WO1996026926A1 - Pyrazolotetracyclines - Google Patents

Pyrazolotetracyclines Download PDF

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Publication number
WO1996026926A1
WO1996026926A1 PCT/EP1996/000815 EP9600815W WO9626926A1 WO 1996026926 A1 WO1996026926 A1 WO 1996026926A1 EP 9600815 W EP9600815 W EP 9600815W WO 9626926 A1 WO9626926 A1 WO 9626926A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
formula
pyrazolotetracyclines
substituted
dimethylamino
Prior art date
Application number
PCT/EP1996/000815
Other languages
English (en)
Inventor
Marco Da Col
Leone Dall'asta
Irene Resta
Ennio Seghetti
Original Assignee
Biochimica Opos S.P.A.
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
Application filed by Biochimica Opos S.P.A. filed Critical Biochimica Opos S.P.A.
Priority to AU48313/96A priority Critical patent/AU4831396A/en
Priority to JP8526020A priority patent/JPH11501022A/ja
Priority to EP96904083A priority patent/EP0812315A1/fr
Publication of WO1996026926A1 publication Critical patent/WO1996026926A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention concers novel tetracycline derivatives, more particularly novel pyrazolotetracyclines, a process for their preparation and pharmaceutical compositions containing them.
  • Tetracyclines are among the most studied antibiotics since their discovery, at the end of years forty. Many books have been dedicated to the chemistry, to the activity of these products and, more particularly, to the relationship between their chemical structure and their antibiotic activity.
  • [4S, (4 ⁇ ,4a ⁇ ,5a ⁇ ,6 ⁇ ,12a ⁇ ) ]-4-(dimethylamino)-1,4,4a,5,5a,6, 11, 12a-octa hydro-3,6,10,12,12a-pentahydroxy-6-methyl-l,ll-dioxo-2-naphthacenecar boxamide, may be irreversibly, but in an appropriate manner, modified in the positions from 4a to 9 in order to obtain compounds still endowed with antibiotic activity, whilst any irreversible modification in the positions 1, 2, 3, 4 and from 10 to 12a involves a loss of the antibiotic activity. Therefore, these positions are considered as "inviolate” (Medical Research Series, Vol. 9, Lester A. Mitscher, The Chemistry of the Tetracycline Antibiotics, Marcel Dekker, Inc., 1978).
  • R is hydrogen, a substituted or unsubstituted (C.-C 8 )alkyl, (C 2 -C,)alkenyl or (C 2 -Cg)alkynyl group, a substituted or unsubstitu ted aryl or heteroaryl group, a substituted or unsubstituted cycloalkyl, cycloalkenyl or cycloalkadienyl group and R' represents a basic group, preferably an amino, dimethylamino, (C.-C- j )alkylamino or formyleunino group, and their acid addition salts, their solvates and their complexes.
  • the solvates and the complexes those which are pharmaceutically acceptable or which allow an easy separation of the pyrazolotetracycline involved are particularly preferred.
  • the preferred salts are the hydrochloride, the hydrogenosulfate, the sulfate.
  • the solvates can be those of the free base or of the salts, the hydrates being preferred.
  • the complexes are generally those which allow an easy isolation of the pyrazolotetracycline, the complex with calcium chloride dihydrate being particularly preferred.
  • a subclass of compounds according to the present invention includes pyrazolotetracyclines of formula I above, wherein R' is as defined above and R is hydrogen or a substituted or unsubstituted (C,-Cg)alkyl, (C 2 -Cg)alkenyl or (C 2 -Cg)alkynyl group; a cycloalkyl group of from 3 to 8 carbon atoms; a cycloalkenyl group of from 4 to 8 carbon atoms, such as cyclohexenyl, more particularly 1-cyclo hexenyl; a phenyl group which may be unsubstituted or substituted with one or more substituents selected from the group consisting of halogens, particularly fluoro, chloro and iodo substituents, ( c ⁇ ⁇ C 3 )alkyl, (C.-C,)alkoxy, trifluoromethyl, pentafluoroethyl, amino, nitro, cyan
  • R is hydrogen or a group as defined above and R* is selected from the group consisting of formylamino, methylamino, isopropylamino and dimethyl amino, as well as their salts, solvates and complexes which are pharmaceutically acceptable or which allow an easy separation of the pyrazolotetracycline involved.
  • the present invention provides a process for the preparation of pyrazolotetracyclines of formula I and of their salts, solvates and complexes which comprises reacting the corresponding tetracycline of formula II
  • R' is as defined above, or a salt or solvate thereof, with a hydrazine of formula III R-NH-NH 2 (III) wherein R is as defined above and isolating the pyrazolotetracycline thus obtained in form of a base or of a complex thereof and, if necessary, transforming the free base in an acid addition salt thereof.
  • the reaction of the tetracycline of formula II or of its salt or solvate with the hydrazine of formula III is easy and rapid. It occurs in an organic or aqueous-organic, preferably alcoholic or hydroalcoholic solvent, preferably in methanol.
  • the reaction is generally over after 1 to 5 hours and the compound I thus obtained is isolated according to the conventional procedures of the tetracyclines chemistry, for example by acidifying the reaction mixture and by forming a complex of the compound obtained therein with a calcium salt, preferably with calcium chloride dihydrate in an aqueous-acidic medium.
  • the desired end product is then recovered from its complex by precipitation of the calcium .with an organic or inorganic acid capable of forming an insoluble calcium salt, separation of the insoluble calcium salt, correction of pH to about 8 and isolation of the pyrazolotetracycline in form of base.
  • the recovery of the end product occurs by treatment with oxalic acid, elimination of the calcium oxalate and isolation of the pyrazolotetracycline by adjustment of the pH to alkaline values (7.5 ⁇ 9.0).
  • the isolation of the end product may also occur without using the calcium complex, by simple evaporation of the solvent and adjustment of the pH of the aqueous phase to about 8.
  • the pyrazolotetracycline base may be converted to their acid addition salts by treatment with an inorganic or organic acid, for example with hydrochloric, hydrobromic, sulfuric, methanesulfonic, p- toluenesulfonic or 2-naphthalenesulfonic acid.
  • the pyrazolotetracyclines of the present invention having the basic structure B can exist in three theoretical tautomeric forms I, I' and I" represented by the following structures:
  • the DL_ 0 of pyrazolominocycline in rat is greater than 4000 g/Kg, in comparison with that of minocycline which, in the same conditions, is of 3300 mg/Kg. Therefore, the novel pyrazolotetracyclines of the present invention may be used as active ingredients of pharmaceutical compounds, in unit doses of from 50 to 500 mg of active ingredient to be administered one to four times daily.
  • novel pyrazolotetracyclines of the present invention may be employed for the preparation of pharmaceutical compositions for oral use, for example in gelatin capsules, tablets, granulates, as such or with the common pharmaceutical carriers.
  • Such pharmaceutical compositions contain the pyrazolotetracyclines of the present invention in an amount equivalent to 50 ⁇ 500 mg of anhydrous pyrazolo tetracycline, the preferred active ingredient being pyrazolo minocycline or one of its pharmaceutically acceptable salts or solvates.
  • the complex thus obtained is suspended in a mixture ethanol/water containing oxalic acid, then the pH of the suspension is adjusted to a value of about 0.7.
  • Dicalite (Dicalite Europa Sud S.p.A., Corsico, Milan, Italy) is then added, the pH is brought to 1.8 and, after a 10-minute stirring, the mixture is filtered in order to obtain a clear solution.
  • 15% sodium hydroxide to a pH of about 8
  • the precipitate is recovered by filtration, washed with water and dried under vacuum to give 13 g of pyrazolominocycline base corresponding to the formula IV

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

Nouvelles pyrazolotétracyclines de formule générale (I) dans laquelle R est hydrogène, un groupe alkyle C1-C6, alcényle C2-C6 ou alcynyle C2-C6 substitué ou non substitué, un groupe aryle ou hétéroaryle substitué ou non substitué, un groupe cycloalkyle, cycloalcényle ou cycloalcadiényle substitué ou non substitué, et R' est un groupe amino, diméthylamino, alkylamino C1-C3 ou formylamino. Lesdites pyrazolotétracyclines sont des antibiotiques utiles pour traiter des maladies infectieuses.
PCT/EP1996/000815 1995-02-28 1996-02-27 Pyrazolotetracyclines WO1996026926A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU48313/96A AU4831396A (en) 1995-02-28 1996-02-27 Pyrazolotetracyclines
JP8526020A JPH11501022A (ja) 1995-02-28 1996-02-27 ピラゾロテトラサイクリン
EP96904083A EP0812315A1 (fr) 1995-02-28 1996-02-27 Pyrazolotetracyclines

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI950376A IT1274653B (it) 1995-02-28 1995-02-28 Pirazolotetracicline
ITMI95A000376 1995-02-28

Publications (1)

Publication Number Publication Date
WO1996026926A1 true WO1996026926A1 (fr) 1996-09-06

Family

ID=11370714

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1996/000815 WO1996026926A1 (fr) 1995-02-28 1996-02-27 Pyrazolotetracyclines

Country Status (5)

Country Link
EP (1) EP0812315A1 (fr)
JP (1) JPH11501022A (fr)
AU (1) AU4831396A (fr)
IT (1) IT1274653B (fr)
WO (1) WO1996026926A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012139191A1 (fr) * 2011-04-15 2012-10-18 Universidade Federal De Minas Gerais - Ufmg Compositions pharmaceutiques contenant de la 11,12-pyrazolminocycline et leur utilisation pour atténuer la douleur d'origine neuropathique
US8338477B2 (en) 2008-07-11 2012-12-25 Neumedics Tetracycline derivatives with reduced antibiotic activity and neuroprotective benefits

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MICHAEL J. MARTELL JR. ET AL.: "The 6-Deoxytetracyclines. VII. Alkylated Aminotetracyclines Possessing Unique Antibacterial Activity", JOURNAL OF MEDICINAL CHEMISTRY, vol. 10, no. 1, January 1967 (1967-01-01), WASHINGTON US, pages 44 - 46, XP000575826 *
UMBERTO VALCAVI ET AL.: "Pirazol-Derivati della Tetraciclina et Chlorotetraciclina", GAZZETTA CHIMICA ITALIANA, vol. 93, 1963, pages 916 - 928, XP000575706 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8338477B2 (en) 2008-07-11 2012-12-25 Neumedics Tetracycline derivatives with reduced antibiotic activity and neuroprotective benefits
US9168265B2 (en) 2008-07-11 2015-10-27 Neumedics Tetracycline derivatives with reduced antibiotic activity and neuroprotective benefits
US9573912B2 (en) 2008-07-11 2017-02-21 Neumedics Tetracycline derivatives with reduced antibiotic activity and neuroprotective benefits
US9896422B2 (en) 2008-07-11 2018-02-20 Neumedics Tetracycline derivatives with reduced antibiotic activity and neuroprotective benefits
WO2012139191A1 (fr) * 2011-04-15 2012-10-18 Universidade Federal De Minas Gerais - Ufmg Compositions pharmaceutiques contenant de la 11,12-pyrazolminocycline et leur utilisation pour atténuer la douleur d'origine neuropathique

Also Published As

Publication number Publication date
IT1274653B (it) 1997-07-18
AU4831396A (en) 1996-09-18
EP0812315A1 (fr) 1997-12-17
ITMI950376A0 (it) 1995-02-28
ITMI950376A1 (it) 1996-08-28
JPH11501022A (ja) 1999-01-26

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