FI62065C - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA ALYLSULFONYLFENOXIPROPANOLAMINER OCH DERAS SYRA-ADDITIONSSA LTR - Google Patents

Description

ΓβΙ ANNOUNCEMENT / λλ / γ 4β3Γα LbJ (11) UTLÄGGNINGSSKRIFT ΟΖϋΟΟ c (45) Patent granted 10 11 1932 i £ ri ^ Patent meddelat V ^ (51) Kv.lk?/tM*CI.^ C 07 C 14-7 / 10 $ UOH I —FI N LAND (21) Nunnlhtk * mu.-Pe «« wrtHcrrtn | 750875 (22) Htkemltpaivt — Aneeknlnfidag 2U.03.75 (23) AlkupUvt — GIK! F! »* Ttd« C 2U.03.75 (41) Tullut | external - Bllvh offantllf 28.09-75 j »rekl * twih * llltu · NihdWMp ^ μ month Publication date and date

Patent- och registeratyrelsan 'Aiwekan utitfd oeh uti. * Krift * n pubiicurmd 30.07.82

(32) (33) (31) hT4 «« y «Mikmia —Bujtrd priorttvt 27.03.7U

USA (US) U55099 (71) Bristol-Myers Company, 3U.5 Park Avenue, New York, N.Y. 10022, USA (US) (72) William T. Comer, Evansville, Indiana, William E. Kreighbaum, Evansville, Indiana, USA (US) (7U) Oy Kolster Ab (5U) Process for the preparation of therapeutically useful alkylsulfonylphenoxypropanolamines and their acid addition salts This invention relates to a process for the preparation of therapeutically useful alkylsulfonylphenoxypropanolamines of the formula -O-CH 2 -CH-CH 2 -NH-R 1, «H 0H (i) R 3 is branched alkyl having 3 to 4 carbon atoms, or 1-phenoxymethylethyl or cycloalkyl having 3 to 6 carbon atoms, R 2 is hydrogen, lower alkyl or lower alkylsulfonyl, R 1 is hydrogen or lower alkyl , R 4 is hydrogen or lower alkylsulfonyl, wherein one and only one of R 1 and R 2 is lower alkylsulfonyl, and pharmaceutically acceptable acid addition salts of these compounds are prepared. istamiseksi.

According to the current understanding, there are at least two subgroups of β-adrenergic receptors; Β-receptors, which are believed to provide cardiac stimulation, and β-receptors, which are likely to cause smooth muscle relaxation, resulting in vasodilator and bronchodilator effects (see CG Dollery, et al., Clinical Pharmalogy and Therapeutics, 10 (6)). 765-799 (1966) and D. Jack, the Pharmaceutical Journal, 237 240 (August 29, 1970)). Various derivatives of phenoxypropanolamines have previously been reported to have β-adrenergic blocking properties (see, e.g., NL Patent 69.07700 and BE Patent 762,629). However, the above-mentioned Dutch patent, although generally comprising pharmaceutical preparations containing a number of substituted (including alkylsulfonyl-substituted) phenoxypropanolamines, does not specifically describe the novel alkylsulfonylphenoxypropanolamines prepared according to the present invention. BE patent 762 629 as well as SE publication 354 851 describe only certain groups of alkylsulfonylalkylphenoxypropanolamine derivatives. Alkylthiophenoxypropanolamines are known from FI patent 46,251.

Preferred compounds according to the invention are those compounds of the formula γ- o-ch2-ch-ch2-nh-r1 ^^^ __ 0_CH2_ch-ch2-nh-r1

'OH l OH

As / \ tai

RS ° 2 R2 XS02R

3 (Ia) ib) wherein R is lower alkyl, R 1 and R 2 are as defined above and only one of R 2 and R 2 is lower alkyl, and pharmaceutically acceptable acid addition salts thereof.

Another preferred group of alkylsulfonylphenoxypropanolamines prepared in accordance with this invention are those of formula IX

3 62065

-0-CH "CH-CHO NH-R

J) OH

Compounds according to R 5 O (IX) R 3, wherein R 1, R 3 and R are as defined above.

Examples of compounds of formula IX include: 1- (isopropylamino-3- / 4- (methylsulfonyl) -m-tolyloxy] -2-propanol, 1- (tert-butylamino) -3- [4- (methylsulfonyl) -m-tolyloxy / - 2-propanol, 1- (isopropylamino) -3- [4- (methylsulfonyl) phenoxy] -2-propanol and 1- (tert-butylamino) -3- [4- (methylsulfonyl) phenoxy] -2 -Pro-Panoli.

A further preferred group of compounds of formula IX is wherein R 1 is isopropyl or tert-butyl and R 1 is methylsulfonyl.

The term "pharmaceutically acceptable acid addition salt" as used herein refers to salts of the compounds of formula I formed with an inorganic or organic acid such as acetic acid, lactic acid, succinic acid, maleic acid, tartaric acid, citric acid, citric acid, gluconic acid, asconic acid, gluconic acid, , with formic acid, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfamic acid or sulfonic acids such as methanesulfonic, benzenesulfonic or p-toluenesulfonic acid. These acid addition salts are prepared, for example, by treating a solution or suspension of the free base with the desired acid in an organic solvent inert to the reaction, and then recovering the salt formed by concentration under reduced pressure or by crystallization methods.

Since the compounds of formula I have at least one asymmetric carbon atom, they may also exist as optically active isomers. Decomposition of racemic mixtures to give optically active isomers of the compounds of formula I is carried out by conventional methods used for the resolution of fethanolamines into optically active components, for example by salt formation with an optically active acid such as d-tartaric acid, dibenzoyl-d-tartaric acid, with mandelic acid followed by co-crystallization.

The process according to the invention is characterized in that a) a phenol of the formula R3 is obtained

wherein 1 * 2, and R 4 are as defined above, to react in formula III

CH - CH - CH_-X

with a compound of formula wherein X is halogen or a compound of formula -N - R>! 1

R

5 wherein R 1 is as defined above and R 2 is a group to be hydrogenated, b) then, when X is halogen, the resulting reaction product is condensed with an amine of formula E 1 NR 2 (IV) wherein R 1 is as defined above. with, or when X is a group of the formula -N - R, I 1 R 5, the resulting reaction product is hydrogenated to remove the protecting group to be hydrogenated, and c) when an acid addition of a compound of formula I is desired. The diol salt, the free base form of the compound of formula I formed in step b) is reacted with a suitable acid.

Alkylsulfonylphenols of formula II are obtained by oxidation of the corresponding alkylthiophenols with hydrogen peroxy according to standard methods (see R. B. Wagner and H. D. Zook, Synthetic Orcanic Chemistry, p. 801 (1953 Wiley)).

Since the epihalohydrin molecules of formula III have two reactive positions, reaction with a phenol of formula II can give a mixture of reaction products of formulas V and VI, in which formulas R 2, R 2, R 2 and X are as defined above: -CH-CH2-X O-CH2 ~ C \ ~ / H2 R2 oh r4 R2 0 R3 R3 (V) (VI)

In a later step of the process, these intermediates of formula V and formula VI condense with the amine of formula IV to give the same final product. Therefore, it is not necessary to separate any mixtures of intermediates of formulas V and VI which may be obtained from the reaction of a phenol of formula II with an epihalohydrin of formula III.

If desired, the epihalohydrin reaction product can be combined in an inert solvent such as chloroform and shaken with excess concentrated hydrochloric acid to convert the epoxides of formula VI to the corresponding sulfonylphenoxy halohydrin of formula V. Conversely, if desired, halohydrins of formula V can be converted to the corresponding epoxide of formula VI by conventional means, for example by treatment with a base (O. Stephenson, J. Chem. Soc. (1954) 1574).

The reaction of phenols of formula II with epihalohydrins of formula III is performed using an excess of epihalohydrin and a catalytic amount of a basic catalyst such as N-benzylisopropylamine hydrochloride or pyrrolidine base. Equally effective are other catalysts such as pyridine, piperidine, piperidine acetate or piperidine hydrochloride.

The reaction of phenols of formula II with epihalohydrins of formula III can also be carried out in a basic medium, e.g. sodium hydroxide and at ambient temperature (V. M. Beasley, et al., J. Pharm. Pharmacol., 10 (1958) 47-59).

The condensation of the epihalohydrin reaction product with the amine of formula IV is preferably carried out in an organic solvent inert under reaction conditions such as ethanol, toluene or dioxane. The condensation can also be carried out without a reaction solvent using an excess of an amine such as isopropylamine or tert-butylamine.

When a compound of formula II is reacted with a compound of formula III wherein X is of formula

- N - R

A group of formula I 1 R5, for example CH-ch-ch2-n-R1 (vii) NO Rc b of formula (VII)

with the compound of formula VIII, the reaction product of formula VIII QJJ is obtained

-O-CH 2 -CH-CH 2 -N-R 1 R 4 I * 2 R 3 in which formulas R 1, R 2, R 2, R 2 and R 2 have the same meaning as above.

The compound of formula VIII is converted to the compound of formula I by hydrogenation. The removal of the hydrophilic protecting group R 1 can be carried out by catalytic hydrogenation, for example in the presence of a palladium-on-carbon catalyst in an inert solvent such as 672065 in ethanol or aqueous ethanol.

The compounds of formula VII can be obtained by known methods. For example, 1 - [(N-benzyl) -isopropylamino] -2,3-epoxypropane is obtained by the reaction of N-benzylisopropylamine and epichlorohydrin in a basic medium such as aqueous potassium hydroxide (L. Villa, et al., Farmaco.,

Ed. Sci., 24 (3), (1969), 349-357).

The selective cardiac β-adrenergic blocking activity of the compounds of this invention can be evaluated in standard in vitro pharmacological assays, such as a spontaneously puncturing rabbit cardiac preparation and a guinea pig tracheal preparation. The following Table 1 compares the potency ratios of 1- (isopropylamino) -3 / 4- (methylsulfonyl) -3-tolyloxy. -2-propanol hydrochloride and the clinically useful β-adrenergic blocker, propranolol; the results show good selectivity of the compound prepared according to the present invention.

Table Molar potencies of 1/3 adrenergic blocker Determined in rabbit cardiac and guinea pig tracheal preparation.

Intensity- Intensity- Cardioselective-Compound ratio ratio: __________________ Atria / Trachea_

Propranolol 1 1 1 1- (isopropylamino) -3- [4- (methylsulfonyl) -3-to-0.37 0.01 37 lyloxy] -2-propanol hydrochloride

The new compound, 1- (isopropylamino) -3- [14- (methylsulfonyl) -3-tolyloxy] -2-propanol hydrochloride, inhibits the increased contractile force and heart rate when administered intravenously to an anesthetized dog at a standard dose of 0.2 mg / kg (intravenously) of isoproterenol, with an ED 2 q of 0.71 mg / kg (contractile force) and 2.02 mg (stroke rate).

8 62065

Another important property of the new compounds is that they are only slightly toxic to mammals.

1- (Isopropylamino) -3- [4- (methylsulfonyl) -m-tolyloxy] -2-propanol hydrochloride has oral LD50 values in mouse and rat 1504 resp. 1792 mg / kg body weight; the intraperitoneal LD50 value in mice is 339 mg / kg body weight.

The novel compounds of formula I are useful in the prevention and treatment of cardiac diseases such as angina pectoris, cardiac arrhythmias, circulatory disorders (neurasthenia) and hypertension. The new compounds are particularly valuable in the treatment of heart disease because of their selective adrenergic blocking activity. Compounds that exhibit this selective activity primarily block the inotropic and chronotropic effects of catecholamines such as epinephrine and isoproterenol without significantly affecting N 2 ardenergic receptors in the tracheal and vascular smooth muscle.

To provide a cardioselective β-ardenergic blocking effect, a compound of formula I may be administered to a mammal orally or parenterally at doses of 0.05 to 20 mg / kg body weight. Preferably, the compound is administered to the mammal in an amount sufficient to reduce the inotropic and chronotropic effect of β-ardenergic agonists without substantially affecting β-adrenergic receptors in the smooth muscle tissue of the mammal.

The nuclear magnetic spectral values reported in the following examples include chemical shift (S) (ppm), multiples of this shift as appropriate, including the binding constant (Hz = J value), and relative area under the curve for each chemical shift corresponding to the number of protons. The symbols used have the following meanings: s single line, bs wide single line, d double line, and m polyline. Tetramethylsilane was used for internal reference.

Example 1 1- (Isopropylamino) -3- / 4- (methylsulfonyl) -m-tolyloxy-2-propanol a) 18.6 g (0.1 mol) of 4- (methylsulfonyl) -m-cresolate lia, a mixture of 60 g (0.65 mol) of epichlorohydrin and 0.6 g of pyrrolidine is heated on a steam bath for 12 hours.

9 6206b

Excess epichlorohydrin is removed under reduced pressure. The chlorochlorohydrin derivative obtained is taken up in 50 ml of anhydrous ethanol and filtered through diatomaceous earth. To the ethanol filtrate of the epichlorohydrin derivative are added 50 g (0.85 mol) of isopropylamine and 0.1 g of potassium iodide. The resulting mixture is refluxed for 18 hours and filtered. Concentration of the filtrate under reduced pressure gives a residue which is taken up in 70 ml of 1N hydrochloric acid and 300 ml of anhydrous ethanol. The distillates are removed under reduced pressure and the resulting residue is mixed with ether to give a crude solid. The crude product is crystallized from a mixture of butanol and methanol, and recrystallized from an ether containing 95% ethanol to give 1- (isopropylamino) -3- [4- (methylsulfonyl) -rt-tolyloxy] -2-propanol hydrochloride, m.p. 177.0-179.0 ° C (corr.); total yield 62%.

Analysis: Calculated for λmax, λmax: HCl: C 49.77, H 7.16, N 4.15.

Found: C 49.72, H 7.16, N 4.08.

Nuclear Magnetic Resonance, DMSO-d 6, δ (ppm): 1.28 δ / d, 6.5 Hz, 6H 7; 2.58 / s, 3H [7i 3.11 / s, 3H7; 3.13 (m, 3 H); 4.11 (in, 3H); 7.01 (m, 2 H); 7.77 / 3, 9.2 Hz, 1H7; 8.9 / bs, 2Hj.

b) Alternatively, the title compound is prepared using aqueous sodium hydroxide as the reaction medium as follows: 37 g (0.4 moles) of epichlorohydrin are added portionwise over 5 minutes to 37.2 g (0.4 moles) of 4- (methylsulfonyl). -m-cresol and a solution of 13 g (0.32 mol) of sodium hydroxide in 250 ml of water at 30 ° C. Stirring is continued for 24 hours. The final pH of the solution is 8 to 8.5. The reaction mixture is extracted with two 250 ml portions of chloroform. The chloroform extract is dried over sodium carbonate and filtered. The filtrate is concentrated under reduced pressure to give a crude epichlorohydrin derivative. The epichlorohydrin derivative is taken up in 150 ml of ethanol and treated with 17 g (0.286 mol) of isopropylamine in 20 ml of water. After stirring for 10 minutes, the mixture is refluxed for 4 hours and the distillates are removed under reduced pressure. The residue obtained is taken up in ethanol and acidified with an ethanolic solution of hydrogen chloride

620 6 S

1- (isopropylamino) -3- [4- (methylsulfonyl) -m-tolyloxy] -2-propanol hydrochloride is obtained.

c) Alternatively, the title compound is prepared, using a hydrophilic-protected epihalohydrin derivative of formula VII, as follows: 1 - [(N-benzyl) isopropylamino] -2,3-epoxypropane is reacted with 4- (methylsulfonyl) -m- with the sodium salt of cresol in ethanol to give 1- [- (N-benzyl) isopropylamino] -3- [4- (methylsulfonyl) -m-tolyloxy] -2-propanol. The catalyst is collected and the filtrate is concentrated to give 1- (isopropylamino) -3- [4- (methylsulfonyl) -m-tolyloxy] -2-propanol hydrochloride.

Example 2 Reaction of the chlorohydrin derivative of 4- (methylsulfonyl) -m-cresol with tert-butylamine according to the method of Example 1 a) upon crystallization from acetonitrile yields 1- (tert-butylamino) -3- [4- (methylsulfonyl) -m-tolyloxy] -2-propanol hydrochloride, m.p. 175.0-176.0 ° C recrystallizes and then melts at 197 ° C (corr.).

Analysis: Calculated for C 18 H 19 NO 2 S · HCl: C 51.20, H 7.45, N 3.98.

Found: C 50.99, H 7.72, N 4.20 ·

Nuclear Magnetic Resonance, DMSO-d 6, δ (ppm): 1.31 / s, 9H7; 2.59 fs, 3Hj; 3.02 fa, 2H7; 3.11 / 5, 3H7; 4.10 / m, 3HJ; 6.97 / in, 2H_7; 7.75 ("d, 9.5 Hz, 1H7; 8.7 / bs, 2HJ.

Example 3 Reaction of a chlorohydrin derivative of 4- (methylsulfonyl) phenol with isonropylamine according to the method of Example 1 a) yields, upon crystallization from ethanol, 1- (isopropylamino) -3- [4- (methylsulfonyl) phenoxy] -2-propanol hydrochloride, m.p.

193.0-195.0 ° C.

Analysis: Calculated for C C 48.22, H 6.85, N 4.32-

Found: C 48.00, H 7.02, N 4.25 · 62065 11

Nuclear Magnetic Resonance, DMSO-d 6, δ (ppm): 1.28 fd, 6.5 Hz, 6 H /; 3.12 fm, 3Hij; 3.14 {s, 3H7; 4.13 fa, 3Hj; 5.91 fd, 4.2 Hz, 1H /; 7.13 / m, 2HJ; 7.80 / m, 2Hj; 8.9 / bs, 2H7.

Example 4 Reaction of the chlorohydrin derivative of 4- (methylsulfonyl) -o-cresol with isopropylamine according to the method of Example 1 a) yields, upon crystallization from butanol, 1- (isopropylamino) -3- [4- (methylsulfonyl) -o-tolyloxy] -7-propanol as the free base mp. 118.0-120.0 ° C.

Analysis: Calculated for C 12 H 22 NO 2 S: He: C 55.79, H 7.69, N 4.65.

Found: C 56.00, H 7.68, N 4.42.

Nuclear Magnetic Resonance, CDCl 3, δ (ppm): 1.10 fa, 6.4 Hz, 6H7; 2.27 fs, 3H7; 2.50 / bs, 2H7; 2.85 / m, 3H7; 2.99 fs, 3KJ; 4.11 / m, 3H7; 6.86 fd, 9.3 Hz, 1H7; 7.65 / m, 2H7.

Example 5 Reaction of a chlorohydrin derivative of 4- (methylsulfonyl) phenol with tert-butylamine according to the method of Example 1 a) affords 1- (tert-butylamino) -3- [4- (methylsulfonyl) phenoxy] -2-propanol as the free base. The free base is converted to the hydrochloride salt, m.p. 221.0-223.0 ° C.

Analysis: Calculated for * HCl: C 49.77, H 7.16, N 4.15.

Found: C 50.10, H 7.33, N 4.00.

Example 6 Reaction of the chlorohydrin derivative of 4- (methylsulfonyl) -m-cresol with cyclopropylamine according to the method of Example 1 a) affords 1- (cyclopropylamino) -3-, 4-methylsulfonyl) -m-tolyloxy-2-propanol as the free base. The free base is converted to the hydrochloride salt, m.p. 144.5-147.5 ° C.

Analysis: Calculated for C 12 H 22 N 2 O 3 • HCl C 50.07, H 6.60, N 4.17.

Found: C 50.23, H 6.76, N 4.02.

Example 7 Reaction of 4- (methylsulfonyl) -m-cresol chlorohydrin derivative with 1-phenoxymethylethylamine according to the method of Example 1 a) 12 e is <1- [-] and yields 1- (1-phenoxymethylethylamino) -3- [4- (methylsulfonyl) -m-tolyloxy-2-propanol as the free base. The free base is converted to the hydrochloride salt, m.p. 143.5-147.5 ° C.

Analysis: Calculated for C 20 H 27 NO 5 S: δ C 61.95, H 6.92, N 3.56.

Found: C 61.12, H 7.14, N 3.32.

Example 8 Reaction of a chlorohydrin derivative of 2- (methylsulfonyl) phenol with isopropylamine according to the method of Example 1 a) affords 1- (isopropylamino) -3- [2- (methylsulfonyl) phenoxy] -2-propanol as the free base. The free base is converted to the hydrochloride salt, m.p. 187.5-189.5 ° C.

Analysis: Calculated for 2H21NO4S * HCl: H-e: C 48.22, H 6.85, N 4.32.

Found: C 48.19, H 7.05, N 4.37.

Example 9 Reaction of the chlorohydrin derivative of 4- (methylsulfonyl-1-m-cresol with cyclopentylamine according to the method of Example 1a) affords 1- (cyclopentylamino) -3- [4- (methylsulfonyl) -m-tolyloxy] -2-propanol hydrochloride, m.p. 183.0-185.0 ° C (corr.).

Analysis: Calculated for C 11 H 2 Cl 2: C 52.81, H 7.20, N 3.85.

Found: C 53.04, H 7.37, N 3.69

Nuclear Magnetic Resonance, DMSO-d 6, δ (ppm): 1.70 (m, 9H); 2.58 (s, 3 H); 3.12 / s, 3H7; 3.15 / m, 3B.J; 4.10 / m, 3H7; 5.84 / bs, 1H7; 6.94 / in, 2H7; 7.76 /, 9.5 Hz, 1HJ; 9.0 / bs, 2Hj.

Claims (2)

62 0 65 1 3 A claim: A process for the preparation of therapeutically useful alkylsulfonyl-phenoxypropanolamines of the formula ΓV | 1-O-CHo-CH-CH_-NH-R 2 and 2 μl of R 4y ^ R 2 (I) R 3 having a branched chain Alkyl of 3 to 4 carbon atoms, or 1-phenoxymethylethyl or cycloalkyl of 3 to 6 carbon atoms, R 2 is hydrogen, lower alkyl or lower alkylsulfonyl, R 1 is hydrogen or lower alkyl and is hydrogen or lower alkylsulfonyl, wherein one and only one of R 2 and R 2 is lower alkylsulfonyl, and for the preparation of pharmaceutically acceptable acid addition salts of these compounds, characterized in that a) a phenol of the formula -OH (II) R 4 T 2 R 3 wherein R 2, R 2 and R 2 are as defined above, to react with a compound of formula CH- -CH-CH.-X / -r T -r \ y 2 (i-II) wherein X is halogen or a compound of formula - N - R 11 I 1 R 5 wherein R 1 is as defined above and R 2 is a group to be hydrogenated, 1 C b. then, when X is halogen, condensing the obtained reaction product with an amine of formula (IV) as defined above, or when X is a group of formula - N - R 11 I 1 R 5, hydrogenating the obtained reaction product to a hydrogenated protecting the group, and c) when an acid addition salt of a compound of formula I is desired, reacting the free base form of the compound of formula I formed in step b) with a suitable acid. 62065 15 For the preparation of therapeutically active alkylsulfonylphenoxypropanol with a formulation 0-CHoCHCHONH-R // · 2 j 2 1 | OH I R3 is R1 is an alkyl group having 3-4 cholatomers, or 1-phenoxymethylethyl or cycloalkyl having 3-6 cholaters, R2 is an alkyl, or an alkylsulfonyl, an alkyl is an alkyl, R4 is an alkyl alkylsulfonyl, colored and itself having the substituent R2 and hydrogenated alkylsulphonyl, and optionally substituted pharmaceutical salts, substituted with a compound of formula (a) to give a phenol with the formula -OH. I II / A * · R3 color R ^, R och R ^ is an anhydrous mixture with the formula CH - CH-CH.-X 2 K 2 III color X is halogen or a group of the formula -N-R1 I 1 R 5