EP0000153A1 - 4-Hydroxy-2-quinolinone-3-carboxylic acids, their preparation and pharmaceutical compositions containing them. - Google Patents

4-Hydroxy-2-quinolinone-3-carboxylic acids, their preparation and pharmaceutical compositions containing them. Download PDF

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Publication number
EP0000153A1
EP0000153A1 EP78100168A EP78100168A EP0000153A1 EP 0000153 A1 EP0000153 A1 EP 0000153A1 EP 78100168 A EP78100168 A EP 78100168A EP 78100168 A EP78100168 A EP 78100168A EP 0000153 A1 EP0000153 A1 EP 0000153A1
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carbon atoms
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hydrogen
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Goetz Eduard Hardtmann
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Sandoz AG
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Sandoz AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to 4-hydroxy-2-quinolinone-3-carboxylic acids and their salts.
  • the invention provides pharmaceutical compositions comprising compounds of formula Ip
  • the compounds of formula I p possess pharmacological activity. In particular they possess disodium chromoglycate (DSCG)-like actiivity, in particular histamine release inhibiting activity, and are therefore indicated for use in the prophylactic treatment of allergic conditions, such as allergic asthma, as indicated in the passive cutaneous anaphylaxis test in the rat.
  • Female rats (180-200 g) are sensitised by subcutaneous administration of 1 mg of egg albumin (Merck Nr. 967) and 200 mg Al(OH) 3 in 1 ml of physiological saline and 0.5 ml of Haemophiluspertussis vaccine (Schwei- zerisches Serum and Impfinstitut, Bern; Nr.
  • egg albumin (5 mg/ml i.v.) dissolved in physiological saline containing 0.25% Evans Blue dye (Merck Nr. 3169).
  • the egg albumin elicits a cutaneous anaphylatic reaction, the intensity of which is proportional to the extent to which the Evans Blue dye diffuses into the tissue surrounding each of the four 'sensitisation sites.
  • the rats are killed with ether, the underside of the skin of the back of each animal is exposed and the diameter of the areas of blue dye surrounding each of the four sensitisation sites are measured.
  • Each dose of test compound is investigated in between four and six rats and the mean diameter compared with the mean value obtained in four solvent-treated control rats. The percentage inhibition is taken as the percentage of the mean diameter in the test animals relative to the mean diameter in the controls.
  • the DSCG-like activity in particular histamine release inhibiting activity, can be confirmed by inhibition of histamine release fn the rat peritoneal mast cell test, basically as described by Kusner et al., J. Pharmacol. Exp. Therap. 184, 41-46 (1973), with the following modification: after sedimentation of the mast cells by centrifugation at 350 x g and 4°C, the sediments are taken up in 1 ml of Hank's balanced salt solution (HBSS) (buffered to a pH of 6.9) and pooled. The resulting suspension is centrifuged, washed again with HBSS and sedimented. The thus purified mast cells are prepared as 2 ml suspensions in HBSS.
  • HBSS Hank's balanced salt solution
  • the 48/80 induced histamine release minus the spontaneous histamine release is taken as 100% histamine release.
  • the 48/80 induced histamine release in the presence of the test compound minus the spontaneous histamine release is then compared with the 100% value to determine the percentage inhibition by the test compound.
  • the histamine determination is effected in conventional manner, for example as described in the above-mentioned Kusner et al. article, or in Kusner and Herzig, Advances in Automated Analysis, 429 (1971).
  • An indicated suitable daily dosage is from 20 to 800 mg preferably administered in divided dosages of from 5 to 400 mg 2 to 4 times a day, or in retard form.
  • the compounds may be used in free acid form or in the form of their pharmaceutically acceptable mono- or di-base salts, which salt forms have the same order of activity as the free acid forms.
  • Suitable salts include the sodium, potassium and lithium mono- and disalts.
  • the compounds of formula I may be admixed with conventional pharmaceutically acceptable diluents or carriers and, optionally, other excipients, and administered in such forms as tablets or capsules.
  • novel compounds within the scope of formula I p above.
  • novel compounds are those of formula I in which either
  • R° are hydrogen, alkyl or alkenyl, more preferably alkyl or alkenyl, particularly allyl.
  • Preferred significances of R 1 and R 2 are dialkoxy, more preferably 6,7-dialkoxy, particularly 6,7-dimethoxy. Combinations of these preferred significances are especially advantageous.
  • the compounds of formula I are in the free acid or disalt form, more preferably the free acid form.
  • the invention also provides a process for the preparation of compounds of formula I, characterised by hydrolysing a compound of formula II
  • a suitable procedure is alkaline hydrolysis of the compound of formula II in an aqueous medium at a temperature of 40-150°C, preferably 80-120°C, followed by recovery under conditions avoiding acidification, which can lead to decarboxylation of the product.
  • M is hydrogen and at least 2 mole equivalents of base are used, preferably sodium or potassium hydroxide to give the disodium or dipotassium salt.
  • base preferably sodium or potassium hydroxide
  • a suitable procedure is mild acid hydrolysis of a compound of formula II in which R is an acid-labile group such as t-butyl.
  • the temperature is suitably from -20° to 60°C, preferably from -10° to 35°C in order to avoid decarboxylation of the product.
  • Suitable acid catalysts are sulphuric acid, hydrochloric acid and perchloric acid, preferably the latter.
  • the reaction medium is suitably a water-miscible non-hydroxylic organic solvent, for example acetonitrile.
  • Example 1 (1-allyl-6,7-dimethoxy-4-hydroxy-7-quinolinone-3-carboxylic acid) (3.0 g) and 800 mg of sodium hydroxide are placed in 75 ml of water and the resulting suspension heated to 50°C until a solution is formed. The water is then evaporated in vacuo and the resulting residue oven dried under high vacuum to obtain 1-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid disodium salt, m.p. 320°C with decomposition.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Quinoline Compounds (AREA)

Abstract

Pharmaceutical compositions comprising 4-hydroxy-2-quinolinone-3- carboxylic acids and their salts, and certain compounds of this class, for example 1-allyl-6,7-dimethoxy-4-hydroxy -2-quinolinone-3- carboxylic acid; of the formula
Figure imga0001
They may be prepared by hydrolysis of the correspond- ling alkyl esters.
The compounds are useful in the prophylactic treatment of allergic asthma.

Description

  • This invention-relates to 4-hydroxy-2-quinolinone-3-carboxylic acids and their salts.
  • The invention provides pharmaceutical compositions comprising compounds of formula Ip
    Figure imgb0001
    • in which R
      Figure imgb0002
       is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl in which the cycloalkyl part is of 3 to 6 carbon atoms and the alkyl part is of 1 or 2 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms in which the unsaturation is on other than the alpha carbon atom, or
      Figure imgb0003
    • in which n is 0 or 1 and
    • Y and Y' are independently hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms, trifluoromethyl or nitro with the proviso that only one of Y and Y' can be from the group consisting of nitro and trifluoromethyl and
    • Rlp and R2p are independently hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro or trifluoromethyl, with the proviso that only one of Rlp and R2p can be from the group consisting of nitro and trifluoromethyl, or R1p and R2p together form a 6,7-methylenedioxy group.
  • The compounds of formula Ip possess pharmacological activity. In particular they possess disodium chromoglycate (DSCG)-like actiivity, in particular histamine release inhibiting activity, and are therefore indicated for use in the prophylactic treatment of allergic conditions, such as allergic asthma, as indicated in the passive cutaneous anaphylaxis test in the rat. Female rats (180-200 g) are sensitised by subcutaneous administration of 1 mg of egg albumin (Merck Nr. 967) and 200 mg Al(OH)3 in 1 ml of physiological saline and 0.5 ml of Haemophiluspertussis vaccine (Schwei- zerisches Serum and Impfinstitut, Bern; Nr. 115 325; 4 x 1010 organism/ml) intraperitoneally. Fourteen days later, the animals are exsanguinated, the blood centrifuged, the serum collected and deep frozen. The serum thus obtained (anti-serum) is injected intradermally (0.1 ml of 1:200 f diluted serum per injection site) at four sites on the backs of untreated, female rats. Twenty-four hours later each rat is administered 0.1 to 5.6 mg/kg i.v. or 0.1 to 100 mg/kg p.o. of the test compound, and either immediately or 5 to 30 minutes afterwards, in the case of intravenous administration, or 15 or 60 minutes afterwards, in the case of oral administration, egg albumin (5 mg/ml i.v.) dissolved in physiological saline containing 0.25% Evans Blue dye (Merck Nr. 3169). The egg albumin elicits a cutaneous anaphylatic reaction, the intensity of which is proportional to the extent to which the Evans Blue dye diffuses into the tissue surrounding each of the four 'sensitisation sites. Thirty minutes after the administration of the egg albumin, the rats are killed with ether, the underside of the skin of the back of each animal is exposed and the diameter of the areas of blue dye surrounding each of the four sensitisation sites are measured. Each dose of test compound is investigated in between four and six rats and the mean diameter compared with the mean value obtained in four solvent-treated control rats. The percentage inhibition is taken as the percentage of the mean diameter in the test animals relative to the mean diameter in the controls.
  • The DSCG-like activity, in particular histamine release inhibiting activity, can be confirmed by inhibition of histamine release fn the rat peritoneal mast cell test, basically as described by Kusner et al., J. Pharmacol. Exp. Therap. 184, 41-46 (1973), with the following modification: after sedimentation of the mast cells by centrifugation at 350 x g and 4°C, the sediments are taken up in 1 ml of Hank's balanced salt solution (HBSS) (buffered to a pH of 6.9) and pooled. The resulting suspension is centrifuged, washed again with HBSS and sedimented. The thus purified mast cells are prepared as 2 ml suspensions in HBSS. To these are added either 2 ml of HBSS, to determine the spontaneous histamine release, or 2 ml of HBSS and 2.24/ug of compound 48/80 (N-methyl- homoanisylamineformaldehyde condensate; a histamine liberator from Burroughs Wellcome and Co. Inc., Tuckahoe, N.Y. USA), to determine the 48/80 induced histamine release, or 2 ml of HBSS with 2.24 µg of 48/80 and from 18 to 180 µg/ml of the test compound, to determine the 48/80 induced histamine release in the presence of the test compound.
  • The 48/80 induced histamine release minus the spontaneous histamine release is taken as 100% histamine release. The 48/80 induced histamine release in the presence of the test compound minus the spontaneous histamine release is then compared with the 100% value to determine the percentage inhibition by the test compound. [The histamine determination is effected in conventional manner, for example as described in the above-mentioned Kusner et al. article, or in Kusner and Herzig, Advances in Automated Analysis, 429 (1971).] An indicated suitable daily dosage is from 20 to 800 mg preferably administered in divided dosages of from 5 to 400 mg 2 to 4 times a day, or in retard form.
  • The compounds may be used in free acid form or in the form of their pharmaceutically acceptable mono- or di-base salts, which salt forms have the same order of activity as the free acid forms. Suitable salts include the sodium, potassium and lithium mono- and disalts.
  • The compounds of formula I may be admixed with conventional pharmaceutically acceptable diluents or carriers and, optionally, other excipients, and administered in such forms as tablets or capsules.
  • The compound l-methyl-4-hydroxy-2-quinoline-3-carboxylic acid has been described in Mitscher et al., "Heterocycles" Vol. 3, No. 11, pp 913-919 (1975), but to our knowledge no useful pharmacological activity has been given for this compound.
  • Accordingly, the invention further provides novel compounds within the scope of formula Ip above. Such novel compounds are those of formula I
    Figure imgb0004
    in which either
    • a) R° is cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl in which the cycloalkyl part is of 3 to 6 carbon atoms and the alkyl part is of 1 or 2 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms in which the unsaturation is on other than the alpha carbon atom, or'
      Figure imgb0005
      in which n, Y and Y' are as defined above, and R1 and R2 have the same significance as R1p and R2p above, provided that R1 and R2 do not together form a 6,7-methylenedioxy group,
    • b) R° is hydrogen, R1 is hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms and R2 is fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro or trifluoromethyl,
    • c) R° is alkyl of 1 to 6 carbon atoms and R1 and R2 are independently alkoxy of 1 to 4 carbon atoms,
    • or d) R° has the same significance as R
      Figure imgb0006
       above, and R1 and R2 together form a 6,7-methylenedioxy group.
  • Preferred significances of R° are hydrogen, alkyl or alkenyl, more preferably alkyl or alkenyl, particularly allyl.Preferred significances of R1 and R2 are dialkoxy, more preferably 6,7-dialkoxy, particularly 6,7-dimethoxy. Combinations of these preferred significances are especially advantageous.
  • Preferably the compounds of formula I are in the free acid or disalt form, more preferably the free acid form.
  • The invention also provides a process for the preparation of compounds of formula I, characterised by hydrolysing a compound of formula II
    Figure imgb0007
    • in which R°, R1 and R2 are as defined above,
    • R is alkyl of 1 to 6 carbon atoms,
    • and M is hydrogen or a pharmaceutically acceptable cation.
  • When it is desired to obtain the compound of formula I in the disalt form, a suitable procedure is alkaline hydrolysis of the compound of formula II in an aqueous medium at a temperature of 40-150°C, preferably 80-120°C, followed by recovery under conditions avoiding acidification, which can lead to decarboxylation of the product. Preferably M is hydrogen and at least 2 mole equivalents of base are used, preferably sodium or potassium hydroxide to give the disodium or dipotassium salt. When M is itself a cation, mixed disalts may be prepared.
  • When it it desired to obtain the free acid form of compounds of formula I, a suitable procedure is mild acid hydrolysis of a compound of formula II in which R is an acid-labile group such as t-butyl. The temperature is suitably from -20° to 60°C, preferably from -10° to 35°C in order to avoid decarboxylation of the product. Suitable acid catalysts are sulphuric acid, hydrochloric acid and perchloric acid, preferably the latter. The reaction medium is suitably a water-miscible non-hydroxylic organic solvent, for example acetonitrile.
  • Compounds of formula I in free acid form may be treated with base in conventional manner to obtain the monosalt form, in which the salt-forming cation is. associated with both the 4-hydroxy and the 3-carboxyl functions, and the disalt form.
  • The same process, with appropriate starting materials, may be used to prepare the other compounds of formula I .
  • The compounds of formula II are described and claimed in our German DOS 2 706 752, and may be prepared by the methods disclosed therein.
  • The following Examples illustrate the invention:
    • EXAMPLE 1: 1-Allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid A:1-Allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3- carboxylic acid t-butyl ester
  • To a solution of 8.3 g of di-t-butyl malonate in 75 ml of dimethylacetamide is added portionwise 1.9 g of pentane-washed 50% sodium hydride. The resulting solution is stirred at room temperature for 30 minutes and there is then added 10.0 g of l-allyl-6,7-dimethoxyisatoic anhydride in 100 ml of dimethylacetamide. The resulting solution is heated at 120°C for 3 hours, the dimethylacetamide removed in vacuo, water added, the resulting mixture washed with methylene chloride, acidified with 2 N. hydrochloric acid and extracted with methylene chloride. The organic phase is dried and evaporated in vacuo to an oil which is crystallized from ether to obtain l-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid t-butyl ester.
    • B: 1-Allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3- carboxylic acid
  • To a solution of 3.1 g of l-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid t-butyl ester in 30 ml of acetonitrile at 0°C is added 0.75 ml of 60% aqueous perchloric acid. The resulting precipitate is recovered by filtering and washed with ether to obtain 1-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid which melts at 169-170°C and decarboxylates at 185-195°C.
    • EXAMPLES 2-26:
  • In manner analogous to Example 1, employing appropriate starting materials in approximately equivalent amounts, the compounds of formula I listed in Table I below may be obtained.
    Figure imgb0008
    Figure imgb0009
    • EXAMPLE 27: Preparation of Disodium salt of compound of Example 1
  • The compound of Example 1 (1-allyl-6,7-dimethoxy-4-hydroxy-7-quinolinone-3-carboxylic acid) (3.0 g) and 800 mg of sodium hydroxide are placed in 75 ml of water and the resulting suspension heated to 50°C until a solution is formed. The water is then evaporated in vacuo and the resulting residue oven dried under high vacuum to obtain 1-allyl-6,7-dimethoxy-4-hydroxy-2-quinolinone-3-carboxylic acid disodium salt, m.p. 320°C with decomposition.

Claims (10)

1. A pharmaceutical composition comprising compounds of formula Ip
Figure imgb0010
in which R
Figure imgb0011
 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon - atoms, cycloalkylalkyl in which the cycloalkyl part is of 3 to 6 carbon atoms and the alkyl part is of 1 or 2 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms in which the unsaturation is on other than the alpha carbon atom, or
Figure imgb0012
in which n is 0 or 1 and
Y and Y' are independently hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 3 carbon atoms, alkoxy of 1 to 3 carbon atoms,trifluoromethyl or nitro with the proviso that only one of Y and Y' can be from the group consisting of nitro and trifluoromethyl and
R1p and R2p are independently hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro or trifluoromethyl, with the proviso that only one of R1p and R2p can be from the group consisting of nitro and trifluoromethyl, or R1p and R2p together form a 6,7-methylenedioxy group,
in free acid or pharmaceutically acceptable mono- or di-base salt form, in association with a pharmaceutically acceptable diluent or carrier.
2. A pharmaceutical composition according to Claim 1 in unit dosage form, each unit dosage comprising 5-400 mg of compound of formula Ip.
3. A process for the prepartion of a compound of formula I,
Figure imgb0013
in which either
a) R° is cycloalkyl of 3 to 6 carbon atoms, cycloalkylalkyl in which the cycloalkyl part is of 3 to 6 carbon atoms and the alkyl part is of 1 or 2 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms in which the unsaturation is on other than the alpha carbon atom, or
Figure imgb0014
in which n, Y and Y' are as defined above, and R1 and R2 have the same significance as R1p and R2p above, provided that R1 and R2 do not together form a 6,7-methylenedioxy group,
b) R° is hydrogen, R1 is hydrogen, fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms and R2 is fluorine, chlorine, bromine, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, nitro or trifluoromethyl,
c) R° is alkyl of 1 to 6 carbon atoms and R1 and R2 are independently alkoxy of 1 to 4 carbon atoms,
or d) R° has the same significance as R° above, and R1 and R2 together form a 6,7-methylene-dioxy group,
characterised by hydrolysing a compound of formula II
Figure imgb0015
in which R°, R1 and R2 are as defined above,
R is alkyl of 1 to 6 carbon atoms,
and M is hydrogen or a pharmaceutically acceptable cation,
provided that when hydrolysis is carried out under acid conditions, R is an acid-labile alkyl group.
4. A compound of formula I, stated in Claim 3, whenever prepared by the process of Claim 3.
5. A compound of formula I, stated in Claim 3.
6. A compound according to Claim 5, in which R° is hydrogen, alkyl or alkenyl.
7. A compound according to Claim 6, in which R° is allyl.
8. A compound according to Claim 5, in which R1 and R2 are dialkoxy.
9. A compound according to Claim 8 in'which R1 and R2 are 6,7-dimethoxy.
10. l-Allyl-6,7-dimethoxy-4-hydroxy-2-quinoline-3-carboxylic acid, in free acid, mono- or di-salt form.
EP78100168A 1977-06-20 1978-06-15 4-Hydroxy-2-quinolinone-3-carboxylic acids, their preparation and pharmaceutical compositions containing them. Ceased EP0000153A1 (en)

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EP0933378A1 (en) * 1998-01-19 1999-08-04 Dainippon Ink And Chemicals, Inc. Quinolinone glycoside, production process, and anti-allergic agent
US7932265B2 (en) 2004-03-31 2011-04-26 Cordis Corporation Solution formulations of sirolimus and its analogs for CAD treatment
US8409601B2 (en) 2008-03-31 2013-04-02 Cordis Corporation Rapamycin coated expandable devices
US8420110B2 (en) 2008-03-31 2013-04-16 Cordis Corporation Drug coated expandable devices
US8557272B2 (en) 2004-03-31 2013-10-15 Cordis Corporation Device for local and/or regional delivery employing liquid formulations of therapeutic agents

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US5179107A (en) * 1990-09-07 1993-01-12 Schering Corporation Antiviral quinolinone compounds
US5179093A (en) * 1991-05-10 1993-01-12 Schering Corporation Quinoline-diones

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
EP0933378A1 (en) * 1998-01-19 1999-08-04 Dainippon Ink And Chemicals, Inc. Quinolinone glycoside, production process, and anti-allergic agent
US6242425B1 (en) 1998-01-19 2001-06-05 Dainippon Ink And Chemicals, Inc. Quinolinone glycoside, production process, and anti-allergic agent
US7932265B2 (en) 2004-03-31 2011-04-26 Cordis Corporation Solution formulations of sirolimus and its analogs for CAD treatment
US8557272B2 (en) 2004-03-31 2013-10-15 Cordis Corporation Device for local and/or regional delivery employing liquid formulations of therapeutic agents
US8409601B2 (en) 2008-03-31 2013-04-02 Cordis Corporation Rapamycin coated expandable devices
US8420110B2 (en) 2008-03-31 2013-04-16 Cordis Corporation Drug coated expandable devices
US8871240B2 (en) 2008-03-31 2014-10-28 Cordis Corporation Rapamycin coated expandable devices

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IL54949A0 (en) 1978-08-31
AT367403B (en) 1982-07-12
ATA443078A (en) 1981-11-15
AU521418B2 (en) 1982-04-01
ZA783515B (en) 1980-02-27
IL54949A (en) 1982-04-30
JPS5495578A (en) 1979-07-28
FI781885A (en) 1978-12-21
DK262678A (en) 1978-12-21
AU3725178A (en) 1980-01-03
PT68192B (en) 1981-06-11
PT68192A (en) 1978-07-01
IT7849938A0 (en) 1978-06-19
CA1105462A (en) 1981-07-21
ES470916A1 (en) 1979-10-01
NZ187618A (en) 1981-02-11
US4187309A (en) 1980-02-05

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