WO1996015105A1 - Derives fluorenyl-hydroxamiques possedant une activite immunodepressive et anti-inflammatoire - Google Patents

Derives fluorenyl-hydroxamiques possedant une activite immunodepressive et anti-inflammatoire Download PDF

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Publication number
WO1996015105A1
WO1996015105A1 PCT/EP1995/004388 EP9504388W WO9615105A1 WO 1996015105 A1 WO1996015105 A1 WO 1996015105A1 EP 9504388 W EP9504388 W EP 9504388W WO 9615105 A1 WO9615105 A1 WO 9615105A1
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WO
WIPO (PCT)
Prior art keywords
formula
compounds
mmoles
fluoren
fluorenyl
Prior art date
Application number
PCT/EP1995/004388
Other languages
English (en)
Inventor
Giorgio Bertolini
Mario Aquino
Francesca Chiaffarino
Gianni Gromo
Alberto Sala
Marinella Valtolina
Original Assignee
Italfarmaco 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 Italfarmaco S.P.A. filed Critical Italfarmaco S.P.A.
Priority to AU39276/95A priority Critical patent/AU3927695A/en
Publication of WO1996015105A1 publication Critical patent/WO1996015105A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring
    • C07C2603/18—Fluorenes; Hydrogenated fluorenes

Definitions

  • the present invention refers to hydroxamic derivatives of fluorenylaminoacids and their use as immunosuppressant and antinflammatory agents.
  • Patent application WO 90/15602 describes pharmaceutical compositions useful in the treatment of inflammatory diseases, containing a N-[(9H-fluoren-9-yl-methoxy)carbonyl]-aminoacid as active ingredient, while patent application WO 91/18596 discloses pharmaceutical compositions containing fluorenyl compounds derivatized with a lipophilic amino acid or an alcohol, an amide or an ester derivative thereof. Further, patent application WO 93/11764 relates to fluorenyl-derivates of antinflammatory aminobenzoic acids.
  • n is an integer from 0 to 3;
  • R 1 and R 2 are independently hydrogen, methyl, (C 2 - 4 )alkyl, halogen, hydroxy, hydroxymethyl, hydroxy(C 2 - 4 )alkyl, (C 1 - 4 )alkoxy;
  • A is methylene, linear or branched (C 2-6 )alkylidene, phenyl-methylidene, phenyl(C 2-6 )alkylidene, phenylene, naphthylene; and their diastereomers and enantiomers and the mixture thereof.
  • a (C 1-4 )alkyl group essentially identifies methyl, ethyl, propyl, i-propyl, butyl, 2-methyl-propyl, and a (C 2-6 )alkylidene is, e.g., ethylidene, propylidene, butylidene, isobutylidene, 2-methyl-butylidene, hexylidene, 2,3-dimethyl-butylidene and the like.
  • an alkoxy group identifies methoxy, ethoxy, propoxy, isopropoxy, butoxy, 2-methylbutoxy and tert-butoxy.
  • the compounds of formula I may be prepared starting from a compound of formula II
  • R 1 , R 2 , A and n are as described above, which is reacted with stoichiometric or slightly exceeding amounts of a carboxylic acid activator such as 1,1-carbonyldiimidazole, at a temperature varying from about -10oC to about 40oC, for about 2-48 hours, in the presence of etheric solvents such as tetrahydrofuran, 1,4-dioxane, diglyme, or in aprotic dipolar solvents such as dimethylformamide.
  • a carboxylic acid activator such as 1,1-carbonyldiimidazole
  • the so activated compound of formula II is added with a stoichiometric or slightly exceeding amount of hydroxylamine hydrochloride, and the mixture is left to react at a temperature between about 0 and about 30oC, for about 1-20 hours, optionally in the presence of an equivalent of a tertiary organic base such as triethylamine or pyridine.
  • a tertiary organic base such as triethylamine or pyridine.
  • R 1 and/or R 2 are groups prone to react with the reactants used to prepare the compounds of formula I, said groups are suitably protected before such reaction and deprotected at the end of the same according to the teachings of the art (cfr., for example, T.W. Greene and P.G.M. Wuts - "Protective groups in organic synthesis", 2o ed., J. Wiley & Son , 1991 ) .
  • a strong base such as sodium hydride, sodium ethoxide or sodium amide
  • 9-fluorenone is employed as reactant, and is reduced, for example, with a alkali metal hydride such as sodium borohydride or lithium-aluminium hydride, to provide an alcohol derivative of formula IV
  • R 1 and R 2 are as defined above.
  • R 1 and R 2 are as above and m is 1 or 2.
  • Said acids are known as commercially available or described by the literature (cfr. Gualtieri F., J. Med. Chem., 28, No.11, 1621-1628, 1985).
  • the acid of formula V is reduced with a suitable reducing agent such as lithium-aluminium hydride, to yield the alcohol derivative of formula III wherein R 1 and R 2 are as above, and n is 2 or 3.
  • the insertion of the substituents R 1 and R 2 may be carried out using known procedures, for example, by direct alkylation or halogenation.
  • R 1 R 2 and n are as defined above, and X is a leaving group which may be easily displaced by the nucleophilic nitrogen atom of an amino acid, for example an halogen atom, particularly chlorine or bromine, a lower alkoxy, mercapto, alkyl-mercapto group or succinylimidoyloxy.
  • an amino-carboxy acid of formula VII is reacted with an amino-carboxy acid of formula VII
  • the reaction is advantageously carried out in a polar organic solvent such as dioxane, tetrahydrofuran, dimethylformamide or pyridine, under alkaline, preferably mild, conditions, and at low temperature, for example from about 0oC to about 25oC, for a period of about 2-3 hours.
  • a higher reaction temperature for example of about 25-50oC, and longer reaction times, for example from about 8 to about 48 hours could be necessary.
  • the compounds of formula II precipitate from the reaction mixture and may be purified, for example, by crystallization.
  • the 1 H-NMR spectra were made in dimethylsulphoxyde (DMSO) with a VARIAN GEMINI 200 spectrometer.
  • the 13 C-NMR spectra were made using a VARIAN GEMINI 200 spectrometer (reference: 39.5 ppm peak of DMSO).
  • Example 2 Substantially following the steps of Example 1, starting from 2 g (6.7 mmoles) of N-[(fluoren-9-yl)-methoxy-carbonyl]-glycine (Nova Biochem 04-12-1001, NPC 14692) dissolved in 27 ml dry THF, 1.32 g (8.1 mmoles) of CDI and 698 mg (10 mmoles) of hydroxylamine hydrochloride, 800 mg of the title product were obtained.
  • the immunosuppressive activity of the present compounds was evaluated by the test of the mixed lymphocitary response, as follows.
  • Spleens were taken from Balb/C and DBA/2 mice.
  • the splenocytes was suspended in a culture medium (RPMI).
  • Balb/C was placed in 96-well plates with 0.1 ml of splenocytes DBA/2 in a ratio of 1:1 stimulator/receptor. At time 0, some compounds of the invention and of the prior art were added at a concentration of from 3.12 to 100 ⁇ M, and the plates were placed in an incubator at 37oC under 5% of carbon dioxide. After 3 days the cells were labelled with tritiated thymidine (1 ⁇ Ci/well) for 18 hours, then the radioactivity was evaluated by a "cell-harvester" and a ⁇ -counter.
  • the antinflammatory activity of the compounds of the invention was evaluated by the test of the polymorphonuclear leukocyte adhesion to endothelial cells, as described hereinbelow.
  • the polymorphonuclears were obtained. by separation from the blood of a healthy donor through sedimentation with Eufusm (Stholl Farmaceutici) followed by lysis of the erythrocytes with a solution of ammonium chloride.
  • the inhibition percentage of the cellular adhesion was calculated according to the following formula. wherein the control is the culture Treated with TNF and medium containing 10% calf foetal serum and 0.1% DMSO only.
  • the compounds of the invention showed an inhibition of the cellular adhesion of about 70-90%, whereas the ones of the prior are of about 40-60%.
  • the compound of Example 3 provided an inhibition percentage of 77.4%, and the corresponding compound of the prior art, NPC 15669, of 58.2%.
  • the toxicity of the compounds of the present invention was evaluated by an acute toxicity model in mouse after mtraperitoneal administration.
  • the compounds of the invention showed to be useful in pathologies such as graft versus host disease, atopic and contact dermatitis, osteoarthritis, psoriasis, rheumatoid arthritis, glomerulonephritis, irritable bowel syndrome, lupus erythematosus, scleroderma, asthma, and, in general, all of those pathologies stimulating the lymphocitary response, or which are characterized by an inflammatory phenomenon.
  • pathologies such as graft versus host disease, atopic and contact dermatitis, osteoarthritis, psoriasis, rheumatoid arthritis, glomerulonephritis, irritable bowel syndrome, lupus erythematosus, scleroderma, asthma, and, in general, all of those pathologies stimulating the lymphocitary response, or which are characterized by an inflammatory phenomenon.
  • Object of the invention is also the use of the compounds of formula (I) as immunosuppressant and antinflammatory agents, and the industrial aspects connected to said use, comprising their incorporation into pharmaceutical compositions.
  • pharmaceutical compositions are tablets, sugar- and film-coated tablets, sy rups, creams, ointments, suppositories, and phials, the latter being suitable both for the oral and the intramuscular or intravenous administration. They contain the active principle alone or in combination with common pharmaceutically acceptable carriers and excipients.
  • the dosages of active principle used to relieve and heal the inflammation may vary within wide limits according to the nature of the compound employed, of the pathology and of the condition of the patient (sex, age, general physical condition).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne des dérivés hydroxamiques de fluorénylaminoacides, ainsi que l'utilisation de ceux-ci en tant qu'agents immunodépresseurs et anti-inflammatoires.
PCT/EP1995/004388 1994-11-15 1995-11-08 Derives fluorenyl-hydroxamiques possedant une activite immunodepressive et anti-inflammatoire WO1996015105A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU39276/95A AU3927695A (en) 1994-11-15 1995-11-08 Fluorenyl-hydroxamic derivatives endowed with immunosuppressive and anti-inflammatory activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ITMI942304A IT1270694B (it) 1994-11-15 1994-11-15 Derivati fluorenil-idrossammici ad attivita' immunosoppressiva ed antiinfiammatoria
ITMI94A002304 1994-11-15

Publications (1)

Publication Number Publication Date
WO1996015105A1 true WO1996015105A1 (fr) 1996-05-23

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/004388 WO1996015105A1 (fr) 1994-11-15 1995-11-08 Derives fluorenyl-hydroxamiques possedant une activite immunodepressive et anti-inflammatoire

Country Status (5)

Country Link
AU (1) AU3927695A (fr)
IL (1) IL115996A0 (fr)
IT (1) IT1270694B (fr)
WO (1) WO1996015105A1 (fr)
ZA (1) ZA959666B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004063146A1 (fr) * 2003-01-10 2004-07-29 Italfarmaco Spa Derives d'acide hydroxamique presentant une action anti-inflammatoire
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0129075A2 (fr) * 1983-05-20 1984-12-27 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés d'amino-acides protégés et leur préparation
WO1991018596A1 (fr) * 1990-05-29 1991-12-12 Moshe Weitzberg Compositions pharmaceutiques et procedes de traitement d'inflammations
WO1992002532A1 (fr) * 1990-08-09 1992-02-20 Genta Incorporated Reactifs de liaison ameliores a base de non nucleotide pour oligomeres

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0129075A2 (fr) * 1983-05-20 1984-12-27 F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft Dérivés d'amino-acides protégés et leur préparation
WO1991018596A1 (fr) * 1990-05-29 1991-12-12 Moshe Weitzberg Compositions pharmaceutiques et procedes de traitement d'inflammations
WO1992002532A1 (fr) * 1990-08-09 1992-02-20 Genta Incorporated Reactifs de liaison ameliores a base de non nucleotide pour oligomeres

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004063146A1 (fr) * 2003-01-10 2004-07-29 Italfarmaco Spa Derives d'acide hydroxamique presentant une action anti-inflammatoire
US7235689B2 (en) 2003-01-10 2007-06-26 Italfarmaco Spa Hydroxamic acid derivatives having anti-inflammatory action
EP2583678A2 (fr) 2004-06-24 2013-04-24 Novartis Vaccines and Diagnostics, Inc. Immunopotentiateurs de petites molécules et dosages pour leur détection

Also Published As

Publication number Publication date
ITMI942304A0 (it) 1994-11-15
ZA959666B (en) 1996-05-29
IL115996A0 (en) 1996-01-31
IT1270694B (it) 1997-05-07
ITMI942304A1 (it) 1996-05-15
AU3927695A (en) 1996-06-06

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