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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Publication number
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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United States
Prior art keywords
dimethoxyphenylmethyl
sulphoxide
mole
formula
compounds
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
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US00201563A
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English (en)
Inventor
K Bentley
W Rushworth
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Reckitt Benckiser Healthcare UK Ltd
Original Assignee
Reckitt and Colman Products Ltd
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Application filed by Reckitt and Colman Products Ltd filed Critical Reckitt and Colman Products Ltd
Priority to US413229A priority Critical patent/US3886285A/en
Application granted granted Critical
Publication of US3804904A publication Critical patent/US3804904A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • 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

Definitions

  • 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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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
US00201563A 1970-12-07 1971-11-23 Substituted phenyl sulphoxides and sulphones and the use thereof as vasodilators Expired - Lifetime US3804904A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US413229A US3886285A (en) 1970-12-07 1973-11-06 Pharmaceutical compositions containing substituted phenyl sulphoxides and sulphones and method of using same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB5806570 1970-12-07
GB5806670 1970-12-07

Publications (1)

Publication Number Publication Date
US3804904A true US3804904A (en) 1974-04-16

Family

ID=26267716

Family Applications (1)

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US00201563A Expired - Lifetime US3804904A (en) 1970-12-07 1971-11-23 Substituted phenyl sulphoxides and sulphones and the use thereof as vasodilators

Country Status (11)

Country Link
US (1) US3804904A (enrdf_load_stackoverflow)
AU (1) AU471813B2 (enrdf_load_stackoverflow)
BE (1) BE776357A (enrdf_load_stackoverflow)
DE (1) DE2160148C2 (enrdf_load_stackoverflow)
ES (1) ES397598A1 (enrdf_load_stackoverflow)
FR (1) FR2116579B1 (enrdf_load_stackoverflow)
HK (2) HK13377A (enrdf_load_stackoverflow)
IE (1) IE35838B1 (enrdf_load_stackoverflow)
KE (1) KE2712A (enrdf_load_stackoverflow)
MY (1) MY7700200A (enrdf_load_stackoverflow)
NL (1) NL7116796A (enrdf_load_stackoverflow)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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 (fr) * 1978-08-02 1980-02-29 Choay Sa Nouveaux medicaments contenant a titre de substance active des composes de type benzenesulfone, nouveaux composes de ce type et procede pour leur preparation
FR2432316A1 (fr) * 1978-08-02 1980-02-29 Choay Sa Nouveaux medicaments contenant, a titre de substance active, des composes de type benzenesulfone, nouveaux composes de ce type et procede pour leur preparation
FR2447909A1 (fr) * 1979-01-31 1980-08-29 Choay Sa Nouveaux composes de type benzenesulfone et procede pour leur preparation
FR2447908B1 (fr) * 1979-01-31 1986-03-21 Choay Sa Nouveaux composes de type benzenesulfone et procede pour leur preparation
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

Also Published As

Publication number Publication date
KE2712A (en) 1977-04-01
FR2116579A1 (enrdf_load_stackoverflow) 1972-07-13
AU471813B2 (en) 1976-05-06
BE776357A (fr) 1972-04-04
NL7116796A (enrdf_load_stackoverflow) 1972-06-09
HK13377A (en) 1977-03-25
MY7700200A (en) 1977-12-31
DE2160148A1 (de) 1972-06-08
HK13477A (en) 1977-03-25
AU3656271A (en) 1973-06-14
FR2116579B1 (enrdf_load_stackoverflow) 1975-10-10
IE35838L (en) 1972-06-07
DE2160148C2 (de) 1984-07-19
ES397598A1 (es) 1975-04-01
IE35838B1 (en) 1976-06-09

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