

Example 1 a d 3

6-Methoxy-10-β-perazino-10,11-dihydfodibenzo (b, β-thiene (I, R = OCH ₃ , R ¹ = E)

A mixture of 14.4 g of 6-methoxy-10-chloro-10,11-dihydrodibenzo (b, phthiepine (Protiva M. et al., Coilleet. Czech. Chem. Commun. 40,2 667, 1975), 15 ml of chloroform and 20.0 g of 1- (ethoxycarbonyl) -plperazine are refluxed for 9.5 hours (bath 110-120 ° C) and after evaporation of the chloroform is treated as in the previous examples to give 17.6 g (85%) of oily substance. 6-methoxy-10- (4-ethoxycarbonylpiperazinol) -10,11-dihydrodibenzo (b, phthiepine (II, R = OCH-, R ¹ = H), which is further processed in the crude state.

10.8 g of this crude product and a solution

7.1 g of potassium hydroxide in 15 ml of ethanol are refluxed under stirring for 6 hours, and the mixture is worked up as in the previous examples. 7.4 g (84%) of 6-methoxy-10-piperazino-10,11-dihydrodibenzo [b] phthiepine (I, R = OCI ¹ ,}, R ¹ = H) are obtained, which crystallizes from benzene-hexane. Melting point: 119 DEG -121 ^DEG C. By neutralizing with diethyl ether in ethanol and addition of ether, dimethainsulfoinate is prepared, and the tetrachloride is poured from methanol as heine hydrate, mp 202 DEG-204 DEG.

Example 4

2-Chloro-6-methyl-10-piperazin-10,11'-dihydrodibenzene (b, phthiepine (I, R-CH ₃ , 'R ¹ = Cl))

A stirred mixture of 37.3 g of 2-methylthiophenol, 53 g of 2,5-dichloroacetophenilium (Rajsner M. et al., Collect. Czech. Chem. Commun. 43, 1276, 1978), 66.5 g of anhydrous potassium carbonate and 1 g. 3 g of copper are heated in a bath at 140 to 160 degrees Celsius for 5 h under nitrogen. After partial cooling, the mixture is diluted with 100 ml of benzene, the inorganic salts are filtered off and washed with warm benzene and the filtrate is evaporated under reduced pressure. The residue is dissolved in 300 ml of ethanol, the solution is filtered with charcoal and the filtrate is evaporated again. Crystallization from 100 ml of ethanol yielded 58.1 g (75%) of 5-chloro-2- (2-methylphenylthiojaicetophenone, mp 61-65 ° C). The analytical pure material was obtained by recrystallization from ethanol, mp 64-66 ° C.

A mixture of 5.5 g of the preceding compound, 1.3 g of sulfur blossom and 6.0 g of morpholine is stirred and refluxed in a bath at 140-160 ° C for 10 h. It is then diluted with 60 ml of ethanol, filtered with charcoal and evaporated in vacuo. The residue was dissolved in ether, washed with water, 2% sodium hydroxide solution, water, 1.5M HCl and water, dried (MgSO4) and evaporated. Crystallization of the residue from ethanol gave 4.1 g (55%) of [5-chloro-2- (2-methylphenylthiophenyl) acetic acid thiomorpholide, mp 127-131 ^° C. An analytical sample was obtained by recrystallization from ethanol, mp 131 up to 133 degrees Celsius.

The above thioimorpholide (14.5 g) was added to a solution of 11.6 g of potassium hydroxide in 40 ml of ethanol, and the mixture was refluxed for 4 h. The ethanol was evaporated in vacuo, the residue was dissolved in 50 ml of water, washed with benzene and ether, and acidified with hydrochloric acid. After standing overnight, the precipitated product is filtered, washed with water and dried in vacuo. There was obtained 9.8 g of [5-chloro-2- (2-methylphenylthio) phenyl] acetic acid (87%), m.p. 123-127 ° C. An analytical sample was obtained by crystallization from a mixture of benzene and petroleum ether, m.p. 127-129 ° C.

A mixture of 7.3 g of the above acid and 40 g of polyfosforeěné was stirred and heated for 5 hours at 100-120 DEG C. ^e Workup as in Example No. 2, 4.6 g (67 ° / o) of pure 2-chloro-6- methyldibenzo (b, f) thiepin-10 (11H) -one, mp 115-117 ° C (benzene,].

A solution of 17.1 g of the previous ketone in 45 ml of benzene and 250 ml of ethanol is reduced, as in the previous examples, with a solution of 5.7 g of soda boron hydride in 50 ml of milliliters / water. containing 1.4 ml of a 10% sodium hydrogen carbonate solution. Workup yielded 14.8 g (86%) of almost pure 2-chloro-6-methyl-10,11-dihydrodibenzo (b, f) triplin-10-ol, m.p. 119-124 ° C. An analytical sample was obtained by crystallization from benzene and melted at 120-123 ° C.

A solution of 14.8 g of the preceding alcohol in 210 ml of benzene is saturated with 14 g of calcium chloride for 4 hours with hydrogen chloride. Working up as in the previous examples yielded 13.7 g (87%) of 2,10-dichloro-6-methyl-10,11-idiililodibenzo (b, phthiepine, mp 90-93 ° C (acetone)).

A mixture of 16.3 g of the preceding chloro derivative, 20 g of 1- (ethoxycarbonyl) piperazine and 20 ml of chloroform is heated to reflux for 10 ml. Workup as in the previous examples yielded 16.4 g (71%) of 2-chloro-6-methyl-10- (4-ethoxycarbonylnylpiperazino) -1,11,1-dihydro-dibenzo [b, phthiepine (II, R CH) R ¹ = Cl), which crystallizes from ethanol and melts in the pure state at 133-136 ° C.

To a solution of 10 g of potassium hydroxide in 20 ml of ethanol was added 16.0 g of the preceding carbamate, and the mixture was stirred and refluxed for 6 hours. Working up as in the previous examples yielded 13.0 g of crude oily base (98%) of 2-chloro-6-methyl-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine (I, R = C +, R ^1). Neutralization with methanesulfonic acid in ethanol and addition of ether converts to dimethanesulfonate, which crystallizes from 95% methanol as the monohydrate and melts at 210-213 ° C.

Example 1 a d 5

2-Chloro-6-methoxy-10-piperazino-10,11-dihydirodibenzo (b, phthiepine (I, R = OCH., R ¹ = Cl))

A mixture of 9.2 g of 2,10-dichloro-6-methoxy-10,11-dihydrodibenzo (b, phthiepine (Protiva M. et al., Collect. Czech. Chem. Commun. 46, 2 245, 1981), 11 g of 1- (ethoxycarbonyl) piperazine and 12 ml of chloroform were refluxed for 10 h, and as in the previous cases, 9.1 g (71%) of the recrystallized and pure 2-chloir-6-methoxy-10- (4) were prepared. (ethoxycarbonyl, nylpiperazino) -10,11-dihydirodibeinzo (b, phthiepine, mp 117-119 ° C (cyclohexane)).

11.3 g of the preceding carbamate are added to a solution of 7.2 g of potassium hydroxide in 17 ml of ethanol, and the mixture is refluxed for 6 hours. Workup as in the previous examples yielded 8.8 g (94%) of recrystallized and pure 2-chloro-6-methoxy-10-piperazin-10,11-dihydrodibenzo (b, phthiepine (I, R = OCH3 ₎₎ , R ⁽⁼ C'l), mp 134-136 ° C (benzene - petroleum ether).

Neutralization (methanesulfonic acid in ethanol gives the dimethanesulfonate, which crystallizes from 95% ethanol and melts at 162-166 ° C.

Claims (1)

6-substituted and 2-chloro-6-substituted 10-piperazino-10,11-dihydrodibenzo (b, phthiepines of formula I), OF THE INVENTION wherein R is methyl, ethyl or methoxy and R ¹ is hydrogen or chlorine, and their methanesulfonates.