WO1999000363A1 - Composes triazine substitues et leur utilisation en medecine - Google Patents

Composes triazine substitues et leur utilisation en medecine Download PDF

Info

Publication number
WO1999000363A1
WO1999000363A1 PCT/EP1998/003453 EP9803453W WO9900363A1 WO 1999000363 A1 WO1999000363 A1 WO 1999000363A1 EP 9803453 W EP9803453 W EP 9803453W WO 9900363 A1 WO9900363 A1 WO 9900363A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
carbonyl
methylpyrrole
naphthalene
triazine
Prior art date
Application number
PCT/EP1998/003453
Other languages
English (en)
Inventor
Nicola Mongelli
Angelo Crugnola
Andrea Lombardi Borgia
Marina Ciomei
Clara Albanese
Francesco Sola
Original Assignee
Pharmacia & Upjohn 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 Pharmacia & Upjohn S.P.A. filed Critical Pharmacia & Upjohn S.P.A.
Priority to AU87274/98A priority Critical patent/AU8727498A/en
Publication of WO1999000363A1 publication Critical patent/WO1999000363A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to new substituted triazinic compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
  • the present invention provides substituted triazinic compounds having the following formula (I)
  • R, R ⁇ and R 2 which may be the same or different is a group (A)
  • R 3 groups which are the same in each single (A) group, is a free or esterified acid group; and the remaining of R, R x and R 2 , if any, is a substituent selected from: a halogen atom, a hydroxy group or an amino acid, an ester thereof, a di-, tri-, tetra-, penta- or hexa-peptide or an ester thereof linked to the triazine ring through the amino group; and the pharmaceutically acceptable salts thereof.
  • a halogen atom is for instance chloro or bromo.
  • An amino acid is preferably selected from Gly, Ala, Phe,
  • a di-, tri-, tetra-, penta-, or hexa-peptide is preferably selected from Phe-Gly, Phe-Phe, Leu-Gly, Val-Ala, Phe-Ala, Leu-Phe, Leu-Ala, Phe-Leu-Gly, Phe-Phe-Leu, Leu-Leu-Gly, Phe-Tyr-Ala, Phe-Gly-Phe, Phe-Phe-Gly, Phe-Leu-Gly-Phe,
  • Gly-Phe-Leu-Gly-Phe Gly- ⁇ Ala, Phe-Gly- ⁇ Ala, Phe-Phe- ⁇ Ala, Leu-Gly- ⁇ Ala, Val-Ala- ⁇ Ala, Phe-Ala- ⁇ Ala, Leu-Phe- ⁇ Ala,
  • An ester of an amino acid or an ester of a di-, tri-, tetra-, penta-, or hexa-peptide is for instance an alkyl or aryl-alkyl ester, having a branched or straight alkyl chain.
  • Cx-Cg-alkyl and phenyl-Cx-Cg-alkyl esters typically methyl, ethyl, propyl, iso-propyl, butyl, benzyl and phenylethyl esters are more preferred.
  • the invention also includes within its scope all the possible isomers, stereoisomers and their mixtures and the metabolites and the metabolic precursors or bio-precursors of the compounds of the formula (I) .
  • R and R 2 is a group (A) , as defined above, m, p and R 3 in each of said groups may be the same or different .
  • the free, salified or esterified R 3 groups may be on either or both the phenyl moieties of the naphthalene group.
  • R 3 acidic groups are those chosen from the group including sulfonic, phosphonic and carboxylic acid groups, the sulfonic and phosphonic acid groups being the preferred.
  • Esters of the acids of formula (I) are for instance alkyl and aryl-alkyl esters, having a branched or straight alkyl chain.
  • Cx-Cg-alkyl and phenyl-C ⁇ _-Cg-alkyl esters typically methyl, ethyl, propyl, iso-propyl, butyl, benzyl and phenylethyl esters are more preferred.
  • Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminum hydroxides, or with organic bases, such as lysine, arginine, N-methylglucamine, triethyl- amine, triethanolamine, dibenzylamine, methylbenzylamine, di- (2-ethylhexyl) amine, piperidine, N-ethylpiperidine,
  • the substituted naphthyl groups are typically 1- or 2- aminonaphthyl groups .
  • the acid substituents are preferably in the 4,6,8-, 3,6,8-,
  • the acid substituents are preferably in the 1,5-, 3,6-, 3,8-, 4,6-, 4,7-, 4,8-, 5,7- or 6,8- positions .
  • the acid substituent is preferably in the 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8- position, of course is not linked to the amino position.
  • the amino and carbonyl groups may be independently linked to any of the 2 to 5 carbon positions of the pyrrole ring; of course, such groups are not both linked to the same carbon position.
  • the disubstituted pyrroles are typically N-methyl-2, 4-disubstituted pyrroles, preferably 1- methylpyrrole-4-amino-2-carbonyl and l-methylpyrrole-2- amino-4-carbonyl derivatives.
  • the invention includes within its scope also the esters and the pharmaceutically acceptable salts of the acids of formula (I) .
  • Only one or both of the two acidic functions of each phosphono (HO) 2PO-group are salified and/or esterified.
  • the salts of the invention preferably only one of the two acidic functions of each phosphono group is in a salified form, whereas in the esters of the invention both the two acidic functions of each phosphono group are preferably in an esterified form.
  • the present invention also includes within its scope pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I) .
  • pharmaceutically acceptable bio-precursors otherwise known as pro-drugs
  • Preferred compounds of the invention are the compounds of formula (I) in which two or three of R, R 1; and R 2 which may be the same or different is a group (A) wherein p is 2 or 3, m is 1 to 3, and each of the R 3 group, which are the same, is a free or esterified phosphonic or sulfonic acid group; and the remaining of R-R 2 , if any, is a substituent selected from halogen and ethyl glycinate; and the pharmaceutically acceptable salts thereof.
  • Examples of preferred compounds of the invention are: 2,4, 6-tris [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] -1,3, 5-triazine; 2,4, 6-tris [2- ( ⁇ 2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] -1,3, 5-triazine; 2,4, 6-tris [2- ( ⁇ 2- [ (naphthalene-1, 5-disulfonic acid-2- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] -1, 3 , 5-triazine;
  • the compounds of formula (I) and the pharmaceutically acceptable salts thereof are hereafter also referred to as “the compounds of the invention” or as “the active agents of the invention” .
  • the compounds of the invention, and the salts thereof can be prepared by a process comprising reacting a compound of formula (II)
  • R 4 , R 5 and R 6 is chloro and the remaining of R 4 -R 6 , if any, is as R-R 2 defined above; and, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, salifying a compound of formula (I) thus obtained, and/or, if desired obtaining a free acid of formula (I) from an ester or a salt thereof, and/or, if desired, esterifying an acid of formula (I) .
  • a salt of a compound of formula (II) may be a salt with organic or inorganic bases, for example those mentioned above as to the pharmaceutically acceptable salts of the invention, the sodium and potassium salts being the preferred.
  • reaction of a compound of formula (II) , or a salt thereof, with a compound of formula (III) is an analogy process and can be carried out according to well known methods.
  • the reaction may be carried out at a molar ratio of compound (II) or a salt thereof: compound
  • the reaction is preferably performed in an organic solvent, such as dichloromethane, dichloroethane, chloroform, toluene, or dimethylsulphoxyde, dimethylformamide, dimethylacetamide, hexamethylphosphoramide, or their aqueous mixtures, or in water/acetone, water/dioxane, water/toluene or water/dichloromethane mixtures, in the presence of either an organic base such as triethylamine, diisopropylet ylamine or pyridine or an inorganic base such as sodium bicarbonate or sodium acetate or a convenient buffer as known in the art .
  • an organic solvent such as dichloromethane, dichloroethane, chloroform, toluene, or dimethylsulphoxyde, dimethylformamide, dimethylacetamide, hexamethylphosphoramide, or their aqueous mixtures, or in water/acetone, water/dioxane, water/to
  • the reaction temperature may vary from about -10°C to about 150°C and the reaction time from about l to about 24 hours .
  • the compounds of formula (I) prepared according to the above described procedures may be purified by conventional methods such as by silica gel, alumina or reversed phase column chromatography, and/or by recrystallization from organic solvents such as lower aliphatic alcohols or dimethylformamide or their mixtures or in water containing mixtures .
  • esterification or salification of an acid of formula (I) can be carried out by known methods in the art.
  • the compounds of formula (II) are known products and can be obtained according to PCT/EP91/00014 or to PCT/EP95/00444.
  • Compounds of formula (III) are known products or may be easily obtained according to known methods from known products.
  • a compound of formula (III) can be obtained starting from 2, 4, 6-trichloro-l, 3 , 5-triazine according to known methods in organic chemistry.
  • the new compounds of the present invention are angiogenesis inhibitors, as shown, e.g., by the fact that they have been found to be active in the chorioallantoic membrane test, according to the Folkman's method [Nature, 297, 307 (1982)]. Therefore the compounds of the present invention are useful in treating several pathological conditions in mammals, including humans, where the growth of new blood vessels is detrimental, for example, in chronic inflammation, diabetic retinopathy, psoriasis, rheumatoid arthritis and tumor growth.
  • the compounds of the invention can be administered alone or in association with antitumor agents such as doxorubicin, etoposide, fluorouracil, melphalan, cyclophosphamide, bleomycin, vinblastin or mitomycin.
  • antitumor agents such as doxorubicin, etoposide, fluorouracil, melphalan, cyclophosphamide, bleomycin, vinblastin or mitomycin.
  • the compounds of the present invention have also been found to be endowed with TNF -neutralising activity and therefore they can be employed in humans for prophylactic and/or therapeutic use in any disease state in which TNF ⁇ is known to play a detrimental role.
  • disease states are cachexia, septic shock, graft-versus-host disease, AIDS, cerebral malaria, rheumatoid arthritis.
  • the TNF ⁇ -inhibiting activity of the compounds according to the present invention is proven, for instance, by the fact that they are active in inhibiting the cytotoxicity activity of human TNF ⁇ on untreated mouse LM cells. Accordingly, the compounds of the invention can be used as angiogenesis inhibitors and/or as TNF ⁇ -neutralising activity agents .
  • the compounds of the invention can thus be used in the preparation of a medicament for use in the treatment of angiogenesis and/or for prophylactic and/or therapeutic use in a disease state in which TNF ⁇ plays a detrimental role.
  • the compounds of the invention can be administered by the usual routes, for example, parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally.
  • the dosage depends on the age, weight and conditions of the patient and on the administration route.
  • a suitable dosage for administration to adult humans may range from about 0.5 to about 250 mg pro dose 1-4 times a day.
  • the compounds of the present invention have been found to act directly as anti-lentivirus agents, in particular against Human Immunodeficiency Virus (HIV) .
  • the representative compounds of the invention 2,4, 6-tris [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] -1, 3, 5-triazine hexasodium salt; 4, 6-bis [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1, 3 , 5- triazine tetrasodium salt;
  • the compounds of the invention can be used to treat an infection attributable to a lentivirus, in particular a human immunodeficiency virus, especially HIV-1 or HIV-2.
  • the compounds of the invention can also be used in the preparation of a medicament for use in the treatment of a human patient suffering from lentivirus infection.
  • the said medicament may be for use as an anti-lentivirus agent, for example an anti-HIV-1 or -HIV-2 agent.
  • the said medicament may also be for use in ameliorating the symptoms of lentivirus-induced disease in a human patient suffering from lentivirus infection.
  • the compounds of the invention can be used in the preparation of an agent to be used in the treatment of a human patient who is seropositive diseased or pathological as a result of infection with a lentivirus, in particular HIV, or who is suffering from induced disease, e.g., lymphoadenopathy syndrome (LS) , AIDS-related complex (ARC), AIDS or Kaposi's sarcoma.
  • LS lymphoadenopathy syndrome
  • ARC AIDS-related complex
  • AIDS Kaposi's sarcoma
  • the compounds of the invention can be administered by usual routes, for example, parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topically or orally, intravenous injection or infusion being preferred.
  • the dosage depends on the age, weight and condition of the patient and on the administration route.
  • a suitable dosage for the compounds of the invention for example 2, 4, 6-tris [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid- 7-amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] -1, 3, 5-triazine or a pharmaceutically acceptable salt thereof, for administration to adult humans is from about 0.4 to about 250 mg per dose 1-4 times a day.
  • the compounds of the invention may be used in a method of treatment of the above mentioned pathological conditions comprising both separate and substantially contemporaneous administration of a composition containing a compound of formula (I) , or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing different pharmaceutically active agents.
  • the present invention therefore further provides products comprising a compound of formula (I) , or a pharmaceutically acceptable salt thereof, and a second active agent as a combined preparation for separate, simultaneous or sequential use in treating a human patient suffering from lentivirus infection, in particular infection with HIV.
  • the second active agent is typically a drug that affects the pathogenesis of HIV-induced diseases.
  • the compounds of the invention may be employed with various active agents, in particular those that affect reverse transcriptase, antimicrobial and antitumor agents or a mixture of two or more thereof .
  • Drugs of interest include non-nucleoside reverse transcriptase inhibitors, e.g. nevirapine,- nucleoside derivatives, e.g.
  • immunomodulating agents in particular immunostimulants, gamma globulin, immune globulin and monoclonal antibody products, antibiotics and antimicrobial products .
  • the antimicrobial agents may include a penicillin in conjunction with an aminoglycoside (e.g. gentamycin, tobramycin) .
  • an aminoglycoside e.g. gentamycin, tobramycin
  • additional agents e.g. cephalosporin, can be utilised.
  • the administration dosage of these drugs will vary, depending upon the disease status of the individual .
  • the dosage regimen must therefore be tailored to the particular of the patient's conditions, response and associate treatments in a manner which is conventional for any therapy, and may need to be adjusted in response to changes in conditions and/or in light of other clinical conditions.
  • the pharmaceutical composition used in the invention may comprise a compound of formula (I) or pharmaceutically acceptable salt thereof, as the active substance, in association with one or more pharmaceutically acceptable excipients and/or carriers.
  • the pharmaceutical compositions are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or, preferably, they may be in the form of sterile aqueous isotonic saline solutions.
  • Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride .
  • the active ingredient may be mixed with conventional oleaginous or emulsifying excipients.
  • the solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch and potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols ; binding agents, e.g. starches, arabic gum, gelatine, methylcellulose, carboxymethylcellulose, polyvinyl- pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, dextrose, saccharose, cellulose, corn starch and potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arabic gum, gelatine, methylcellulose, carboxymethylcellulose, polyvinyl-
  • a starch alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylsulphates ; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in a known manner, for example by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The following examples illustrate but do not limit the invention.
  • reaction mixture was diluted with H 2 0 to 50 ml, the acetone evaporated under reduced pressure and the precipitated gel was filtered, washed with H 2 0 and acetone and dried to give a brown solid. Further purification by reversed-phase liquid chromatography eluting with a gradient from H 2 0 to H 2 0:CH 3 CN 80:20 afforded the title compound as a yellow solid (191 mg) .
  • Intramuscular injection 30 mg/ml An injectable pharmaceutical preparation can be manufactured by dissolving 30 g of 4, 6-Bis [2- ( ⁇ 2-

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés triaziniques de la formule (I) dans laquelle au moins un des restes R, R1 et R2 qui peuvent être identiques ou différents, désigne un groupe (A) dans lequel m désigne un nombre entier compris entre 1 et 6; p est un nombre entier compris entre 1 et 3; chacun des groupes R3 qui sont identiques dans chaque groupe (A) simple, désigne un groupe acide libre ou estérifié; les groupes de R, R1 et R2 éventuellement restants désignant un substituant sélectionné parmi: un atome d'halogène, un groupe hydroxy ou un aminoacide, un de ses esters, un di-, tri-, tétra-, penta- ou hexapeptide ou un de ses esters lié au composé cyclique triazine par un groupe amino. L'invention concerne également les sels pharmaceutiquement acceptables de ces composés. Lesdits composés s'utilisent comme inhibiteurs d'angiogenèse, comme agents à activité neutralisatrice du TNFα et comme agents anti-lentivirus.
PCT/EP1998/003453 1997-06-27 1998-05-30 Composes triazine substitues et leur utilisation en medecine WO1999000363A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU87274/98A AU8727498A (en) 1997-06-27 1998-05-30 Substituted triazine compounds and their use in medicine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9713732.7A GB9713732D0 (en) 1997-06-27 1997-06-27 Substituted triazinic compounds
GB9713732.7 1997-06-27

Publications (1)

Publication Number Publication Date
WO1999000363A1 true WO1999000363A1 (fr) 1999-01-07

Family

ID=10815105

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1998/003453 WO1999000363A1 (fr) 1997-06-27 1998-05-30 Composes triazine substitues et leur utilisation en medecine

Country Status (3)

Country Link
AU (1) AU8727498A (fr)
GB (1) GB9713732D0 (fr)
WO (1) WO1999000363A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999034796A1 (fr) * 1997-12-31 1999-07-15 Pharmacia & Upjohn S.P.A. Composition antitumorale synergique contenant un derive d'acide naphthalensulphonique
WO2001087849A2 (fr) * 2000-05-12 2001-11-22 Genzyme Corporation Modulateurs de marquage du tnf-alpha
US6335339B1 (en) 1998-01-13 2002-01-01 Scriptgen Pharmaceuticals, Inc. Triazine antiviral compounds
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991010649A1 (fr) * 1990-01-11 1991-07-25 Farmitalia Carlo Erba S.R.L. Nouveaux derives ureido de composes de poly-4-amino-2-carboxy-1-methyle
WO1995023806A2 (fr) * 1994-03-01 1995-09-08 Pharmacia S.P.A. Derives ureido des acides naphtalene-phosphoniques et leur procede de preparation
WO1996026950A1 (fr) * 1995-03-01 1996-09-06 Pharmacia S.P.A. Amelioration de la biodisponibilite de composes biologiquement actifs par liaison a des derives de polypyrrolecarboxamidonaphtalene

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991010649A1 (fr) * 1990-01-11 1991-07-25 Farmitalia Carlo Erba S.R.L. Nouveaux derives ureido de composes de poly-4-amino-2-carboxy-1-methyle
WO1995023806A2 (fr) * 1994-03-01 1995-09-08 Pharmacia S.P.A. Derives ureido des acides naphtalene-phosphoniques et leur procede de preparation
WO1996026950A1 (fr) * 1995-03-01 1996-09-06 Pharmacia S.P.A. Amelioration de la biodisponibilite de composes biologiquement actifs par liaison a des derives de polypyrrolecarboxamidonaphtalene

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CLANTON D J ET AL: "NOVEL SULFONATED AND PHOSPHONATED ANALOGS OF DISTAMYCIN WHICH INHIBIT THE REPLICATION OF HIV", ANTIVIRAL RESEARCH, vol. 27, no. 4, 1995, pages 335 - 354, XP000602605 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999034796A1 (fr) * 1997-12-31 1999-07-15 Pharmacia & Upjohn S.P.A. Composition antitumorale synergique contenant un derive d'acide naphthalensulphonique
US6335339B1 (en) 1998-01-13 2002-01-01 Scriptgen Pharmaceuticals, Inc. Triazine antiviral compounds
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
WO2001087849A2 (fr) * 2000-05-12 2001-11-22 Genzyme Corporation Modulateurs de marquage du tnf-alpha
WO2001087849A3 (fr) * 2000-05-12 2002-06-06 Genzyme Corp Modulateurs de marquage du tnf-alpha
US6969728B2 (en) 2000-05-12 2005-11-29 Genzyme Corporation Modulators of TNF-α signaling
US7034031B2 (en) 2000-05-12 2006-04-25 Genzyme Corporation Modulators of TNF-α signaling
US8518999B2 (en) 2000-05-12 2013-08-27 Genzyme Corporation Modulators of TNF-αsignaling
US8921547B2 (en) 2000-05-12 2014-12-30 Genzyme Corporation Modulators of TNF-α signaling
US9579325B2 (en) 2000-05-12 2017-02-28 Genzyme Corporation Modulators of TNF-α signaling
EP2087908A1 (fr) 2001-06-26 2009-08-12 Amgen, Inc. Anticorps opgl
EP3492100A1 (fr) 2001-06-26 2019-06-05 Amgen Inc. Anticorps pour opgl

Also Published As

Publication number Publication date
AU8727498A (en) 1999-01-19
GB9713732D0 (en) 1997-09-03

Similar Documents

Publication Publication Date Title
RU2078079C1 (ru) Производные пирролзамещенных уреидов, и их фармацевтически приемлемые соли, способ их получения и фармацевтическая композиция, обладающая ингибирующей ангиогенезис активностью
US5700788A (en) Ureido derivatives of naphthalenephosphonic acids
AU696470B2 (en) Increased bioavailability of biologically active compounds by linking to polypyrrolecarboxamidonaphthalene derivatives
JPH1081666A (ja) フタルイミド誘導体又はその塩、それらの製造方法及びそれらを含有する医薬組成物
WO1999000363A1 (fr) Composes triazine substitues et leur utilisation en medecine
WO1999000364A1 (fr) Composes polycarboxamido a ramifications multiples
MXPA97001949A (en) Derivatives of distamycine substituted with bis- (2-haloethyl) aminophenylene as anatomy agents yantivira
GB2310207A (en) Antiviral ureido derivatives of substituted heterocyclic compounds
CN116870187A (zh) N-氧杂环烷基取代的喜树碱衍生物的抗体偶联药物
CN116726192A (zh) N-烷氧烷基取代的喜树碱衍生物的抗体偶联药物
AU670194B2 (en) Biologically active ureido derivatives useful in the treatment of lentivirus-induced disease
JPH06184098A (ja) 治療上有効なナフタレンスルホン系ピロールカルボキサミド誘導体
GB2289274A (en) Angiogenesis inhibiting sialic acid derivatives and process for their preparation
JPH10109975A (ja) 医薬組成物
WO2023050037A1 (fr) Inhibiteur de la cyclophiline extracellulaire et son utilisation
JPS6335575A (ja) マイトマイシン誘導体
JPH06192076A (ja) 抗原虫薬

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BG BR CA CN CZ EE HU IL JP KR LT LV MX NO NZ PL RO SG SI TR UA US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
NENP Non-entry into the national phase

Ref country code: CA

NENP Non-entry into the national phase

Ref country code: JP

Ref document number: 1999505242

Format of ref document f/p: F

122 Ep: pct application non-entry in european phase