US3870720A - Potassium derivatives of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone - Google Patents

Potassium derivatives of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone Download PDF

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US3870720A
US3870720A US356403A US35640373A US3870720A US 3870720 A US3870720 A US 3870720A US 356403 A US356403 A US 356403A US 35640373 A US35640373 A US 35640373A US 3870720 A US3870720 A US 3870720A
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quinazolinone
starting
sulphamyl
derivative
excreted
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Expired - Lifetime
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US356403A
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English (en)
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Massimo Carissimi
Franco Ravenna
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3

Definitions

  • the monopotassium derivative is obtained by replacing either hydrogen of the sulphamyl group of the starting quinazolinone by a potassium atom
  • the dipotassium derivative is obtained by replacing either hydrogen of the sulphamyl group of the starting quinazolinone and also the hydrogen atom lying in the 3-position of the tetrahydroquinazolinone ring of same starting quinazolinone by a potassium atom each.
  • This invention relates to non-mercurial diuretics and, more particularly, to compounds capable of enhancing the diuresis without exhibiting obrioxious side effects.
  • the above named compound has proven to be capable, under different experimental conditions, of enhacing the diuresis and also both the elimination of sodium and potassium ions. It has been ascertained, moreover, that the elimination of potassium ions had a slower increase, as the dosage was increased, than that of sodium ions and exhibited a tendency towards a maximum boundary value: this fact wad doubtless a favorable circumstance from the clinical viewpoint.
  • the above identified quinazolinone in addition, displayed the above described diuretic action while being completely inactive as a carboanhydrase inhibitor.
  • the invention relates to both the monopotassiumand the dipotassium derivatives of 2- phenyl-6-sulphamyl-7-chloro-l ,2,3,4-tetrahydro-4- quinazolinone, as diuretics. These derivatives are obtained by replacing, for the former, either hydrogen of the sulphamyl group by a potassium atom, and, for the latter, by replacing either hydrogen of the sulphamyl group and the hydrogen lying in the 3-position of the tetrahydroquina-zolinone ring by one potassium atom each, respectively. Both the monoand the dipotassium derivatives are water soluble.
  • a 1 percent aqueous solution of the monopotassium derivative has a pH of about 9.9, and, after a certain period of time a precipitate is observed, which is the starting sulphonamide, a product of hydrolysis. Conversely, the dipotassium derivative yields a stable 1 percent aqueous solution which has a pH of about 11.5.
  • both the monoand the dipotassium derivatives are best characterized by their IR spectra, as will be set forth in more detail hereinafter.
  • FIGS. 2 and 2a For the monopotassium derivative, FIGS. 2 and 2a, (or ethoxide) in methanol (or ethanol).
  • the potassium the bands at 3420, 3330, 1335 and 1160 cm disapalkoxide solution can be conveniently replaced by a l pear, this fact being an evidence of the substitution percent solution of potassium hydroxide in methanol.
  • EXAMPLE 1 The final product is a yellow crystalline powder whose IR spectrum is very much the same as that M th df th 0 tas um der'v tive of e 0 or preparing 8 p0 1 a shown in FIGS. 3 and 3a.
  • the monopotassium derivative was precipitated from this solution by adding thereto 5,000 mls of ether.
  • the isolated product is a yellow crystalline powder which is very soluble in water and has an infrared spec- Method for preparing the monopotassium derivative of "um very much the same as Shown in FIGS 3 and 3a.
  • both the potassium derivatives of this invention exhibit an increased diuretic activity over that of the starting quinazolinone. This action is due to a more intensive absorption of the derivatives in question by the system. This exalted absorption is evidenced by a more pronounced elimination through the urinary tract.
  • a method for dosing in the urines both the starting quinazolinone and the two potassium derivatives of this invention has been envisaged by the applicants and has an. accuracy as high as l microgram per milliliter.
  • the urines are collected at regular intervals and brought to a pH of 8, and repeatedly extracted with ethyl acetate. The latter, dried upon sodium sulphate, is evaporated to dryness and the residue, redissolved in DMF (dimethylformamide), is quantitatively placed on a glass plate carrying a layer of 0.25 mms. of silica gel containing a fluorescent detector. Chromatographic analysis has been carried out by using a 70/30 (by vol.) mixture ofchloroform and methanol as the eluant. The quinazolinone spot (this is valid in any case.
  • a dog weighing 8.9 kgs. was treated with 97.9 mgms. of the dipotassium derivative, as defined above. This dose is equivalent to 9 mgms./kg.b.w. of the starting quinazolinone.
  • the excreted urine vol ume was 2,070 mls., the excreted starting quinazolinone 31.7 mgms., that is, the 39.66 percent of the amount as administered originally.
  • Test Dog Administered Urine Starting Excreted percentage No. wt. amount of excreted quinazolinone of the starting dipotassium after 72 hrs. excreted quinazolinone derivative kgs. milligrams milliliters milligrams "/t 17D 9.9 12.07 773 2.9 30.1% 18D 13.6 16.6 1,005 3.1 23,192 19D 10.6 12.9 1,060 3.3 31.7% 20D 11.4 13.9 1,175 3.2 28.7%
  • the minimum diuresis-promoting unit dose for humans is, for both the monopotassium and the dipotassium derivatives as hereinbefore defined, in the vicinity of 0.1 milligrams per kilogram of body weight, and that the average therapeutic dose is 0.3 1 milligram per kilogram of body weight.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US356403A 1972-05-05 1973-05-02 Potassium derivatives of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone Expired - Lifetime US3870720A (en)

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Application Number Priority Date Filing Date Title
IT2392572 1972-05-05

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US3870720A true US3870720A (en) 1975-03-11

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US356403A Expired - Lifetime US3870720A (en) 1972-05-05 1973-05-02 Potassium derivatives of 2-phenyl-6-sulphamyl-7-chloro-1,2,3,4-tetrahydro-4-quinazolinone

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US (1) US3870720A (en:Method)
JP (1) JPS49132221A (en:Method)
AU (1) AU469087B2 (en:Method)
BE (1) BE799087A (en:Method)
CA (1) CA982578A (en:Method)
DE (1) DE2322699C2 (en:Method)
DK (1) DK131033B (en:Method)
FR (1) FR2183806B1 (en:Method)
GB (1) GB1413008A (en:Method)
NL (1) NL7306164A (en:Method)
SE (1) SE400768B (en:Method)
ZA (1) ZA732937B (en:Method)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004017964A1 (en) 2002-08-19 2004-03-04 Pfizer Products Inc. Combination therapy for hyperproliferative diseases
US20060247272A1 (en) * 2004-09-23 2006-11-02 Pfizer Inc 4-Amino Substituted-2-Substituted-1,2,3,4-tetrahydroquinoline Compounds
WO2007062314A2 (en) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Heterocyclic cetp inhibitors
WO2008070496A2 (en) 2006-12-01 2008-06-12 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
EP2392567A1 (en) 2005-10-21 2011-12-07 Bristol-Myers Squibb Company Benzothiazine derivatives and their use as lxr modulators
WO2014170786A1 (en) 2013-04-17 2014-10-23 Pfizer Inc. N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases
WO2016055901A1 (en) 2014-10-08 2016-04-14 Pfizer Inc. Substituted amide compounds
WO2020150473A2 (en) 2019-01-18 2020-07-23 Dogma Therapeutics, Inc. Pcsk9 inhibitors and methods of use thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2952680A (en) * 1960-09-13 Derivatives of x-quevazolone
US3360518A (en) * 1966-01-03 1967-12-26 Wallace & Tiernan Inc Tetrahydro-halo-sulfamyl quinazolinones
US3440244A (en) * 1958-02-17 1969-04-22 Pfizer & Co C 3,6-disubstituted-7-sulfamyl-1,2,4-benzthiazide-1,1-dioxides

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US987847A (en) * 1910-04-12 1911-03-28 Rubin W Weeks Harness.
US3072656A (en) * 1960-01-22 1963-01-08 Ciba Geigy Corp 2-cycloaliphatic-6-sulfamyl-7-halo(or trihalomethyl)-1, 2, 3, 4-tetrahydro-4-quinazolones

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2952680A (en) * 1960-09-13 Derivatives of x-quevazolone
US3440244A (en) * 1958-02-17 1969-04-22 Pfizer & Co C 3,6-disubstituted-7-sulfamyl-1,2,4-benzthiazide-1,1-dioxides
US3360518A (en) * 1966-01-03 1967-12-26 Wallace & Tiernan Inc Tetrahydro-halo-sulfamyl quinazolinones

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004017964A1 (en) 2002-08-19 2004-03-04 Pfizer Products Inc. Combination therapy for hyperproliferative diseases
US20060247272A1 (en) * 2004-09-23 2006-11-02 Pfizer Inc 4-Amino Substituted-2-Substituted-1,2,3,4-tetrahydroquinoline Compounds
EP2392567A1 (en) 2005-10-21 2011-12-07 Bristol-Myers Squibb Company Benzothiazine derivatives and their use as lxr modulators
WO2007062314A2 (en) 2005-11-23 2007-05-31 Bristol-Myers Squibb Company Heterocyclic cetp inhibitors
WO2008070496A2 (en) 2006-12-01 2008-06-12 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
WO2014170786A1 (en) 2013-04-17 2014-10-23 Pfizer Inc. N-piperidin-3-ylbenzamide derivatives for treating cardiovascular diseases
WO2016055901A1 (en) 2014-10-08 2016-04-14 Pfizer Inc. Substituted amide compounds
WO2020150473A2 (en) 2019-01-18 2020-07-23 Dogma Therapeutics, Inc. Pcsk9 inhibitors and methods of use thereof
EP4470609A2 (en) 2019-01-18 2024-12-04 Astrazeneca AB Pcsk9 inhibitors and methods of use thereof

Also Published As

Publication number Publication date
SE400768B (sv) 1978-04-10
NL7306164A (en:Method) 1973-11-07
FR2183806A1 (en:Method) 1973-12-21
GB1413008A (en) 1975-11-05
DE2322699A1 (de) 1974-01-10
ZA732937B (en) 1974-03-27
FR2183806B1 (en:Method) 1976-05-14
DK131033C (en:Method) 1975-10-06
DK131033B (da) 1975-05-20
DE2322699C2 (de) 1983-10-27
AU5516173A (en) 1974-11-07
BE799087A (fr) 1973-08-31
JPS49132221A (en:Method) 1974-12-18
CA982578A (en) 1976-01-27
AU469087B2 (en) 1976-02-05

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