US3445573A - Pharmaceutical compositions with salidiuretic and reserpine antagonist activity comprising n-(2',6'-dimethyl-piperidyl-(1'))-3-sulfamyl - 4 - chlorobenzoic acid amide - Google Patents

Pharmaceutical compositions with salidiuretic and reserpine antagonist activity comprising n-(2',6'-dimethyl-piperidyl-(1'))-3-sulfamyl - 4 - chlorobenzoic acid amide Download PDF

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Publication number
US3445573A
US3445573A US560062A US3445573DA US3445573A US 3445573 A US3445573 A US 3445573A US 560062 A US560062 A US 560062A US 3445573D A US3445573D A US 3445573DA US 3445573 A US3445573 A US 3445573A
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United States
Prior art keywords
chloro
dimethyl
sulfamyl
acid amide
piperidyl
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Expired - Lifetime
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US560062A
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English (en)
Inventor
Ernst Jucker
Adolf J Lindenmann
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Sandoz AG
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Sandoz AG
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Priority claimed from CH1254760A external-priority patent/CH396905A/de
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Classifications

    • 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
    • C07D295/28—Nitrogen atoms
    • C07D295/32—Nitrogen atoms acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/46—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with hetero atoms directly attached to the ring nitrogen atom
    • C07D207/50—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D245/00—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms
    • C07D245/02—Heterocyclic compounds containing rings of more than seven members having two nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen 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
    • C07D265/02—1,2-Oxazines; Hydrogenated 1,2-oxazines
    • 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

Definitions

  • the present invention relates to a diuretic composition in unit dosage form containing as the active ingredient thereof N- [2,6' dimethylpiperidyl-(1)] 3-sulfamyl-4- chloro-benzoic acid amide of the Formula I,
  • the source of the glomerular filtrate is extracellular fluid.
  • the reabsorption of sodium and accompanying anion by the renal tubule is the process which requires the greatest expenditure of energy by the kidney since the sodium ion is the principal cation of extracellular fluid. Interference with its reabsorption represents a significant mechanism for withdrawing sodium from the extracellular fluid, e.g. for the elimination of sodium from the body.
  • the organic mercurial inhibitors inhibit SH-activated enzyme systems through release of the mercuric ion.
  • the diuretic action of the organic mercurial is inhibited by certain mercaptans.
  • the sulfhydryl inhibition is believed to implicate the succinic dehydrogenase enzyme system.
  • the extreme toxicity of mercury represents its principal disadvantage.
  • Urine excreted in response to a mercurial diuretic contains chloride as the predominant ion and the loss of fixed sodium is secondary. Persistent systemic alkalosis develops quite readily and the patient becomes refractory to the desired action of the diuretic.
  • acetazoleamide depresses tubular reabsorption transport of electrolyte by promoting the bicarbonate excretion and serves as a specific inhibitor of carbonic anhydrase enzyme.
  • This compound shares with sulfanilamide the specific inhibition of carbonic anhydrase to thereby create acidification of the urine.
  • Carbonic anhydrase enzyme is present in red blood cells, renal cortex, pancreas, and the gastric mucosa, and functions to provide a source of hydrogen and bicarbonate ions. In the renal tubular cell, hydrogen is exchanged with sodium. The source of the hydrogen is carbonic acid.
  • the Unexpected Properties of the Present Composition The dosages of the present invention which are smaller than the maximum diuretically active dose, e.g. at dosages of between 20 and 40 milligrams per day, provide completely unexpected interference with catecholamine dependent functions which makes the present composition in unit dosage form outstandingly useful for the treatment of hypertension in which there is a benefit from the control of sodium chloride diuresis within narrow limits.
  • N-[2,6-dimethyl-piperidyl (1)]-3-sulfamyl-4-chloro-benzoic acid amide is much greater than that of each of the following:
  • the present active ingredient N-[2',6'-dimethyl-piperi dyl-(1)]-3-sulfamyl 4 chloro-benzoic acid amide has shown an unexpectedly high antagonistic activity in reserpine hypothermia which is effective, remarkably, in doses smaller than the maximally diuretic active dose.
  • compounds (a), (b), (c), (d) and (e) above are inactive in this respect, reserpine hypothermia) when administered in dosages throughout each of their effective diuretic ranges and even up to the maximally diuretic active dose.
  • the ED value of the compound of the present invention for the inhibition of reserpine hypothermia over 3 hours was found to be 0.05 mg./ kg.
  • N-[pyrrolidinyl-(1')-3 sulfamyl 4- chloro-benzoic acid amide appears to be explained by assuming an interference with the catecholamine metabolism of the body. This assumption is substantiated by the fact that continuous treatment of animals with the present active ingredient also increases the sensitivity of their vascular walls to Noradrenaline, just as happens with continuous treatment of animals with reserpine.
  • a process for the preparation of the new compound is characterized in that a 3-sulfamyl-4-chloro-benzoyl-halide of the Formula II,
  • halogen signifies a chlorine and bromine atom
  • the liquid phase in the process may be homogeneous or not homogeneous and may be achieved by an excess of 1-amino-2,6-dimethyl-piperidine when this is liquid under the reaction conditions otherwise, the presence of an inert organic solvent, e.g. a halogenated hydrocarbon such as chloroform, is necessary.
  • a proton acceptor for example, a tertiary organic base
  • Triethylamine is added to a suspension of 1-amin0-2,6- dimethyl-piperidine or a salt thereof in chloroform.
  • a 3- sulfamyl-4-chloro-benzoyl-halide is then added to the solution and the mixture is stirred at room temperature for 1 to 4 days.
  • the mixture is then evaporated to dryness, the residue taken up with a water immiscible solvent, e.g. ethyl acetate, and washed with water.
  • N-[2',6-dimethyl-piperidyl-l-(l)]-3-sulfamyl-4-chloro benzoic acid amide obtained as a residue, is purified in accordance with known methods.
  • 3-sulfamyl-4-chloro benzoyl-halides may be mentioned 3-sulfamyl-4 chloro-benzoyl chloride or bromide.
  • halogen 013 wherein halogen has the above significance, is reacted with a 1-am'ino-2,6-dimethyl piperidine and the resulting compound of general Formula IV,
  • halogen S O 2 Ha IV wherein halogen has the above significance, is treated with ammonia to give the N-[2,6'-dimethyl-piperidyl-(1)]-3- sulfamyl-4-chloro-'benzoic acid amide.
  • the 1-amino-2,6- dimethyl piperidine can be reacted with a compound of general Formula III, as well as in the form of a free base as in the form of a salt.
  • the process mentioned above can be effected as follows:
  • the suspension or solution of a 3-halogeno-sulfonyl-4- chloro-benzoyl halogenide of general Formula 1111 is reacted with 1-amino-2,6-dimethyl piperidine in an indifferent solvent, e.g. acetone, chloroform or chlorobenzene, and heated for several hours. After the cooling down of the reaction mixture, the eventually crystallized reaction product is either sucked off or the solution is evaporated to dryness, the residue is dissolved in an indifferent organic solvent, e.g. chloroform, and treated with ammonia.
  • the ammonia can be added as an aqueous solution, in the form of liquid ammonia, as ammonia gas in chloroform or diluted in alcohol.
  • Suitable 3-ha1ogeno-sulfonyl-4-ch1oro-benzoyl-halogenides are, for example, the 3-chloro-sulfonyl-4-chlorobenzoyl chloride, the 3-bromo-sulfonyl-4-chloro-benzoyl chloride, the 3-chlonO-sulfonyl-4-chloro-benzoyl bromide, the 3-'bromo-sulfonyl-4-chl0ro-benzoyl bromide.
  • the acid chlorides have been found to be the most suitable, but the acid bromides can also be used.
  • the 3-chloro-su1fionyl-4-chloro-benzoyl chloride is preferably produced by heating a mixture of 3-chloro-sulfony1- 4-chloro-benzoic acid and thionyl chloride to C. It can also be obtained 'by reacting equimolecular quantities of 3-chloro-sulonyl-4-chloro-benzoic acid and thionyl chloride in the presence of a little dimethyl formamide and using chlorobenzene as a solvent.
  • 7.6 g. of 3-sulfamyl-4-chloro-benzoyl chloride are added to a solution of 3.8 g. of 1-amino-2,G-dimethyI-piperidine and 3.0 g. of triethylamine in 150 cc. of chloroform within '20 minutes while stirring at 20-25 and the yellow reaction solution is then stirred for another 48 hours at room temperature.
  • the mixture is then evaporated to dryness in a vacuum, the residue taken up in 200 cc.
  • the solution is then heated at reflux for 8 hours to 100-105 and, after cooling down to room temperature, the crystalline precipitated N [2,6-dimethyl-piperidyl-(l)]-3-chlorosulfonyl-4-chloro benzoic acid amide is filtered off. After drying in a vacuum at 100, the sulfochloride is suspended in 15 cc. of chloroform and added carefully to 60 cc. of liquid ammonia. The reaction mixture is left to stand at room temperature until the excess ammonia has volatilized and it is then evaporated to dryness in a vacuum.
  • N-[2',6'-dimethyl piperidyl (1')]- 3-sulfamyl-4-chloro-benzoic acid amide can also be obtained from 3-chloro-sulfonyl-4-chloro-benzoyl chloride and 1 amino 2,6 dimethyl piperidine hydrochloride using acetone as a solvent.
  • N-[2,6' dimethyl piperidyl- (1')]-3-sulfamyl-4chloro-benzoic acid amide is a crystalline compound useful as a pharmaceutical or as an intermediate for the production of other compounds.
  • the exemplified compound is administered in therapeutic dosages of 2-100 mg. per day, preferably 20-40 mg. per day, in conventional pharmaceutically acceptable vehicles as well as in the form of tablets.
  • the dosage of the present invention is effective upon enteral and parenteral administr ation.
  • the compounds of the invention are worked up with organic or inorganic adjuvants which are physiologically a cceptable and inert. Examples of such adjuvants or carriers for various medicinal preparations are as follows:
  • Injectable solutions --Water, physiologically acceptable alcohols, glycerine and physiologically acceptable vegetable fats,
  • the preparations may contain suitable preserving, stabilizing or wetting agents, solubilizers, sweetening and colouring substances or flavourings, with the proviso that they must be physiologically acceptable.
  • a pharmaceutical composition having salidiuretic and reserpine antagonistic activity comprising a pharmaceutically acceptable and inert carrier selected from the class consisting of water, sugar, starch, talc, magnesium stearate gelatin, stearic acid, glycerine, physiologically acceptable vegetable fats, oils and waxes, parafiin, bentonite, petroleum jelly, physiologically acceptable alcohol and cellulose and N-[2,6'-dimethyl-piperidyl (1')] 3- sulfamyl-4-chloro-benzoic acid amide as the active agent in a minimum amount for etfecting diuretic activity.
  • a pharmaceutically acceptable and inert carrier selected from the class consisting of water, sugar, starch, talc, magnesium stearate gelatin, stearic acid, glycerine, physiologically acceptable vegetable fats, oils and waxes, parafiin, bentonite, petroleum jelly, physiologically acceptable alcohol and cellulose and N-[2,6'

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
US560062A 1960-11-09 1966-06-24 Pharmaceutical compositions with salidiuretic and reserpine antagonist activity comprising n-(2',6'-dimethyl-piperidyl-(1'))-3-sulfamyl - 4 - chlorobenzoic acid amide Expired - Lifetime US3445573A (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CH1254760A CH396905A (de) 1960-11-09 1960-11-09 Verfahren zur Herstellung von neuen Hydrazin-Derivaten
CH1354460 1960-12-02
CH654761A CH418335A (de) 1960-11-09 1961-06-06 Verfahren zur Herstellung von neuen Hydrazin-Derivaten
CH1047461 1961-09-11
CH1518864A CH412892A (de) 1960-11-09 1961-09-11 Verfahren zur Herstellung von neuen Hydrazin-Derivaten

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US3445573A true US3445573A (en) 1969-05-20

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US560062A Expired - Lifetime US3445573A (en) 1960-11-09 1966-06-24 Pharmaceutical compositions with salidiuretic and reserpine antagonist activity comprising n-(2',6'-dimethyl-piperidyl-(1'))-3-sulfamyl - 4 - chlorobenzoic acid amide
US645082A Expired - Lifetime US3459756A (en) 1960-11-09 1967-04-17 N-(2',6'-dimethyl-piperidyl-(1'))-3-sulfamyl-4-chloro-benzoic acid amide

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US645082A Expired - Lifetime US3459756A (en) 1960-11-09 1967-04-17 N-(2',6'-dimethyl-piperidyl-(1'))-3-sulfamyl-4-chloro-benzoic acid amide

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US (2) US3445573A (en:Method)
BR (1) BR6134007D0 (en:Method)
CH (2) CH418335A (en:Method)
FR (1) FR1748M (en:Method)
GB (1) GB939468A (en:Method)
LU (1) LU40792A1 (en:Method)
NL (1) NL270803A (en:Method)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4367232A (en) * 1976-10-29 1983-01-04 Fordonal, S.A. Piperidine derivatives

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1545519B1 (en) 2002-08-19 2011-03-23 Pfizer Inc. Combination therapy for hyperproliferative diseases
US20060063803A1 (en) * 2004-09-23 2006-03-23 Pfizer Inc 4-Amino substituted-2-substituted-1,2,3,4-tetrahydroquinoline compounds
US7741317B2 (en) 2005-10-21 2010-06-22 Bristol-Myers Squibb Company LXR modulators
US7888376B2 (en) 2005-11-23 2011-02-15 Bristol-Myers Squibb Company Heterocyclic CETP inhibitors
EP2094643B1 (en) 2006-12-01 2012-02-29 Bristol-Myers Squibb Company N-((3-benzyl)-2,2-(bis-phenyl)-propan-1-amine derivatives as cetp inhibitors for the treatment of atherosclerosis and cardiovascular diseases
CN105143203A (zh) 2013-04-17 2015-12-09 辉瑞大药厂 用于治疗心血管疾病的n-哌啶-3-基苯甲酰胺衍生物
WO2016055901A1 (en) 2014-10-08 2016-04-14 Pfizer Inc. Substituted amide compounds
ES3007652T3 (en) 2019-01-18 2025-03-20 Astrazeneca Ab 6'-[[(1s,3s)-3-[[5-(difluoromethoxy)-2-pyrimidinyl]amino]cyclopentyl]amino][1(2h),3'-bipyridin]-2-one as pcsk9 inhibitor and methods of use thereof

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3043874A (en) * 1960-05-09 1962-07-10 Parke Davis & Co 4-halo-3-sulfamoylbenzoic acid derivatives and methods for producing same

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CH430711A (de) * 1963-12-20 1967-02-28 Sandoz Ag Verfahren zur Herstellung von neuen heterocyclischen Verbindungen

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3043874A (en) * 1960-05-09 1962-07-10 Parke Davis & Co 4-halo-3-sulfamoylbenzoic acid derivatives and methods for producing same

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4367232A (en) * 1976-10-29 1983-01-04 Fordonal, S.A. Piperidine derivatives

Also Published As

Publication number Publication date
CH418335A (de) 1966-08-15
NL270803A (en:Method)
BR6134007D0 (pt) 1973-05-31
GB939468A (en) 1963-10-16
FR1748M (fr) 1963-03-25
CH412892A (de) 1966-05-15
LU40792A1 (en:Method) 1962-05-07
US3459756A (en) 1969-08-05

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