DE2723635A1 - SUBST. 2-AMINOMETHYLPHENYL HYDROGEN SULPHATES - Google Patents

Description

Dr.-lng. Wa ^ r .-. Bitz Dr. Dieter F l / i ο rf Dipl.-Phys. M. Griischneder 8 Munich 8b, Pienzenauerstr. 28

25th MA! 1977

15th

MERCK & CO., IHC. Rahv / ay, New Jersey 07065, V.St.A.

Subst.-2-aminomethylphenyl hydrogen sulfate

709849/106?

The invention relates to substituted 2-aminomethylphenyl hydrogen sulfates and their pharmaceutically acceptable salts in which the phenyl nucleus is further substituted with 2 to 4 nucleus substituents and which are useful as diuretics and saluretics. The products can be obtained by reacting a substituted 2-aminomethylphenol or its salt with chlorosulfonic acid pyridine or a pyridine-sulfur trioxide complex will.

The invention relates to a new class of chemical compounds, generally called substituted 2-aminomethylphenyl hydrogen sulfates and their non-toxic, pharmaceutically acceptable salts. The present invention is also the object of a new process for the preparation of the new substituted 2-aminomethylphenyl hydrogen sulfate to provide.

Pharaacological studies show that the invention Products are effective diuretic and saluretic agents used in the treatment of such conditions associated with electrolyte and fluid retention and high pressure. Will the products according to the invention When used in therapeutic dosage units in conventional carriers, they reduce the amount of sodium and chloride ions in the body, lower dangerous excess fluid levels to acceptable levels and generally eliminate them the conditions usually associated with edema and hypertension.

The substituted 2-aminomethylphenyl hydrogen sulfates according to the invention are compounds of the following structural formula

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OSO, H
X ⁶ -

in the

Y? Denotes hydrogen, lower alkyl with 1 to 3 carbon atoms or lower alkoxy with 1 to 3 carbon atoms,

X signifies halogen or straight-chain or branched-chain lower alkyl, the alkyl group being up to Contains 5 carbon atoms,

yp signifies hydrogen, halogen, lower alkyl with up to 5 carbon atoms or lower alkoxy with up to 5 carbon atoms, and

X represents halogen or trifluoromethyl, and their non-toxic, pharmaceutically acceptable salts.

Preferred compounds according to the invention are those compounds of the formula I in which

X ^ is hydrogen, methyl or methoxy,

X chlorine or lower-alkyl, either branched or straight-chain, with up to 5 carbon atoms means

X ^ hydrogen, lower alkyl with up to 3 carbon atoms or is lower-alkoxy with up to 3 carbon atoms, and

X is chlorine, bromine, iodine or trifluoromethyl, and their non-toxic, pharmaceutically acceptable salts.

The above-mentioned nontoxic, pharmaceutically acceptable salts are preferably the nontoxic, pharmaceutically acceptable salts Acid addition salts, which are different from non-toxic, pharmaceutically acceptable acids such as hydrochloric acid, Hydrobromic acid, hydroiodic acid, sulfuric acid, Methanesulfonic acid, isethionic acid and others. The salts

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also include those made from alkali metal and strong nitrogen bases, such as sodium hydroxide, potassium hydroxide, guanidine, Tetramethylammonium hydroxide and the like.

Preferred specific compounds according to the invention are, for example:

2-aminomethyl-4- (1,1-dimethylethyl) -6-iodophenyl hydrogen sulfate; 2-aminomethyl-4- (1,1-dimethylethyl) -6-chlorophenyl hydrogen

sulfate;

2-aminomethyl-3,5-dimethoxy-4,6-dichlorophenyl hydrogen sulfate; 2-aminomethyl-4- (1,1-dimethylethyl) -6-bromophenyl hydrogen sulfate; 2-aminomethyl-4- (1,1 -dimethylethyl) -6- trifluoromethylphenyl-

hydrogen sulfate;

2-aminomethyl-3-methyl-4,6-dichloro-5-ethylphenyl hydrogen sulfate.

The substituted 2-aromethylphenyl hydrogen sulfates according to the invention of the formula I can by reacting a substituted-2-aminophenol, as shown in Formula II below, with an equimolar mixture of chlorosulfonic acid and pyridine (reagent A, which is shown in the following equation) or with a pyridine-sulfur trioxide complex, which is shown in the following Reagent B shown in equation, obtained from ground. The starting material used at the beginning can be other than that in the following 2-aminomethylphenol represented in formula II as well a salt, preferably a non-toxic, pharmaceutically acceptable salt thereof.

The reactions described above are explained by the following equation:

CH ₂ MH ₂

or the salts thereof (II)

Reagent A: ClSO ^ H- or pyridine Reagent B: pyridine SCU complex

X-

OSO, H

(D

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where X ^:
sit.

where X, X, X and X have the meanings given above

If reagent A, namely chlorosulfonic acid, is used in the presence of pyridine, an equimolar amount of chlorosulfonic acid and pyridine is generally used as the reagent. Furthermore, the mixture of chlorosulfonic acid and pyridine itself is generally used in a 2- to 10-fold excess based on the starting material 2-aminomethylphenol or its salt (Formula II) This reaction using reagent A in the above equation can be carried out in a suitable inert solvent such as methylene chloride, dimethylformamide and tetrahydrofuran Any solvent can be used as long as it is inert to the reaction conditions, but there is no need to use a solvent if a greater than equivalent amount of pyridine is used based on the amount of chlorosulfonic acid used the reagent A used in the above equation can also be used at a temperature from 0 to 50 ⁰ C, preferably from 10 ° C to room temperature, are performed. The reaction is carried out to completion, which generally takes 1/2 to 6 hours. The reaction is preferably carried out over a period of about 2 hours. The end product (I) obtained in this process can be prepared from the reaction mixture by processes known per se, for example by evaporating the reaction mixture in vacuo, triturating the remaining product with water and filtering the aqueous slurry to isolate the desired product.

Similarly, if the reagent used becomes the pyridine-sulfur trioxide reagent is, as represented by reagent B in the above equation, the amount of pyridine-sulfur trioxide complex generally 2 to 3 times the

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equimolar amount of 2-aminomethylphenol or its salt (formula II above). The pyridine-sulfur trioxide complex with excess pyridine can be used as the solvent, or the reaction can be carried out using pyridine-sulfur trioxide and an inert organic solvent such as methylene chloride, tetrahydrofuran or dimethylformamide. The reaction in which the pyridine Schvefeltrioxid complex is used as a reagent, can be at a temperature of 0 to 50 ⁰ C, preferably from 10 ° C to room temperature, are performed. The reaction is generally complete in 1/2 to 6 hours. The reaction is preferably carried out over a period of about 2 hours. The products can be isolated in the same manner as described for the use of reagent A above.

The following examples explain the substituted 2-aminomethylphenyl hydrogen sulfates according to the invention and methods of making them. All products encompassed by Formula I above v / ground can be prepared in an analogous manner using the appropriate starting materials instead of used starting materials listed in the examples.

example 1

Production of 2-aminomethyl-4- (i, 1-dimethylethyl) -6-iodine phenyl hydrogen sulfate

14 g (Of12 mol) chlorosulfonic acid are added dropwise over half an hour to a stirred solution of 6 g (0.02 mol) 2-aminomethyl-4- (1,1-dimethylethyl) -6-iodophenol and 9.5 g ( 0.12 mol) of pyridine in 200 ml of methylene chloride, which is cooled in an ice bath. The resulting reaction solution is stirred at 20 to 25 ° C. for 16 h. After evaporation of the reaction mixture in vacuo (water aspirator) at 40 to 50 ⁰ C a residual solid which 500 ml of water with vigorous stirring at room temperature remains currencies

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rend is rubbed in for 1/2 hour. The insoluble solid is isolated, washed with water and dried in vacuo for 5 hours at room temperature; 229 to obtain the desired product (5.4 g, 70So), mp. to 230 ⁰ C (dec.). Recrystallization of this material from ethanol-water (1: 1.5, V: V) gives the analytical sample of 2-aminomethyl-4- (1,1-dimethylethyl) -6-iodophenyl hydrogen sulfate as colorless crystals (4.6 g , 59.7-0 »m.p. 231-232 ° C (dec.).

Elemental analysis for C ^ H ^ JNO ^ S

calculated: C 34.30fa H 4.19? S N 3.64% found: 34.11 4.08 3.63.

Example 2

Production of 2-aminomethyl-4- (1,1-dimethylethyl) -6-iodine phenol hydrogen sulfate

17.5 g (0.15 mol) of chlorosulfonic acid are added dropwise over half an hour to a stirred solution of 7.5 g (0.025 mol) of 2-alinomethyl-4- (i, 1-dimethylethyl) -6-iodophenol in 250 ml of dry pyridine at ambient temperature. After stirring at room temperature, the resulting reaction mixture in vacuo (Viasserstrahlpumpe) at 40 is evaporated to 50 ⁰ C. A mass remains, which is triturated with 500 ml of water while stirring vigorously for 1/2 hour at room temperature. The insoluble solid is isolated, washed with water, ^{dried for several hours at 40 to 50 °} C. in vacuo and recrystallized from ethanol-water (1: 1, V: V); 2-aminomethyl-4- (i, 1-dimethylethyl) -6-iodophenyl hydrogen sulfate is obtained (1.25 g, 1350, melting point 231 ° to 232 ° C. (decomp.).

Example 3

Production of 2-aminomethyl-4- (1,1-dimethylethyl) -6-iodine phenyl hydrogen sulfate

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This connection is made in essentially the same way as as described in Example 2, with the exception that the 2-aminomethyl-4- (i, 1-dimethylethyl) -6-iodophenol is replaced by the corresponding hydrochloride rate. The following reagents are used:

2-aminomethyl-4- (1,1-dimethylethyl) -6-iodophenol hydrochloride 1.7 g, 5 »0 nmoles

Chlorosulfonic acid 3.5 g »30.0 mmol

dry pyridine 50 ml

V / ater 100 ml Ethanol V / water (1: 1, V: V)

2-aminomethyl-4- (1,1 -dimethyläthyl) -6-iodophenyl hydrogen sulfate is obtained in the form of colorless crystals (0.2 g, 18%), mp. 232-233 ⁰ C (dec.).

Example 4

Production of 2-aminoethyl-4- (i, 1-dimethylethyl) -6-iodine-

phenyl hydro?; en sulfate

9.6 g (0.06 mol) of pyridine-sulfur trioxide complex are added at room temperature to a stirred solution of 3.4 g (0.01 mol) of 2-aminoethyl-4- (1,1-dimethylethyl) -6-iodophenol hydrochloride in 100 ml of pyridine. After stirring for 18 hours at room temperature, the resulting reaction mixture is filtered to remove excess pyridine-sulfur trioxide complex. After the filtrate has been evaporated in vacuo at 40 to 50 ^° C., a mass remains which is suspended in 200 ml of water. The resulting suspension is cooled to 5 ° C. and filtered; is obtained 2-aminomethyl-4- (i, 1-dimethylethyl) -6-iodophenyl-hydrogensulf at (g 0.4, 10%) as a sticky solid, mp. 210-225 ⁰ C (dec.). The material is identical to an authentic sample (Example 1) according to the thin-layer chromatography comparative analysis.

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Example 5

Preparation of 2-aminomethyl-4- (i, 1-dimethylethyl) -6-iodine phenyl hydrogen sulfate

1 »6 g (0.01 mol) of pyridine-sulfur trioxide complex v / earth Room temperature to a stirred solution of 3 g of 2-aminomethyl-4- (i, 1-dimethylethyl) -6-iodophenol placed in 75 ml of anhydrous tetrahydrofuran. The resulting reaction mixture is stirred for 72 hours at room temperature and filtered. Evaporate of the filtrate in vacuo at 40 to 50 ° C. gives a residue which crystallizes from ethanol-water (1: 1, V: V) will. 2-aminomethyl-4- (1,1-dimethylethyl) -6-iodophenyl hydrogen sulfate is obtained in the form of colorless crystals (1.2 g, 31%), m.p. 231 to 232 ° C. (decomp.).

Example 6

2-aminomethyl-4- (1,1-dimethylethyl) -δ-chloroplienyl hydrogen sulfate

This compound is borrowed in the v / es using the same procedure, prepared as described in Example 1 using the following reagents:

2-aminomethyl-4- (1,1-dimethylethyl) -

6-chlorophenol 2.13 g, 0.01 mole

Chlorosulfonic acid 7.00 g, 0.06 mole

dry pyridine 4.80 g, 0.06 mole

Methylene chloride 150 ml

In this method, we obtain 2.5 g of a crude solid, m.p. 130 to 220 ⁰ C (dec.) "The after crystallization from ethanol-water. (1: 2, v: v) of pure 2-Aminomethy1-4- ( 1,1-dimethylethyl) -6-chlorophenyl hydrogen sulfate gives in the form of colorless crystals (1.3 g, 44%), melting point 272 ° to 273 ° C. (decomp.).

Elemental analysis for C ^ H ^^

calculated: C 44.97% H 5.49% N 4.77% found: 45.06 5.39 4.73.

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Example 7

2-aminomethyl-5,5-dimethoxy-4,6-dichlorophenyl hydrogen sulfate

This connection is made in essentially the same way as prepared as described in Example 1 using the following reagents:

2-aminomethyl-3,5-dimethoxy-4,6-

dichlorophenol 2.52 g, 0.01 mole

Chlorosulfonic acid 7.00 g, 0.06 mole

dry pyridine 4.80 g, 0.06 mole

Methylene chloride 200 ml

In this method, one first obtains 1.1 g of a solid, m.p. 238-242 ⁰ C. (dec.), "The to-.the crystallization from ethanol-water (2: 1, V: V). Analytisch'reines 2 Aminomethyl-3,5-dimethoxy-4,6-dichlorophenyl hydrogen sulfate in the form of colorless crystals gives (0.8 g, 24%), melting point 237 to 238 ° C. (decomp.).

Elemental analysis for C ₉ H ₁₁ Cl ₂ NO ₆ S

calculated: C 32.54? 6 H 3.34? $ N h, Z2%
found: 32.18 3.38 4.29.

If the procedure of Examples 1 to 5 is followed, but the corresponding amount of a particularly substituted 2-aminomethylphenol is used, that is shown in Formula II below, the corresponding amount becomes that listed End products of the following formula I obtained.

Table I Core Subst. 2-Aminomethylphenyl Hydrogen Sulphate

-s »

or its salt

> ^ ^Λ γ ^Λ \ _χ 3

χ ⁴

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15 887 X ³ k X ⁴ X ⁵ 2723b3b Example No. H tert.-C ^ Hg H X ⁶ m.p., ° C (dec.) 1-5 H tert.-C ^ Hg H J 231-232 6th OCH ₃ Cl OCH, Cl 272-273 7th H UC ₃ H ₇ H Cl 237-238 8th H coir —Γ * Η
ÖtStt ..— ^ ₄ IIg H Cl 9 H tert-C ₄ Hg H Cl 10 H tert-CcH ₁₁ H Br 11 H + Q ₁ -II- _p TJ
LtJi & - V'cn.yj ₁ H Cl 12th H tert-C ₄ Hg H J 13th H tert-C ₄ H _g H F. 14th OCH, tert-C ₄ Hg H CF ₃ 15th H Cl Cl Cl 16 CH ₃ Cl C ₂ H ₅ Cl 17th CH ₃ CH ₃ Cl Cl 18th CH ₃ Br CH ₃ Cl 19th OCH ₃ Cl OCH ₃ Br 20th H XSo-C ₃ H ₇ F. Br 21 H iso-C _r H ₇ H Cl 22nd H J H J 23 OCH ₃ Cl OCH ₃ J 24 CH ₃ Cl H J 25th H Cl H J 26th J

The novel compounds of the invention are diuretic and saluretic agents that are used in a wide variety of therapeutic applications Dosage units in excipients known per se, such as, for example, by oral administration in the form of tablets or by intravenous injection. The daily dose of the products can be within a wide range vary and range from 5 to 2000 mg. The product is preferably in divided dosage units in the form of notched Tablets containing 5, 10, 25, 50, 100, 150, 250 and 500 mg of active ingredient for symptomatic on

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setting of the dose administered to the patient to be treated. These dose units are far below the toxic ones or lethal dose of the products in a total daily dose of 100 to 2000 rag in a pharmaceutical acceptable carriers.

A suitable unit dosage form for those of the invention Products can be administered by adding 50 mg of substituted 2-aminomethylphenyl hydrogen sulfate (i) or its suitable salt mixed with 149 mg of lactose and 1 mg of magnesium stearate and place the 200 mg mixture in a No. 1 gelatin capsule. Similarly, one can use more active ingredient and less lactose fill other dosage forms in No. 1 gelatin capsules, and should it be required more than If you mix 200 mg of the ingredients together, you can use larger capsules. Compressed tables, pills or other recommended dosage unit forms may be obtained by incorporation of the compounds according to the invention are prepared by processes known per se, and optionally the compounds can be in the form of elixirs or as injectable solutions according to known pharmacists Procedure to be prepared.

According to the invention, two or more of the inventive Compounds may be mixed in unit dosage form, or one or more of the present invention may be used Associations with others got diuretics and saluretics or with other desired therapeutic agents and / or Mix or combine nutrients in unit dose form.

The following example explains the production of an exemplary Dosage form.

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Per capsule mg 50 mg 149 ης 1

Example 27

dry-filled capsules containing 50 mg of active ingredient per

Capsule included

2-aminomethyl-4- (1,1-dimethylethyl) -6-iodophenyl hydrogen sulfate

Lactose Magnesium Stearate

Capsule (size # 1) 200 mg

The 2-aminomethyl-4- (1,1-dimethylethyl) -6- ₎ iodophenyl hydrogen sulfate is comminuted to a No. 60 powder (corresponding to a sieve with 0.25 mm openings), and then lactose and magnesium stearate are ground through Sieve a No. screen cloth (0.25 mm openings) onto the powder and the combined ingredients are mixed for 10 minutes and then filled into No. 1 dry gelatin capsules.

Similar dry-filled capsules can be made by using the active ingredient of the example above replaces any other novel compound of the invention.

The substituted 2-aminoethylphenyl hydrogen sulfates according to the invention (I) or their pharmaceutically acceptable salts are a valuable class of compounds that have not been seen before were manufactured.

End of description.

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Claims (15)

Merck & Co., Inc. 15,887 Claim e2 / 23635 1 .J compound of the formula OSO ^ H ^r6 - CH ₂ NH ₂ X ⁴
in the X ^ hydrogen, lower alkyl with 1 to 3 carbon atoms or lower alkoxy of 1 to 3 carbon atoms means, X halogen or straight or branched chain denotes lower-alkyl, the alkyl group having up to 5 carbon contains atones, X hydrogen, halogen, lower-alkyl with up to 5 carbon atoms or lower-Alko :: y with up to 5 carbon atoms means, and X ° represents halogen or trifluoromethyl, and their non-toxic, pharmaceutically acceptable salts. 2. Compound of formula OSO ₃ H
X ⁶ v ^ v ^ CH ₂ MH ₂ in the Jr is hydrogen, methyl or methoxy, X is chlorine or lower-alkyl, either branched or straight-chain, with up to 5 carbon atoms, Jr denotes hydrogen, lower alkyl with up to 3 carbon atoms or lower alkoxy with up to 3 carbon atoms, - 1 -
7 (19849/1062 'NSPECTED 15837 I 272363b X is chlorine, bromine, iodine or trifluoromethyl , and their non-toxic, pharmaceutically acceptable salts. 3. A compound according to claim 2, characterized in that X ³ and X ^{5 are} hydrogen; X ⁴ tert-butyl; and X ^{6 is} iodine and forms 2-aminomethyl-4- (i, 1-dimethylethyl) -6-iodophenyl hydrogen sulfate. 4. A compound according to claim 2, characterized in that X ³ and X ⁵ Y / hydrogen; X 1, tert-butyl; and X is chlorine and forms 2-aromethyl-4- (1,1-dimethylethyl) -6-chlorophenyl hydrogen sulfate. 5. A compound according to claim 2, characterized in that X ³ and X ^{5 are} methoxy; and X ^ and X ^{6 are} chlorine and form 2-aminonethyl-3,5-dinethoxy-4,6-dichlorophenyl-liydrogensulfate. 6. A compound according to claim 2, characterized in that X ³ and X ⁵ V / hydrogen; X tert-butyl; and X is bromine and forms 2-aminonethyl-4- (1,1-diinethylethyl) -6-bromophenyl hydrogen sulfate. 7. A compound according to claim 2, characterized in that X ³ and X ⁵ V / hydrogen; X ⁴ tert-butyl; and X ⁶ denotes trifluoromethyl and forms 2-aminomethyl-4- (i, 1-dimethylethyl) -6-trifluoromethylphenyl hydrogen sulfate. 8. A compound according to claim 2, characterized in that X ^{3 is} methyl; X ⁴ and X ⁶ chlorine; and X ⁵ denote ethyl and form 2-aminomethyl-3-methyl-4, o-dichloro ^ ethylphenyl hydrogen sulfate. 9. Process for the preparation of compounds of the formula 709849/1062 ₁₅ 387 «i LI lob6 3 OSO ^ H
X ⁶ '' X ⁴
in the Y? Denotes hydrogen, lower-alkyl with 1 to 3 carbon atoms or lower-alkoxy with 1 to 3 carbon atoms, X halogen or straight or branched chain means lower-alkyl, where the alkyl group contains up to 5 carbon atoms, X ^ hydrogen, halogen, lower-alkyl with up to Means 5 carbon atoms or lower alkoxy with up to 5 carbon atoms, X is halogen or trifluoromethyl, and their non-toxic, pharmaceutically acceptable salts, characterized in that a compound of the formula ■ st L 5 fi or its salt, in which X, X, X and X have the meanings given above own, with a mixture of chlorosulfonic acid and pyridine or a pyridine-sulfur trioxide complex. 10. The method according to claim 9 »characterized in that an inert organic solvent as the reaction medium is used. 11. Process for the preparation of compounds of the formula OSO ₃ H X ⁶ ^> y CH ₂ NH ₂ 709849 in the X ^ is hydrogen, methyl or methoxy, λ
X chlorine or lower-alkyl, either branched or straight-chain, with up to 5 carbon atoms means X ^ hydrogen, lower alkyl with up to 3 carbon atoms or is lower-alkoxy with up to 3 carbon atoms, and X is chlorine, bromine, iodine or trifluoromethyl, and their non-toxic, pharmaceutically acceptable salts, characterized in that a compound of the formula CH ₂ NH ₂ χ λ 5 6 in which X, X, X and X have the meanings given above, or one of its salts with a mixture of chlorosulfonic acid and pyridine or a pyridine-sulfur trioxide complex implements. 12. The method according to claim 11, characterized in that an inert organic solvent is used as the reaction medium is used. 13. The method according to claim 11, characterized in that that X ³ and X ^{5 are} hydrogen; X tert-butyl; and X ^{6 is} iodine and 2-aminomethyl-4- (i, 1-dimethylethyl) -6-iodophenyl hydrogen sulfate "is produced. 709849/106? 14. A pharmaceutical preparation suitable for the treatment of edema and hypertension, characterized in that that they are a compound of the formula OSO, H 'CH ₂ NH ₂ in the Y? Denotes hydrogen, lower-alkyl with 1 to 3 carbon atoms or lower-alkoxy with 1 to 3 carbon atoms, X signifies halogen or straight-chain or branched-chain lower alkyl, the alkyl group being up to Contains 5 carbon atoms, X " ³ denotes hydrogen, halogen, lower-alkyl with up to 5 carbon atoms or lower-alkoxy with up to 5 carbon atoms, X ° signifies halogen or trifluoromethyl, and / or their non-toxic, pharmaceutically acceptable salts and contains a pharmaceutically acceptable carrier. 15. A pharmaceutical preparation suitable for the treatment of edema and hypertension, characterized in that that they contain 50 to 500 mg of a compound of the formula in the X is hydrogen, methyl or methoxy, X chlorine or lower-alkyl, either branched or straight-chain, with up to 5 carbon atoms means - 5 709849/106? X denotes hydrogen, lower alkyl with up to 3 carbon atoms or lower alkoxy with up to 3 carbon atoms,
5 X is chlorine, bromine, iodine or trifluoromethyl, and / or their non-toxic, pharmaceutically acceptable salts and a pharmaceutically acceptable carrier. l6. Pharmaceutical preparation according to claim 15, characterized in that it has 2-aminomethyl 1-4- (1,1-dinethylethyl) -6-iodophenyl hydrogen sulfate as the active ingredient contains. 709849/1 06?