US3804904A - Substituted phenyl sulphoxides and sulphones and the use thereof as vasodilators - Google Patents

Substituted phenyl sulphoxides and sulphones and the use thereof as vasodilators Download PDF

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US3804904A
US3804904A US00201563A US20156371A US3804904A US 3804904 A US3804904 A US 3804904A US 00201563 A US00201563 A US 00201563A US 20156371 A US20156371 A US 20156371A US 3804904 A US3804904 A US 3804904A
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dimethoxyphenylmethyl
sulphoxide
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K Bentley
W Rushworth
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Reckitt Benckiser Healthcare UK Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups

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  • U.S. Cl. 260-607 A 7 Claims ABSTRACT OF THE DISCLOSURE
  • the invention relates to a method of producing peripheral vasodilation which comprise the oral or parenteral administration in unit dosage form of a compound having the formula:
  • n 1 or 2
  • p l or 2
  • R, R and R represent specified radicals.
  • the above compounds are preferably administered together with a pharmaceutically acceptable diluent or carrier therefor, in the form of a pharmaceutical composition.
  • n is an integer 1 or 2
  • p is an integer 1 or 2
  • R represents an alkoxy or alkyl group having 1 to 3 carbon atoms
  • (R) represents alkoxy or alkyl groups having 1 to 3 carbon atoms, chlorine atoms or when attached to adjacent carbon atoms of the benzene ring the group O(OH O- where m is an integer 1, 2 or 3,
  • R represents a hydrogen atom or when (R) represents at least one alkoxy group R may also represent a chlorine atom, a bromine atom, an alkoxy or alkyl group having 1 to 3 carbon atoms, a nitro group, an amino group or a pharmaceutically acceptable salt of an amino group,
  • R represents an alkyl group having 1 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to carbon atoms or a hydroxyalkyl group having 2 or 3 carbon atoms; together with one or more pharmaceutically acceptable diluents or carriers.
  • compositions comprising sulphoxides of the formula ice in which R, R R and n are as hereinbefore defined together with one or more pharmaceutically acceptable diluents or carriers.
  • compositions comprising sulphones of the formula in which R, R R and n are as hereinbefore defined together with one or more pharmaceutically acceptable diluents or carriers.
  • the invention also includes compounds of the formula CHaO (g) in which R represents a hydrogen atom or a methoxy group, and R represents an alkyl group having 1 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 5 carbon atoms, or a hydroxyalkyl group having 2 or 3 carbon atoms.
  • compositions produce a significant reduction in blood pressure when administered to normotensive, DOCA or renal rats and also cats and dogs and have utility in the treatment of those conditions in man for which an anti-hypertensive or vasodilator drug is employed.
  • compositions may be in a form suitable for oral administration or in a form suitable for parenteral administration.
  • Compositions intended for oral use may be in the form of tablets, packaged powder or granules, aqueous or oily suspensions, emulsions, hard or soft capsules, lozenges or syrups.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more sweetening, flavoring, coloring or preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the compound of said formula in admixture with excipients which are suitable for manufacture of tablets.
  • excipients may be inert diluents, such as, calcium phosphate, lactose, sucrose or dextrose; granulating and disintegrating agents, such as starch or alginic acid; binding agents such as starch, gelatine or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc.
  • compositions for oral use in the form of hard gclatine capsules contain the compound of said formula mixed with an inert solid diluent such as calcium phosphate, lactose or kaolin, or as soft gelatine capsules in which the compound of said formula is mixed with an oily medium such as arachis oil, liquid paraffin or olive oil.
  • an inert solid diluent such as calcium phosphate, lactose or kaolin
  • an oily medium such as arachis oil, liquid paraffin or olive oil.
  • compositions intended for parenteral administration may be in the form of sterile injectable preparations such as solutions or suspensions in water, saline or 1,3-butane diol.
  • the preparations may also contain suitable wetting agents and suspending agents.
  • the compositions are advantageously employed in a unit dosage form.
  • the unit dosage form contains from 1 mg. to 500 mg, preferably from 10 mg. to mg, of the compound of said formula.
  • Parenteral unit dosage forms contain from 1 mg. to 10 mg. of the compound of said formula per 1 ml. of the preparation.
  • the compounds of said formula may be prepared by oxidizing the corresponding thioethers.
  • the oxidation may be carried out employing as the oxidizing agent hydrogen peroxide, N-halosuccinimides, l-chlorobenzo-triazole and other known chemical equivalents.
  • suitable methods for carrying out this oxidation include the use of hydrogen peroxide in acetic acid, N-bromosuccinimide or N-chlorosuccinimide in methanol, and l-chlorobenzotriazole in methanol or methylenechloride.
  • an equimolar proportion of the oxidizing agent should be employed, and the oxidation conducted at 20 C.
  • the thioethers used as starting materials may be readily prepared from thiols for example by treatment with an organo-halide or sulphate.
  • EXAMPE 7 6-amino-3,4-dirnethoxyphenylmethyl sulphone Analysis.--Calcd. for C H NO S: C, 46.8; H, 5.7; N, 6.1; S, 13.9%. Found: C, 46.9; H, 5.6; N, 6.2; S, 13.8%.
  • EXAMPLE II A mixture of 1 part of 3,4-dimethoxyphenylmethyl sulphoxide, and 9 parts of a tablet base comprising starch with the addition of 1% magnesium stearate was compressed into tablets.
  • the tablets are of such a size as to contain 10 or 25 mg. of 3,4-dimethoxyphenylrnethyl sulphox- TABLE Analysis, percent Substituent on benzene ring P Calculated Found Example 2 s 4 5 e R p o.' Formula 0 H s 11 1 iii 8 CHzCHzOH Me
  • the compound of Example 24 had B.P. 125-8 C./ 1 mm.
  • tablets containing 50 mg. of 3,4-dimethoxyphenylmethyl sulphoxide were prepared from a mixture of 2 parts of the sulphoxide, 9 parts of starch together with 1% magnesium stearate.
  • the above ingredients may be screened through a 40 13.5.8. mesh screen before being mixed and filled into hard gelatin capsules.
  • EXAMPLE IV Ampoules were prepared containing 5 mls. of an isotonic solution prepared from 1 gm. 3,4-dimethoxyphenylmethyl sulphoxide and 0.735 gm. sodium chloride in 100 mls. distilled water. The solution was stable to steam autoclaving at psi. for 35 minutes.
  • test resuts obtained with compounds of said formula were administered intraperitoneally at a dose of 100 mg./ kg. to groups of DOCA hypertensive rats, and the figures are for the maximum percentage fall in the blood pressure.
  • Percent fall in blood pressure It is expected that the likely human oral dose of a composition of the invention will be 200-500 mg. of active ingredient per day for the relief of hypertension.
  • the compounds have hypotensipe activity in spinalized cats and pithed rats.
  • the compounds are active against vasoconstriction produced by noradrenaline and vasopressin in a variety of isolated perfused blood vessel preparation e.g. rabbit ear, rat mesenteric vessels.
  • GUI-BUN References Cited Burton and Hogarth, J. Chem. Soc., No. 5, 1945. Brownah, Jour. Indian Chem. Soc., vol. 38, No. 1, 1961.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)

Abstract

THE INVENTION RELATES TO A METHOD OF PRODUCING PERIPHERAL VASODILATION WHICH COMPRISE THE ORAL OR PARENTERAL ADMINISTRATION IN UNIT DOSAGE FORM OF A COMPOUND HAVING THE FORMULA

(R2-S(=O)P-),R1,(R)N-BENZENE

WHERE N IS 1 OR 2, P IS 1 OR 2, R, R1 AND R2 REPRESENT SPECIFIED RADICALS. THE ABOVE COMPOUNDS ARE PREFERABLY ADMINISTERED TOGETHER WITH A PHARMACEUTICALLY ACCEPTABLE DILUENT OR CARRIER THEREFOR, IN THE FORM OF A PHARMACEUTICAL COMPOSITION.

Description

-United States Patent 3,804,904 SUBSTITUTED PHENYL SULPHOXIDES AND SULPHONES AND THE USE THEREOF AS VASODILATORS Kenneth Walter Bentley, Hull, and William Ian Rushworth, Beverley, England, assignors to Reckitt & Colman Products Limited, Hull, England No Drawing. Filed Nov. 23, 1971, Ser. No. 201,563 Claims priority, application Great Britain, Dec. 7, 1970, 58,065/70, 58,066/70 Int. Cl. C07c 14.7/14
U.S. Cl. 260-607 A 7 Claims ABSTRACT OF THE DISCLOSURE The invention relates to a method of producing peripheral vasodilation which comprise the oral or parenteral administration in unit dosage form of a compound having the formula:
(Rln
where n is 1 or 2, p is l or 2, R, R and R represent specified radicals. The above compounds are preferably administered together with a pharmaceutically acceptable diluent or carrier therefor, in the form of a pharmaceutical composition.
in which n is an integer 1 or 2,
p is an integer 1 or 2,
when n=1, R represents an alkoxy or alkyl group having 1 to 3 carbon atoms,
when n =2, (R) represents alkoxy or alkyl groups having 1 to 3 carbon atoms, chlorine atoms or when attached to adjacent carbon atoms of the benzene ring the group O(OH O- where m is an integer 1, 2 or 3,
R represents a hydrogen atom or when (R) represents at least one alkoxy group R may also represent a chlorine atom, a bromine atom, an alkoxy or alkyl group having 1 to 3 carbon atoms, a nitro group, an amino group or a pharmaceutically acceptable salt of an amino group,
R represents an alkyl group having 1 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to carbon atoms or a hydroxyalkyl group having 2 or 3 carbon atoms; together with one or more pharmaceutically acceptable diluents or carriers.
In particular the present invention provides pharmaceutical compositions comprising sulphoxides of the formula ice in which R, R R and n are as hereinbefore defined together with one or more pharmaceutically acceptable diluents or carriers.
In particular the present invention provides pharmaceutical compositions comprising sulphones of the formula in which R, R R and n are as hereinbefore defined together with one or more pharmaceutically acceptable diluents or carriers.
The invention also includes compounds of the formula CHaO (g) in which R represents a hydrogen atom or a methoxy group, and R represents an alkyl group having 1 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 5 carbon atoms, or a hydroxyalkyl group having 2 or 3 carbon atoms.
These compositions produce a significant reduction in blood pressure when administered to normotensive, DOCA or renal rats and also cats and dogs and have utility in the treatment of those conditions in man for which an anti-hypertensive or vasodilator drug is employed.
The pharmaceutical compositions may be in a form suitable for oral administration or in a form suitable for parenteral administration. Compositions intended for oral use may be in the form of tablets, packaged powder or granules, aqueous or oily suspensions, emulsions, hard or soft capsules, lozenges or syrups.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more sweetening, flavoring, coloring or preserving agents in order to provide pharmaceutically elegant and palatable preparations.
Tablets contain the compound of said formula in admixture with excipients which are suitable for manufacture of tablets. These excipients may be inert diluents, such as, calcium phosphate, lactose, sucrose or dextrose; granulating and disintegrating agents, such as starch or alginic acid; binding agents such as starch, gelatine or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc.
Compositions for oral use in the form of hard gclatine capsules contain the compound of said formula mixed with an inert solid diluent such as calcium phosphate, lactose or kaolin, or as soft gelatine capsules in which the compound of said formula is mixed with an oily medium such as arachis oil, liquid paraffin or olive oil.
Compositions intended for parenteral administration may be in the form of sterile injectable preparations such as solutions or suspensions in water, saline or 1,3-butane diol. The preparations may also contain suitable wetting agents and suspending agents.
For the purposes of convenience and accuracy of dosing the compositions are advantageously employed in a unit dosage form. For oral administration the unit dosage form contains from 1 mg. to 500 mg, preferably from 10 mg. to mg, of the compound of said formula. Parenteral unit dosage forms contain from 1 mg. to 10 mg. of the compound of said formula per 1 ml. of the preparation.
The compounds of said formula may be prepared by oxidizing the corresponding thioethers. The oxidation may be carried out employing as the oxidizing agent hydrogen peroxide, N-halosuccinimides, l-chlorobenzo-triazole and other known chemical equivalents.
In the preparation of compounds of said formula in which p=l (sulphoxides) suitable methods for carrying out this oxidation include the use of hydrogen peroxide in acetic acid, N-bromosuccinimide or N-chlorosuccinimide in methanol, and l-chlorobenzotriazole in methanol or methylenechloride. In order to minimize the formation of a further oxidation product, namely the sulphone (p=2) an equimolar proportion of the oxidizing agent should be employed, and the oxidation conducted at 20 C.
In the preparation of compounds of said formula in which p=2 (sulphones) a convenient process for carrying out the oxidation is in acetic acid using a 2-3 fold excess of hydrogen peroxide and heating the mixture on a steam bath.
The thioethers used as starting materials may be readily prepared from thiols for example by treatment with an organo-halide or sulphate.
The following examples illustrate the preparation of compounds of said formula:
EXAMPLE 1 3,4-dimethoxyphenylmethyl sulphoxide 3,4-dimethoxythiophenol (28.3 g., 0.17 mole; A. A. Levi and S. Smiles. J. Chem. Soc. 520 (1931)) was added to sodium (3.83 g., 0.17 mole) in absolute ethanol. Dimethyl sulphate (20.8 g., 0.17 mole) was slowly added to the mixture which was then refluxed for two hours. The solvent was removed under reduced pressure. The residue was extracted with chloroform. The extracts were washed with water, dried over magnesium sulphate and evaporated to give 3,4-dimethoxyphenylmethyl sulphide (28.6 g.) B.P. 110 C./0.8 mm.
Analysis.Calcd. for C H O S: C, 58.7; H, 6.6; S,
17.4%. Found: C, 58.5; H, 6.4; S, 17.2%.
30% hydrogen peroxide (11.3 ml., 0.1 mole) was added to the 3,4-dimethoxyphenylmethyl sulphide (18.4 g., 0.1 mole) in glacial acetic acid (100 ml.) with cooling. The mixture after remaining at room temperature for 24 hours was made akaline by the slow addition of ice-cold aqueous sodium hydroxide. The mixture was extracted with chloroform. The extracts were washed with water, dried over magnesium sulphate and evaporated to dryness under reduced pressure to give white crystalline 3,4-dimethoxyphenylmethyl sulphoxide (15.1 g.). A sample recrystallized from diisopropyl ether had M.P. 82-84" C.
Analysis.-Calcd. for C H O S: C, 54.1; H, 6.1; S,
16.0%. Found: C, 53.9; H, 6.3; S, 15.7%.
EXAMPLE 2 3,4-dimethoxyphenylethyl sulphoxide 3,4-dimethoxythiophenol (8.6 g., 0.05 mole), sodium (1.15 g., 0.05 mole), ethanol (50 ml.) and ethyl iodide (7.8 g., 0.05 mole) were reacted according to the manner of Example 1 to give 3,4-dimethoxyphenylethyl sulphide (7.3 g.), B.P. 100-108 C./0.2 mm.
Analysis.C H O S requires: C, 60.7; H, 7.1; S,
16.2%. Found: C, 60.7; H, 7.0; S, 15.9%.
The 3,4-dimethoxyphenylethyl sulphide (1.98 g.) was oxidized, according to the manner of Example 1, to give 3,4dimethoxyphenylethyl sulphoxide (1.6 g.).
Amzlysis.-Calcd. for C H O S: C, 56.1; H, 6.6%.
Found: C, 56.0; H, 6.4%.
EXAMPLE 3 3,4-dich1oropheny1methyl sulphoxide (a) 3,4-dichlorothiophenol (8.9 g., 0.05 mole; S. M. Dandin et al. Chem. Abs. 52, 8071), sodium (1.15 g., 0.05 mole), ethanol (50 ml.) and methyl iodide (7.1 g., 0.05 mole) were reacted according to the manner of Example 1 to give 3,4-dichlorophenylmethyl sulphide (7.2 g.). B.P. 76-80 c./o.2
The 3,4-dicholrophenylmethyl sulphide (5.7 g., 0.03 mole) was dissolved in dry methanol ml.) and cooled to 0 C. in an ice-bath. N-chlorosuccinimide (4 g., 0.03 mole) was added in increments whilst keeping the temperature below 10 C. The mixture was allowed to stand for an hour. The solvent was removed under reduced pressure. The residue was extracted with chloroform. The extracts were washed with water, dried over magnesium sulphate and evaporated to give a white oil, which on trituration with light petroleum ether afforded crystalline 3,4-dichlorophenylmethyl sulphoxide (4.8 g.) M.P. 72- 74 C.
Analysis.-Calcd. for C H Cl OS: C, 402.2; H, 2.9; CI, 34.0; S, 15.3%. Found: C, 39.7; H, 2.7; CI, 34.2; S, 15.8%.
(b) The 3,4-dichlorophenylmethyl sulphide (4.0 g., 0.03 mole) was dissolved in dry methylene chloride (50 ml.) and cooled to 78 C. in a Dry Ice/alcohol bath. 1- chlorobenzotriazole (3.6 g., 0.03 mole) was added and the mixture was allowed to warm to room temperature (45-60 minutes). The mixture was washed successively with 10% aqueous sodium hydroxide then water, and finally dried over magnesium sulphate. The solvent was evaporated off under reduced pressure, to give a produce (3.5 g.) M.P. 7274 (3., identical to that obtained in (a) above.
EXAMPLE 4 2,5-dimethoxyphenylmethyl sulphoxide 2,5-dimethoxythiophenol (2.8 g., 0.017 mole; Suter and Hansen J. Am. Chem. Soc. 54, 4102 1932)) was added to sodium (0.4 g., 0.017 mole) in absolute ethanol. Dimethyl sulphate (2.1 g., 0.017 mole) was slowly added to the mixture which was then refluxed for two hours. The solvent was removed under reduced pressure. The residue was extracted with chloroform. The extracts were washed with water, dried over magnesium sulphate and evaporated to give 2,5-dimethoxyphenylmethyl sulphide (2.8 g.) B.P. 9296 C./0.3 mm. Analysis.-Calcd. for C H O S: C, 58.7; H, 6.6; S,
17.4%. Found: C, 59.0; H, 6.5; S, 17.5%.
The 2,5-dimethoxyphenylmethyl sulphide (2.3 g.) was oxidized according to the manner of Example 1 to give 2,5-dimethoxyphenylmethyl sulphoxide (1.8 g.) M.P. 70- 72 C.
Analysis.Calcd. for C H O S: C, 54.1, H, 6.1; S,
16.0%. Found: C, 53.5; H, 6.0; S, 16.5%.
EXAMPLE 5 3,4-dimethoxyphenylmethyl sulphone 3,4-dimethoxyphenylmethyl sulphide (6.1 g., 0.03 mole) and 30% hydrogen peroxide (11.3 ml., 0.1 mole) were heated on a steam bath for 2 hours in glacial acetic acid ml.). The mixture was poured onto ice (300 g.) and the resulting white precipitate filtered, washed well with water and recrystallized from ethanol to give 3,4-dimethoxyphenylmethyl sulphone (5.7 g.). M.P. l15117 C.
Analysis.Calcd. for C H O 'S: C, 50.0; H, 5.6; S,
14.8%. Found: C, 49.8; H, 5.8; S, 14.7%.
EXAMPLE 6 3,4-dimethoxy-6nitrophenylmethyl sulphone 3,4-dimethoxyphenylmethyl sulphone (6.5 g., 0.03 mole) was dissolved in concentrated nitric acid (20 ml.) and allowed to stand at room temperature for 1 hour. The mixture was poured onto ice and the yellow precipitate filtered off and recrystallized from ethanol to give 3,4-dimethoxy-6-nitrophenylmethyl sulphone (5.8 g.), M.P. 186-188 C.
Analysis.-Calcd. for C H NO S: C, 41.4; H, 4.2; N,
5. s, 12.3%. Found: c, 41.4; H. 4.1; N, 5.4, s,
EXAMPE 7 6-amino-3,4-dirnethoxyphenylmethyl sulphone Analysis.--Calcd. for C H NO S: C, 46.8; H, 5.7; N, 6.1; S, 13.9%. Found: C, 46.9; H, 5.6; N, 6.2; S, 13.8%.
The table below sets out details of further examples of compounds of said formula. The compounds in which p=1 (sulphoxides) were prepared by the method of Example 1, and those in which p=2 (sulphones) were prepared by the method of Example 5.
6 EXAMPLE I A mixture of 1 part of 3,4-dimethoxyphenylmethyl sulphoxide, 5 parts of lactose and 5 parts of starch, together with 1% of magnesium stearate was compressed into tablets. Conveniently the tablets are of such a size as to contain 10 or mg. of 3,4-dimethoxyphenylmethyl sulphoxide. Similarly tablets containing mg. of 3,4- dimethoxyphenylmethyl sulphoxide were prepared from a mixture of 2 parts of the sulphoxide, 5 parts of lactose, 5 parts of starch together with 1% magnesium stearate.
EXAMPLE II A mixture of 1 part of 3,4-dimethoxyphenylmethyl sulphoxide, and 9 parts of a tablet base comprising starch with the addition of 1% magnesium stearate was compressed into tablets.
Conveniently the tablets are of such a size as to contain 10 or 25 mg. of 3,4-dimethoxyphenylrnethyl sulphox- TABLE Analysis, percent Substituent on benzene ring P Calculated Found Example 2 s 4 5 e R p o.' Formula 0 H s 11 1 iii 8 CHzCHzOH Me The compound of Example 24 had B.P. 125-8 C./ 1 mm.
The invention is further illustrated by the following examples of compositions in which all parts are by weight.
56. 5 5. 9 18. 9 56. 2 6. 1 18. 5 1 56. 5 5. 9 18. 9 56. 4 5. 8 18. 6 1 56. 5 5. 9 18. 9 56. 3 6. 1 18. 2 1 62. 4 6. 6 20. 8 62. 7 6. 8 20. 4 1 54. 1 6. 1 16. 0 54. 1 6. 0 16.2 1 54. 1 6. 1 16. 0 53. 6 6. 2 15. 7 1 54. 1 6. 1 16. 0 54. 3 6. 2 16. 0 1 47. 0 4. 4 15. 7 46. 9 4. 5 15. 7 1 84 0711001208 40. 4 2. 9 15. 4 40. 2 3. 0 15. 5 1 76 0111c 0120 S 40. 4 2. 9 15. 4 40. 4 2. 9 15. 2 1 92-94 CIHsClzOS 40. 4 2. 9 15. 4 40. 1 2. 9 15. 6 1 69-71 CIHO C120 S 40. 4 2. 9 15. 4 40. 1 2. 9 15. 0 1 -71 CaHoClOS 51. 1 4. 5 17. 1 51. 0 4. 8 17. 6 1 53-55 091112028 58. 7 6. 6 17. 4 58. 6 6. 4 17. 5 1 67. 4 8. 2 16. 4 66. 5 8. 3 16. 4 1 61. 0 7. 9 12. 5 60. 7 8. 2 12. 0 1 61. 0 7. 9 12.5 60. 6 8. 0 12. 0 1 63. 4 8. 5 11.3 63. 4 8. 5 11. 4 1 56. 1 6. 6 15. 0 56. 0 6. 5 14. 9 1 52. 2 6. 1 13. 9 51. 7 6. 2 12. 5 1 091150120 8 43.1 3. 6 14. 4 42. 9 3. 6 14. 2 1 C10H12C12O S 47. 9 4. 8 12. 8 48. 1 4. 7 13. 0 1 CuHloClzOS 45. 6 4. 3 13. 5 45. 8 4. 2 13. 5 1 CaHgClzOS 43. 1 3. 6 14. 4 4.3. 2 3. 6 15. 1 1 0 11 01208 43.1 3. 6 14. 4 42. 6 3.6 14. 7 1 (30111001205 45. 6 4. 3 13. 5 45. 6 4. 2 13. 8 1 CwHuChOzs 47. 9 4. 8 12. 8 47. 6 4. 8 13. 2 1 (3105112012023 47. 9 4. 8 12. 8 47. 9 4. 9 12. 9 1 00111001208 45. 6 4. 3 13. 5 45. 7 4. 3 13. 6 2 141-142 10 14 4B 52. 2 6. 1 13. 9 52. 0 6. 2 14. 1 2 179-80 CDHIIBI'OAS 36. 6 3. 2 10. 9 36. 5 3. 9 11. 0 2 193-4 CwHuOsS 48. 8 5. 7 13. 0 48. 6 5. 6 12. 6 2 77-8 0101114053 48. 8 5. 7 13. 0 49. 7 5. 7 14. 6 2 104-6 001112048 50. 0 5. 6 14. 9 49. 7 5. 6 15. 2 2 84-5 001112048 50. 0 5. 6 14. 9 49. 8 5. 5 15. 1 2 115-6 CnH12O4S 50. 0 5. 6 14. 9 49. 9 5. 6 15. 0 2 108-110 011315012028 37. 4 2. 8 14. 3 37. 6 2. 9 14. 0 2 -2 CuHeClzOzS 47. 0 4. 4 95. 7 46. 7 4. 5 15. 3 2 68 091112025 58. 7 6. 6 17. 4 58. 6 6. 5 17. 2
ide. Similarly tablets containing 50 mg. of 3,4-dimethoxyphenylmethyl sulphoxide were prepared from a mixture of 2 parts of the sulphoxide, 9 parts of starch together with 1% magnesium stearate.
EXAMPLE n1 Various strength capsules are prepared containing 3,4- dimethoxyphenylmethyl sulphoxide and the following ingredients (amounts are in mg.):
The above ingredients may be screened through a 40 13.5.8. mesh screen before being mixed and filled into hard gelatin capsules.
EXAMPLE IV Ampoules were prepared containing 5 mls. of an isotonic solution prepared from 1 gm. 3,4-dimethoxyphenylmethyl sulphoxide and 0.735 gm. sodium chloride in 100 mls. distilled water. The solution was stable to steam autoclaving at psi. for 35 minutes.
EXAMPLE V The 3,4-dimethoxyphenylmethyl sulphoxide in each of the foregoing Examples I-IV may be replaced by 2,4-dimethoxyphenylmethyl sulphoxide, 3,4-dimethoxyphenylethyl sulphoxide, 2,5-dimethoxyphenylmethyl sulphoxide, 6-amino-3,4-dimethoxyphenylmethyl sulphone, 3,4-dimethoxyphenylmethyl sulphone, 2,S-dimethoxyphenylmethyl sulphone, 3,4-dimethoxyphenylpropyl sulphoxide, 3,5-clichlorophenylmethyl sulphoxide, 3,4,6-trirnethoxyphenylmethyl sulphoxide, 3,S-dimethoxyphenylmethyl sulphoxide, or 3,4-diethylphenylmethyl sulphoxide.
Screening for antihypertensive activity has been carried out employing known pharmacological tests such as those using normotensive, DOCA and renal hypertensive rats according to the method of Stanton, H. C., and White, J. B., Archs. Int. Pharmacodyn. Ther. 154, No. 2, 351 (1966) and Weeks, I. R., and Jones, J. A., Proc. Exper. Biol. & Med. 104, No. 4, 646 (1960).
The following are some of the test resuts obtained with compounds of said formula. The compounds were administered intraperitoneally at a dose of 100 mg./ kg. to groups of DOCA hypertensive rats, and the figures are for the maximum percentage fall in the blood pressure.
The following are some of the results when compounds were administered orally to groups of DOCA hypertensive rats at dosage levels of 20, 50 and mg./kg. At each dose level a group of 6 rats was employed for each compound. The figures are for the maximum percentage fall in the blood pressure.
Percent fall in blood pressure It is expected that the likely human oral dose of a composition of the invention will be 200-500 mg. of active ingredient per day for the relief of hypertension.
It has been shown that these compounds possess interesting and prolonged vasodilator actions which are exerted on the smooth muscle fibres of the blood vessels of the peripheral circulation. There is no action on the autonomic nervous system. That the vasodilator activity is of peripheral origin is demonstrated by the following findings:
(1) The compounds have hypotensipe activity in spinalized cats and pithed rats.
(2) The compounds are active against vasoconstriction produced by noradrenaline and vasopressin in a variety of isolated perfused blood vessel preparation e.g. rabbit ear, rat mesenteric vessels.
Further the compounds antagonize the pressor effects of noradrenaline, tyramine and angiotensin in the anaesthetized cat and dog at 3 to 10 mg./kg. nictitating membrane contractions were also antagonized.
We claim:
1. Compounds of the formula:
GUI-BUN References Cited Burton and Hogarth, J. Chem. Soc., No. 5, 1945. Baliah, Jour. Indian Chem. Soc., vol. 38, No. 1, 1961.
LEWIS GOTIS, Primary Examiner D. R. PHILLIPS, Assistant Examiner US. Cl. X.R.
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Cited By (11)

* Cited by examiner, † Cited by third party
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US3952036A (en) * 1974-09-09 1976-04-20 Richardson-Merrell Inc. 1,1-(Thiadialkylidene) ferrocene S-oxides
US3962345A (en) * 1973-07-19 1976-06-08 Nippon Kayaku Co., Ltd. Alkyl phenyl ether derivatives
US4006183A (en) * 1975-07-08 1977-02-01 Sandoz, Inc. Substituted α-methylsulfinyl-o-toluidines
US4105786A (en) * 1975-05-14 1978-08-08 William H. Rorer, Inc. Ethynylbenzene compounds and derivatives thereof
US4388326A (en) * 1979-08-15 1983-06-14 Merck & Co., Inc. Phenyl hydroxypropyl sulfoxide enzyme inhibitors
US5112861A (en) * 1986-11-28 1992-05-12 Orion-Yhtyma Oy Method of treating parkinson's disease using pentanedione derivatives
US5225595A (en) * 1990-11-30 1993-07-06 Basf Aktiengesellschaft Arylsulfonyl compounds with unsaturated radicals
US5241120A (en) * 1989-11-09 1993-08-31 Hoechst Aktiengesellschaft Process for the preparation of alkyl 3-chlorophenyl sulfones
US5446194A (en) * 1986-11-28 1995-08-29 Orion-Yhtyma Oy Pharmacologically active catechol derivatives
US5489614A (en) * 1987-11-27 1996-02-06 Orion-Yhtyma Oy Catechol derivatives, their physiologically acceptable salts, esters and use
US20030105095A1 (en) * 2001-10-10 2003-06-05 Cheil Jedang Corporation 4'-Methanesulfonyl-biphenyl derivatives as a highly selective cyclooxygenase-2 inhibitor

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2432315A1 (en) * 1978-08-02 1980-02-29 Choay Sa NOVEL MEDICINAL PRODUCTS CONTAINING BENZENESULFONE-LIKE COMPOUNDS AS ACTIVE SUBSTANCE, NOVEL SUCH COMPOUNDS AND PROCESS FOR THEIR PREPARATION
FR2432316A1 (en) * 1978-08-02 1980-02-29 Choay Sa NOVEL MEDICINAL PRODUCTS CONTAINING, AS ACTIVE SUBSTANCE, BENZENESULFONE-LIKE COMPOUNDS, NOVEL SUCH COMPOUNDS AND PROCESS FOR THEIR PREPARATION
FR2447908B1 (en) * 1979-01-31 1986-03-21 Choay Sa NOVEL BENZENESULFONE TYPE COMPOUNDS AND PROCESS FOR THEIR PREPARATION
FR2447909A1 (en) * 1979-01-31 1980-08-29 Choay Sa Alkyl phenyl sulphone(s) - used as antilipaemic agents, act on the central nervous system, and affect mitosis
YU213587A (en) * 1986-11-28 1989-06-30 Orion Yhtymae Oy Process for obtaining new pharmacologic active cateholic derivatives

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3962345A (en) * 1973-07-19 1976-06-08 Nippon Kayaku Co., Ltd. Alkyl phenyl ether derivatives
US3952036A (en) * 1974-09-09 1976-04-20 Richardson-Merrell Inc. 1,1-(Thiadialkylidene) ferrocene S-oxides
US4105786A (en) * 1975-05-14 1978-08-08 William H. Rorer, Inc. Ethynylbenzene compounds and derivatives thereof
US4006183A (en) * 1975-07-08 1977-02-01 Sandoz, Inc. Substituted α-methylsulfinyl-o-toluidines
US4388326A (en) * 1979-08-15 1983-06-14 Merck & Co., Inc. Phenyl hydroxypropyl sulfoxide enzyme inhibitors
US5112861A (en) * 1986-11-28 1992-05-12 Orion-Yhtyma Oy Method of treating parkinson's disease using pentanedione derivatives
US5446194A (en) * 1986-11-28 1995-08-29 Orion-Yhtyma Oy Pharmacologically active catechol derivatives
US5489614A (en) * 1987-11-27 1996-02-06 Orion-Yhtyma Oy Catechol derivatives, their physiologically acceptable salts, esters and use
US5241120A (en) * 1989-11-09 1993-08-31 Hoechst Aktiengesellschaft Process for the preparation of alkyl 3-chlorophenyl sulfones
US5225595A (en) * 1990-11-30 1993-07-06 Basf Aktiengesellschaft Arylsulfonyl compounds with unsaturated radicals
US20030105095A1 (en) * 2001-10-10 2003-06-05 Cheil Jedang Corporation 4'-Methanesulfonyl-biphenyl derivatives as a highly selective cyclooxygenase-2 inhibitor
US6583321B1 (en) * 2001-10-10 2003-06-24 Cheil Jedang Corporation 4′-methanesulfonyl-biphenyl derivatives as a highly selective cyclooxygenase-2 inhibitor

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