US3639432A - 2-hydroxy-1 4-naphthoquinone aminobenzoates - Google Patents

2-hydroxy-1 4-naphthoquinone aminobenzoates Download PDF

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Publication number
US3639432A
US3639432A US736285A US3639432DA US3639432A US 3639432 A US3639432 A US 3639432A US 736285 A US736285 A US 736285A US 3639432D A US3639432D A US 3639432DA US 3639432 A US3639432 A US 3639432A
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hydroxy
naphthoquinone
methyl
naphthohydroquinone
hydrogen
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US736285A
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English (en)
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Giancarlo Berti
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FINANZ KOMPENSATIONS ANST
FINANZ und KOMPENSATIONS ANSTALT
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FINANZ KOMPENSATIONS ANST
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
    • C07C229/58—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids

Definitions

  • the present invention is directed to antihaemorrhagic and capillary protective agents of the formula E 0 NHg g m- Q,
  • R is either hydrogen or lower alkyl, e.g. methyl, ethyl,
  • each of R and R" is, independently, either hydrogen; lower alkyl, e.g. methyl, ethyl, propyl, isopropyl and butyl; or lower alkoxy, e.g. methoxy, ethoxy, propoxy and butoxy;
  • the preferred compounds of this invention are those wherein each of R and R" is hydrogen and R is either hydrogen or methyl.
  • R" is other than hydrogen, it is preferably in the 6- or 7-position.
  • the amino group is preferably in the para-position.
  • a further object is to produce compounds having a marked antihaemorrhagic activity and which can be administered orally.
  • Another object is to obtain compounds which provide a capillary protective action.
  • An additional object is to synthesize compounds having the noted properties. Still further objects will be apparent from the description and examples.
  • the compounds of this invention (esters I) have such a low toxicity that no deaths resulted from administering per os up to 2.0 grams/kilogram of body weight to mice, rats and rabbits. Said compounds produce a marked antihaemorrhagic activity in dosages of as little as 0.2 mg./kg. and retain such action when administered in doses up to '0 mg./kg. or higher. The consequent utility as antihaemorrhagic agents is confirmed by standard pharmacological tests in rabbits and mice.
  • Compounds I are also useful as capillary protective agents. For this purpose they are administered, e.g., orally in doses of from 0.2 to 20 mg./kg. The capillary protective action has been confirmed by standard tests on albino rabbits.
  • Compounds I are administered to mammals orally in standard dosage forms, e.g. tablets and capsules.
  • the average daily dose varies, but is ordinarily Within the range of from 0.2 to 50 milligrams (mg.) per kilogram (kg) of body weight. It may be administered either as a single dose or in divided doses at regular intervals from two to four times per day.
  • Each of the compounds of this invention may be, e.g., incorporated, for oral administration, in a tablet as the sole active ingredient.
  • a typical tablet is constituted by from 1 to 3 percent binder, e.g. tragacanth; from 3 to 10 percent disintegrating agent, e.g. corn starch; from 2 to 10 percent lubricant, e.g. talcum; from 0.25 to 1.0 percent lubricant, e.g. magnesium stearate; an average dosage of active ingredient; and q.s. 100 percent of filler, e.g. lactose; all percentages being by weight.
  • Tablets are prepared according to standard tabletting techniques, which are well-known in the art, employing the necessary amounts of conventional granulating liquids, e.g. alcohol SD-30 and purified water.
  • An exemplary tabletting formulation is:
  • Alcohol SD-3 purified water, q.s.
  • DETAILS Esters I are prepared by reacting a 2-hydroxy-1,4-naphthoquinone of the formula with a nitrobenzoyl halide of the formula zN E X X Q (III) wherein X is halo, e.g. :bromo and iodo, but preferably chloro;
  • Compounds II and HI are either known compounds or are prepared according to published procedures from available starting materials.
  • Exemplary Compounds II include:
  • the nitrobenzoic acid esters IV are catalytically reduced with hydrogen in an inert solvent, e.g. dioxane and tetrahydrofuran, at a pressure of from 1 to atmospheres and at a temperature of from 20 to 60 C.
  • the catalyst employed for the catalytic reduction is a finely divided metal catalyst, e.g. platinum, palladium and nickel, which is in intimate contact with said nitrobenzoic acid esters during the reduction.
  • the naphthoquinonic system is thus first reduced to the corresponding naphthohydroquinonic system with the absorption of one mole of hydrogen per mole of ester, yielding the corresponding 2 (nitrobenzoyloxy)-1,4-dihydroxy-naphthalene.
  • a further three moles of hydrogen, per mole of ester are absorbed, corresponding to the reduction of the nitro group to primary amino, to produce the corresponding Compound I with yields in the order of from 70 to 80 percent.
  • Example I In a 1 litre flask fitted with a cooler having a calcium chloride closure, a solution of 50 grams (g.) of dry 2-,
  • precipitate is collected by suction filtering and washed formed at 84 g. of 2 hydroxy 3-mcthyl-L4-naphtho 4 quinone p-nitrobenzoate; yellow crystals; melting point (M.P.) 178-182 C.
  • the product is re-crystallized by solution in boiling chloroform, followed by dilution in ethanol, melting then at 180182 C.
  • a solution of 50 g. of 2-hydroxy-3-methyl-1,4-naphthoquinone p-nitrobenzoate in 500 ml. of pure dioxane is admixed with 0.5 g. of platinum dioxide and stirred in the presence of hydrogen under normal pressure and at the temperature of 50 C., measuring the gas absorption. Absorption is stopped after 13 litres of gas have been absorbed, which takes 3-4 hours.
  • the catalyst is removed by filtering, and the filtrate is diluted with 2 litres of petroleum ether (M.P. 40-70 C.). An oily layer is separated; the supernatant liquid is decanted and the residue taken up in 200 ml. of benzene, heating a few minutes to boiling.
  • Example II A solution of 10 g. of 2-hydroxy-1,4-naphthoquinone, 12 g. of p-nitrobenzoyl chloride and 8 ml. of pyridine in 100 ml. of benzene is refluxed for 45 minutes.
  • the same procedure used in Example I is successively repeated and, after treatment with water, 16.2 g. of Z-hydroxynaphthoquinone p-nitro-benzoate as yellow prisms are recovered; the same, re-crystallized from chloroform, melt at 190-192 C.
  • Example HI A solution of 30 g. of 2-hydroxy-3-methyl-1,4-naphthoquinone, 35 g. of m-nitrobenzoyl chloride and 20 m1. of anhydrous pyridine in 250 ml. of dry tetrahydrofuran is refluxed for 30 minutes. The solution is hot filtered to remove the insoluble pyridinium chloride. The filtrate is dry distilled over a water bath, and the residue is taken up in 100 ml. of ethanol by boiling for minutes. After cooling, a yellow crystalline precipitate of 2-hydroxy-3-methyl- 1,4-naphthoquinone-m-nitrobenzoate, M.P. 167 -169 C., is formed and collected. A 10 g.
  • Example IV From 10 g. of 2-hydroxy-1,4-naphthoquinone, 12 g. of m-nitrobenzoyl chloride and 8 ml. of anhydrous pyridine there are obtained, according to the procedure described in Example I, Z-hydroxy-naphthoquinonem-nitrobenzoate as yellow crystals, M.P. l87189 C. Reduction of this product is carried out as described in Example II, but using 200 ml. of dioxane and 0.2 g. of platinum dioxide for 10 g. of nitro-ester; 2-hydroxy-1,4-naphthohydroquinone-2-(m-amindbenzoate), M.P. 2l42l6 C. with decomposition, is thus obtained.
  • Example V From 10 g. of 2-hydroxy-3-methyl-l,4-naphthoquinone, 11 g. of o-nitrobenzoyl chloride, 6 g. of pyridine and 100 ml. of benzene, operating according to Example I, 2- hydroxy 3 methyl-1,4-naphthoquinone-o-nitrobenzoate, M.P. l78180 C., is obtained. 10 g. of this product in 100 ml. of dioxane are reduced as described in Example I, providing 2 hydroxy-3-methyl-1,4-naphthohydroquinone-2- (o-aminobenzoate), M.P. l68l72 C. with decomposition.
  • each of the final products prepared according to this invention is useful as an antihaemorrhagic agent, the final products prepared as per the specific examples are merely exemplary.
  • the corresponding nitrobenzoates and naphthoquinones are useful as intermediates in the preparation of said final products.
  • R is a member selected from the group consisting of hydrogen and lower alkyl
  • each of R and 'R" is, independently, a member selected from the group consisting of hydrogen, lower alkyl and lower alkoxy. 2.
  • a compound according to claim 1 of the formula 3 A compound according to claim 1 of the formula H N03 HQ n i R,
  • a compound according to claim 1 of the formula 5 A compound according to claim 4 wherein each of R and R" is hydrogen.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US736285A 1964-10-05 1968-06-12 2-hydroxy-1 4-naphthoquinone aminobenzoates Expired - Lifetime US3639432A (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
AT847264A AT252224B (de) 1964-10-05 1964-10-05 Verfahren zur Herstellung von neuen 2-Aminobenzoyloxy-naphthohydrochinonen

Publications (1)

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US3639432A true US3639432A (en) 1972-02-01

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US (1) US3639432A (de)
AT (1) AT252224B (de)
CH (1) CH482646A (de)
DE (1) DE1493746C3 (de)
ES (1) ES318115A1 (de)
GB (1) GB1055606A (de)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4943550A (en) * 1989-06-14 1990-07-24 Phillips Petroleum Company Catalysts for oxidation of carbon monoxide
WO2007116297A3 (en) * 2006-04-11 2008-01-10 Fond Irccs Istituto Di Ricover Use of aminapthone for the preparation of a medicament for treating arteriophaties
ITMI20100960A1 (it) * 2010-05-27 2011-11-28 Baldacci Lab Spa Nuovo processo per la preparazione dell'aminaftone
ITMI20130703A1 (it) * 2013-04-30 2014-10-31 Baldacci Lab Spa Nuovo processo di sintesi dell'aminaftone
IT201900006572A1 (it) 2019-05-06 2020-11-06 Laboratori Baldacci Spa Nuovo metodo di analisi hplc dell'aminaftone

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4943550A (en) * 1989-06-14 1990-07-24 Phillips Petroleum Company Catalysts for oxidation of carbon monoxide
US8202903B2 (en) * 2006-04-11 2012-06-19 Fondazione IRCCS “CA' Granda—Ospedale Maggiore Policlinico” Use of aminaphtone for the preparation of a medicament for treating arteriopathies
US20090182045A1 (en) * 2006-04-11 2009-07-16 Fondazione Irccs Istituto Di Ricovero E Cura A Carattere Scientifico Di Natura Use of aminaphtone for the preparation of a medicament for treating arteriopathies
EP2335695A1 (de) * 2006-04-11 2011-06-22 Fondazione Irccs ''ca' Granda - Ospedale Maggiore Policlinico'' Verwendung des Aminaphtones zur Herstellung eines Arzneimittels zur Behandlung von arteriellen Erkrankungen
WO2007116297A3 (en) * 2006-04-11 2008-01-10 Fond Irccs Istituto Di Ricover Use of aminapthone for the preparation of a medicament for treating arteriophaties
US10028929B2 (en) 2006-04-11 2018-07-24 Laboratori Baldacci S.P.A. Method of treating raynaud's disease secondary to connectivitis using aminaphtone
ITMI20100960A1 (it) * 2010-05-27 2011-11-28 Baldacci Lab Spa Nuovo processo per la preparazione dell'aminaftone
EP2390246A1 (de) * 2010-05-27 2011-11-30 Laboratori Baldacci S.P.A. Verfahren zur Herstellung von Aminaphton
ITMI20130703A1 (it) * 2013-04-30 2014-10-31 Baldacci Lab Spa Nuovo processo di sintesi dell'aminaftone
EP2799426A1 (de) 2013-04-30 2014-11-05 Laboratori Baldacci S.p.A. Neues Verfahren zur Synthese von Aminaphton
US8987503B2 (en) 2013-04-30 2015-03-24 Laboratori Baldacci Spa Process for the synthesis of aminaphtone
IT201900006572A1 (it) 2019-05-06 2020-11-06 Laboratori Baldacci Spa Nuovo metodo di analisi hplc dell'aminaftone
WO2020225264A1 (en) 2019-05-06 2020-11-12 Laboratori Baldacci S.P.A. Mixture of isomers of aminaphtone, analytical method for identifying them and pharmaceutical composition comprising said isomers

Also Published As

Publication number Publication date
DE1493746C3 (de) 1975-01-02
CH482646A (de) 1969-12-15
GB1055606A (en) 1967-01-18
DE1493746B2 (de) 1974-05-22
DE1493746A1 (de) 1969-02-06
ES318115A1 (es) 1966-03-16
AT252224B (de) 1967-02-10

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