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WO1997028118A1 - Procede de preparation d'acides anthreniliques - Google Patents

Procede de preparation d'acides anthreniliques Download PDF

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Publication number
WO1997028118A1
WO1997028118A1 PCT/US1997/001862 US9701862W WO9728118A1 WO 1997028118 A1 WO1997028118 A1 WO 1997028118A1 US 9701862 W US9701862 W US 9701862W WO 9728118 A1 WO9728118 A1 WO 9728118A1
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set forth
atoms
acid
alkyl
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Apurba Bhattacharya
Diane E. Allen
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CNA Holdings LLC
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Hoechst Celanese Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups

Definitions

  • the present invention relates to a simple and efficient preparation of a series of 4- quinazolone analogs from the corresponding amino acids such as anthranilic acids.
  • Angiotensin II an octapeptide, formed by the action of angiotensin converting enzyme (ACE) on the decapeptide angiontensin I, is a powerful endogeneous vasoconstrictor.
  • ACE angiotensin converting enzyme
  • Existing methods for treating hypertension involve ACE inhibitors e.g. captopril and enalapril, which also affect hormones other than AII, causing unwanted side effects.
  • AII-antagonists play an important role in post myocardial infarction therapy, slowing AII-induced cardiac hypertrophy slowing the progression of heart failure, preventing post angioplasty restinosis, and in slowing the progress of renal disease.
  • 4-Quinazolone and their analogs are also being developed as a new class of anti-tumor treatment.
  • Niementowski synthesis involves condensation of an anthranilic acid amide with ethyl orthoformate. It suffers from lack of generality and unavailability of higher analogs of the orthoformate ester.
  • the cyclization can also be effected by the action of dilute alkali or ammonia albeit in poor yield,
  • Acetanilide reacts with ethyl carbamate in the presence of phosphorous pentoxide to produce 4-quinazolone.
  • this reaction produces a mixture of regioisomers, thereby complicating the isolation and lowering the yield.
  • the intermediate benzoxazone is extremely moisture sensitive; water present even in trace amounts hydrolyzes the benzoxazone to the starting anthranilic acid which upon further treatment with ammonia during the process is converted to the ammonium salt and eventually to the corresponding amide thereby complicating the isolation/purification of the quinazolone and also lowering the yield in the process.
  • a process to prepare 4-quinazolones which circumvents these critical deficiencies and is also amenable to large scale synthesis will be highly desirable.
  • the present invention thus provides a simple, efficient one-pot conversion of anthranilic acids to 4-quinazolones which obviates the problems associated with the current technologies.
  • U.S. 3,714,354 discloses a process of producing bronchial dilation which comprises administering to a subject an effective amount of a substituted quinazoline carboxylic acid ester.
  • U.S. 3,793,326 discloses 6,7-disubstituted-quinazolinones useful as analgesic and tranquilizer agents.
  • U.S. 4,695,569 discloses bicyclic heterocyclyl containing N-(bicyclic heterocyclyl-4-piperidinamines having antihistaminic and serotonin-antagonistic properties which compounds are useful agents in the treatment of allergic diseases.
  • U.S. 4,981,856 discloses quinazoline derivatives which possess anti-tumor activity.
  • U.S. 5,025,014 discloses the same compounds as U.S. 4,695,569 but which are useful agents in the treatment of allergic diseases.
  • U.S. 5,126,339 discloses the same compounds as U.S. 4,695,569 and U.S. 5,025,014 and which are also useful agents in the treatment of allergic diseases.
  • the present invention provides a process for preparing a quinazolone which comprises the steps of (a) dehydrating a N-acyl beta amino acid (such as an anthranilic acid) in the presence of a dehydration agent and an organic solvent for a sufficient period of time and under suitable temperature and pressure conditions to form an oxazone (b) adding a carboxylic acid and a primary amine salt of a carboxylic acid to said oxazone to form a mixture, (c) distilling azeotropically said mixture for a suitable period of time and under suitable temperature and pressure conditions to substantially remove said dehydration agent and said organic solvent, and (d) heating the product of step (c) for a sufficient period of time and under suitable temperature and pressure conditions to form said quinazolone.
  • a N-acyl beta amino acid such as an anthranilic acid
  • the present invention thus provides a novel process for preparing quinazolones which overcomes the prior deficiencies mentioned above.
  • a process for preparing a quinazolone which comprises the steps of (a) dehydrating a N-acyl beta amino acid in the presence of a dehydration agent and an organic solvent for a sufficient period of time and under suitable temperature and pressure conditions to form an oxazone (b) adding a carboxylic acid and a primary amine salt of a carboxylic acid to said oxazone to form a mixture, (c) distilling azeotropically said mixture for a suitable period of time and under suitable temperature and pressure conditions to substantially remove said dehydration agent and said organic solvent, and (d) heating the product of step (c) for a sufficient period of time and under suitable temperature and pressure conditions to form said quinazolone.
  • the starting materials of the present invention process are N-acyl beta amino acids (such as N-acyl anthranilic acids) which have the general formula
  • R 1 , R 2 , R 3 , and R 4 are each independently selected form the group consisting of hydrogen, halogen, alkoxy, alkyl, hydroxy, nitro and aryl;
  • R 1 and R 2 , R 2 and R 3 , and R 3 and R 4 may also (in addition to the above) form a cyclic ring containing a total of 2 to 6 atoms selected from the group consisting of carbon atoms, oxygen atoms, nitrogen atoms, sulfur atoms, and mixtures thereof, with the proviso that said ring can be substituted or unsubstituted; and
  • R 5 is selected from the group consisting of hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aryl and substituted aryl.
  • R 1 , R 2 , R 3 , R, and R 5 are the same as set forth above in formula I, and R 6 is selected from the group consisting of substituted alkyl, unsubstituted alkyl, substituted aryl and unsubstituted aryl.
  • halogen includes chlorine, fluorine, bromine and iodine.
  • alkyl includes straight and branch chained saturated hydrocarbon radicals having from 1 to 20 carbon atoms such as, for example, methyl; ethyl; 1-methylethyl; 1,1- dimethylethyl; propyl; 2-methylpropyl; butyl; pentyl; hexyl and the like.
  • alkoxy includes the alkyl definition above plus the oxygen atom, e.g. methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.
  • aryl includes phenyl, naphthyl, anthryl, phenanthyl and the like.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described hereinabove.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valencies of the heteroatoms.
  • This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.
  • Typical quinazolones that can be prepared by the novel processes of the present invention include without limitation, the compounds having the following formulae:
  • step (a) of the present invention process the N-acyl beta amino acid is subject to dehydration in the presence of a dehydration agent and an organic solvent at a temperature of from about 50°C to about 300°C, preferably from about 75°C to about 200°C.
  • the reaction time is not critical and generally is accomplished in about 1 minute to about 24 hours.
  • the reaction pressure is not critical and can be atmospheric, sub-atmospheric or super-atmospheric. Under these conditions, the end product is an oxazone having the general formula
  • R 1 - R 5 have the same designations as set forth above.
  • the dehydration agent employed in the present invention process is any material which removes water from the N-acyl beta amino acid (e.g. N-acyl anthranilic acid) in order to form an oxazone.
  • N-acyl beta amino acid e.g. N-acyl anthranilic acid
  • Such agents include without limitation, acid anhydrides of the carboxylic acids, e.g.
  • the dehydration agent employed can be used in any amount as long as it functions in the desired manner and accomplishes the desired end result.
  • such agent is used in a molar ratio of from about 1 : 1 to about 5:1, based on one mole of N-acyl beta amino acid. Higher ratios than 5:1 can be used if so desired.
  • the organic solvent used with the dehydration agent in step (a), is any solvent which functions in a manner to have an azeotropic relationship with the carboxylic acid and the dehydration agent mentioned herein.
  • One such solvent which falls into this category is heptane; another is octane; other higher hydrocarbons can be employed as long as they meet the criteria of providing the azeotropic relationship.
  • the use of this particular type organic solvent is critical to the overall process.
  • the organic solvent employed can be used in any amount as long as it functions in the desired manner and accomplishes the desired end result. In general, the solvent is used in a molar ratio of from about 1 :2 to about 20: 1 , based on one mole of the N-acyl beta amino acid. Higher ratios than 20:1 can be used if so desired.
  • step (b) of the present invention a carboxylic acid and a primary amine salt of a carboxylic acid are added to said oxazone to form a mixture.
  • This addition and mixing can be accomplished at any temperature and pressure conditions as long as the desired end result is obtained. In general, such temperature is from about 0°C to about 50°C, preferably from about 20°C to about 40°C.
  • the carboxylic acid employed in the present invention is used as a second solvent and is employed as such to assist in the azeotropic distillation [with the organic solvent in step (a)] to remove the dehydration agent. It is critical to remove the dehydration agent in order to convert the oxazone to the quinazolone.
  • the carboxylic acid employed includes, without limitation, formic acid, acetic acid, propanoic acid, butyric acid, valeric acid, caproic acid, heptanoic acid, octanoic acid, nonanoic acid, undecanoic acid, isobutyric acid, isovaleric acid, cyclohexanone carboxylic acid, and mixtures thereof.
  • the carboxylic acid employed can be used in any amount as long as it functions in the desired manner and accomplishes the desired end result.
  • such acid is used in a molar ratio of 1 : 1 to about 20:1, based on one mole ratio of oxazone. Higher ratios than 20:1 can be used if so desired.
  • the primary amine salt of a carboxylic acid has the general formula
  • R 6 NH 3 + •RCOO - IV wherein R 6 is the same as set forth above in Formula II.
  • R is hydrogen or alkyl (C 1 - C 20 ), or mixtures thereof.
  • step (c) of the present invention the resultant mixture from step (b) is subjected to azeotropic distillation in order to remove or substantially remove the residual dehydration agent from said mixture.
  • azeotropic distillation it is critical that said agent remaining be removed in order that the oxazone can be converted to the quinazolone.
  • Such distillation can be conducted under any temperature, pressure and time conditions as long as the desired end result is achieved. In general, such temperatures are from about 70°C to about 300°C.
  • step (d) of the present invention process the resultant product of step (c) is heated, generally under reflux in a carboxylic acid medium, for a sufficient period of time and under suitable temperature and pressure conditions to form said quinazolone.
  • the heating conditions of temperature, pressure and time are not critical as long as the desired end result is achieved.
  • the temperature is from about 30°C to about 300°C, preferably from about 100°C to about 200°C.
  • the preparation of 4-quinazolones from N-acetylanthranilic acids can be typified by the synthesis 2,6,7-trimethyl-4(3H)-quinazolone (7) .
  • the synthesis of 4-quinazolone (7) was efficiently accomplished by a sequence involving acetic anhydride promoted ring closure of the N-acetylanthranilic acid (4) obtained after the Pd-catalyzed carboxylation in Scheme 2, to the corresponding benzoxazone (6) followed by ammonolysis of the benzoxazone (6) with ammonium acetate in acetic acid producing the corresponding 2,6,7-trimethyl-4(3H)-quinazolone (7) in 80% yield (Scheme 3).
  • Anthranilic acid (5) instead of N-acylanthranilic acid (4), can also function as the starting material whereby it gets acylated first in situ to the N-acetylanthranilic acid (4), consuming an extra equivalent of acetic anhydride, prior to the benzoxazone formation.
  • 2,6,7-Trimethyl-3,1,4-benzoxazone was readily prepared by treating the corresponding N-acetyl anthranilic acid with acetic anhydride (1 .4 eq) in heptane (reflux, 3h). Ammonium acetate (5 eq per mol of substrate) was added to the reaction mixture and the residual acetic anhydride was removed by azeotropic distillation of heptane under atmospheric pressure.
  • the water formed hydrolyzes the 4-benzoxazone to the starting anthranilic acid which upon further treatment with ammonia during the process is converted to the ammonium salt and eventually to the corresponding amide, thereby complicating the isolation/purification of the quinazolone and also lowering the yield in the process (Scheme 4).
  • Example 4 was repeated twenty-one (21) times using the same procedure but using different starting materials, i.e. anthranilic acids and acid anhydrides.
  • the end product (quinazolone) was characterized by 1 H and 13 C NMR. The results of these twenty-one examples are shown in Table I.
  • pyrimidin 5,6-dihydro-3H-pyrimidin-4-one derivatives
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, alkoxy, alkyl, hydroxy, nitro and aryl; (b) R 1 and R 2 , may also (in addition to the above) form a cyclic ring containing a total of 2 to 6 atoms selected from the group consisting of carbon atoms, oxygen atoms, nitrogen atoms, sulfur atoms, and mixtures thereof, with the proviso that said ring can be substituted or unsubstituted; and (c) R 3 is selected from the group consisting of hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aryl and substituted aryl; and (d)
  • R 4 is selected from the group consisting of substituted and unsubstituted alkyl and aryl.
  • N-acyl beta amino acids which, in this case, have the general formula
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, alkoxy, alkyl, hydroxy, nitro and aryl; (b) R 1 and R 2 may also (in addition to the above) form a cyclic ring containing a total of 2 to 6 atoms selected from the group consisting of carbon atoms, oxygen atoms, nitrogen atoms, sulfur atoms, and mixtures thereof, with the proviso that said ring can be substituted or unsubstituted; and (c) R 3 is selected from the group consisting of hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aryl and substituted aryl.
  • a process for preparing a 5,6-dihydro-3H-pyrimidin-4-one derivatives which comprises the steps of (a) dehydrating a N-acyl beta amino acid in the presence of a dehydration agent and an organic solvent for a sufficient period of time and under suitable temperature and pressure conditions to form an oxazone (b) adding a carboxylic acid and a primary amine salt of a carboxylic acid to said oxazone to form a mixture, (c) distilling azeotropically said mixture for a suitable period of time and under suitable temperature and pressure conditions to substantially remove said dehydration agent and said organic solvent, and (d) heating the product of step (c) for a sufficient period of time and under suitable temperature and pressure conditions form said pyrimidin.
  • this new invention provides a process for preparing an anthranilic acid which comprises the steps of (a) acylating an aniline derivative to form the corresponding acylated product, (b) subjecting said acetylated product to halogenation conditions in the presence of an oxidizing agent to form a halogenated product, and (c) subjecting said halogenated product to carbonylation conditions including suitable temperature and pressure to form said anthranilic acid.
  • An example of this novel process is disclosed above in Scheme 1.
  • the anthranilic acids have the formula
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen, halogen, alkoxy, alkyl, hydroxy, nitro and aryl;
  • R 1 and R 2 , R 2 and R 3 , and R 3 and R 4 may also (in addition to the above) form a cyclic ring containing a total of 2 to 6 atoms selected from the group consisting of carbon atoms, oxygen atoms, nitrogen atoms, sulfur atoms, and mixtures thereof, with the proviso that said ring can be substituted or unsubstituted; and
  • R 5 is selected from the group consisting of hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aryl and substituted aryl.
  • the starting materials in this new process are the aniline derivatives which have the formula
  • R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen, halogen, alkoxy, alkyl, hydroxy, nitro and aryl;
  • R 1 and R 2 , R 2 and R 3 , and R 3 and R 4 may also (in addition to the above) form a cyclic ring containing a total of 2 to 6 atoms selected from the group consisting of carbon atoms, oxygen atoms, nitrogen atoms, sulfur atoms, and mixtures thereof, with the proviso that said ring can be substituted or unsubstituted; and
  • R 5 is selected from the group consisting of hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted aryl and substituted aryl.
  • step (b) such conditions include subjecting the acylated product from step (a) to a halogen (Cl, F, Br, or I) containing material in the presence of an oxidizing agent under suitable conditions of temperature, pressure and time to form a halogenated product.
  • a halogen Cl, F, Br, or I
  • the temperatures of this reaction are generally in the range of from about 0°C to about 250°C.
  • the pressure and time of reaction are not critical.
  • the amount of halogen employed is at least about
  • the oxidizing agent is any material which will facilitate an oxidizing reaction and includes, without limitation, organic peroxides (ROOR where R is an alkyl C 1 - C 20 group) and H 2 O 2 .
  • the amount employed is at least about 1 : 1 (molar ratio) based on the acylated product being processed; preferably the ratio is from about 1 : 1 to about 20: 1.
  • the acylation conditions of step (a) encompass the use of an acylation agent such as an anhydride of a carboxylic acid, such as those previously mentioned, e.g. acetic anhydride.
  • an acylation agent such as an anhydride of a carboxylic acid, such as those previously mentioned, e.g. acetic anhydride.
  • the temperatures employed are from about 0°C to about 200°C. although higher temperatures can be used as long as the desired end result is obtained. Pressure and time of reaction are not critical features.
  • the amount of acylation agent used is in a molar ratio of at least about 1 :1 to about 5:1 based on one mole of the aniline derivative.
  • the halogenated product from step (b) is subjected to a carbonylation procedure in order to produce the anthranilic acid.
  • the carbonylation is carried out at temperatures of from about 10°C to about 200°C under suitable pressures and reaction times to form said acid.
  • This carbonylation is obviously carried out with CO or a CO generating material such as syngas and in the presence of (1) a carbonylation catalyst, (2) an organic solvent such as those described herein, and (3) a basic material such as a tertiary amine, alkali metal carbonate, and the like.
  • Typical carbonylation conditions which can be used in this step (c) include those conditions outlined in U.S. 4,981,995 and which is incorporated herein by reference in its entirety.

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Abstract

L'invention concerne un procédé de préparation d'un acide anthrenilique comprenant les étapes consistant (a) à acyler avec un agent d'acylation un dérivé d'aniline dans des conditions appropriées de température et de pression afin de former le produit acylé correspondant, (b) à soumettre ledit produit acétylé à des conditions d'halogénation en présence d'un agent oxydant afin de former un produit halogéné, (c) à soumettre ledit produit halogéné à des conditions de carbonylation, à une température et une pression appropriées, afin de former ledit acide anthrenilique.
PCT/US1997/001862 1996-02-05 1997-01-30 Procede de preparation d'acides anthreniliques Ceased WO1997028118A1 (fr)

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1669346A1 (fr) 2004-12-10 2006-06-14 Lanxess Deutschland GmbH Procédé de préparation des dérivés d'esters d'acide carbamique
US7074831B2 (en) 2004-02-06 2006-07-11 Active Biotech Ab Compounds, methods for their preparation and use thereof
US7825244B2 (en) 2005-06-10 2010-11-02 Janssen Pharmaceutica Nv Intermediates useful in the synthesis of alkylquinoline and alkylquinazoline kinase modulators, and related methods of synthesis
US7846915B2 (en) 2004-10-20 2010-12-07 Resverlogix Corporation Stilbenes and chalcones for the prevention and treatment of cardiovascular diseases
US7960399B2 (en) 2004-06-08 2011-06-14 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US8053440B2 (en) 2007-02-01 2011-11-08 Resverlogix Corporation Compounds for the prevention and treatment of cardiovascular diseases
US8071768B2 (en) 2005-06-10 2011-12-06 Janssen Pharmaceutica, N.V. Alkylquinoline and alkylquinazoline kinase modulators
US8114995B2 (en) 2008-06-26 2012-02-14 Resverlogix Corp. Methods of preparing quinazolinone derivatives
US8263658B2 (en) 2007-02-06 2012-09-11 Chelsea Therapeutics, Inc. Anthranilic acid derivatives
US8410109B2 (en) 2005-07-29 2013-04-02 Resverlogix Corp. Pharmaceutical compositions for the prevention and treatment of complex diseases and their delivery by insertable medical devices
US8952021B2 (en) 2009-01-08 2015-02-10 Resverlogix Corp. Compounds for the prevention and treatment of cardiovascular disease
US9073878B2 (en) 2012-11-21 2015-07-07 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
US9238640B2 (en) 2009-03-18 2016-01-19 Resverlogix Corp. Anti-inflammatory agents
US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
US9610251B2 (en) 2011-11-01 2017-04-04 Resverlogix Corp. Pharmaceutical compositions for substituted quinazolinones
US9757368B2 (en) 2009-04-22 2017-09-12 Resverlogix Corp. Anti-inflammatory agents
US9765039B2 (en) 2012-11-21 2017-09-19 Zenith Epigenetics Ltd. Biaryl derivatives as bromodomain inhibitors
US10111885B2 (en) 2015-03-13 2018-10-30 Resverlogix Corp. Compositions and therapeutic methods for the treatment of complement-associated diseases

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0034292A2 (fr) * 1980-02-06 1981-08-26 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé pour la préparation de dérivés d'acide anthranilique
DE3014972A1 (de) * 1980-04-18 1981-10-22 Chemische Fabrik Kalk GmbH, 5000 Köln Verfahren zur herstellung von 2,4-dinitro-6-bromanilin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0034292A2 (fr) * 1980-02-06 1981-08-26 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Procédé pour la préparation de dérivés d'acide anthranilique
DE3014972A1 (de) * 1980-04-18 1981-10-22 Chemische Fabrik Kalk GmbH, 5000 Köln Verfahren zur herstellung von 2,4-dinitro-6-bromanilin

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"BEILSTEINS HANDBUCH DER ORGANISCHEN CHEMIE, fourth Edition, third supplement, vol. 12, pages 2159, 2384, 2454", 1972, SPRINGER VERLAG, XP002032879 *
"HOUBEN-WEYL, METHODEN DER ORGANISCHEN CHEMIE, VOL. VIII, pages 655-660", 1952, GEORG THIEME VERLAG, STUTTGART, DE, XP002032878 *
SHOJI KAJIGAESHI ET AL.: "Halogenation using quaternary ammonium polyhalides...", BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 61, no. 7, 1988, TOKYO JP, pages 2681 - 2683, XP002032877 *

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US7074831B2 (en) 2004-02-06 2006-07-11 Active Biotech Ab Compounds, methods for their preparation and use thereof
US8809528B2 (en) 2004-06-08 2014-08-19 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US7960399B2 (en) 2004-06-08 2011-06-14 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US9102653B2 (en) 2004-06-08 2015-08-11 Novartis Ag Substituted quinazolinones as vanilloid antagonists
US8211902B2 (en) 2004-06-08 2012-07-03 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US8093273B2 (en) 2004-10-20 2012-01-10 Resverlogix Corp. Flavanoids and isoflavanoids for the prevention and treatment of cardiovascular diseases
US8242130B2 (en) 2004-10-20 2012-08-14 Resverlogix Corp. Flavanoids and isoflavanoids for the prevention and treatment of cardiovascular diseases
US7846915B2 (en) 2004-10-20 2010-12-07 Resverlogix Corporation Stilbenes and chalcones for the prevention and treatment of cardiovascular diseases
EP1669346A1 (fr) 2004-12-10 2006-06-14 Lanxess Deutschland GmbH Procédé de préparation des dérivés d'esters d'acide carbamique
US7396952B2 (en) 2004-12-10 2008-07-08 Lanxess Deutschland Gmbh Process for preparing carbamic ester derivatives
US8071768B2 (en) 2005-06-10 2011-12-06 Janssen Pharmaceutica, N.V. Alkylquinoline and alkylquinazoline kinase modulators
US7825244B2 (en) 2005-06-10 2010-11-02 Janssen Pharmaceutica Nv Intermediates useful in the synthesis of alkylquinoline and alkylquinazoline kinase modulators, and related methods of synthesis
US8410109B2 (en) 2005-07-29 2013-04-02 Resverlogix Corp. Pharmaceutical compositions for the prevention and treatment of complex diseases and their delivery by insertable medical devices
US8889698B2 (en) 2007-02-01 2014-11-18 Resverlogix Corp. Compounds for the prevention and treatment of cardiovascular diseases
US10532054B2 (en) 2007-02-01 2020-01-14 Resverlogix Corp. Compounds for the prevention and treatment of cardiovascular diseases
US8053440B2 (en) 2007-02-01 2011-11-08 Resverlogix Corporation Compounds for the prevention and treatment of cardiovascular diseases
US9199990B2 (en) 2007-02-01 2015-12-01 Resverlogix Corp. Compounds for the prevention and treatment of cardiovascular diseases
US8461205B2 (en) 2007-02-06 2013-06-11 Chelsea Therapeutics, Inc. Anthranilic acid derivatives
US8263658B2 (en) 2007-02-06 2012-09-11 Chelsea Therapeutics, Inc. Anthranilic acid derivatives
US8114995B2 (en) 2008-06-26 2012-02-14 Resverlogix Corp. Methods of preparing quinazolinone derivatives
US8952021B2 (en) 2009-01-08 2015-02-10 Resverlogix Corp. Compounds for the prevention and treatment of cardiovascular disease
US10131640B2 (en) 2009-03-18 2018-11-20 Resverlogix Corp. Anti-inflammatory agents
US9238640B2 (en) 2009-03-18 2016-01-19 Resverlogix Corp. Anti-inflammatory agents
US10882828B2 (en) 2009-03-18 2021-01-05 Resverlogix Corp. Anti-inflammatory agents
US11407719B2 (en) 2009-03-18 2022-08-09 Resverlogix Corp. Anti-inflammatory agents
US9757368B2 (en) 2009-04-22 2017-09-12 Resverlogix Corp. Anti-inflammatory agents
US9610251B2 (en) 2011-11-01 2017-04-04 Resverlogix Corp. Pharmaceutical compositions for substituted quinazolinones
US10016426B2 (en) 2011-11-01 2018-07-10 Resverlogix Corp. Pharmaceutical compositions for substituted quinazolinones
US9278940B2 (en) 2012-11-21 2016-03-08 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
US9765039B2 (en) 2012-11-21 2017-09-19 Zenith Epigenetics Ltd. Biaryl derivatives as bromodomain inhibitors
US9073878B2 (en) 2012-11-21 2015-07-07 Zenith Epigenetics Corp. Cyclic amines as bromodomain inhibitors
US9271978B2 (en) 2012-12-21 2016-03-01 Zenith Epigenetics Corp. Heterocyclic compounds as bromodomain inhibitors
US10111885B2 (en) 2015-03-13 2018-10-30 Resverlogix Corp. Compositions and therapeutic methods for the treatment of complement-associated diseases
US10772894B2 (en) 2015-03-13 2020-09-15 Resverlogix Corp. Compositions and therapeutic methods for the treatment of complement-associated diseases

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