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 PDFInfo
- 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
- Authority
- US
- United States
- Prior art keywords
- chloro
- dimethyl
- sulfamyl
- acid amide
- piperidyl
- 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
Links
- DNXIKVLOVZVMQF-UHFFFAOYSA-N (3beta,16beta,17alpha,18beta,20alpha)-17-hydroxy-11-methoxy-18-[(3,4,5-trimethoxybenzoyl)oxy]-yohimban-16-carboxylic acid, methyl ester Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(C(=O)OC)C(O)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 DNXIKVLOVZVMQF-UHFFFAOYSA-N 0.000 title description 7
- LCQMZZCPPSWADO-UHFFFAOYSA-N Reserpilin Natural products COC(=O)C1COCC2CN3CCc4c([nH]c5cc(OC)c(OC)cc45)C3CC12 LCQMZZCPPSWADO-UHFFFAOYSA-N 0.000 title description 7
- QEVHRUUCFGRFIF-SFWBKIHZSA-N Reserpine Natural products O=C(OC)[C@@H]1[C@H](OC)[C@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)C[C@H]2[C@@H]1C[C@H]1N(C2)CCc2c3c([nH]c12)cc(OC)cc3 QEVHRUUCFGRFIF-SFWBKIHZSA-N 0.000 title description 7
- BJOIZNZVOZKDIG-MDEJGZGSSA-N reserpine Chemical compound O([C@H]1[C@@H]([C@H]([C@H]2C[C@@H]3C4=C([C]5C=CC(OC)=CC5=N4)CCN3C[C@H]2C1)C(=O)OC)OC)C(=O)C1=CC(OC)=C(OC)C(OC)=C1 BJOIZNZVOZKDIG-MDEJGZGSSA-N 0.000 title description 7
- 229960003147 reserpine Drugs 0.000 title description 7
- MDMGHDFNKNZPAU-UHFFFAOYSA-N roserpine Natural products C1C2CN3CCC(C4=CC=C(OC)C=C4N4)=C4C3CC2C(OC(C)=O)C(OC)C1OC(=O)C1=CC(OC)=C(OC)C(OC)=C1 MDMGHDFNKNZPAU-UHFFFAOYSA-N 0.000 title description 7
- 230000000054 salidiuretic effect Effects 0.000 title description 5
- 230000000694 effects Effects 0.000 title description 4
- 239000008194 pharmaceutical composition Substances 0.000 title description 3
- 239000005557 antagonist Substances 0.000 title description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 30
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 150000001875 compounds Chemical class 0.000 description 27
- 239000000243 solution Substances 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- 229910021529 ammonia Inorganic materials 0.000 description 11
- 239000000203 mixture Substances 0.000 description 10
- PNEYBMLMFCGWSK-UHFFFAOYSA-N Alumina Chemical compound [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- 239000002934 diuretic Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- UAHWWAIVYPJROV-UHFFFAOYSA-N 2,6-dimethylpiperidin-1-amine Chemical compound CC1CCCC(C)N1N UAHWWAIVYPJROV-UHFFFAOYSA-N 0.000 description 7
- 230000001882 diuretic effect Effects 0.000 description 7
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
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- 239000011734 sodium Substances 0.000 description 6
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- PNXMCBFANZCXMB-UHFFFAOYSA-N 4-chloro-3-chlorosulfonylbenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C(S(Cl)(=O)=O)=C1 PNXMCBFANZCXMB-UHFFFAOYSA-N 0.000 description 5
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- WRLKLPDTRUYBBV-UHFFFAOYSA-N 4-chloro-3-sulfamoylbenzamide Chemical compound NC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 WRLKLPDTRUYBBV-UHFFFAOYSA-N 0.000 description 4
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- 238000001035 drying Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
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- 229940124530 sulfonamide Drugs 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 230000009471 action Effects 0.000 description 3
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- 150000003943 catecholamines Chemical class 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 3
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- FDDDEECHVMSUSB-UHFFFAOYSA-N sulfanilamide Chemical compound NC1=CC=C(S(N)(=O)=O)C=C1 FDDDEECHVMSUSB-UHFFFAOYSA-N 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- IOHPVZBSOKLVMN-UHFFFAOYSA-N 2-(2-phenylethyl)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1CCC1=CC=CC=C1 IOHPVZBSOKLVMN-UHFFFAOYSA-N 0.000 description 2
- XKQKCGDIIVQYKP-UHFFFAOYSA-N 2-chloro-5-(hydrazinecarbonyl)benzenesulfonamide Chemical compound NNC(=O)C1=CC=C(Cl)C(S(N)(=O)=O)=C1 XKQKCGDIIVQYKP-UHFFFAOYSA-N 0.000 description 2
- FHQAWINGVCDTTG-UHFFFAOYSA-N 4-chloro-3-sulfamoylbenzoic acid Chemical compound NS(=O)(=O)C1=CC(C(O)=O)=CC=C1Cl FHQAWINGVCDTTG-UHFFFAOYSA-N 0.000 description 2
- SCYSJFKWFQZRJW-UHFFFAOYSA-N 4-chloro-3-sulfamoylbenzoyl chloride Chemical compound NS(=O)(=O)C1=CC(C(Cl)=O)=CC=C1Cl SCYSJFKWFQZRJW-UHFFFAOYSA-N 0.000 description 2
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- 235000021355 Stearic acid Nutrition 0.000 description 2
- BZKPWHYZMXOIDC-UHFFFAOYSA-N acetazolamide Chemical compound CC(=O)NC1=NN=C(S(N)(=O)=O)S1 BZKPWHYZMXOIDC-UHFFFAOYSA-N 0.000 description 2
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- XRHGYUZYPHTUJZ-UHFFFAOYSA-N 4-chlorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1 XRHGYUZYPHTUJZ-UHFFFAOYSA-N 0.000 description 1
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- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000010245 tubular reabsorption Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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'
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
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 |
Publications (1)
Publication Number | Publication Date |
---|---|
US3445573A true US3445573A (en) | 1969-05-20 |
Family
ID=43798563
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
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 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US645082A Expired - Lifetime US3459756A (en) | 1960-11-09 | 1967-04-17 | N-(2',6'-dimethyl-piperidyl-(1'))-3-sulfamyl-4-chloro-benzoic acid amide |
Country Status (7)
Country | Link |
---|---|
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)
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)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MXPA05001958A (es) | 2002-08-19 | 2005-04-28 | Pfizer Prod Inc | Terapia de combinacion para enfermedades hiperproliferativas. |
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 |
ATE547394T1 (de) | 2006-12-01 | 2012-03-15 | Bristol Myers Squibb Co | N-((3-benzyl)-2,2-(bis-phenyl)-propan-1- aminderivate als cetp-hemmer für die behandlung von atherosklerose und herz-kreislauf- erkrankungen |
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 |
JOP20210193A1 (ar) | 2019-01-18 | 2023-01-30 | Astrazeneca Ab | مثبطات pcsk9 وطرق استخدامها |
Citations (1)
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)
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 |
-
0
- NL NL270803D patent/NL270803A/xx unknown
-
1961
- 1961-06-06 CH CH654761A patent/CH418335A/de unknown
- 1961-09-11 CH CH1518864A patent/CH412892A/de unknown
- 1961-10-18 GB GB37295/61A patent/GB939468A/en not_active Expired
- 1961-11-07 LU LU40792A patent/LU40792A1/xx unknown
- 1961-11-08 BR BR134007/61A patent/BR6134007D0/pt unknown
-
1962
- 1962-02-06 FR FR887088A patent/FR1748M/fr not_active Expired
-
1966
- 1966-06-24 US US560062A patent/US3445573A/en not_active Expired - Lifetime
-
1967
- 1967-04-17 US US645082A patent/US3459756A/en not_active Expired - Lifetime
Patent Citations (1)
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)
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 |
---|---|
GB939468A (en) | 1963-10-16 |
LU40792A1 (en:Method) | 1962-05-07 |
FR1748M (fr) | 1963-03-25 |
NL270803A (en:Method) | |
BR6134007D0 (pt) | 1973-05-31 |
CH418335A (de) | 1966-08-15 |
CH412892A (de) | 1966-05-15 |
US3459756A (en) | 1969-08-05 |
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