WO1994017075A1 - Derives de diazepine et compositions antivirales - Google Patents

Derives de diazepine et compositions antivirales Download PDF

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Publication number
WO1994017075A1
WO1994017075A1 PCT/EP1994/000102 EP9400102W WO9417075A1 WO 1994017075 A1 WO1994017075 A1 WO 1994017075A1 EP 9400102 W EP9400102 W EP 9400102W WO 9417075 A1 WO9417075 A1 WO 9417075A1
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WO
WIPO (PCT)
Prior art keywords
pyrido
carbon atoms
group
dihydro
diazepin
Prior art date
Application number
PCT/EP1994/000102
Other languages
English (en)
Other versions
WO1994017075B1 (fr
Inventor
Danilo Giannotti
Vittorio Pestellini
Giovanni Viti
Daniela Bellarosa
Rossano Nannicini
Antonio Giachetti
Original Assignee
A. Menarini Industrie Farmaceutiche Riunite S.R.L.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from IT000007 external-priority patent/IT1271453B/it
Priority claimed from ITFI930216A external-priority patent/IT1262569B/it
Application filed by A. Menarini Industrie Farmaceutiche Riunite S.R.L. filed Critical A. Menarini Industrie Farmaceutiche Riunite S.R.L.
Priority to AU58837/94A priority Critical patent/AU5883794A/en
Publication of WO1994017075A1 publication Critical patent/WO1994017075A1/fr
Publication of WO1994017075B1 publication Critical patent/WO1994017075B1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/14—Ortho-condensed systems

Definitions

  • the present invention relates to diazepin derivatives suitable for the treatment of viral infections , particularly for the treatment of human infections from HIV , the process for their preparation, the use thereof in pharmaceutical formulations and their pharmaceutically acceptable salts .
  • the present invention relates to diazepin derivatives having the following general formula ( I ) :
  • n 0, 1;
  • R 1 and R 2 equal or different from each other, are selected from the group consisting of hydrogen, alkyl or fluoroalkyl of from 1 to 6 carbon atoms, cycloalkyl of from 3 to 5 carbon atoms, alkenyl or alkinyl of from 3 to 5 carbon atoms, alkoxy-alkyl of from 2 to 6 carbon atoms, benzyl, C 2-6 alkylacyl, phenylacyl wherein the phenyl group is optionally substituted with a group selected from NO 2 , CN, halogen;
  • R 8 , R 9 , R 4 and R 6 are selected from the group consisting of hydrogen , alkyl of from 1 to 3 carbon atoms, hydroxyalkyl of from 1 to 3 carbon atoms, alkoxy of from 1 to 3 carbon atoms, halogen, trihalomethyl, hydroxy, amino or acetamino, nitro, cyano and azido group, or R 8 and R 9 linked to each other form a R 3 ring wherein R 3 has the same meaning as
  • R 7 is selected from the group consisting of H, C 1- 3 alkyl, C 2- 6 alkylacyl, phenylacyl wherein the phenyl group is optionally substituted with a group selected from : NO 2 , CN, halogen; the ring having the substituents R 8 and R 9 can be saturated, unsaturated or partially saturated
  • R 2 is alkyl of from 1 to 3 carbon atoms
  • R 1 and R 4 are hydrogen atoms or alkyl groups containing from 1 to 3 carbon atoms.
  • the invention also regards the pharmaceutically acceptable salts of general formula (I) with acids, commonly used in the pharmaceutical practice, as for example hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, mono and bifunctional carboxylic acids as for example acetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid.
  • acids commonly used in the pharmaceutical practice, as for example hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, mono and bifunctional carboxylic acids as for example acetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid.
  • tricyclic compounds with a heptaatomic diazepinonic ring may have an antiviral activity while tricyclic compounds having heptaatomic thiodiazepin ring (U.S. P. 3.274.058 and 5-011.833) may act on the central nervous system and be myorelaxant agents.
  • Another essential characteristic of the present invention relates to the pharmaceutically acceptable salts of the compounds of formula (I) with the acids, commonly used in the pharmaceutical practice.
  • Preferred acids are hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, mono and bifunctional carboxylic acids as for example acetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid.
  • a further characteristic of the present invention concerns the pharmaceutical compositions comprising the compounds of general formula (I) and their pharmaceutically acceptable salts and the use of these compounds or salts in the preparation of the above mentioned pharmaceutical compositions.
  • a further characteristic of the present invention refers to pharmaceutical compositions particularly suitable for parenteral or oral administration.
  • Another essential characteristic of the present invention consists in the preparation of compounds of general formula (I).
  • R 4 , R 5 , Z and B have been previously defined for the compounds of formula (I);
  • R 1 and R 2 have the same meanings of the corresponding substituents of the compounds of formula (I) or represent a protecting group as for example acetyl, benzoyl, benzyl, Hal represents a halogen atom, preferably chlorine or bromine.
  • the cyclization reaction is carried out in an organic solvent, preferably in the presence of a base and optionally can be used copper or its salts in a catalytic amount.
  • the preferred organic solvents are dimethylformamide, dioxane, tetrahydrofuran, dimethylsulfoxide and alcohols, while the preferred bases are the alkaline carbonates, preferably potassium carbonate and alkaline hydrides, preferably sodium hydride.
  • the reaction mixture is preferably heated up to temperatures comprised between 60 ° - 200 °C.
  • the compounds of general formula (I) wherein R 1 and R 2 are different from hydrogen can be obtained by means of a reaction carried out in a single step, that is by treating in situ salts of the compounds of general formula (I) wherein R 1 and R 2 , also individually are hydrogen with a R'Q compound wherein R' is selected from the group consisting of alkyl or fluoroalkyl of from 1 to 6 carbon atoms, cycloalkyl of from 3 to 5 carbon atoms, alkenyl or alkynyl of from 3 to 5 carbon atoms and wherein Q is a suitable leaving group as for example a halogen, preferably chlorine, bromine or iodine, or an appropriate aliphatic or aromatic ester of the sulphonic acid.
  • R'Q compound wherein R' is selected from the group consisting of alkyl or fluoroalkyl of from 1 to 6 carbon atoms, cycloalkyl of from 3 to 5 carbon atoms, alkenyl or alkyny
  • organic bases as alkaline metal hydrides, for example sodium hydride
  • alkyl lithium as for example n-butyl lithium
  • amides of alkaline metals as for example sodium amide or lithium dialkylamides, as for example lithium diisopropylamides
  • R'Q is added to the suspension of the salt in in
  • R 1 and R 2 are hydrogen and these two atoms are to be substituted, two moles of base and two moles of R'Q shall be used, whereas, in case only the substitution on the sulphamidic nitrogen atom is requested, a mole of base and a mole of R'Q shall be added.
  • R 1 and R 2 are hydrogen and these two atoms are to be substituted, two moles of base and two moles of R'Q shall be used, whereas, in case only the substitution on the sulphamidic nitrogen atom is requested, a mole of base and a mole of R'Q shall be added.
  • R 1 a protecting group, as for example arylmethyl or arylacyl group
  • the sulfonamides of general formula (II) and (III) are prepared by already known methods, used for analogous derivatives (D. Giannotti. et. al. J. Med. Chem. 1991, 34, 1356-1362).
  • X O, S or NR 7 , R 8 and R 9 form a ring R 3 wherein A represent a
  • the compounds of formula (VI) are not isolated because the condensation reaction proceedes up to the formation of the compounds of formula (VII) or (VIII), (see example 11 and 12).
  • R 1 , R 2 , R 3 , R 4 R 5 , A, B, X have the same meanings as in the compounds of formula (I), Hal is halogen (preferably chlorine and bromine).
  • the cyclization reaction is carried out in an organic solvent in the presence of a base and optionally of copper or its salts in a catalytic amount.
  • the preferred organic solvents are dimethylformamide, dioxane, dimethylsulfoxide, pyridine and alcohols, while the preferred bases are the alkaline carbonates, preferably potassium or sodium carbonate and alkaline hydrides, preferably sodium hydride.
  • the reaction mixture is preferably heated up to temperatures comprised between 60 ° - 200 °C.
  • salts can be obtained by treating compounds of general formula (VIII) with inorganic bases such as alkaline metals hydrides, for example sodium hydride, with alkyl lithium, as for example n-butyl lithium, amides of alkaline metals as for example sodium amide, or lithium dialkyl amides as for example lithium diisopropylamide; R 2 M is added to the salt suspension in inert organic solvents, preferably dioxane, tetrahydrofuran and dimethylformamide, at a temperature comprised between the room and the reflux temperature, thus obtaining the desired compounds.
  • inorganic bases such as alkaline metals hydrides, for example sodium hydride, with alkyl lithium, as for example n-butyl lithium, amides of alkaline metals as for example sodium amide, or lithium dialkyl amides as for example lithium diisopropylamide;
  • R 2 M is added to the salt suspension in inert organic solvents, preferably dioxane
  • the reaction is carried out in an organic solvent as for example benzene or toluene at a temperature comprised between the room and the reflux temperature.
  • organic solvent as for example benzene or toluene
  • the invention relates also to products obtained by the reduction of the double bond joining the pentaatomic ring with the heptaatomic ring.
  • the compounds of formula (XI) are obtained by reducing the compounds of formula (IX) with hydrogen at a pressure ranging from 1 to 10 atm, in the presence of a catalyst as for example 10 % Pd/C or Nickel-Raney (as described in example 10).
  • inorganic and organic acids commonly used in the pharmaceutical practice, preferably hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, mono and bifunctional carboxylic acid, preferably acetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid are used in the preparation of pharmaceutically acceptable salts.
  • a therapeutically effective dose of the compound of general formula (I) or of its pharmaceutically acceptable salts, prepared as above described, is used as active principle in combination with suitable excipients and diluents, in the preparation of pharmaceutically acceptable compositions.
  • a therapeutically effective dose of the compound of general formula (I) is further used in combination with suitable excipients, in the preparation of pharmaceutical compositions particularly suitable for parenteral and oral administration.
  • the compounds of general formula (I) show antiviral activity, particularly against HIV-1 virus in human infections.
  • the antiviral activity evaluation is carried out by using : a) lynphoblastoid cellular line CD4+ known as C8l66 containing HTLV-I genoma expressing only "TAX" gene which is infected by HIV-1 (strain 3B);
  • PBMC human blood
  • MTB methyl-tetrazole bromide
  • the product is solubilized in 20 ml of a methanol solution containing 0.184 g (8 mmoles) of sodium, then 1 ml of methyl hydride is added, the resulting mixture is kept two days under rest, brought to dryness, solubilized in ethyl acetate, washed with water, dried and concentrated obtaining 1.9 g of a white crystalline solid. Yield 35 % , m.p.: 145 - 146 °C.
  • the solid product is purified by chromatography on Si02 column by using as the eluant ethyl ether/hexane 1/1, collecting 1.1 g of product, yield 70%. Melting point 149 - 150 °C.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

L'invention se rapporte à des dérivés de diazépine répondant à la formule générale (I), à leur préparation et aux compositions antivirales les contenant.
PCT/EP1994/000102 1993-01-20 1994-01-17 Derives de diazepine et compositions antivirales WO1994017075A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU58837/94A AU5883794A (en) 1993-01-20 1994-01-17 Diazepin derivatives and antiviral compositions

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IT000007 IT1271453B (it) 1993-01-20 1993-01-20 Tiodiazepine, loro processi di preparazione e composizioni farmaceutiche che le contengono
ITFI93A000007 1993-01-20
ITFI93A000216 1993-11-03
ITFI930216A IT1262569B (it) 1993-11-03 1993-11-03 Derivati tetraciclici diazepinici, loro processi di preparazione e composizioni farmaceutiche che li contengono

Publications (2)

Publication Number Publication Date
WO1994017075A1 true WO1994017075A1 (fr) 1994-08-04
WO1994017075B1 WO1994017075B1 (fr) 1994-09-15

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Country Status (2)

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AU (1) AU5883794A (fr)
WO (1) WO1994017075A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995024408A1 (fr) * 1994-03-07 1995-09-14 Warner-Lambert Company Thiazepinones de benzothiophene, de benzofurane et d'indole, oxazepinones et diazepinones utilisees comme inhibiteurs d'adherence cellulaire et du vih
WO1995029900A1 (fr) * 1994-04-29 1995-11-09 Takeda Chemical Industries, Ltd. COMPOSES HETEROCYCLIQUES CONDENSES, LEUR PRODUCTION ET LEUR UTILISATION COMME ANTAGONISTS DE GnRH
US5612330A (en) * 1994-03-07 1997-03-18 Warner-Lambert Company Methods for inhibiting and controlling viral growth
US5866567A (en) * 1995-06-01 1999-02-02 Takeda Chemical Industries, Ltd. Diazepinones, their production and use
WO2002014324A2 (fr) * 2000-08-16 2002-02-21 Warner-Lambert Company Diazepinones utilisees comme agents antiviraux
FR2850654A1 (fr) * 2003-02-03 2004-08-06 Servier Lab Nouveaux derives d'azepines tricycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP1582521A1 (fr) * 2003-01-09 2005-10-05 Tanabe Seiyaku Co., Ltd. Compose de furane condense
EP2539341A1 (fr) * 2010-02-16 2013-01-02 Boehringer Ingelheim International GmbH Dérivés de 1-phényl-1,5-dihydro-benzo[b][1.4]diazépine-2.4-dione en tant qu'inhibiteurs de la réplication du vih
CN114432308A (zh) * 2022-01-27 2022-05-06 华南理工大学 一种含氮螺环化合物或其药学上可接受的盐在制备抗甲型流感病毒药物中的应用

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EP0268990A2 (fr) * 1986-11-21 1988-06-01 Fujisawa Pharmaceutical Co., Ltd. Dérivés de benzothiadiazine, leurs procédés de préparation et compositions pharmaceutiques les contenant
EP0393604A2 (fr) * 1989-04-20 1990-10-24 Boehringer Ingelheim Pharmaceuticals Inc. 6,11-Dihydro-5H-pyrido(2,3-b)(1,5)benzodiazépine-5-ones et thiones et leur utilisation pour la prévention ou le traitement du SIDA
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GB948833A (en) * 1960-09-27 1964-02-05 Bayer Ag 6-dibenzo-(c,e)-o-thiazine-5-dioxides
GB1090252A (en) * 1965-04-13 1967-11-08 Ici Ltd Dibenzothiazine derivatives
GB1360365A (en) * 1972-01-12 1974-07-17 Rhone Poulenc Sa Thiazolidine derivatives
EP0268990A2 (fr) * 1986-11-21 1988-06-01 Fujisawa Pharmaceutical Co., Ltd. Dérivés de benzothiadiazine, leurs procédés de préparation et compositions pharmaceutiques les contenant
EP0393604A2 (fr) * 1989-04-20 1990-10-24 Boehringer Ingelheim Pharmaceuticals Inc. 6,11-Dihydro-5H-pyrido(2,3-b)(1,5)benzodiazépine-5-ones et thiones et leur utilisation pour la prévention ou le traitement du SIDA
EP0393530A1 (fr) * 1989-04-20 1990-10-24 Boehringer Ingelheim Pharmaceuticals Inc. 5,11-Dihydro-6H-pyrido(2,3-b)(1,4)benzodiazépine-6-ones et thiones et leur utilisation pour la prévention et le traitement du SIDA
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D. GIANNOTTI ET AL.: "New dibenzothiadiazepine derivatives with antidepressant activities", JOURNAL OF MEDICINAL CHEMISTRY, vol. 34, no. 4, 1991, WASHINGTON US, pages 1356 - 1362 *
D. HELLWINKEL ET AL.: "Heterocyclic synthesis via carbanionically induced rearrangement reactions", TETRAHEDRON, (INCL. TETRAHEDRON REPORTS), vol. 39, no. 12, 1983, OXFORD GB, pages 2073 - 2084 *
F.A. DAVIS ET AL.: "Chemistry of the sulphur-nitrogen bond. II. A mechanistic study of the rearrangement of 2-nitrobenzenesulfenanilides to 2-aminobenzenesulfonanilides", JOURNAL OF ORGANIC CHEMISTRY, vol. 37, no. 6, 1972, EASTON US, pages 854 - 859 *
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Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995024408A1 (fr) * 1994-03-07 1995-09-14 Warner-Lambert Company Thiazepinones de benzothiophene, de benzofurane et d'indole, oxazepinones et diazepinones utilisees comme inhibiteurs d'adherence cellulaire et du vih
US5489586A (en) * 1994-03-07 1996-02-06 Warner-Lambert Company Method for treating inflammatory disease in humans
US5565446A (en) * 1994-03-07 1996-10-15 Warner-Lambert Company Benzothiophene, benzofuran and indole-thiazepinones, oxazepinones and diazepinones as inhibitors of cell adhesion and as inhibitors of HIV
US5612330A (en) * 1994-03-07 1997-03-18 Warner-Lambert Company Methods for inhibiting and controlling viral growth
US5703069A (en) * 1994-03-07 1997-12-30 Warner-Lambert Company Method for inhibiting and controlling viral growth
MD1688G2 (ro) * 1994-03-07 2002-01-31 Уорнер-Ламберт Кампэни Benzotiofen, benzofuran şi indoltiazepinone, oxazepinone şi diazepinone, compoziţie farmaceutică, metodă de inhibare a aderării leucocitelor la celulele endoteliale pentru tratamentul proceselor inflamatorii şi metodă de tratament al mamiferelor infectate cu HIV infecţie .
WO1995029900A1 (fr) * 1994-04-29 1995-11-09 Takeda Chemical Industries, Ltd. COMPOSES HETEROCYCLIQUES CONDENSES, LEUR PRODUCTION ET LEUR UTILISATION COMME ANTAGONISTS DE GnRH
US5834463A (en) * 1994-04-29 1998-11-10 Takeda Chemical Industries, Ltd. Condensed heterocyclic compounds, their production and use
US5866567A (en) * 1995-06-01 1999-02-02 Takeda Chemical Industries, Ltd. Diazepinones, their production and use
WO2002014324A3 (fr) * 2000-08-16 2002-05-02 Warner Lambert Co Diazepinones utilisees comme agents antiviraux
WO2002014324A2 (fr) * 2000-08-16 2002-02-21 Warner-Lambert Company Diazepinones utilisees comme agents antiviraux
EP1582521A1 (fr) * 2003-01-09 2005-10-05 Tanabe Seiyaku Co., Ltd. Compose de furane condense
EP1582521A4 (fr) * 2003-01-09 2007-09-19 Tanabe Seiyaku Co Compose de furane condense
US7514449B2 (en) 2003-01-09 2009-04-07 Mitsubishi Tanabe Pharma Corporation Fused furan compound
US7737161B2 (en) 2003-01-09 2010-06-15 Mitsubishi Tanabe Pharma Corporation Condensed furan compounds
FR2850654A1 (fr) * 2003-02-03 2004-08-06 Servier Lab Nouveaux derives d'azepines tricycliques, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
EP2539341A1 (fr) * 2010-02-16 2013-01-02 Boehringer Ingelheim International GmbH Dérivés de 1-phényl-1,5-dihydro-benzo[b][1.4]diazépine-2.4-dione en tant qu'inhibiteurs de la réplication du vih
EP2539341A4 (fr) * 2010-02-16 2013-07-31 Boehringer Ingelheim Int Dérivés de 1-phényl-1,5-dihydro-benzo[b][1.4]diazépine-2.4-dione en tant qu'inhibiteurs de la réplication du vih
CN114432308A (zh) * 2022-01-27 2022-05-06 华南理工大学 一种含氮螺环化合物或其药学上可接受的盐在制备抗甲型流感病毒药物中的应用
CN114432308B (zh) * 2022-01-27 2023-09-26 华南理工大学 一种含氮螺环化合物或其药学上可接受的盐在制备抗甲型流感病毒药物中的应用

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