ES2362698T3 - DERIVATIVES OF SULFANILO AND ITS USE AS SYNTHESIS INTERMEDIATES. - Google Patents

Abstract

Compounds of formula (I), and salts thereof, in which: X is O or N-C (NH) NH2; M + is hydrogen, sodium, disodium, potassium, dipotassium, ammonium (NH4) +, diamonium, quaternary ammonium, calcium or magnesium.

Description

The present invention relates to new sulfanyl derivatives and their use as synthesis intermediates, especially for the preparation of pharmaceutical active compounds.

5 The sodium salt of 2-mercaptoethanesulfonic acid (1: 1) (HS CH2CH2SO3Na), also known by the generic name of mesna (sodium 2-mercaptoethane sulfate), has proven useful as a therapeutic agent for the treatment of some diseases; It is known for its mucolytic activity (US Patent 3 576 835); but also as an antiviral agent, particularly as an anti-influenza agent (Patent EP 1 596 851 B). The topical use of mesna in surgical procedures that include tissue dissection is known (Patent EP0 930 878 B). The mesna protects the

10 urinary tract of urotoxic symptoms in the treatment of tumors with ifosfamide (US Patent 6 322 812). Schramm, C.H. et al. (J.Tm. Chem.Sx.77 (23), p6231-6233 (1955) and US 2 695 310 describe a process and intermediates for the preparation of mesna.

Now we have found an alternative procedure to prepare mesna.

Now we have found an improved procedure to prepare mesna, using a safe and economical route.

In a first aspect, the present invention relates to compounds of formula (I), and their salts,

image 1

in which: X is O or N-C (NH) NH2; M + is hydrogen, sodium, disodium, potassium, dipotassium, ammonium (NH4) +, diamonium, quaternary ammonium, calcium or

20 mg M + is usually hydrogen, sodium or disodium. Usually the compounds of the invention are 2- (2-sulfo-ethylsulfanylguanidinosulfanyl) -ethanesulfonic acid and their

you go out. Usually the compounds of the invention are also 2- (2-sulfo-ethylsulfanylcarbonylsulfanyl) ethanesulfonic acid and salts thereof. A preferred compound of the invention is the disodium salt of 2- (2-sulfoethylsulfanylguanidinosulfanyl) ethanesulfonic acid ((C6H11N3S4O6) 2Na2).

Another preferred compound of the invention is the disodium salt of 2- (2-sulfoethylsulfanylcarbonylsulfanyl) ethanesulfonic acid ((C5H8S4O7) 2Na2).

The compounds of formula (I) may be in the form of a salt, any pharmaceutically acceptable salt; usually an alkaline salt; preferably sodium, disodium, potassium, dipotassium, ammonium (NH4) +, diamonium, quaternary ammonium, calcium, magnesium. More preferably the compounds of formula (I) are in the form of disodium salt.

The compounds of formula (I) are as follows:

image 1

image 1

5

10

fifteen

twenty

25

30

35

40

The compounds of formula (I) may be in the form of solvate, which are included within the scope of the present invention. Such solvates include, for example, hydrates, alkoxides and the like.

The compounds of formula (I) are very stable and can be used as synthesis intermediates. In particular the hydrolysis of the compounds of the invention gives mesna and dimesna.

The compounds of the invention can be obtained by coupling (ethyl xanthate) O-ethyl ester carbonodithium acid, potassium salt with (2 sodium bromoethanesulfonate) sodium salt of 2-bromo-ethanesulfonic acid to give sodium salt of ethyl acid -2- sulfoethyl ester-xanthane followed by a radical reaction to generate the disodium salt of 2- (2-sulfoethylsulfanylcarbonylsulfanyl) -ethanesulfonic acid. To obtain the disodium salt of 2- (2-sulfoethylsulfanylguanidinosulfanyl) -ethanesulfonic acid, guanidine is added in the above reaction medium.

In another aspect, the present invention relates to the use of compounds of general formula (I) as synthesis intermediates, especially for the preparation of pharmaceutically active compounds.

According to a first embodiment, compounds of formula (I) are used for mesna synthesis.

Mesna can be obtained by hydrolysis of a compound of formula (I), followed by isolation.

The use of compounds of general formula (I) as synthesis intermediates allows to produce mesna with a high yield (at least 80%) and with a high purity (at least 85%, usually more than 90% and preferably more than 95%) , using a simple route and also mainly a safe and economical route.

The present invention may be better understood with the following examples.

EXAMPLES

Example 1: Preparation of sodium salt of ethyl -2-sulfoethylesteric acid.

Potassium O-ethylxantate (3 x 95 mg, 0.60 mmol) was added portionwise for 1.5 hours to a solution of sodium 2-bromoethanesulfonate (0.42 g, 2.00 mmol) in acetonitrile (15 ml). The reaction mixture was heated at 85 ° C, under a nitrogen atmosphere, for a total of 6 hours. After cooling the suspension was filtered, washed with acetonitrile and air dried to provide a white solid.

1 H NMR (DMSO d6) � (ppm) 4.67 (c, 2H), 3.40 (2H, m), 3.26 (m, 2H), 1.39 (t, 3H).

Example 2: Preparation of 2- (2-sulfo-ethylsulfanylcarbonylsulfanyl) -ethanesulfonic acid disodium salt.

The sodium salt of ethyl -2-sulfoethylesteric acid, obtained in example 1, (0.20 g, 0.79 mmol) was added to 1,2-dichloroethane (5 ml) and heated to reflux (85 ° C). Then lauroyl peroxide in portions (8 x 157 mg, 0.40 mmol) was added to the reaction mixture over a period of 3 days. After cooling the resulting solid was filtered, washed with 1,2-dichloroethane, followed by dichloromethane, then air dried.

The solid mentioned above (100 mg, 0.28 mmol) was suspended in ethanol (5 ml) and heated under gentle reflux (stable compound by 1 H NMR analysis). Water (~ 0.5 ml) was then added to give a complete solution, and reflux was continued for 2h (stable compound by 1 H NMR analysis). The solution was allowed to cool overnight to give a suspension that was filtered. The white solid was washed with cold ethanol (1 mL) and dried by suction to give the purified compound, 75 mg (75% recovered). The compound is pure by 1 H NMR analysis.

Melting point: 284.8 ° C.

1 H NMR (DMSO d6) � (ppm) 3.26 (4H, m), 3.08 (4H, m)

13C NMR (DMSO d6) � (ppm) 51.4, 26.8

Example 3: Preparation of mesna from the compound obtained in example 2.

The compound obtained in example 2 (2 g, 5.65 mmol) was dissolved in 1N aqueous sodium hydroxide (20 ml, 20 mmol) and stirred at room temperature under a nitrogen atmosphere. The resulting reaction mixture was heated at 80 ° C for 3 hours. After this time the reaction mixture was allowed to cool before removing the excess solvent by evaporation under reduced pressure. The resulting white solid was then triturated with ethanol (40 ml), under a nitrogen atmosphere, to give a white suspension to which glacial acetic acid (2.4 ml) was then added. After stirring for 5 minutes, then the suspension was filtered rapidly, washed with ethanol (20 ml) and dried briefly by suction. The resulting white solid was then dried under vacuum (40 ° C) for 30 minutes to give a plateau as a solid

5 blank, 2.0 g, containing only minor impurities by 1 H NMR (less than 0.1%).

This procedure leads to an active ingredient, mesna, with a high purity profile.

The starting material (sodium salt of ethyl -2-sulfoethylesteric acid) is safe and easy to use. In fact its use does not require specific precautions, since it is not an explosive compound. Primarily this compound makes it possible to avoid using dangerous synthesis intermediates such as thiourea and sulfo-ethyl-thiourea.

10 1 H NMR (DMSO d6) � (ppm) 3.26 (4H, m), 3.08 (4H, m)

Example 4: Preparation of 2- (2-sulfo-ethylsulfanylguanidinosulfanyl) -ethanesulfonic acid disodium salt.

The sodium salt of xanthane acid, as obtained in example 1, (0.20 g, 0.9 mmol) was added to 1,2-dichloroethane (5 ml) and heated to reflux (85 ° C ). Then guanidine (1.25 eq.) Was added. Then lauroyl peroxide was added portionwise (8 x 157 mg, 0.40 mmol) to the reaction mixture over a period of 3 days. After cooling the solid

The resulting was filtered, washed with 1,2-dichloroethane, followed by dichloromethane, then air dried.

Example 5: Preparation of mesna from the compound obtained in example 4.

The compound obtained in Example 4 was recrystallized in accordance with the procedure described in Example 2. The compound obtained was carried to the table following the procedure described in Example 3.

Claims (4)

1. Compounds of formula (I), and their salts, image 1 wherein: 5 X is O or N-C (NH) NH2; M + is hydrogen, sodium, disodium, potassium, dipotassium, ammonium (NH4) +, diamonium, quaternary ammonium, calcium or magnesium.

2.

A compound according to claim 1, wherein X is N-C (NH) NH2.

3.

A compound according to claim 1, wherein X is O.

A compound according to claim 1 or 2, in which it is the disodium salt of 2- (2-sulfoethylsulfanylguanidinosulfanyl) -ethanesulfonic acid. 5. A compound according to claim 1 or 3, wherein it is the disodium salt of 2- (2-sulfoethylsulfanylcarbonylsulfanyl) -ethanesulfonic acid.