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WO1999000363A1 - Substituted triazine compounds and their use in medicine - Google Patents

Substituted triazine compounds and their use in medicine Download PDF

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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
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WIPO (PCT)
Prior art keywords
amino
carbonyl
methylpyrrole
naphthalene
triazine
Prior art date
Application number
PCT/EP1998/003453
Other languages
French (fr)
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 AU87274/98A priority Critical patent/AU8727498A/en
Publication of WO1999000363A1 publication Critical patent/WO1999000363A1/en

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    • 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-

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Abstract

New triazinic compounds of formula (I) wherein at least one of R, R1 and R2 which may be the same or different is a group (A) in which m is an integer of 1 to 6; p is an integer of 1 to 3; each of the R3 groups, which are the same in each single (A) group, is a free or esterified acid group; and the remaining of R, R1 and R2, 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, for use as angiogenesis inhibitors, TNFα-neutralizing activity agents and anti-lentivirus agents, are provided.

Description

SUBSTITUTED TRIAZINE COMPOUNDS AND THEIR USE IN MEDICINE
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)
Figure imgf000003_0001
wherein at last one of R, Rλ and R2 which may be the same or different is a group (A)
Figure imgf000003_0002
in which m is an integer of 1 to 6 ; p is an integer of 1 to 3; each of the R3 groups, which are the same in each single (A) group, is a free or esterified acid group; and the remaining of R, Rx and R2, 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,
Leu, β-Ala, γ-aminocaproic acid, Val, Tyr, Asp, Glu, Gin, Asn, His and Arg. 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-βAla, Phe-Gly-βAla, Phe-Phe-βAla, Leu-Gly-βAla, Val-Ala-βAla, Phe-Ala-βAla, Leu-Phe-βAla,
Phe-Leu-Gly-βAla, Phe-Phe-Leu-βAla, Leu-Leu-Gly-βAla,
Phe-Tyr-Ala-βAla, Phe-Gly-Phe, Phe-Phe-Gly-βAla,
Phe-Leu-Gly-Phe-βAla and Gly-Phe-Leu-Gly-Phe-βAla.
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) .
When two or three of R, R and R2 is a group (A) , as defined above, m, p and R3 in each of said groups may be the same or different .
The free, salified or esterified R3 groups may be on either or both the phenyl moieties of the naphthalene group.
Examples of R3 acidic groups, according to the present invention, 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 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-Cτ_-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,
N, -diethylaminoethylamine, N-ethylmorpholine, -phenethylamine, N-benzyl- -phenethylamine, N-benzyl-N,N- dimethylamine and the other acceptable organic amines .
Sodium and potassium salts are preferred.
The substituted naphthyl groups are typically 1- or 2- aminonaphthyl groups . When the naphthyl groups are substituted by three free, esterified or salified acid groups, as defined above, the acid substituents are preferably in the 4,6,8-, 3,6,8-,
3,7,8- positions.
When they are substituted by two free, esterified or salified acid groups, 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 .
When they are substituted by one free, esterified or salified acid group, 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.
As already said, 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. In 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.
As stated above, 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 two or three of R, R1; and R2 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 R3 group, which are the same, is a free or esterified phosphonic or sulfonic acid group; and the remaining of R-R2, 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;
2,4, 6-tris [2- ( {2- [ (naphthalene-1, 3, 5-trisulfonic 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-diphosphonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4-amino] -1,3, 5-triazine; 2,4, 6-tris [2- ({2- t (naphthalene-1, 5-diphosphonic acid-3- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -1,3, 5-triazine; 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; 4, 6-bis [2- ( {2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1, 3 , 5- triazine; 4, 6-bis [2- ({2- [ (naphthalene-1, 5-disulfonic acid-2- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1, 3, 5- triazine,- 4, 6-bis [2- ({2- [ (naphthalene-1, 3, 5-trisulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1,3,5- triazine; , 6-bis [2- ({2- [ (naphthalene-1, 7-diphosphonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1,3,5- triazine; , 6-bis [2- ({2- [ (naphthalene-1, 5-diphosphonic acid-3- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1, 3 , 5- triazine; , 6-bis [2- ( {2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine; , 6-bis [2- ({2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine; , 6-bis [2- ( {2- [ (naphthalene-1, 5-disulfonic acid-2- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine; , 6-bis [2- ( {2- [ (naphthalene-1, 3 , 5-trisulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3,5-; , 6-bis [2- ( {2- [ (naphthalene-1, 7-diphosphonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3,5-; , 6-bis [2- ( {2- [ (naphthalene-1, 5-diphosphonic acid-3- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine; , 4, 6-tris{2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} -1,3, 5-triazine; ,4, 6-tris {2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino}-l, 3, 5-triazine; 2,4, 6-tris{2- [ (naphthalene-1, 3, 5-trisulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} -1,3, 5-triazine; 2,4, 6-tris (2-{ [2- ({2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] carbonyl} -1-methylpyrrole-4-amino) -
1,3, 5-triazine; 2,4, 6-tris (2-{[2-({2-[ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] carbonyl} -l-methylpyrrole-4-amino) -
1,3, 5-triazine; 2,4, 6-tris (2-{[2-({2-[ (naphthalene-1, 3, 5-trisulfonic acid-
7-amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] carbonyl} -l-methylpyrrole-4-amino) - 1, 3 , 5-triazine; and the Ci-Cg-alkyl and phenyl-C-L-Cg-alkyl esters and the pharmaceutically acceptable salts thereof.
Particularly preferred are the methyl, ethyl and benzyl esters and the sodium and potassium salts of the said examples of specific compounds of the invention.
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)
Figure imgf000009_0001
wherein m, p and R3 are as defined above, or a salt thereof, with a compound of formula (III)
Figure imgf000010_0001
wherein at least one of R4, R5 and R6 is chloro and the remaining of R4-R6, if any, is as R-R2 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. The 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. Preferably 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 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 . 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 .
Analogously, 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.
For instance 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.
PHARMACOLOGY
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. In particular, in the cancer therapy 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.
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 TNFα is known to play a detrimental role. Typically such disease states are cachexia, septic shock, graft-versus-host disease, AIDS, cerebral malaria, rheumatoid arthritis. The TNFα-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 TNFα on untreated mouse LM cells. Accordingly, the compounds of the invention can be used as angiogenesis inhibitors and/or as TNFα-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 TNFα plays a detrimental role. In these therapeutical applications 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. For example, 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.
Moreover, the compounds of the present invention have been found to act directly as anti-lentivirus agents, in particular against Human Immunodeficiency Virus (HIV) . For instance, 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;
4, 6-bis [2- ({2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine tetrasodium salt have been found to be active in the biological test described in J. Natl . Cancer Inst . .81, 557-586 (1989). A uman 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. In this way, 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. In particular 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. The condition of a human patient can thus be ameliorated or improved . In these therapeutical applications 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. For example, 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-in erferon; 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 .
Typically, the antimicrobial agents may include a penicillin in conjunction with an aminoglycoside (e.g. gentamycin, tobramycin) . However several well 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. For instance, 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 .
In the form for topical application, e.g. creams, lotions or pastes for use in dermatological treatment, the active ingredient may be mixed with conventional oleaginous or emulsifying excipients.
The solid oral forms, e.g. tablets and capsules, 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. 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.
Example 1
4, 6-bis [2- ( {2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine tetrasodium salt [PNU 157015, compound(I), R3=S03H, m=2, p=2] . A solution of 2,4, 6-trichloro-l, 3, 5-triazine (35 mg, 0.189 mmol) in acetone (5 ml) was added to a stirred, ice-cooled suspension of 7- ( {4- [ (4-amino-1-methylpyrrole-2-carbonyl) amino] -l-methylpyrrole-2-carbonyl}amino) naphthalene-1, 3- disulfonic acid disodium salt hydrochloride (237 mg, 0.378 mmol) in water (10 ml) . A first equivalent of NaHC03 (31.7 mg, 0.378 mmol) dissolved in water (1 ml) was added dropwise at 0-5°C and a second equivalent (31.7 mg) was then added at room temperature. The whole was stirred at RT for 2 h. The solvent was removed under reduced pressure and the residue purified by reversed-phase liquid chromatography eluting with a gradient from H20 to H20:CH3CN 80:20. The product containing eluate was concentrated under reduced pressure, treated with 50 ml of acetone and stirred for 30 min. The solid was filtered, washed with acetone and vacuum-dried to give the title compound as a yellow solid
(122 mg) .
(-)FAB MS (m/z) : 1270 (M-Na) "
XH NMR (DMS0-d6, T=75°C): 56.8-7.3 (m, 4H) ; 7.82 (d, 1H) ; 7.89 (dd, 1H) , 8.02 (s, 1H) ; 8.28 (d, 1H) ; 8.98 (s, 1H) ;
9.70 (bs, 1H) ; 9.73-9.97 (two s, 2H) .
By proceeding analogously, with the appropriate starting materials, the following compounds can be obtained:
4, 6-bis [2- ( {2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4 -amino] -2-chloro-l, 3 , 5-triazine tetrasodium salt;
4, 6-bis [2- ( {2- [ (naphthalene-1, 5-disulfonic acid-2- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3, 5-triazine tetrasodium salt;
4, 6-bis [2- ({2- [ (naphthalene-1, 3, 5-trisulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4 -amino] -2-chloro-l, 3 , 5-triazine hexasodium salt;
4, 6-bis [2- ( {2- [ (naphthalene-1, 7-diphosphonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine tetrasodium salt; and 4, 6-bis [2- ({2- [ (naphthalene-1, 5-diphosphonic acid-3- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine tetrasodium salt.
Example 2
2- (N- [ethyl glycinate] ) -4, 6-dichloro-l, 3 , 5-triazine [ compound ( III ) ]
A solution of ethyl glycinate hydrochloride (5.0 g, 35.8 mmol) and KHC03 (3.58 g, 35.8 mmol) in H20 (15 ml) and acetone (10 ml) was added to an ice-cooled, stirred mixture of 2,4, 6-trichloro-l, 3, 5-triazine (6.61 g, 35.8 mmol), crushed ice (25 g) and acetone (50 ml) . Additional KHC03 (3.58 g, 35.8 mmol) was added in small portions in 1 h. The ice-bath was then removed and the whole was stirred at room temperature for 6 h. The organic layer was separated and treated with 75 ml of water. The precipitated crystalline white solid was filtered, washed with H20 and dried at 40°C under vacuum for 1 h to give the title compound (5.18 g) .
XE NMR (DMS0-d6) : δ 6.8 (bt, 1H) ; 4.2-4.3 (d + q, 4H) ; 1.3 (t, 3H) .
Example 3
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 [PNU 157914, compound(I), R3=S03H, m=2, p=2]
A solution of 2- (N- [ethyl glycinate] ) -4 , 6-dichloro-l, 3 , 5- triazine of Example 4 (95 mg, 0.379 mmol) in acetone (5 ml) was added to a stirred suspension of 7- ( {4- [ (4-amino-l- methylpyrrole-2 -carbonyl) amino] -1-methylpyrrole-2-carbonyl} amino) naphthalene-1, 3-disulfonic acid disodium salt hydrochloride (238 mg, 0.379 mmol) in H20 (10 ml). A solution of NaHC03(64 mg, 0.758 mmol) in H20 (3 ml) was added dropwise and the whole was stirred at RT for 3h.
A second equivalent of 7- ( {4- [ (4-amino-l-methylpyrrole-2- carbonyl) amino] -l-methylpyrrole-2 -carbonyl} amino) naphthalene-1, 3-disulfonic acid disodium salt hydrochloride (238 mg, 0.379 mmol) was then added, followed by addition of NaHC03(64 mg, 0.758 mmol) in H20 (3 ml) and the whole was stirred at 80-90 °C for 4 h.
The volatiles were evaporated and the residue purified by reversed-phase liquid chromatography eluting with a gradient from H20 to H20:CH3CN 85:15. The product containing eluate was concentrated under reduced pressure, treated with 100 ml of acetone and stirred for 30 min. The solid was filtered, washed with acetone and vacuum-dried at 35 °C to give the title compound as a white solid (288 mg) . (-)FAB MS (m/z) : 1337 (M-Na) " XH NMR (DMSO-d6, T=50°C): δ 1.16 (t, 3H) ; 4.14 (m, 4H) ; 3.88 (s, 12H) ; 6.8-7.5 (m, 8H) ; 7.82 (d, 2H) ; 7.89 (dd, 2H) ; 8.00 (m, 2H) ; 8.25 (d, 2H) ; 8.96 (m, 2H) ; 9.6 (bs, 2H) ; 9.81, 10.09 (two S, 4H) .
By proceeding analogously, with the appropriate starting materials, the following compounds can be obtained: 4, 6-bis [2- ({2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4 -amino} carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1, 3, 5- triazine tetrasodium salt; 4, 6-bis [2- ( {2- [ (naphthalene-1, 5-disulfonic acid-2- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1,3,5- triazine tetrasodium salt;
4, 6-bis [2- ({2- [ (naphthalene-1, 3, 5-trisulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4 -amino} carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1, 3, 5- triazine hexasodium salt; 4, 6-bis [2- ({2- [ (naphthalene-1, 7-diphosphonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1,3,5- triazine tetrasodium salt; and 4, 6-bis [2- ( {2- [ (naphthalene-1, 5-diphosphonic acid-3- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1, 3 , 5- triazine tetrasodium salt.
Example 4
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 [PNU 157666, compound (I), R3=S03H, m=2 , p=2] . A solution of 2 , 4, 6-trichloro-l, 3 , 5-triazine (70 mg, 0.378 mmol) in acetone (5 ml) was added to an ice-cooled, stirred suspension of 7- ( {4- [ (4-amino-l-methylpyrrole-2- carbonyl) amino] -l-methylpyrrole-2- carbonyl}amino) naphthalene-1, 3-disulfonic acid disodium salt hydrochloride (475 mg, 0.757 mmol) in H20 (15 ml). A solution of NaHC03 (64 mg, 0.757 mmol) in H20 (2 ml) was added dropwise, the ice-bath removed and a second equivalent of NaHC03 (64 mg, 0.757 mmol) in H20 (2 ml) was added at RT. After stirring for 2 h, 7- ( {4- [ (4-amino-l- methylpyrrole-2 -carbonyl) amino] -l-methylpyrrole-2- carbonyl}amino) naphthalene-1, 3-disulfonic acid disodium salt hydrochloride (238 mg, 0.378 mmol) was added and the reaction mixture warmed to 90°C. A third equivalent of NaHC03 (64 mg, 0.757 mmol) in 2 ml of H20 was then added and the whole stirred at 90°C for 5 h.
The reaction mixture was diluted with H20 to 50 ml, the acetone evaporated under reduced pressure and the precipitated gel was filtered, washed with H20 and acetone and dried to give a brown solid. Further purification by reversed-phase liquid chromatography eluting with a gradient from H20 to H20:CH3CN 80:20 afforded the title compound as a yellow solid (191 mg) .
XH NMR (DMS0-d6, T=75°C) : δ 3.89, 3.90 (two S, 6H) ; 6.89, 7.20, 7.28 (three d, 3H) ; 7.37 (bs, 1H) ; 7.81 (d, 1H) ; 7.88 (dd, 1H) ; 8.01 (S, 1H) ; 8.28 (d, 1H) ; 8.72 (bs, 1H) ; 8.98 (d, 1H) ; 9.64, 9.97 (two S, 2H) . By proceeding analogously, with the appropriate starting materials, the following compounds can be obtained: 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 hexasodium salt; 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 hexasodium salt; 2,4, 6-tris [2- ({2- [ (naphthalene-1, 3 , 5-trisulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -1, 3, 5-triazine nonasodium salt; 2,4, 6-tris [2- ( {2- [ (naphthalene-1, 7-diphosphonic acid-4 - amino) carbonyl] -l-methylpyrrole-4 -amino} carbonyl) -1- methylpyrrole-4-amino] -1, 3, 5-triazine hexasodium salt; 2,4, 6-tris [2- ( {2- [ (naphthalene-1, 5-diphosphonic acid-3- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4 -amino] -1, 3, 5-triazine hexasodium salt; 2,4,6-tris{2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4 -amino} -1, 3 , 5-triazine hexasodium salt; 2,4, 6-tris{2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} -1, 3 , 5-triazine hexasodium salt;
2,4, 6-tris{2- [ (naphthalene-1, 3, 5-trisulfonic acid-7- amino) carbonyl] -1-methylpyrrole-4-amino} -1, 3, 5-triazine nonasodium salt; 2,4, 6-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) -
1, 3, 5-triazine hexasodium salt;
2,4, 6-tris (2-{[2-({2-[ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4-amino] carbonyl} -l-methylpyrrole-4-amino) -
1, 3, 5-triazine hexasodium salt; and
2,4, 6-tris (2-{ [2- ({2- [ (naphthalene-1, 3 , 5-trisulfonic acid-
7-amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] carbonyl} -l-methylpyrrole-4-amino) -
1, 3, 5-triazine nonasodium salt.
Example 5
Intramuscular injection 30 mg/ml . An injectable pharmaceutical preparation can be manufactured by dissolving 30 g of 4, 6-Bis [2- ( {2-
[ (naphthalene-1, 3-disulfonic acid-7-amino) carbonyl] -1- methylpyrrole-4-amino} carbonyl) -l-methylpyrrole-4-amino] -2-
(N- [ethyl glycinate] ) -1, 3 , 5-triazine tetrasodium salt in water for injection (1000 ml) and sealing ampoules of 1-10 ml.

Claims

1. A triazinic compound of formula ( T,
Figure imgf000024_0001
wherein at least one of R, Rx and R2 which may be the same or different is a group (A)
Figure imgf000024_0002
in which m is an integer of 1 to 6; p is an integer of 1 to 3; each of the R3 groups, which are the same in each single (A) group, is a free or esterified acid group; and the remaining of R, R and R2, 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; or a pharmaceutically acceptable salt thereof.
2. A compound of formula (I), according to claim 1, wherein each R3 acid group is independently chosen from sulfonic, phosphonic and carboxylic acid groups.
3. An ester of a compound of formula (I), as defined in claim 1, wherein said ester is a
Figure imgf000024_0003
alkyl or a phenyl- Ci-Cg alkyl ester.
4. A compound of formula (I), as defined in claim 1, in which two or three of R, R , and R2 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 R3 group, which are the same, is a free or esterified phosphonic or sulfonic acid group; and the remaining of R-R2, if any, is a substituent selected from halogen and ethyl glycinate; or a pharmaceutically acceptable salts thereof.
5. A compound selected from:
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; 2,4, 6-tris [2- ( {2- [ (naphthalene-1, 3, 5-trisulfonic 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-diphosphonic 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-diphosphonic acid-3- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4-amino] -1, 3 , 5-triazine;
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; , 6-bis [2- ( {2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1, 3, 5- triazine,- , 6-bis [2- ( {2- [ (naphthalene-1, 5-disulfonic acid-2- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4-amino] - 2 - (N- [ethyl glycinate] ) -1, 3 , 5- triazine; , 6-bis [2- ( {2- [ (naphthalene-1, 3, 5-trisulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1, 3 , 5- triazine,- , 6-bis [2- ({2- [ (naphthalene-1, 7-diphosphonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1, 3, 5- triazine; , 6-bis [2- ( {2- [ (naphthalene-1, 5-diphosphonic acid-3- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2- (N- [ethyl glycinate] ) -1,3,5- triazine; , 6-bis [2- ({2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine; , 6-bis [2- ( {2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine; , 6-bis [2- ( {2- [ (naphthalene-1, 5-disulfonic acid-2- amino) carbonyl] -l-methylpyrrole-4-amino}carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine; , 6-bis [2- ({2- [ (naphthalene-1, 3, 5-trisulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -l- methylpyrrole-4-amino] -2-chloro-l, 3,5-; , 6-bis [2- ( {2- [ (naphthalene-1, 7-diphosphonic acid-4- a ino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3,5-;
4, 6-bis [2- ( {2- [ (naphthalene-1, 5-diphosphonic acid-3- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] -2-chloro-l, 3 , 5-triazine; 2,4, 6-tris{2- [ (naphthalene-1, 3-disulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} -1, 3 , 5-triazine; 2,4, 6-tris{2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} -1, 3, 5-triazine,- 2,4, 6-tris{2- [ (naphthalene-1, 3 , 5-trisulfonic acid-7- amino) carbonyl] -l-methylpyrrole-4-amino} -1, 3 , 5-triazine,- 2,4, 6-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) -
1,3, 5-triazine; 2,4, 6-tris (2- { [2- ({2- [ (naphthalene-1, 7-disulfonic acid-4- amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] carbonyl} -l-methylpyrrole-4-amino) -
1, 3 , 5-triazine; and 2,4, 6-tris (2-{[2-({2-[ (naphthalene-1, 3, 5-trisulfonic acid-
7-amino) carbonyl] -l-methylpyrrole-4-amino} carbonyl) -1- methylpyrrole-4-amino] carbonyl} -l-methylpyrrole-4-amino) -
1,3, 5-triazine; or a Ci-Cg-alkyl and phenyl-Ci-Cg-alkyl ester, or a pharmaceutically acceptable salts thereof.
6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and, as an active compound, a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.
7. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for use as angiogenesis inhibitor.
8. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for use as
TNFα-neutralizing activity agent.
9. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, for use as anti-lentivirus agent.
10. Process for the preparation of a compound of formula (I) , as defined in claim 1, or a salt thereof, said process comprising reacting a compound of formula (II)
Figure imgf000028_0001
wherein m, p and R3 are as defined in claim 1, or a salt thereof, with a compound of formula (III)
Figure imgf000028_0002
wherein at least one of R4, R5 and R6 is chloro and the remaining of R4-R6, if any, is as R-R2 defined in claim 1; 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) .
PCT/EP1998/003453 1997-06-27 1998-05-30 Substituted triazine compounds and their use in medicine WO1999000363A1 (en)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999034796A1 (en) * 1997-12-31 1999-07-15 Pharmacia & Upjohn S.P.A. Synergistic antitumor composition containing a naphthalensulphonic acid derivative
US6335339B1 (en) 1998-01-13 2002-01-01 Scriptgen Pharmaceuticals, Inc. Triazine antiviral compounds
WO2001087849A3 (en) * 2000-05-12 2002-06-06 Genzyme Corp Modulators of tnf- alpha signaling
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL
EP1992636A2 (en) 1999-11-12 2008-11-19 Amgen Inc. Process for correction of a disulfide misfold in Fc molecules

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991010649A1 (en) * 1990-01-11 1991-07-25 Farmitalia Carlo Erba S.R.L. New ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds
WO1995023806A2 (en) * 1994-03-01 1995-09-08 Pharmacia S.P.A. Ureido derivatives of naphthalenephosphonic acids and process for their preparation
WO1996026950A1 (en) * 1995-03-01 1996-09-06 Pharmacia S.P.A. Increased bioavailability of biologically active compounds by linking to polypyrrolecarboxamidonaphthalene derivatives

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991010649A1 (en) * 1990-01-11 1991-07-25 Farmitalia Carlo Erba S.R.L. New ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds
WO1995023806A2 (en) * 1994-03-01 1995-09-08 Pharmacia S.P.A. Ureido derivatives of naphthalenephosphonic acids and process for their preparation
WO1996026950A1 (en) * 1995-03-01 1996-09-06 Pharmacia S.P.A. Increased bioavailability of biologically active compounds by linking to polypyrrolecarboxamidonaphthalene derivatives

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 (en) * 1997-12-31 1999-07-15 Pharmacia & Upjohn S.P.A. Synergistic antitumor composition containing a naphthalensulphonic acid derivative
US6335339B1 (en) 1998-01-13 2002-01-01 Scriptgen Pharmaceuticals, Inc. Triazine antiviral compounds
EP1992636A2 (en) 1999-11-12 2008-11-19 Amgen Inc. Process for correction of a disulfide misfold in Fc molecules
WO2001087849A3 (en) * 2000-05-12 2002-06-06 Genzyme Corp Modulators of tnf- alpha signaling
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
US7364736B2 (en) 2001-06-26 2008-04-29 Amgen Inc. Antibodies to OPGL
EP2087908A1 (en) 2001-06-26 2009-08-12 Amgen, Inc. Antibodies to opgl
EP3492100A1 (en) 2001-06-26 2019-06-05 Amgen Inc. Antibodies to opgl

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