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WO1999000364A1 - Composes polycarboxamido a ramifications multiples - Google Patents

Composes polycarboxamido a ramifications multiples Download PDF

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Publication number
WO1999000364A1
WO1999000364A1 PCT/EP1998/003470 EP9803470W WO9900364A1 WO 1999000364 A1 WO1999000364 A1 WO 1999000364A1 EP 9803470 W EP9803470 W EP 9803470W WO 9900364 A1 WO9900364 A1 WO 9900364A1
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WO
WIPO (PCT)
Prior art keywords
amino
carbonyl
methylpyrrole
naphthalene
tris
Prior art date
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PCT/EP1998/003470
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English (en)
Inventor
Nicola Mongelli
Angelo Crugnola
Andrea Lombardi Borgia
Marina Ciomei
Clara Albanese
Francesco Sola
Original Assignee
Pharmacia & Upjohn S.P.A.
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Publication date
Application filed by Pharmacia & Upjohn S.P.A. filed Critical Pharmacia & Upjohn S.P.A.
Priority to AU81103/98A priority Critical patent/AU8110398A/en
Publication of WO1999000364A1 publication Critical patent/WO1999000364A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/572—Five-membered rings

Definitions

  • the present invention relates to new poly-branched polycarboxamido compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use in medicine.
  • the compounds of the invention may be regarded as derivatives of Distamycin A which is a known compound having the following formula
  • the present invention provides polycarboxamido compounds having the following formula (I)
  • 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) .
  • di,tri or tetra-carboxylic acids are: 1, 2 , 3-propanetricarboxylic acid (tricarballilic acid), N,N-Bis (carboxymethyl)glycine (nitrilotriacetic acid),
  • carboxylic esters of acid (A) are for instance alkyl and aryl-alkyl esters, having a branched or straight alkyl chain.
  • the free, salified or esterified R groups may be on either or both the phenyl moieties of the naphthalene group.
  • R acidic groups for instance are those chosen from the group including sulfonic, phosphonic and carboxylic acid groups, the sulfonic and phosphonic acid groups being the preferred.
  • Esters of said acidic groups are for instance alkyl and aryl-alkyl esters, having a branched or straight alkyl chain.
  • C -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, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di- (2-ethylhexyl) amine, piperidine, N-ethylpiperidine, N,N- diethylaminoethylamine, N-ethylmorpholine,
  • the (B) groups may be the same or different. They may differ each other for the different acidic R groups and/or the different values of m and/or p, however they are preferably the same .
  • the substituted naphthyl groups are typically 1- or 2- aminonaphthyl groups.
  • the acid substituents are preferably in the 4,6,8-, 3,6,8-, 3,7,8- positions.
  • 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.
  • each phosphono (HO) 2PO-group 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) .
  • Preferred compounds of the invention are the compounds of formula (I) in which [A] is as defined above; m is 1 to 3; p is 2 or 3; n is 3 or 4 ; and each of the R groups, which are the same, is a free or esterified phosphonic or sulfonic acidic group; and the pharmaceutically acceptable salts thereof.
  • Examples of preferred compounds of the invention are: 1,2, 3-tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -1-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonyl ⁇ propane ; ,2, 3-tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonyl ⁇ propane; ,2, 3-tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 5-disulfonic acid-2- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonyl ⁇ propane ; ,2, 3-tris ⁇ [2- ( ⁇
  • methyl, ethyl and benzyl esters and the sodium and potassium salts of the said examples of specific compounds of the invention are particularly preferred.
  • 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)
  • each of the X groups which may be the same or different, is a leaving group; and [A] and n are as 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.
  • X may denote any suitable leaving group. It may denote ⁇ a good leaving group, preferably a halogen atom, in particular chlorine, or another easily displaceable group such as imidazolyl, triazolyl, p-nitrophenoxy or trichlorophenoxy .
  • 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; for example according to the conditions described in organic chemistry for this kind of reaction, i.e. for synthesis of peptides .
  • the reaction may be carried out at a molar ratio of compound (II), or a salt thereof : compound (III) from about 1 : 0.2 to about 1 : 4.
  • 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.
  • the compounds of formula (III) are known compounds or may be obtained from known di-, tri-, or tetra-carboxylic acids according to well known methods in organic chemistry.
  • the compounds of formula (I) , and the pharmaceutically acceptable salts thereof, according to 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.
  • 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 a on untreated mouse LM cells.
  • the new 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) .
  • HIV Human Immunodeficiency Virus
  • the representative compounds of the invention 1, 2, 3-tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonyl ⁇ propane hexasodium salt, 1,1', l"-tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonyl ⁇ trimethylamine hexasodium salt, have been found to be active in the biological test described in J.
  • a human patient suffering from lentivirus infection can thus be treated by a method comprising administering thereto an effective amount of one of the compounds of the invention.
  • 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, stressed 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.
  • a human patient who is seropositive diseased, stressed 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 1,1', 1" -tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid-7-amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonyl ⁇ trimethylamine hexasodium salt 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. zidovudine and didanosine; acyclovir; ribavirin; ascorbic acid; protease inhibitors; cytokine, e.g. IL-1, IL-2, IL-3 or IL-4; growth factors; interferons, e.g. alpha- or gamma-interferon; antitumor agents, e.g.
  • doxorubicin daunomycin, epirubicin, idarubicin, etoposide
  • fluorouracil melphalan
  • cyclophosphamide bleomycin, vinblastin and mitomycin
  • 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, polyvinylpyrrolidone; disaggregating agents, e.g.
  • 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.
  • the precipitated microcrystalline solid was filtered, washed with DMF and diethyl ether and vacuum dried to give the title compound (1.68 g) .
  • the acid eluate is neutralised to pH 7.0 with NaHC0 3 and purified by reversed-phase liquid chromatography eluting with a gradient from H 2 0 to H 2 0:CH 3 CN 90:10.
  • the product containing eluate is evaporated under reduced pressure and vacuum-dried to give the title compound as a yellow solid (134 mg) .
  • Example 4 With the imidazolyl derivative of 2- (carboxymethyl) -1, 3- propanedicarboxylic acid prepared as described in Example l, by proceeding analogously to the procedure of Example 2, with the appropriate starting materials, the following compounds can be obtained: tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonylmethyl ⁇ methane hexasodium salt; tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonylmethyl ⁇ methane hexasodium salt; tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 5-disulfonic acid-2- amino)
  • the solid thus obtained was dissolved in water and passed through a sulfonic acid ion-exchange resin in H + form.
  • the acid eluate was neutralised to pH 7.0 with NaOH IN and purified by reversed-phase liquid chromatography eluting with a gradient from H 2 0 to H 2 0:CH 3 CN 88:12 to give, after evaporation of the product containing fractions, 195 mg of the title compound as an orange solid.
  • 1,1', 1" -tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -1-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonyl ⁇ trimethylamine hexasodium salt; 1, 1' , l"-tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 5-disulfonic acid-2- a ino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4 -amino] carbonyl ⁇ trimethylamine hexasodium salt; 1,1', l"-tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 3, 5-trisulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino
  • 1, 1' , l"-tris ( ⁇ 2- [ (naphthalene-1, 3, 5-trisulfonic acid-7- amino) carbonyl] -1-methylpyrrole-4- amino ⁇ carbonyl) trimethylamine nonasodium salt; 1, 1' , l"-tris [ (2- ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid- 7-amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonyl ⁇ -l-methylpyrrole-4- amino) carbonyl] trimethylamine hexasodium salt; 1, 1' , l"-tris [ (2- ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 7-disulfonic acid- 4-amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino
  • N,N,N' ,N' -tetra ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonylmethyl ⁇ ethane-1, 2-diamine octasodium salt; N,N,N' ,N' -tetra ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -1-methylpyrrole-4-amino ⁇ carbonyl) -1- methylpyrrole-4-amino] carbonylmethyl ⁇ ethane-1, 2-diamine octasodium salt; N,N,N' ,N' -tetra ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 5-disulfonic acid-2- amino) carbonyl] -l-methylpyr
  • Example 8 Intramuscular injection 30 mg/ml .
  • An injectable pharmaceutical preparation can be manufactured by dissolving 30 g of 1, 2, 3-tris ⁇ [2- ( ⁇ 2- [ (naphthalene-1, 3-disulfonic acid-7-amino) carbonyl] -1- methylpyrrole-4-amino ⁇ carbonyl) -1-methylpyrrole-4- amino] carbonyl ⁇ propane hexasodium salt in water for injection (1000 ml) and sealing ampoules of 1-10 ml.

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Abstract

L'invention concerne de nouveaux composés polycarboxamido de la formule (I) dans laquelle n est un nombre entier compris entre 1 et 4; m est un nombre entier compris entre 1 et 6; p est un nombre entier compris entre 1 et 3; chaque des groupes R qui sont identiques dans chaque groupe (B) simple, désigne un groupe acide libre ou estérifié; [A] désigne un acide di-, tri-, ou tétracarboxylique dans lequel au moins un groupe carboxylique est lié à un groupe (B) par le biais d'une liaison amide, le(s) groupe(s) restant(s) étant des groupes carboxyliques libres ou estérifiés. L'invention concerne également les sels pharmaceutiquement acceptables de ces composés. Lesdits composés et leurs sels sont des inhibiteurs d'angiogenèse et des agents anti-lentivirus, et ont une activité neutralisatrice du TNFα.
PCT/EP1998/003470 1997-06-27 1998-05-30 Composes polycarboxamido a ramifications multiples WO1999000364A1 (fr)

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GB9713733.5 1997-06-27

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US6777425B2 (en) 2001-06-13 2004-08-17 Genesoft Pharmaceuticals, Inc. Isoquinoline compounds having antiinfective activity
WO2005009457A1 (fr) * 2003-05-15 2005-02-03 Sangstat Medical Corporation Compositions de rdp58 et procedes d'inhibition de la vascularisation de populations de cellules
US7129214B2 (en) 2002-12-10 2006-10-31 Oscient Pharmaceuticals Corporation Antibacterial compounds having a (pyrrole carboxamide)-(benzamide)-(imidazole carboxamide) motif
US7265129B2 (en) 2002-10-25 2007-09-04 Genesoft Pharmaceuticals, Inc. Anti-infective biaryl compounds
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL
EP1992636A2 (fr) 1999-11-12 2008-11-19 Amgen Inc. Procédé pour la correction d'un mauvais repliement de bisulfure dans les molécules Fc
US7498349B2 (en) 2002-08-02 2009-03-03 Genesoft Pharmaceuticals, Inc. Biaryl compounds having anti-infective activity

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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
GB2261661A (en) * 1991-11-21 1993-05-26 Erba Carlo Spa Derivatives of poly-4-amino-2-carboxy-1-methyl pyrroles
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