US3867390A - 2 and 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides - Google Patents

2 and 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides Download PDF

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Publication number
US3867390A
US3867390A US386854A US38685473A US3867390A US 3867390 A US3867390 A US 3867390A US 386854 A US386854 A US 386854A US 38685473 A US38685473 A US 38685473A US 3867390 A US3867390 A US 3867390A
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carbon atoms
compounds
compound
hydrogen
chloro
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Expired - Lifetime
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US386854A
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Peter Edward Cross
Brian Gadsby
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Pfizer Corp Belgium
Pfizer Corp SRL
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Pfizer Corp Belgium
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Priority to US05/512,012 priority Critical patent/US3932649A/en
Priority to US05/512,010 priority patent/US3932636A/en
Priority to US05/512,007 priority patent/US3932639A/en
Priority to US05/512,008 priority patent/US3974155A/en
Priority to US05/512,009 priority patent/US3957796A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
    • C07D265/36—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D267/02—Seven-membered rings
    • C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D267/10—Seven-membered rings having the hetero atoms in positions 1 and 4 not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B31/00—Disazo and polyazo dyes of the type A->B->C, A->B->C->D, or the like, prepared by diazotising and coupling
    • C09B31/02—Disazo dyes
    • C09B31/12—Disazo dyes from other coupling components "C"
    • C09B31/14—Heterocyclic components

Definitions

  • R is 3-trifluoromethyl, chloro, bromo or fluoro; n and m are each two or three; X is oxygen or sulphur; R and R when taken separately, are each hydrogen or alkyl having 1 to 4 carbon atoms; R and R when taken together, are alkylene having 2 to 4 carbon atoms; Y is methylene or a single bond; R and when taken separately, are each hydrogen, hydroxy or alkoxy having I to 4 carbon atoms, and R and R when taken together, are oxo or alkylene dioxy having 2 to 4 carbon atoms, each oxygen atom in R and R when taken separately, and in R and R when taken together, being separated from the nitrogen
  • Particularly useful compounds according to this aspect of the invention are those which have a selective effect on the cerebral vasculature, with a comparatively small effect on blood vessels in other tissues such as peripheral tissue and the kidneys, and so do not cause a serious fall in blood pressure or increase in diuresis.
  • the aforesaid derivatives include compounds of the n n-s x (I) those of the formula and the salts thereof with pharmaceutically acceptable cations wherein R is 3-trifluoromethyl, chloro, bromo or fluoro; n and m are each two or three; X is oxygen or sulphur; R and R, when taken separately, are each hydrogen or alkyl having 1 to 4 carbon atoms; R and R, when taken together. are alkylcne having 2 to 4 can bon atoms; Y is methylene or a single bond; R and R when taken separately, are each hydrogen, hydroxy or alkoxy having 1 to 4 carbon atoms and R and R when taken together.
  • n and m are each 2 or 3;
  • X is oxygen; R and R when taken separately, are each alkyl having 1 to 4 carbon atoms; R and R when taken together, are alkylene having 2 to 4 carbon atoms; Y is methylene; R", when taken separately, is hydroxy or alkoxy having 1 to 4 carbon atoms; R when taken separately, is hydrogen, hydroxy or alkoxy having 1 to 4 carbon atoms and R and R when taken together, are oxo or alkylene dioxy having 2 to 4 carbon atoms, each oxygen atom in R and R when taken separately. and in R and R when taken together, being separated from the nitrogen atom of the heteroeyclie ring by two or more carbon atoms.
  • Preferred compounds of the invention having cerebral vasodilator activity are those of formula (I) in which X is an oxygen atom.
  • Another preferred group are those compounds of formula (ll) in which Y is a methylene group and R and R together represent an oxo group or an alkylenc dioxy group having I to 4 carbon atoms, each of these being attached to the methylene group, i.e., to Y.
  • Another preferred group of compounds are those of formula (ll) wherein Y is methylene, R is hydroxy or alkoxy having 1 to 4 carbon atoms and R is hydrogen.
  • those preferred compounds of formula (I) in which X is an oxygen atom particularly preferred are those in which R and R are each alkyl having 1 to 4 carbon atoms.
  • Y is a methylene group or an oxygen atom
  • particularly preferred are those in which n and m are each 2, i.e., the heterocyclic ring is a 4- piperidone ring or a dialkyl or alkylene ketal thereof, or a morpholine ring.
  • R is 2-chloro, Z-bromo or 3' trifluoromethyl.
  • the compounds of this invention may be prepared from 4-sulphamoyl-benzene sulphonyl chlorides of the formula:
  • the reaction is carried out in the presence of an excess of the amine reactant or in the presence of an equivalent amount of an organic tertiary amine to remove the hydrochloric acid formed in the reaction.
  • the reaction is completed in from l to 24 hours at 20C. or may be carried out at elevated temperatures, i.e., 30 to 100C. for periods of from I to 8 hours.
  • the product may be isolated by simply adding the reaction mixture to normal aqueous hydrochloric acid solution, filtering, washing and recrystallizing from a suitable 5 solvent.
  • R is a chlorine, bromine or fluorine atom or a trifluoromethyl group and R and R together, are not an oxo group, and the compound of formula (VIII) or (IX) is then reduced to the corresponding amino compound and the latter is converted to the corresponding sulphamoyl compound by diazotization, treatment with sulphur dioxide in the presence ofa cupric salt and then with ammonia.
  • the salts of the present invention include those based on any pharmaceutically acceptable cation.
  • the preferred pharmaceutically acceptable cations are those of the alkali metals, particularly sodium and potassium. Said salts are easily obtained in accordance with conventional methods. For example, the selected compound of formula (I) or formula (II) is dissolved in an aqueous or alcoholic solution of an alkali metal hydroxide such as sodium or potassium hydroxide and the resulting solution is simply concentrated.
  • the herein described compounds car. be administered to an affected subject via the oral or parenteral route.
  • the oral or parenteral route generally, there is a significant effect in increasing cerebral blood flow in cats, dogs and baboons at dose levels of from 2.5 to mg/kg intravenously or from 10 to 50 mg/kg orally when administered three times a day, the effect being cumulative.
  • the physician will determine the precise dosage for a human patient, it generally will range from 0.5 to mg/kg for intravenous administration and from 2 to 200 mg/kg for oral administration, each dosage form being administered four times a day.
  • the compounds of the invention may be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice.
  • a non-ionic wetting agent as dispersion aid e.g. a polyoxyethylene monostearate of average molecular weight about 1,000 such as Myrj" 52, is preferably also included.
  • the compound together with the dispersion aid may be dissolved in the molten polyethylene glycol and cooled, or alternatively may be mixed as an aqueous dispersion with the polyethylene glycol to form a paste and dried, and then, together with other excipients if desired, either granulated prior to compression into tablets or filled directly into capsules, by techniques well known in the art.
  • tablets may be formed in which a major part of the excipient is composed of a material which, when compressed, has a slower rate of dissolution than that normally achieved by standard tableting practice.
  • materials include sugars and edible aminoacids such as glycine.
  • the compound (in finely divided form) is preferably first mixed with the said material and then granulated with a comparatively small amount of the high molecular weight polyethylene glycol and a dispersion aid, before forming into tablets in the usual way.
  • the compounds are best used in the form of sterile aqueous solutions of their alkali metal (e.g. sodium) salts and such solutions may contain other solutes (e.g. sodium chloride) to ensure the stability of the solutions and their compatibility with body fluids, e.g. blood, when the compound is to be administered intravenously, intramuscularly or subcutaneously.
  • the alkali metal salt solution may conveniently be formed by dissolving the compound (and any other solute required) in the sterile water and adjusting the pH to a value in the range from 10.5 to 12.0 with the appropriate alkali metal hydroxide.
  • the activity of compounds of the invention as cerebral vasodilators is determined by the following method. Cats are anaesthetised with chloralose (80 mg/kg, intravenously) after induction with halothane, nitrous oxide/oxygen (3:1 v/v). The animals are allowed to breathe normal room air and the rate and depth of respiration, heart rate and femoral arterial pressure are recorded. An electromagnetic flow probe is placed around the ipsilateral vertebral artery. Zero flow is established by momentarily occluding the artery in order to calibrate the flow probe.
  • test compound dissolved in N/l0 sodium hydroxide in isotonic saline with warming and mixing and then back titration to pH with dilute hydrochloric acid
  • 10 or 25 mg/kg via a femoral vein and readings are taken at intervals for up to 2 hours.
  • Control observations after administration of the saline vehicle alone are also made.
  • the criterion for selecting the preferred compounds is on the basis of increases in ipsilateral vertebral arterial flow at 10 mg/kg which are sustained over a period of 30 minutes as shown in Table 11. Blood flow is assessed by measuring the peak (systolic) pulsatile flow and the mean pulsatile flow.
  • Example Vlll, XXII, l, 111 and V have been found to give significant increases in peak and mean pulsatile flow at 10 mg/kg.
  • the product of Example VIII is outstanding at that dosage.
  • Table 11 hereinafter summarizes results obtained with representative cerebral vasodilators of the present invention in accordance with this method.
  • the active compound and glycine are granulated with an aqueous solution of the PEG 6,000, Myrj 52 and gelatin, prior to adding the magnesium stearate and tableting in the usual way.
  • Example XXV mean particle diameter less than 3 microns. and as in Example XXV The active compound is ball-milled in water to achieve the small particle size, mixed with the PEG 6,000 and Myrj 52 as a paste and then dried at 40C. to form a powder which is then filled into capsules in the usual way.
  • EXAMPLE XXVll Parenteral formulation mg/ml Active ingredient 7.5 sodium chloride 7 9 (sufficient in pl-l adjustment) sodium hydroxide (sufficient to make up volume) water o (ca R1 '0 (CHQ H N-ISI Y and the salts thereof with pharmaceutically acceptable cations wherein R is 3-trifluoromcthyl. chloro, bromo or fluoro; n and m are each 2 or 3; Y is methylene; R, when taken separately, is hydroxy or alkoxy having 1 to 4 carbon atoms; R when taken separately, is hydrogen, hydroxy or alkoxy having 1 to 4 carbon atoms; and R and R when taken together, are oxo. each oxygen atom in R and R when taken separately. and in R and R when taken together. being separated from the 7. The compound of claim 6 wherein R 8. The compound of claim 6 wherein R is trifluoromethyl.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Vascular Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Hydrogenated Pyridines (AREA)
  • Pyrrole Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
US386854A 1972-07-19 1973-08-09 2 and 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides Expired - Lifetime US3867390A (en)

Priority Applications (5)

Application Number Priority Date Filing Date Title
US05/512,012 US3932649A (en) 1972-08-12 1974-10-04 2 And 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides as cerebral vasodilators
US05/512,010 US3932636A (en) 1972-08-12 1974-10-04 2 And 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides as cerebral vasodilators
US05/512,007 US3932639A (en) 1972-07-19 1974-10-04 2 And 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides as cerebral vasodilators
US05/512,008 US3974155A (en) 1972-08-12 1974-10-04 2 AND 3-Substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides
US05/512,009 US3957796A (en) 1972-08-12 1974-10-04 2 and 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB3772072A GB1380009A (en) 1972-08-12 1972-08-12 Cyclic derivatives of 1,4-benzene disulphonamide

Related Child Applications (5)

Application Number Title Priority Date Filing Date
US05/512,008 Division US3974155A (en) 1972-08-12 1974-10-04 2 AND 3-Substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides
US05/512,012 Division US3932649A (en) 1972-08-12 1974-10-04 2 And 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides as cerebral vasodilators
US05/512,007 Division US3932639A (en) 1972-07-19 1974-10-04 2 And 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides as cerebral vasodilators
US05/512,010 Division US3932636A (en) 1972-08-12 1974-10-04 2 And 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides as cerebral vasodilators
US05/512,009 Division US3957796A (en) 1972-08-12 1974-10-04 2 and 3-substituted-4-(heterocyclic-amino-sulfonyl)benzene sulfonamides

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US (1) US3867390A (OSRAM)
JP (2) JPS59508B2 (OSRAM)
AT (1) AT331248B (OSRAM)
AU (1) AU5908473A (OSRAM)
BE (1) BE803373A (OSRAM)
CA (1) CA978945A (OSRAM)
DE (1) DE2340010A1 (OSRAM)
ES (1) ES417806A1 (OSRAM)
FR (1) FR2195449B1 (OSRAM)
GB (1) GB1380009A (OSRAM)
IE (1) IE38177B1 (OSRAM)
IN (1) IN139006B (OSRAM)
LU (1) LU68211A1 (OSRAM)
NL (1) NL162641C (OSRAM)
SE (1) SE385008B (OSRAM)
ZA (1) ZA735474B (OSRAM)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4070361A (en) * 1977-04-21 1978-01-24 E. R. Squibb & Sons, Inc. Mercaptoalkylsulfonyl proline and pipecolic acid and esters thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2720654A1 (de) * 1977-05-07 1978-11-16 Bayer Ag Azolyl-alkancarbonsaeure-derivate, verfahren zu ihrer herstellung und ihre verwendung als fungizide
GB1572226A (en) * 1977-11-03 1980-07-30 Hoechst Uk Ltd Pharmaceutical preparations in solid unit dosage form
JPS5922023A (ja) * 1982-07-27 1984-02-04 Hoya Corp ビ−ムスプリツタ−

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3165550A (en) * 1960-06-29 1965-01-12 Pfizer & Co C N-substituted p-benzenedisulfonamides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3165550A (en) * 1960-06-29 1965-01-12 Pfizer & Co C N-substituted p-benzenedisulfonamides

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4070361A (en) * 1977-04-21 1978-01-24 E. R. Squibb & Sons, Inc. Mercaptoalkylsulfonyl proline and pipecolic acid and esters thereof

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AT331248B (de) 1976-08-10
IE38177L (en) 1974-02-12
JPS4985066A (OSRAM) 1974-08-15
JPS5857431B2 (ja) 1983-12-20
NL162641B (nl) 1980-01-15
IE38177B1 (en) 1978-01-18
LU68211A1 (OSRAM) 1975-05-21
CA978945A (en) 1975-12-02
GB1380009A (en) 1975-01-08
NL7311000A (OSRAM) 1974-02-14
IN139006B (OSRAM) 1976-04-24
JPS59508B2 (ja) 1984-01-07
SE385008B (sv) 1976-05-31
BE803373A (fr) 1974-02-08
ATA691573A (de) 1975-11-15
AU5908473A (en) 1975-02-13
FR2195449B1 (OSRAM) 1977-09-09
ZA735474B (en) 1974-08-28
FR2195449A1 (OSRAM) 1974-03-08
DE2340010A1 (de) 1974-03-14
JPS57131774A (en) 1982-08-14
ES417806A1 (es) 1976-03-01
NL162641C (nl) 1980-06-16

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