AU6537194A - Biologically active ureido derivatives useful in the treatment of lentivirus-induced disease - Google Patents

Biologically active ureido derivatives useful in the treatment of lentivirus-induced disease

Info

Publication number
AU6537194A
AU6537194A AU65371/94A AU6537194A AU6537194A AU 6537194 A AU6537194 A AU 6537194A AU 65371/94 A AU65371/94 A AU 65371/94A AU 6537194 A AU6537194 A AU 6537194A AU 6537194 A AU6537194 A AU 6537194A
Authority
AU
Australia
Prior art keywords
imino
bis
carbonyl
methyl
pyrrole
Prior art date
Legal status (The legal status 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 status listed.)
Granted
Application number
AU65371/94A
Other versions
AU670194B2 (en
Inventor
Giovanni Biasoli
Marina Ciomei
Maria Cristina Geroni
Maria Grandi
Nicola Mongelli
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Italia SRL
Original Assignee
Pharmacia and Upjohn SpA
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 and Upjohn SpA filed Critical Pharmacia and Upjohn SpA
Publication of AU6537194A publication Critical patent/AU6537194A/en
Application granted granted Critical
Publication of AU670194B2 publication Critical patent/AU670194B2/en
Assigned to PHARMACIA & UPJOHN S.P.A. reassignment PHARMACIA & UPJOHN S.P.A. Request to Amend Deed and Register Assignors: FARMITALIA CARLO ERBA S.R.L.
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pyridine Compounds (AREA)

Description

"BIOLOGICALLY ACTIVE UREIDO DERIVATIVES USEFUL IN THE TREATMENT OF LENTIVIRUS-INDUCED DISEASE"
The present invention relates to the use of ureido derivatives of substituted pyrroles in the treatment of lentivirus-induced diseases in mammals. The development of compounds useful for the prophylaxis and therapy of viral disease has presented more difficult problems than those encountered in the search of drugs effective ^ disorders produced by other microorganisms. This is typically the case with lentivirus-induced diseases, in particular human immunodeficiency viruses (HIV) that as known induce acquired immunodeficiency syndrome (AIDS). AIDS is a secondary immunodeficiency syndrome resulting from HIV infection.
Two closelyrelated viruses, HIV-1 and HIV-2, have been identified as causing AIDS in different geographic regions. HIV-1 causes most cases of AIDS in the Western Hemisphere, Europe and Central, South and East Africa; HIV-2, which appears less virulent than HIV-1, is the principal agent of AIDS in West Africa. In certain areas of West Africa, both organisms are prevalent. AIDS is characterized by opportunistic infections, malignancies, neurological dysfunction and a variety of other syndromes.
During the course of the disease, which can be extended over years, the patient is severely debilitated, unable to work or fulfil simple domestic functions. Accordingly, there is a need in therapy for drugs which are active against lentivirus, in particular against human deficiency virus and/or able to ameliorate symptoms of lentivirus-induced disease in a human suffering from lentivirus infection.
WO 91/10649 provides ureido derivatives of poly-4- amino-2-carboxyl-l-methylpyrrole compounds which have angiogenesis inhibitor activity and TNF-α neutralizing activity.
Accordingly, these prior art compounds can be useful in treating several pathological conditions in mammals where the growth of new blood vessels is detrimental and in which TNF-α is known to play a detrimental role. It has now- been found that a selected class of com¬ pounds previously disclosed in WO 91/10649 are active as anti-lentivirus agents, in particular against HIV. Accordingly the present invention provides the use of a compound of formula (I)
wherein each of and n, being the same, is' an integer of 1 to 3; and each of the R groups, which are the same, is a naphthyl group substituted by 1 to 3 sulfonic acid groups, or a pharmaceutically acceptable salt thereof, 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 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 present invention also provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof , for use in the treatment of a human patient suffering from lentivirus infection. The compound or salt may be for use as an anti-lentivirus agent, for example an anti-HIV agent. The compound or salt may also be for use in ameliorating the symptoms of lentivirus-induced disease in a human patient suffering from lentivirus infection.
The substituted naphthyl group is preferably a 5-, 6-, 7- or 8-naphthyl group, typically a 7- or 8-naphthyl group. When the naphthyl group is substituted by three sulfonic acid groups, the sulfonic acid substituents are preferably in the 1-, 3- and 5- or 1, 3- and 6- positions. When it is substituted by 2 acid groups the sulfonic acid substituents are preferably in the 1- and 3-, 1- and 5-, 3- and 5- or 3- and 6-positions. When it is substituted by one acid group the sulfonic acid substituent is preferably in the 1-, 3- or 5-position. 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 formula (I). As already said, the invention includes within its scope also the pharmaceutically acceptable salts of the compounds of formula (I). Examples of pharmaceutically acceptable salts are either those with inorganic bases, such as sodium, potassium, calcium and aluminium hydroxides, or with organic bases, such as lysine, arginine, N-methyl- gluca ine, triethylamine, triethanolamine, dibenzyl- amine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N-ethγlpiperidine, N,N-diethylaminoethγl- amine, N-ethylmorpholine, B-phenethylamine, N-benzyl- -β-phenethylamine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines. Sodium and potassium salts are preferred. 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 formula (I) are the compounds wherein m and n are each 2 and each of the R groups is as defined above; and the pharmaceutically acceptable salts thereof.
Examples of specific preferred compounds are: 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- -imino( -methyl-4,2-pyrrole)carbonylimino) )bis(3,5- -naphthalendisulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methγl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis( 3 ,6- naphthalendisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino( -methy1-4,2-pyrrole)carbonylimino) )bis(1,3,5- naphthalentrisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino( -methyl-4,2-pyrrole)carbonylimino) )bis(1,3,6- naphthalentrisulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,3- naphthalendisulfonic acid) ;
7,7'-(carbonyl-bis(imino- -methyl-4,2-pyrrolecarbonyl- imino(N-methγl-4,2-pyrrole)carbonylimino) )bis(2,4- naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis( 2, 4- naphthalendisulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino( -methγl-4,2-pyrrole)carbonylimino) )bis(1,3,5- naphthalentrisulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino( -methyl-4 ,2-pyrrole)carbonylimino) )bis( 5- naphthalensulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methγl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(l,3- naphthalendisulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methγl-4,2-pyrrole)carbonylimino) )bis( 3 ,5- naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonyl- imino( -methyl-4,2-pyrrole)carbonylimino) )bis(1,5- -naphthalendisulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonyl- imino(N-methyl-4 , 2-pyrrole)carbonylimino) )bis( 3- naphthalensulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonyl- imino(N-methy1-4 ,2-pyrrole)carbonylimino) )bis( 1- naphthalensulfonic acid) ;
2,2'-(carbonyl-bis(imino-N-methy1-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,5- naphthalendisulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methγl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,6- naphthalendisulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonγl- imino(N-methyl-4 ,2-pyrrole)carbonylimino) )bis(2,6- naphthalendisulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,5- naphthalendisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis( 2,5- naphthalendisulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methy1-4,2-pyrrolecarbony1- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis( 2,3- naphthalendisulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- -imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,6- naphthalendisulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonγl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,6- naphthalendisulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,5- naphthalendisulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methyl-4',2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis( 3 ,6- naphthalendisulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonγl- imino( -methyl-4,2-pyrrole)carbonylimino) )bis(2,3,5- naphthalentrisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methγl-4,2-pyrrolecarbonγl- imino(N-methy1-4,2-pyrrole)carbonylimino) )bis(1,4,6- naphthalentrisulfonic acid) ;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbony1- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,4,6- naphthalentrisulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbony1- imino(N-methyl-4 ,2-pyrrole)carbonylimino) )bis( 1- naphthalensulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonyl- imino(N-methyl-4 ,2-pyrrole)carbonylimino) )bis( 2- naphthalensulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonyl- imino(N-methyl-4 ,2-pyrrole)carbonylimino) )bis(3- naphthalensulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methγl-4,2-pyrrolecarbonγl- imino(N-methyl-4 ,2-pyrrole)carbonylimino) )bis(4- naphthalensulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonγl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,4,6- naphthalentrisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pγrrole)carbonylimino) )bis(1,3,6- naphthalentrisulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonγl- imino(N-methyl-4,2-pγrrole)carbonylimino) )bis(2,4,6- naphthalentrisulfonic acid) ;
7,7'-(carbonyl-bis(imino-N-methγl-4,2-pyrrolecarbonγl- imino(N-methy1-4,2-pyrrole)carbonylimino) )bis(2,3,5- naphthalentrisulfonic acid) ; and the pharmaceutically acceptable salts thereof, in particular the sodium or potassium salt.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof, hereafter referred to as "the compounds of the invention" or "the active agents" have been found to be active as anti-lentivirus agents, in particular against Human Immunodeficiency Virus (HIV) . For instance the representative compounds of the invention
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonγl- imino(N-methyl-4,2-pγrrole)carbonylimino) )bis(1,3,5- naphthalentrisulfonic acid) hexasodium salt;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonγl- imino(N-methyl-4 ,2-pyrrole)carbonylimino) )bis( 3,5- naphthalendisulfonic acid) tetrasodiu salt; and 7,7'-(carbonyl-bis(imino-N-methy1-4',2-pyrrolecarbony1- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis( 1,3- naphthalendisulfonic acid) tetrapotassium salt, have been found to be active in the biological test described in J. Natl. Cancer Inst. 81:557-586, 1989. A human patient can thus be treated by a method com- prising 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.
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, stressed or pathological as a result of infection with a lentivirus, in particular HIV, or who is suffering from induced disease e.g. lymphadenopathy syndrome (LS), AIDS-related complex (ARC), AIDS or Kaposi's sarcoma. The condition of a human patient can thus be ameliorated or improved.
The compounds of formula (I) or pharmaceutically acceptable salts thereof 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 formula (I), for example 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonγl- imino(N-methγl-4,2-pyrrole)carbonylimino)bis(1,3,5- naphthalentrisulfonic acid) or a pharmaceutically acceptable salt thereof, e.g. the hexasodium salt, for administration to adult humans is from about 0.5 to about 300 mg per dose 1-4 times a day. The pharmaceutical composition used in the invention may comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, as the active substance, in association with one or more pharmaceutically acceptable excipients and/or carriers. The pharmaceutical composition 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 oleoginous 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, stea-ric acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethyl cellulose, polyvinylpyrrolidone; disaggregating agents, e.g. a starch, alginic acid, alginates, sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, for instance, lecithin, polysorbates, laurylεulphates; 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 compounds of formula (I) , or pharmaceutically acceptable salts thereof, 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 pharma¬ ceutically acceptable salt thereof, and a pharmaceu- tical compositioncontaining 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; cytokines e.g. IL-1, IL-2, IL-3 or IL-4; growth factors; interferons e.g. alpha-or gamma interferon; antitumor agents e.g. doxorub'icin, daunomycin, epirubicin, idarubicin, etoposide, fluorouracil, melphalan, cyclophosphamide, bleomycin, vinblastin and mitomycin; immuno-modulating 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 known additional agents, e.g. cephalosporins, can be utilized.
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 particulars 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 compounds of formula (I) and the pharmaceutically acceptable salts thereof can be obtained according to WO 91/10649, for instance by reacting a compound of formula (II)
wherein n and B are as defined above, or a salt thereof, with a compound of formula (III)
x-co-x (III)
wherein each of the X groups, which may be the same or different, is a good leaving group, and if desired, salifying a compound of formula (I) thus obtained; and/or, if desired, obtaining a free compound of formula (I) from a salt thereof.
A salt of a compound of formula (II) may be a salt with inorganic bases, for example those mentioned above as pharmaceutically acceptable salts used in the in¬ vention, the sodium and potassium salts being the preferred.
Preferred examples of leaving groups, according to the meaning of X, are halogen atoms, in particular chlorine, or other easily displaceable groups such as imidazolyl, triazolyl, p-nitrophenoxy, trichlorophenoxy or trichloromethyloxy. 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; for example according to the conditions described in organic chemistry for this kind of reaction, i.e. for synthesis of urea derivatives. Preferably when in a compound of formula (III) X is a halogen atom, e.g. chlorine, the reaction may be carried out at a molar ratio of compound (II) , or a salt thereof: compound (III) from about 1.1 to about 1.4. The reaction is preferably performed in organic solvents such as dimethylsulphoxide, hexamethylphospho- triamide, dimethylacetamide or, preferably, dimethyl- formamide, or their aqueous mixtures, or in water/ dioxane or water/toluene mixtures, in the presence of either an organic base such as triethylamine or diiso- propylethylamine, or an inorganic base such as sodium bicarbonate or sodium acetate. The reaction temperature may vary from about -10°C to about 50°C and the reaction time from about 1 to about 12 hours. The compounds of formula (I) prepared according to the above described procedures may be purified by conven- tional methods such as by silica gel or alumina column chromatography, and/or by rechrystallization from organic solvents such as lower aliphatic alcohols or dimethylformamide.
Analogously salification of a compound of formula (I) can be carried out by known methods in the art, as well as the conversion of a salt of a compound of formula (I) into a free product and the conversion of a compound of formula (I) into a pharmaceutically acceptable salt thereof.
The following examples further illustrate the present invention:
EXAMPLE 1
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbony1- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(3,5- naphthalendisulfonic acid) tetrasodium salt.
To a solution of 8-(amino-N-methγl-4 2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) ) (3,5- naphthalendisulfonic acid) disodium salt hydrochloride (1256 mg, 2 mmols) in water (60 ml) and dioxane (20 ml), NaOH IN (2 ml) and sodium acetate (328 mg, 4 mmols) was added under stirring.
The whole was cooled to 5°C with an ice bath, then a solution of bis(trichloromethyl)carbonate (149 mg, 0.5 mmols) in dioxane (15 ml) was added dropwise in an hour. The mixture was stirred for 2 hours at room temperature. The solvents were evaporated under vacuum and the residue was chromatographed on a silica gel column with ethylene chloride : methanol : water (300:200:20) as eluant, affording 856 mg of the title compound;
N.M.R. (DMSO-de): δ 3.85 (6H,s); 6.83 (lH,d,J=l.8) ;
7.06 ( lH,d, J=l .8 ) ; 7.26 (lH,d,J=1.8); 7.38 (lH,d,J=l.08) ; 7.50 ( 1H ,d, J = 7.8 ) ; 7.72
( lH,dd , J = l .7 , J = 8.9 ) ; 7.98
(lH,d,J=7.8) ; 8,25 (lH,bs); 9.19 (lH,d,J=1.7) ; 9.91 (lH,bs); 10.03 (lH,bs);
U.V. (H20) nm : λ max (E-^) : 310 (431); 231 (1027) F.A.B. M.S. m/z : 1209, M*+H; 640; 618; 614; 592.
By proceeding analogously, the following compounds can be prepared:
7,7'-(carbonyl-bis(imino-N-methyl-4 ,2-pγrrolecarbonyl- imino( -methyl-4,2-pγrrole)carbonylimino) )bis(3,5- naphthalendisulfonic acid) tetrasodium salt;
N.M.R. (DMSO-d6): δ 3.85 (3H,s); 3.90 (3H,s); 6.81
(lH,d,J=1.8) ; 6.90 (lH,d,J=l.8) ;
7.12 ( lH,d, J=l .8 ) ; 7.32 (lH,d,J=1.8); 7.70 (lH,dd,J=l.6,
J=8.6); 7.80 (lH,d, J=8.6); 8.11 (lH,d,J=1.6) ; 8.15 (1H, bs), 8.58 (lH,d,J=1.7) ; 8.78 (lH,d, J=1.7); 10,05 (lH,bs); 10.94 (lH,bs); F.A.B. M.S. m/z: 1209, M*+H; 1187, M~-Ne+H;
U.V. (H20) nm : λ max (E ^ : 321 (416); 231 (721);
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonγl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis( 3,6- naphthalendisulfonic acid) tetrasodium salt;
N.M.R. (DMSO-d6): δ 3.85 (3H,s); 3.93 (3H,s); 6.81
(lH,d,J=1.8); 6.91 (lH,d,J=l.8) ; 7.08 ( lH,d, J=l .8 ) ; 7.51 (lH,d,J=1.8); 7.68 (lH,dd,J=l.6, J=8.6); 7.78 (lH,d,J=8.6) ; 8.04
(lH,s); 8.12 (lH,bs); 8.23 (lH,s); 8.89 (lH,s); 10,02 (lH,bs); 10,98 (lH,bs); F.A.B. M.S. m/z: 1209, M*+H; 1187, M*-Ne+H; U.V. (H20) nm : λ max (E ^ : 323,4 (540); 227,7
(732);
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbony1- imino(N-methy1-4,2-pγrrole)carbonylimino) )bis(1,3,5- naphthalentrisulfonic acid) hexasodium salt; N.M.R. (DMSO-d6): δ 3.85 (3H,s); 3.89 (3H,s); 6.78
(lH,d,J=1.8) ; 7.08 (lH,d,J=l.8) ; 7.22 ( lH,d, J=l .8 ) ; 7.35 (lH,d,J=1.8) ; 8.25 (lH,d,J=l.9) ; 5 8.30 (lH,bs); 8.36 (lH,bs); 9.00
(lH,bs); 9.07 (lH,d,J=1.6) ; 9.82 (lH,bs); 10,20 (lH,bs);
U.V. (H20) nm : λ max (E 1i%l, lcifl : 320 (374); 254 (444);
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- 0 imino(N-methy1-4,2-pyrrole)carbonylimino) )bis(1,3,6- naphthalentrisulfonic acid); hexasodium salt;
N.M.R. (DMSO-dβ): δ 3.84 (3H,s); 3.88 (3H,s); 6.81
(lH,d,J=1.8); 7.07 (lH,d,J=l.8) ; 7.11 ( lH,d, J=l .8) ; 7.42 5 (lH,d,J=1.8); 7.87 (lH,d,J=l.9) ;
7.87 ( lH,d, J=l .9) ; 8.06 (lH,d,J=1.9); 8.12 (lH,bs); 8,33 (lH,d,J=1.9) ; 8,54 (lH,d,J=l.9) ; 9.93 (lH,bs); 12.19 (lH,bs);
: 320 (374); 254 (444);
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,3- naphthalendisulfonic acid) tetrapotassium salt; I.R. (KBr) c "1 : 3450 (b) ; 1650; 1580; 1530; 1190;
1030
N.M.R. (DMSO-d6): δ 3.84 (3H,s); 3.87 (3H,s); 6.80
(lH,d); 7.05 (lH,d; 7.18 (lH,d); 7.33 (lH,d); 7.86 (2H,m);8.00
(lH,d,); 8.16 (lH,bs); 8.21 (lH,d); 8,95 (lH,bs); 9,86 (lH,bs) ; 10.21 *(lH,bs) ;
U.V. (H20) nm : λ max (E^) : 316.8 (371); 248.95
(444)
F.A.B. M.J. m/z : 1273 (M*+H) ; 1311 ( (M*+K) ;
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonγl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,4- naphthalendisulfonic acid) tetrasodium salt;
N.M.R. (DMSO-d6): δ 3.85 (3H,s); 3.89 (3H,s); 6.81 (lH,d,J=1.7); 7.06 (lH,d,J=l.7) ;
7.22 ( lH,d, J=1.7 ) ; 7.33 (lH,d,J=1.7); 7.33 (lH,d,J=1.7) ; 7.38 (lH,dd,J=2.0,J=9.5) ; 7.92 (lH,bs); 8.10 (lH,d,J=1.7) ; 8.20 (lH,bs); 8,32 (lH,d,J=2.0) ; 8,69
(lH,d,J=9.4) ; 9.88 (lH,bs); 10.08 (lH,bs); 8,8'-(carbonyl-bis(imino-N-methy1-4,2-pyrrolecarbony1- imino(N-methyl-4 , 2-pyrrole)carbonylimino) )bis( 2, 4- naphthalendisulfonic acid) tetrasodium salt;
N.M.R. (DMSO-d6): δ 3.85 (6H,S); 6.81 (lH,d,J = 1.7 HZ); 7.06 (lH,d,J = 1+Hz);
7.25 (lH,d,J = 1.7 Hz); 7.34 (lH,d,J = 1.7 Hz); 7.4 ÷ 7.6 (2H,m); 8.14 (lH,bs);8.25 (2H,s,); 8.73 (lH,dd,J = 13 Hz, J = 8,3 Hz); 9.92
(lH,bs); 10.07 (lH,bs);
U.V. (H20) nm : λ max : 307 (435); 231 (932)
F.A.B. m/z : 1209 (M*+l); 1231 (M*+Ne) ;
1128 (M*-S03);
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino( -methy1-4,2-pyrrole)carbonylimino) )bis(1,3,5- naphthalentrisulfonic acid) hexasodium salt; I.R. (KBr) cm"1 : 3440 b, 1640, 1590, 1190, 1030
N.M.R. (DMSO-d6): δ 3.80 (3H,s); 3.83 (3H,s); 6.80
(lH,d); 7.06 (2H,m); 7.40 (lH,d);
7.88 (lH,d); 7.99 (lH,d);8.02 (lH,bs); 8.57 (lH,d); 9.33 (lH,d);
9.91 (lH,bs); 12.29 (lH,bs).
U.V. (H2) nm : λ max (E ^ : 311 (266); 233 (551)
F.A.B.-M.S. m/z 1411, M~-H;1389, M"-Na;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4 ,2-pyrrole)carbonylimino) )bis(5- naphthalensulfonic acid) disodium salt;
N.M.R. (DMSO-d6): δ 3.85 (6H,s); 6.84 (lH,d,J=l.8) ;
7.05 ( lH,d, J=l .8) ; 7.25
(lH,d,J=1.8) ; 7.35 (lH,d,J=l.8) ; 7.46-7.56 (3H,m); 7.92-8.00
(2H,m); 8.15 (lH,bs); 8,87 (lH,m); 9,89 (lH,bs); 10.03 (lH,bs);
U.V. (H20) nm : λ max (E J^J : 310 (531); 227 (1043)
F.A.B. M.S. m/z : 1005, (M*+H) ; 1027 (M*+Ne) ;512; 8,8 ' -(carbonyl-bis ( imino-N-me thγl-4, 2-pyrrolecarbonyl- imino(N-methyl-4 , 2-pyrrole ) carbonylimino) )bis (1,3- naphthalendisulf onic acid) tetrasodium salt;
N.M.R. (DMSO-d6): δ 3.84 (3H,s); 3.86 (3H,s); 6.81 (lH,d,J=1.8) ; 7.08 (2H,bs); 7.41 lH,d,J=1.8) ; 7.50 ( lH,t, J=7.0) ; 7.78 ( lH,d', J = 7.0 ) ; 8.02
(lH,d,J=7.0); 8.11 (2H,m); 8.53 (lH,d,J=2.02) ; 9.93 (lH,bs); 12.21 (lH,bs);
U.V. (H20) nm : λ max (E,^*) : 309.05 (403); 229,65
735
F.A.B. M.S. m/z : 1209, M*+H; 1231,M*+Ne; 1187,
M*-Ne+H; 1129; 640; 618; 614; 592;
2,2'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonγl- imino( -methyl- ,2-pyrrole)carbonylimino) )bis(1,5- naphthalendisulfonic acid) tetrasodium salt; N.M.R. (DM δ 0-d6): 3.85 (3H, s); 3.91 (3H, s); 6.90
(1H, d, J=1.8); 6.98 (1H, d, J=1.8); 7.09 (1H, d, J=1.8); 7.35
(1H, dd, J=7, J=8.8); 7.47 (1H, d, J=1.8); 7.9 (1H, d, J=7) ; 9.15 (1H, bs); 8.67-8.82 (2H, dd,
J=9.6); 8.99 (1H, d, J=8.8) ; 9.98 (1H, bs); 12.64 (1H, bs) .
F.A.B. M.S.: m/z 1207, [M-H]"; 1185, [M-23]~; 1105 (M-S03Na)_. U.V. (H20): nm : λ max 298; ) 522;
8,8'-(carbonyl-bis(imino-N-methyl-4,-2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,5- naphthalendisulfonic acid) tetrasodium salt;
I.R. (KBr) cm"1: 3440 b, 1660, 1640, 1585, 1180, 1030. N.M.R. (DMSO-de): δ 3.84 (3H,s); 3.85 (3H,s); 6.80 lH,d); 7.07 (2H,m); 7.41 2H,m) ;
7.92 (2H,dd); 8.12 (1.12 (lH,s);
8,27 (lH,dd); 9.07 (lH,dd); 9.90 (lH,bs); 12.27 (lH,bs).
U.V. (H20) ήm : λ max (E^) : 316 (331); 229 (478) F.A.B. -M.S. m/z : 1209, M*+l ; 1231, M-+23; 1128, M-80;
8 , 8 ' - ( carbonyl-bis ( imino-N-methy 1- 4 , 2 -pyrrolecarbony 1- imino( N-methy 1-4 , 2 -pyrrole) carbonylimino) )bis( 3- naphthalensulfonic acid) disodium salt; I.R. (KBr)cπT1: 3430 b, 1640, 1585, 1200, 1030
N.M.R. (DMSO-d6): δ 3.84 (6H,s); 6.86 (lH,d); 7.05
(lH,d); 7.24 (lH,d); 7.35 (lH,d)
7.54 (2H,m); 7.70 (lH,dd); 7.90 (2H,m); 8.15 (lH,d); 8.15 (lH,d);
8.95 (lH,bs); 9.94 (lH,bs); 10.03 (lH,bs).
1%
U.V. (H20) nm : λ max (En_) : 304 (366); 226 (1002) ''lcm
F.A.B. M.S.:m/z 1005, M*+H; 1027, M*+2Na;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino( N-methyl-4 , 2-pyrrole) carbonylimino) )bis( 1- naphthalensulfonic acid) disodium salt;
N.M.R. (DMSO-dβ): δ 3.84 (3H,s); 3.85 (3H,s); 6.82
(lH,d,J=1.8) ; 7.06(lH,d,J=1.8) ; ' 7.09 (lH,d,J=1.8); 7.39-7.54
(3H,m); 7.74 (lH,dd,J=l.3 ,J=.3, J=8.2); 7.93-8.02 (2H,m); 8.13 (lH,bs); 8.26 (lH,dd,J=1.5,J=7.3) ; 9.93 (lh,bs); 12.20 (lH,bs); F.A.B. M.S. : m/z 1005, M-+H; 1027 ,M*+Ne;
U.V. (H20) nm : λ max (E^) : 312 (490); 224 (831); 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,6- naphthalendisulfonic acid) tetrasodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,6- naphthalendisulfonic acid) tetrasodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,5- naphthalendisulfonic acid) tetrasodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,5- naphthalendisulfonic acid) tetrasodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino( -methyl-4,2-pyrrole)carbonylimino) )bis(2,3- naphthalendisulfonic acid) tetrasodium salt;
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbony1- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,6- naphthalendisulfonic acid) tetrasodium salt; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,6- naphthalendisulfonic acid) tetrasodium salt; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,5- naphthalendisulfonic acid) tetrasodium salt; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonγl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis( 3,6- naphthalendisulfonic acid) tetrasodium salt; 8,8'-(carbonyl-bis(imino-N-methγl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,3,5- naphthalentrisulfonic acid) hexasodium salt, 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbony1- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,4,6- naphthalentrisulfonic acid) hexasodium salt; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbony1- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,4,6- naphthalentrisulfonic acid) hexasodium salt;
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pγrrolecarbonyl- imino(N-methyl-4 ,2-pyrrole)carbonylimino) )bis( 1- naphthalensulfonic acid) disodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino(N-methyl-4 ,2-pyrrole)carbonylimino) )bis(2- naphthalensulfonic acid) disodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonγl- imino(N-methy1-4 ,2-pyrrole)carbonylimino) )bis( 3- naphthalensulfonic acid) disodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbony1- imino(N-methyl-4 ,2-pyrrole)carbonylimino) )bis( 4- naphthalensulfonic acid) disodium salt; 7,7'-(carbonyl-bis(imino-N-methγl-4,2-pyrrolecarbonyl- imino(N-methyl-4,2-pγrrole)carbonylimino) )bis(1,4,6- naphthalentrisulfonic acid) hexasodium salt;
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonyl- imino( -methyl-4,2-pyrrole)carbonylimino) )bis(1,3,6- naphthalentrisulfonic acid) hexasodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonγl- imino( -methyl-4,2-pyrrole)carbonylimino) )bis(2,4,6- naphthalentrisulfonic acid) hexasodium salt; and
7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonγl- imino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,3,5- naphthalentrisulfonic acid) hexasodium salt.
EXAMPLE 2
8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbony1- imino(N-methγl-4,2-pyrrole)carbonylimino) )-bis(3,5- naphthalenedisulfonic acid) .
A solution of 8,8'-(carbonyl-bis(imino-N-methγl-4,2- pγrrolecarbonγl-imino(N-methyl-4,2-pyrrole)carbonyl- imino) )-bis(3,5-naphthalenedisulfonic acid) tetraso¬ dium salt (400 mg) in water (10 ml), is chromatographed on an Amberlite 1R-120(H) column (20 ml), with water as eluent. The solution is evaporated to dryness in vacuum, affording 0.3 g of the title compound. EXAMPLE 3
Intramuscular injection 40 mg/ml.
An injectable pharmaceutical preparation can be manufactured by dissolving 40 g of 8,8'-(carbonyl- bis(imino-N-methyl-4,2-pyrrolecarbonγl-imino(N-methγl- 4,2-pyrrole)carbonylimino) )-bis(3,5-naphthalene- disulfonic acid) tetrasodium salt in water for injection (1000 ml) and sealing ampoules of 1-10 ml.

Claims (6)

  1. Use of a compound of formula (I)
    wherein each of m and n, being the same, is an integer of 1 to 3; and each of the R groups, which are the same, is a naphthyl group substituted by 1 to 3 sulfonic acid groups, or a pharmaceutically acceptable salt thereof; in the preparation of a medicament for use in the treatment of lentivirus infection.
  2. 2. Use according to claim 1 wherein the lentivirus is a human immunodeficiency virus.
  3. 3. Use according to claim 1 wherein m and n are each 2.
  4. 4. Use according to any one of claims 1 to 3 wherein the compound is: 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pγrrole- carbony1imino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(3,5-naphthalendisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(3,6-naphthalendisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(1,3,5-naphthalentrisulfonic acid) ; 8,8'-(carbonyl-bis( imino-N-methyl-4,2-pγrrole- carbonylimino(N-methy1-4,2-pyrrole)carbonyl¬ imino) )bis(l,3,6-naphthalentrisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbony1imino(N-methyl-4,2-pyrroleJcarbonyl- imino) )bis(l,3-naphthalendisulfonic acid);
    7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methγl-4,2-pγrrole)carbonyl¬ imino) )bis(2,4-naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methγl-4,2-pγrrole- carbonylimino(N-methyl-4,2-pγrrole)carbonyl¬ imino) )bis(2,4-naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pγrrole- carbonylimino(N-methyl-4 ,2-pyrrole)carbonyl¬ imino) )bis(1,3,5-naphthalentrisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methy1-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl- imino) )bis(5-naphthalensulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methγl-4,2-pyrrole)carbonyl- imino) )bis(1,3-naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methγl-4,2-pyrrole- carbonylimino(N-methγl-4,2-pyrrole)carbonyl¬ imino))bis(3,5-naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methy1-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(1,5-naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbony1imino(N-methyl-4,2-pyrrole)carbonγl- imino) )bis(3-naphthalensulfonic acid);
    8,8'-(carbonyl-bis(imino-N-methγl-4,2-pγrrole- carbony1imino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(1-naphthalensulfonic acid) ; 2,2'-(carbonyl-bis(imino-N-methyl-4,2-pγrrole- carbonγlimino(N-methγl-4,2-pyrrole)carbonyl¬ imino) )bis(1,5-naphthalendisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbony1imino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(1,6-naphthalendisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(2,6-naphthalendisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(1,5-naphthalendisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(2,5-naphthalendisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonγlimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(2,3-naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pγrrole- carbonylimino(N-methγl-4,2-pyrrole)carbonγl- imino) )bis(l,6-naphthalendisulfonic acid);
    8,8'-(carbonyl-bis(imino-N-methyl-4,2-pγrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(2,6-naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbo-nylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(2,5-naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methγl-4,2-pyrrole- carbonγlimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(3,6-naphthalendisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pγrrole- carbonylimino(N-methγl-4,2-pyrrole)carbonyl¬ imino) )bis(2,3,5-naphthalentrisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methγl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(1,4,6-naphthalentrisulfonic acid) ; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(2,4,6-naphthalentrisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(1-naphthalensulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonγl- imino) )bis(2-naphthalensulfonic acid);
    7,7'-(carbonyl-bis(imino-N-methy1-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(3-naphthalensulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbσnylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(4-naphthalensulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pγrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(l,4,6-naphthalentrisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(l,3,6-naphthalentrisulfonic acid) ; 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl¬ imino) )bis(2,4,6-naphthalentrisulfonic acid) ; or 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbony1imino(N-methy1-4,2-pyrrole)carbonyl¬ imino) ) is(2,3,5-naphthalentrisulfonic acid) ; or a pharmaceutically acceptable salt thereof.
  5. 5. A use according to any one of claims 1 to 4 wherein the pharmaceutically acceptable salt is the sodium or potassium salt.
  6. 6. Use adcording to any one of claims 1 to 5 wherein the medicament is for ameliorating the symptoms manifested by a human patient who is seropositive diseased, stressed or pathological as a result of infection with a lentivirus or who is suffering from lentivirus-induced disease. Products containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as de¬ fined in any one of claims 1 and 3 to 5 and a second active agent as a combined preparation for simultaneous, separate or sequential use in the treatment of a human patient suffering from lentivirus infection.
AU65371/94A 1993-04-16 1994-03-29 Biologically active ureido derivatives useful in the treatment of lentivirus-induced disease Ceased AU670194B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GB9307948 1993-04-16
GB939307948A GB9307948D0 (en) 1993-04-16 1993-04-16 Biologically active ureido derivatives useful in the treatment of lentivirus-induced disease
PCT/EP1994/000984 WO1994023718A1 (en) 1993-04-16 1994-03-29 Biologically active ureido derivatives useful in the treatment of lentivirus-induced disease

Publications (2)

Publication Number Publication Date
AU6537194A true AU6537194A (en) 1994-11-08
AU670194B2 AU670194B2 (en) 1996-07-04

Family

ID=10733998

Family Applications (1)

Application Number Title Priority Date Filing Date
AU65371/94A Ceased AU670194B2 (en) 1993-04-16 1994-03-29 Biologically active ureido derivatives useful in the treatment of lentivirus-induced disease

Country Status (15)

Country Link
EP (1) EP0646004A1 (en)
JP (1) JPH07508044A (en)
KR (1) KR950701812A (en)
AU (1) AU670194B2 (en)
CA (1) CA2137148A1 (en)
CZ (1) CZ282988B6 (en)
GB (1) GB9307948D0 (en)
HU (1) HU216834B (en)
IL (1) IL109235A (en)
NO (1) NO307126B1 (en)
PL (1) PL306798A1 (en)
RU (1) RU2142798C1 (en)
TW (1) TW308593B (en)
UA (1) UA42693C2 (en)
WO (1) WO1994023718A1 (en)

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9504065D0 (en) * 1995-03-01 1995-04-19 Pharmacia Spa Poly-pyrrolecarboxamidonaphthalenic acid derivatives
GB9602721D0 (en) * 1996-02-09 1996-04-10 Pharmacia Spa Biologically active ureido derivatives useful in the treatment of multiple sclerosis
GB2310207A (en) * 1996-02-15 1997-08-20 Pharmacia Spa Antiviral ureido derivatives of substituted heterocyclic compounds
GB9713733D0 (en) * 1997-06-27 1997-09-03 Pharmacia & Upjohn Spa Poly-branched polycarboxamido compounds
EP3381897A1 (en) 2017-03-27 2018-10-03 Leadiant Biosciences SA Derivatives of the disodium 2,2'-{carbonylbis[imino-3,1-phenylenecarbonylimino(1-methyl-1h-pyrrole-4,2-diyl)carbonylimino]}dinaphthalene-1,5-disulfonate salt and related compounds as heparanase inhibitors for the treatment of cancer

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9000644D0 (en) * 1990-01-11 1990-03-14 Erba Carlo Spa New ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds
AU1224392A (en) * 1991-02-06 1992-09-07 Synphar Laboratories, Inc. Oligopeptide antiretroviral agents

Also Published As

Publication number Publication date
CZ10795A3 (en) 1995-09-13
CZ282988B6 (en) 1997-12-17
IL109235A (en) 1998-09-24
RU2142798C1 (en) 1999-12-20
EP0646004A1 (en) 1995-04-05
TW308593B (en) 1997-06-21
HUT71838A (en) 1996-02-28
HU216834B (en) 1999-09-28
UA42693C2 (en) 2001-11-15
GB9307948D0 (en) 1993-06-02
IL109235A0 (en) 1994-07-31
RU94046312A (en) 1996-10-20
NO307126B1 (en) 2000-02-14
WO1994023718A1 (en) 1994-10-27
AU670194B2 (en) 1996-07-04
NO944809D0 (en) 1994-12-12
PL306798A1 (en) 1995-04-18
JPH07508044A (en) 1995-09-07
HU9500120D0 (en) 1995-03-28
NO944809L (en) 1994-12-12
CA2137148A1 (en) 1994-10-27
KR950701812A (en) 1995-05-17

Similar Documents

Publication Publication Date Title
EP0462258B1 (en) Ureido derivatives of poly-4-amino-2-carboxy-1-methyl compounds
RU2136692C1 (en) Ureido-derivatives of naphthalenephosphonic acids or their pharmaceutically acceptable salts and pharmaceutical composition on said
IE64654B1 (en) Acryloyl substituted pyrrole derivatives
US5534539A (en) Biologically active ureido derivatives useful as anit-metastic agenst
MXPA97001949A (en) Derivatives of distamycine substituted with bis- (2-haloethyl) aminophenylene as anatomy agents yantivira
EA000033B1 (en) Bis(2-haloethyl) aminophenyl substituted distamycin derivatives as antitumor and antiviral agents
AU6537194A (en) Biologically active ureido derivatives useful in the treatment of lentivirus-induced disease
EP0583161B1 (en) 4-Aminopyrrole-2-carboxamide derivatives as antiviral agents
WO1999000364A1 (en) Poly-branched polycarboxamido compounds
US5859046A (en) Biologically active oreido derivatives useful in the treatment of multiple sclerosis
WO1999000363A1 (en) Substituted triazine compounds and their use in medicine
MXPA97007673A (en) Ureido derivatives biologically active, effective in the treatment of multiple sclerosis

Legal Events

Date Code Title Description
MK14 Patent ceased section 143(a) (annual fees not paid) or expired