DE2160148C2 - Medicines and certain sulphoxides as such - Google Patents

Description

CH ₃ O

(IV)

in which R ^{1 is} a hydrogen atom, a methyl or a methoxy group and R ^{2 is} an alkyl radical having 1 to 7 carbon atoms, the allyl or the /? - hydroxyethyl group.

The invention relates to medicaments which, by containing a compound of the general Formula I.

(D

in which ρ has the value 1 or 2, (R) 2 alkoxy radicals having 1 to 3 carbon atoms, R ^{1 is} a hydrogen atom, an alkoxy or alkyl radical having 1 to 3 carbon atoms and R ^{2 is} an alkyl radical having 1 to 7 carbon atoms, the Allyl or the /? - hydroxyethyl group is identified as an active ingredient, as well as customary pharmacologically acceptable diluents, carriers and / or auxiliaries,
The medicaments of the invention preferably contain sulfoxides of the general formula 11

in which R, R ¹ and R ^{2 have} the above meanings, as active ingredients.

The medicaments of the invention can preferably also contain sulfones of the general formula III

(R) ₂ ^

S— R ² (III)

N H

R ¹ O

in which R, R ¹ and R ^{2 have} the above meanings, contain as active ingredients.

The invention also relates to new sulfoxides of the general formula IV CH ₃ O

⁵ ~ ^Ri (IV)

in which R ^{1 is} a hydrogen atom, a methyl or a methoxy group and R ^{2 is} an alkyl radical with 1 Dis 7 carbon atoms, which means the allyl or the>? - hydroxyethyl group

The compounds of the general formulas I to IV are valuable medicaments because they are significant Induce reduction in blood pressure, if given rats with normal blood pressure, with deoxycorticosterone acetate treated rats or "experimental kidney rats" (i.e. rats in which a artery leading to the kidney - the second kidney has been removed - artificially a high blood pressure condition was produced) as well as cats and dogs. You can therefore be used to treat High pressure or used for vasodilation.

The medicaments can be administered in customary forms for oral or parenteral administration getting produced. Forms of preparation for oral administration can be e.g. B. in the form of tablets, packaged Powders or granules, aqueous or oily suspensions, emulsions, as hard gelatine or soft gelatine capsules or syrups.

Medicines for oral use can be prepared by conventional methods. These medicines may contain one or more flavor corrections, colorings or preservatives.

In addition to the active ingredient, tablets can also contain excipients. Inert diluents, such as calcium phosphate, lactose, cane sugar or glucose can be used. Furthermore can these tablets granulating and disintegrating agents such as starch or alginic acid, binders such as starch, gelatin or Gum arabic and lubricants such as magnesium stearate, stearic acid or talc.

Medicines for oral administration in the form of hard gelatin capsules can contain the active ingredient with an inert solid diluent such as calcium phosphate, lactose or kaolin. at Soft gelatin capsules can mix the active ingredient with an oily diluent such as peanut oil or liquid paraffin or olive oil.

Medicines ζ!, Τ parenteral administration can be in the form of sterile injection preparations, such as solutions or suspensions in water, physiological saline solution or 13-butanediol. These preparations may also contain wetting agents or suspending agents.

For better and more precise administration, the medicaments are preferably used in the form of dosage units. For oral administration, the dosage unit contains 1 to 500 mg, preferably 10 to 100 mg of the active ingredient. Dosage units for oral administration contain 1 to 10 mg of active ingredient per 1 ml of des Preparation.

The compounds of the general formulas I to IV can be prepared by oxidation of the corresponding thioethers getting produced. The oxidation can be carried out with hydrogen peroxide, N-halosuccinimides, l-carbon-benzotriazole or other known oxidizing agents.

Hydrogen peroxide in acetic acid, N-bromosuccinimide or N-chlorosuccinimide in methanol or 1-chlorobenzotriazole in methanol or methylene chloride are preferably used as the oxidizing agent to produce the sulfoxides (ρ = 1). To suppress the formation of sulfones (ρ = 2), the oxidizing agent is preferably used in an equimolar amount and the oxidation reaction is carried out ^{at temperatures from 0 to 20 ° C.}

To prepare the sulfones, the oxidation is preferably carried out in acetic acid with a 2 to 3-fold excess carried out on hydrogen peroxide and heating the reaction mixture on a steam bath.

The thioethers used as starting compounds can be extracted in a simple manner from the corresponding Making thiophenols.

The examples explain the preparation of the active ingredients or ingredients contained in the agents according to the invention. of the agents according to the invention.

example 1
3,4-dimethoxyphenylmethyl sulfoxide

a) 28.3g (0.17 mol) 3,4-dimethoxythiophenol (compare A.A. Levi and S.Smiles, J.Chem.Soc. (1931), p.520) are added to a solution of 3.83 g (0.17 mol) of sodium in anhydrous ethanol. The mixture will 20.8 g (0.17 mol) of dimethyl sulfate are then slowly added and the mixture is then refluxed for 2 hours. The solvent is then distilled off under reduced pressure and the residue with chloroform extracted. The combined chloroform extracts are washed with water over magnesium sulfate dried and evaporated. There are 28.6 g of 3,4-dimethoxyphenylmethyl sulfide with a boiling point of 110 ° C / 106.66 Pa obtain.

C ₉ H ₁₂ O ₂ S; C 58.7 H 6.6 S. 17.4 ber .: C 58.5 H 6.4 S. 17.2 eef .:

J b) A solution of 18.4 g (0.1 mol) of 3,4-dimethoxyphenylmethyl sulfide in 100 ml of glacial acetic acid is added with cooling

mixed with 11.3 ml (0.1 mol) of 30 percent hydrogen peroxide solution. After that, the mixture is 24 hours

% left to stand at room temperature and made alkaline by slowly adding ice-cold sodium hydroxide solution.

d The mixture is extracted with chloroform, the combined chloroform extracts are washed with water, see ¹ J 5, evaporated, dried over magnesium sulfate and concentrated under reduced pressure to dryness. It behind-

ϊ 15.1 g of crystalline 3,4-DimethoxyphenylmethylsuIfoxid remain, which after recrystallization from diisopropyl ether

% melts at 82 to 84 ° C

,}, found : C 53.9 H 63 S 15.7

;;; Example 2

15 3,4-dimethoxyphenylethyl sulfoxide

a) 8.6 g (0.05 mol) 3,4-dimethoxythiophenol, 1.15 g (0.05 mol) sodium, 50 ml ethanol and 7.8 g (0.05 mol) Ethyl iodide are reacted according to Example 1. There are 73 g of 3,4-dimethoxyphenylethyl sulfide of bp 100 up to 108 ° C / 26.66 Pa.

C ₉ H ₁₂ O ₃ S; C 54.1 H 6.1 S. 16.0 ber .: C 53.9 H 63 S. 15.7 found:

CuHhO ₂ S; C 60.7 H 7.1 S. 16.2 ber .: C 60.7 H 7.0 S. 15.9 found:

b) 1.98 g of 3,4-dimethoxyphenylethyl sulfide are oxidized according to Example 1. There are 1.6 g of 3,4-Direethoxyphenyläthylsulfoxid obtain.

CI0HI4O3S; C 56.1 H 6.6 ber .: C 56.0 H 6.4 found:

C ₉ Hi ₂ O ₂ S: C 58.7 H 6.6 S. 17.4 ber .: C 59.0 H 6.5 S. 17.5 found:

b) 2.3 g of 2,5-dimethoxyphenylmethyl sulfide are oxidized according to Example 1. Yield 1.8 g of 2,5-dimethoxyphenylmethyl sulfoxide from 70 to 72 ° C.

Example 3

2,5 dimethoxyphenyl methyl sulfoxide 35

a) 2.8 g (0.017 mol) of 2,5-dimethoxythiophenol (see Suter and Hansen, J. Am. Chem. Soc, Vol. 54 (1932), p. 4102) become a solution of 0.4 g (0.017 mol) sodium in anhydrous ethanol. 2.1 g (0.017 mol) of dimethyl sulfate are slowly added to the mixture and the mixture is then refluxed for 2 hours. The solvent is then distilled off under reduced pressure and the residue is extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate and evaporated. Yield 2.8 g of 2,5-Dimethoxyphenylme ^<: yl sulphide, bp 92 to 96 ° C / 40 Pa..

6.1 g (0.03 mol) of 3,4-dimethoxypheny ', methyl sulfide (see Example Ib) and 11.3 ml (0.1 mol) of 30 percent hydrogen peroxide solution in 100 ml of glacial acetic acid are heated on the steam bath for 2 hours . The mixture is then poured onto 300 g of ice, the white precipitate formed is filtered off, washed thoroughly with water and recrystallized from ethanol. Yield 5.7 g of 3,4-dimethoxyphenylmethylsulfone with a melting point of 115 to 11 ° C.

C ₉ H ₁₂ O ₄ S;

calc .: C 50.0 H 5.6 S 14.8 65 found: C 49.3 H 5.8 S 14.7

The table below gives further examples of active ingredients used according to the invention. The sulfoxides (p = 1) are produced according to Example 1 and the sulfones (p = 2) are produced according to Example 4.

C ₉ H ₁₂ O ₃ :
ber .:
found: C 54.1
C 53.5 H
H 6.1
6.0 S.
S. 16.0
16.5 3.4- Example 4 Dimethoxyphenylmethyl sulfone

Tabel

example Substituent on the benzene ring 3 4th 5 6th R ² f 68-70 Molecular formula % ber. H S. % found H S. to 14.1 2 MeO MeO - C. 7.1 14.1 C. 7.0 13.6 13.9 £ ξ 5 ") MeO MeO n-Pr 1 C ₁₁ Hi ₆ O ₃ S. 57.9 7.1 14.1 57.7 6.9 14.1 14.0 ^ö 6th MeO MeO i-Pr 1 _ C ₁₁ Hi ₆ O ₃ S. 57.9 7.5 57.9 7.6 16.2 H- * 7th MeO MeO n-Bu 1 125-6 C ₁₂ H ₁₈ O ₃ S 59.5 7.5 59.5 7.4 ¹⁵⁷ & 8th MeO MeO i-Bu - C ₁₂ H ₁₈ O ₃ S 59.5 6.2 58.9 6.3 16.0 °° 9 MeO MeO CH ₂ CH-CH ₂ 1 - CnHi ₄ O ₃ S 58.5 6.1 13.9 58.5 6.1 13.8 12.0 10 MeO CH ₂ CH ₂ OH 1 Ci ₀ H ₁₄ O ₄ S 52.2 6.1 51.8 6.0 12.0 11th MeO MeO Me - C ₉ H ₁₂ O ₃ S 54.1 7.1 53.7 7.3 11.4 12th MeO MeO n-Pr - C ₁₁ Hi ₆ O ₃ S. 57.9 7.1 57.9 6.9 14.9 13th MeO MeO i-Pr - C ₁₁ H ₁₆ O ₃ S 57.9. 7.5 13.3 57.7 7.2 12.8 12.5 14th MeO MeO n-Bu 108-110 C ₁₂ H ₁₈ O ₃ S 59.5 7.5 59.3 7.2 14.1 15th MeO MeO i-Bu 74-6 C ₁₂ H ₁₈ O ₃ S 59.5 6.2 59.3 6.3 12.6 16 MeO MeO CH ₂ CH-CH ₂ 61-2 C ₁₁ H ₁₄ O ₃ S 58.5 6.1 13.9 58.8 6.1 14.6 17th MeO MeO MeO MeO CH ₂ CH ₂ OH - C ₁₀ H ₁₄ O ₄ S 52.2 6.1 13.9 52.4 6.1 15.2 18th EtO EtO Me 97-8 C ₁₀ H ₁₄ O ₄ S 52.2 7.1 14.1 52.2 6.9 15.1 19th MeO Me 74-6 C ₁₁ H ₁₆ O ₃ S 57.9 6.1 16.0 57.6 6.0 15.0 20th MeO MeO Me C ₉ H ₁₂ O ₃ S 54.1 6.1 16.0 54.1 6.2 21 MeO MeO MeO Me C ₉ H ₁₂ O ₃ S 54.1 6.1 16.0 53.6 6.2 22nd EtO EtO Me C ₉ H ₁₂ O ₃ S 54.1 7.9 12.5 54.3 8.2 23 MeO MeO n-Pr 92-3 Ci ₃ H ₂₀ O ₃ S 61.0 7.9 12.5 60.7 8.0 24 MeO MeO n-Am 117-9 Ci ₃ H ₂₀ O ₃ S 61.0 8.5 11.3 60.6 8.5 25th MeO MeO Me nC? H ₁₅ 2 141-142 C ₁₅ H ₂₄ O ₃ S 63.4 6.6 15.0 63.4 6.5 26th MeO MeO MeO Me 2 193-4 Ci ₀ Hi ₄ O ₃ S 56.1 6.1 13.9 56.0 6.2 27 MeO MeO Me Me 2 77-8 Ci ₀ H ₁₄ O ₄ S 52.2 6.1 13.9 51.7 6.2 28 MeO MeO MeO Me: 2 104-6 C] ₀ H ₁₄ O ₄ S 52.2 5.7 13.0 52.0 5.6 29 MeO Me 2 84-5 C ₁₀ H ₁₄ O ₅ S 48.8 5.6 14.9 48.6 5.7 30th MeO MeO Me 2 115-6 C ₉ H ₁₂ O ₄ S 50.0 5.6 14.9 49.7 5.6 31 MeO MeO Me C ₉ H ₁₂ O ₄ S 50.0 5.6 14.9 49.7 5.5 32 MeO MeO MeO Me C ₉ Hi ₂ O ₄ S 50.0 5.6 14.9 49.8 5.6 33 Me C ₉ Hi ₂ O ₄ S 50.0 49.9

Remarks:

Me - CH ₃ ; Et - C ₂ H ₅ ; Pr - C ₃ H ₇ IBu-C ₄ H ₉ JAm - C ₃ Hn ") The compound of Example 5 is an oil with the NMR spectrum in CDCI ₃ : δ ·

2.70 (s, 3H); 3.89 (s. 3H); 3.92 (s, 3H) and 6.9-7.4 (m, 3H).

The manufacture of pharmaceuticals is explained below. The parts are based on weight.

Example A.

A mixture of 1 part 3,4-Dimethoxyphenyimethylisulfoxid, 5 parts lactose and 5 parts starch is mixed with 1 percent magnesium stearate and compressed into tablets. Preferably the tablet size is such that each tablet contains 10 or 25 mg of active ingredient. Similar tablets with 50 mg of active ingredient are made A mixture of 2 parts of the sulfoxide, 5 parts of lactose and 5 parts of starch and 1 percent magnesium stearate manufactured.

Example B.

A mixture of 1 part 3,4-dimethoxyphenylmethyl sulfoxide and 9 parts of a starch tablet base with the addition of 1 percent magnesium stearate, tablets are compressed. Preferably the tablet size is such that they contain 10 or 25 mg of drug. Similar tablets with 50 mg of drug are made from one Mixture made from 2 parts of the sulfoxide, 9 parts starch and 1 percent magnesium stearate.

Example C

There are capsules with different levels of 3,4-dimethoxyphenylmethyl sulfoxide and the following Components manufactured:

The aforementioned ingredients can be sieved before mixing and then put into hard gelatin capsules be bottled.

Example D

Ampoules are produced which contain 5 ml of an isotonic solution of 1 g of 3,4-dimethoxyphenylmethyl sulfoxide and 0.735 g of sodium chloride in 100 ml of distilled water. The solution will last for 35 minutes 0.7 atmospheres steam sterilized.

B e i s ρ i e 1 E

The 3,4-dimethoxyphenylmethyl sulfoxide used in Examples A through D above can be by 2,4-Dimethoxyphenylmethylsulfoxid, 3,4-Dimethoxyphenyläthylsulfoxid, 2i5-DimethoxyphenylmethyIsulfoxid, 3,4-dimethoxyphenylmethylsulfone, 2,5-dimethoxyphenylmethylsulfone, 3,4-dimethoxyphenylpropylsulfoxide. 3,4,6-Trimethoxyphenylmethylsulfoxid or 3,5-Dimethoxyphenylmethylsulfoxid be replaced.

The blood pressure-lowering effect was tested using known pharmacological test methods using rats with normal blood pressure, rats treated with deoxycorticosterone acetate or experimental kidney rats according to the method described by C. Stanton and JB White, Archs. Int. Pharmacodyn. Therap, Vol. 154, (1966), No. 2, p. 351 and JR Weeks and JA Jones, Proc. Exper. Biol & Med "Vol. 104 (1960), No. 4, p. 646 determined

Experimental results are compiled in the tables below. The compounds are administered intraperitoneally at a dose of 100 mg / kg in rats treated with deoxycorticosterone acetate under high pressure administered The numbers indicate the maximum percentage decrease in blood pressure.

Sulfoxiu, Magnesium stearate. Calcium phosphate, Lactose, mg mg mg mg 10 2 _ 190 25th 2 - 175 50 3 - 150 100 3 - 100 10 20th 170 25th _ 20th 155 50 20th 130 100 20th 80

Table I.

Test compound percentage decrease in blood pressure of the example

1 65 2 50 3 46 4th 59 5 30th 22nd 50 27 51 Diazoxide (for 42 Comparison)

10

Table II summarizes the results of experiments in which the drugs were administered orally to groups administered by deoxycorticosterone acetate treated rats at a dose of 20.50 and 100 mg / kg became. A group of 6 rats was used for each dose.

Tables

Test compound of the example percentage decrease in blood pressure

20 50 100 mg / kg

25th

30th 36 53 21 34 50 5 14th 21 33 41 50 16 28 42 18th 18th 26th 24 28 44 25th 33 43

1
2
3

11th 19th 26th

Diazoxide (for comparison) 15 *) 33 41

*) Dose: 25 mg / kg

For humans, the daily dose for treating hypertension is around 200 to 500 mg of drug.

It could be shown that the compounds of the general formulas I to IV compared to diazoxide have prolonged vasodilatory effects, affecting the smooth muscle fibers of the peripheral blood vessels Circulatory shows. The drugs have no effect on the autonomic nervous system. The fact that the vasodilator activity attacks peripherally is evident from the following findings:

1. The drugs have an antihypertensive effect on the spinal cat and decapitated rat.

2. The drugs show activity against the vasoconstricting effects of norepinephrine and vasopressin with various isolated perfused blood vessel preparations, ζ. B. the rabbit ear and the mesenteric vessels the rat.

Furthermore, the drugs have an antagonistic effect on the pressor effects of. Norepinephrine, Tyramine and angiotensin in the anesthetized cat and dog in doses of 3 to 10 mg / kg. the Contraction of the nictitating membrane is also antagonized.

55 eo

Claims (4)

Patent claims: 1. Medicinal product, characterized in that it contains a compound of the general formula (D in which ρ has the value 1 or 2, (R) 2 alkoxy radicals having 1 to 3 carbon atoms, R ^{1 is} a hydrogen atom, an alkoxy or alkyl radical having 1 to 3 carbon atoms and R ^{2 is} an alkyl radical having 1 to 7 carbon atoms, the Allyl or the / 2-hydroxyethyl group represents, as an active ingredient, as well as customary pharmacologically acceptable diluents, carriers and / or auxiliaries. 2. Medicament according to claim 1, characterized in that there are 3,4-dimethoxyphenylmethylsulfoxide, 3,4-dimethoxyphenyl-n-propylsulfoxide, 3,4-dimethoxyphenylethylsulfoxide, 2 ^ 5-dimethoxyphenylmethylsulfoxide, 3,5-dimethoxyphenylmethylsulfoxide, 3,4- Diethoxyphenylmethylsulfoxid or 3,4,6-Trimethoxypi <' ⁼ yiylmethylsulfoxid contains. 3. Medicament according to claim 1, characterized in that it is ö-methyl-S ^ -dimethoxyphenylmethyl- contains sulfoxide.
4. Sulphoxides of the general formula IV