IL109235A - Pharmaceutical compositions containing ureido derivatives for the treatment of lentivirus induced diseases - Google Patents

Description

in 'oi? π'κηικ ηπί η o^Onn mnpn '"neon Pharmaceutical compositions containing ureido derivatives for the treatment of lentivirus-induced diseases Pharmacia & Upjohn S.p.A.

The inventors are: Nicola Mongelli Giovanni Biasoli Maria Grandi Marina Ciomei Maria Cristina Geroni C. 93011 "BIOLOGICALLY ACTIVE UREIDO DERIVATIVES USEFUL IN THE TREATMENT OF LENTIVIRUS-INDUCED. DISEASE" The present invention relates to the use of ureido derivatives of substitiued pyrroles in the preparation of a pharmaceutical composition for use in the treatment of lentivirus-incluced diseases in mammals.

The development of compounds useful for the prophylaxis and therapy of viral disease has presented more difficult problem.; than those encountered in the search of drugs effective in 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 secondary immunodeficiency syndrome resulting from HIV infection.

Two closely related 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. 109235/3 - 2 - 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. . . ■ US patent No. 4,912,199 discloses oligopeptide compounds, related to netropsin and distamycin, having anti-viral and anti-cancer activity. wo 91/10649 (corresponding to IL 96875) provides ureido derivatives of poly-4-amino-2-carboxyl-l-methylpyrrole compounds which have angiogenesis inhibitor activity and TNF-d 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-a is known to play a detrimental role.

It has now been found that a selected class of compounds 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 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 pharmaceutical composition for use in the treatment of a human patient suffering from lentivirus infection. The said pharmaceutical composition may be for use as an anti-lentivirus agent, for example an anti-HIV agent. The said pharmaceutical.compositions 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-glucamine, triethylamine , triethanolamine , dibenzyl-amine, methylbenzylarnine , di- ( 2-ethyl-hexyl ) -amine , piperidine, N-ethylpiperidine , N,N-diethylaminoethyl- amine, N-ethylmorpholine , β-phenethylamine , N-benzyl--β-phenethylamine , N-benzyl- ,Ν-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(N-methy1-4 , 2-pyrrole) carbonylimino) )bis( 3 ,5--naphthalendisulfonic acid) ; 7 ,7 ' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino( N-methy1-4 , 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-methy1-4 , 2-pyrrolecarbonyl iraino(N-methyl-4 , 2-pyrrole ) carbonylimino ) ) bis ( 1 , 3 naphthalendisulfonic acid) ; 7,7 ' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino(N-methy1-4 , 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 ( N-methy1-4 , 2-pyrrole)carbonylimino) )bis (1,3,5 naphthalentrisulfonic acid) ; 8,8' -(carbonyl-bis( imino-N-methyl-4 , 2-pyrrolecarbonyl imino ( N-methy1- 4 , 2-pyrrole ) carbonylimino ) ) bis ( 5 naphthalensulfonic acid) ; 8,8 ' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino(N-methyl-4 , 2-pyrrole ) carbonylimino ) )bis ( 1 , 3 naphthalendisulfonic acid) ; 8,8' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino(N-methyl-4 , 2-pyrrole ) carbonylimino ) ) bis ( 3 , 5 naphthalendisulfonic acid) ; 8,8' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino(N-methy1-4 , 2-pyrrole ) carbonylimino) )bis (1,5- -naphthalendisulfonic acid) ; 8,8' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino ( N-me thy 1 - 4 , 2 -pyrrole ) carbonylimino ) )bis( 3 naphthalensulfonic acid) ; 8 , 8 ' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbony1 imino ( N -methyl - 4 , 2-pyrrole ) carbonylimino ) ) bis ( 1 naphthalensulfonic acid) 2,2' - (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( 1 , 6 naphthalendisulfonic acid) ; 7,7' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino(N-methyl-4 , 2-pyrrole ) carbonylimino ) )bis( 2 , 6 naphthalendisulfonic acid) ; 7 ,7 ' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbony1 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-methyl-4 , 2-pyrrolecarbonyl imino(N-methyl-4 , 2-pyrrole ) carbonylimino ) ) bis ( 2 , 3 naphthalendisulfonic acid) ; 8,8' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl -imino (N-methy1-4 , 2-pyrrole ) carbonylimino ) ) bis ( 1 , 6 naphthalendisulfonic acid) ; 8 , 8 ' - ( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino (N-methy1-4 , 2-pyrrole ) carbonylimino ) )bis (2,6 naphthalendisulfonic acid) ; 8,8' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino ( N-methy1-4 , 2-pyrrole ) carbonylimino ) ) bis ( 2 , 5 naphthalendisulfonic acid) ; 8,8' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino( -methy1-4 , 2-pyrrole ) carbonylimino ) ) bis ( 3 , 6 naphthalendisulfonic acid) ; 8,8' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino ( N-methy1-4 , 2-pyrrole ) carbonylimino) )bis ( 2 , 3 , 5 naphthalentrisulfonic acid) ; 8,8' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino ( N-methy1-4 , 2-pyrrole ) carbonylimino) )bis (1,4,6 naphthalentrisulfonic acid) ; 8,8' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino ( -methy1- 4 , 2-pyrrole ) carbonylimino ) ) bis (2,4,6 naphthalentrisulfonic acid) ; 7,7 ' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino ( N-methy 1- 4 , 2-pyrrole ) carbonylimino ) ) bis ( 1 naphthalensulfonic acid) ; 7,7' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino ( N-methy 1- 4 , 2-pyrrole ) carbonylimino ) ) bis ( 2 naphthalensulfonic acid) ; 7,7 ' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino (N-methyl - 4 , 2-pyrrole ) carbonylimino) )bis ( 3 -naphthalensulfonic acid) ; 7 ,7 ' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino ( N-methyl - 4 , 2-pyrrole ) carbonylimino ) ) bis ( 4-naphthalensulfonic acid) ; 7, ' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino ( -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-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 ( 2 , 4 , 6-naphthalentrisulfonic acid) ; 7,7 ' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino (N-methyl- 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-pyrrolecarbonyl-imino ( N-methyl-4 , 2-pyrrole )carbonylimino) )bis (1,3,5-naphthalentrisulfonic acid) hexasodium salt; 8,8' -(carbonyl-bis( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino( N-methyl-4 , 2-pyrrole ) carbonylimino ) )bis ( 3 , 5-naphthalendisulfonic acid) tetrasodium salt; and 7,7' - (carbonyl-bis( imino-N-methyl-4 , 2-pyrrolecarbonyl-iminoi 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 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.

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-pyrrolecarbonyl-imino(N-methyl-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, stearic 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 , 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 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 pharmaceutically acceptable salt thereof , and a pharmaceutical composition containing different pharmaceutically active agents. The present invention therefore further provides pharmaceutical compositions 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 antitvimor 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. doxorubicin, 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 R 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 invention, 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, dimethylaceta ide 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 conventional, 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-pyrrolecarbonyl-imino(N-methyl-4 , 2 -pyrrole ) carbonylimino ) ) bis ( 3 , 5-naphthalendisulfonic acid) tetrasodium salt.

To a solution of 8- ( amino-N-methyl-4 , 2-pyrrolecarbonyl-imino(N-methyl-4 , 2-pyrrole) carbonylimino) ) (3,5-naphthalendisulfonic acid) dxsodium 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 methylene chloride : methanol : water (300:200:20) as eluant, affording 856 mg of the title compound; N.M.R. (DMSO-d6): 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=1.08) ; 7.50 (lH,d,J=7.8) ; 7.72 ( 1H , 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, IVT+H; 640; 618; 614; 592.

By proceeding analogously, the following compounds can be prepared: 7,7' -(carbonyl-bis( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino(N-methyl-4 , 2 -pyrrole ) 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=l .7 ) ; 10,05 (lH,bs); 10.94 (lH,bs); F.A.B. M.S. m/z: 1209, IVT+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-pyrrolecarbonyl-imino(N-methyl- , 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=1.8) ; 7.51 (lH,d,J=1.8) ; 7.68 ( 1H ,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 (1H,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-pyrrolecarbonyl-imino (N-methyl- 4, 2-pyrrole) carbonylimino) )bis( 1, 3 , 5-naphthalentrisulfonic acid) hexasodium salt; N.M.R. (DMSO-de): 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=1.8) ; 7.35 (lH,d, J=1.8) ; 8.25 ( lH,d, J=l .9 ) ; ,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 : 320 (374); 254 (444); 8,8' - (carbonyl-bis ( imino-N-methy1-4 , 2-pyrrolecarbonyl-imino ( -methyl-4 , 2-pyrrole) carbonylimino) )bis( 1 ,3,6-naphthalentrisulfonic acid); hexasodium salt; N.M.R. (DMSO-de): 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 ( 1H , d , J=l .8 ) ; 7.42 (lH,d, J=1.8) ; 7.87 ( lH,d, J=l .9) ; 7.87 (lH,d,J=1.9) ; 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); U.V. (H20) nm : λ max ( ^icm ^ : 320 (374) ; 254 7 ,71 -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino( N-methyl-4 , 2-pyrrole ) carbonylimino) )bis ( 1 , 3-naphthalendisulfonic acid) tetrapotassium salt; I.R. (KBr) cm-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 (NT+H) ; 1311 ( (M*+K) ; 7,7' -(carbonyl-bis( imino-N-methyl-4 , 2-pyrrolecarbonyl-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 ( 1H,d,J=l .7 ) ; 7.38 (lH,dd,J=2.0,J=9.5) ; 7.92 (lH,bs); 8.10 ( lH,d, J=l .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-methyl-4 , 2-pyrrolecarbonyl-imino(N-methyl-4 , 2 -pyrrole ) carbonylimine- ) ) bis ( 2 , 4-naphthalendisulfonic acid) tetrasodium salt; N.M.R. (DMSO-de): 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) run : λ max (E^ ) : 307 (435); 231 (932) 1209 (NT+l); 1231 (M*+Ne) 1128 (WT-SOa); 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) cnr1 : 3440 b, 1640, 1590, 1190, 1030 N.M.R. (DMSO-de): 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-iraino ( N -methy 1- 4 , 2 -pyrrole ) carbonylimino ) ) bis ( 5-naphthalensulfonic acid) disodium salt; N.M.R. (DMSO-de): δ 3.85 (6H,s); 6.84 ( lH,d, J=l .8 ) ; 7.05 (lH,d,J=1.8) ; 7.25 (lH,d,J=1.8) ; 7.35 ( 1H ,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 ^ : 310 (531); 227 (1043) F.A.B. M.S. m/z : 1005, (M^+H); 1027 (M-+Ne ) ; 512 ; 8,8' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino(N-methyl-4 ,2-pyrrole) carbonylimino) )bis ( 1 , 3-naphthalendisulfonic acid) tetrasodium salt; N.M.R. (D SO-de): 5 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 ( 1H, 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); m : 309.05 (403); 229,65 1209, M*+H; 1231,M*+Ne; 1187, NT-Ne+H; 1129; 640; 618; 614; 592; 2,2 ' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino(N-methyl-4 , 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; (E * ) 522; 8,8' - (carbonyl-bis ( imino-N-methy1-4 , 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) nm : λ max (Εχ^) : 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-methyl-4 , 2-pyrrolecarbonyl-imino ( -me thy 1 - 4 , 2-pyrrole ) carbonylimino ) ) bis ( 3 -naphthalensulfonic acid) disodium salt; I.R. ( KBr ) cm-1 : 3430 b, 1640, 1585, 1200, 1030 N.M.R. (DMSO-de): 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).

U.V. (H20) nm : λ max : 304 ( 366); 226 (1002) F.A.B. M.S.:ra/z 1005, M^+H; 1027, M^+2Na; 8,8' -(carbonyl-bis( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino(N-met yl-4 , 2 -pyrrole ) carbonylimino ) )bis ( 1-naphthalensulfonic acid) disodium salt; N.M.R. (DMSO-de): 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 ( 1H ,dd , J=l .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-J) : 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) tetrasodi m salt; 7 ,7 ' -(carbony1-bis ( imino-N-methyl-4 , 2-pyrrolecarbony1-imino(N-methyl-4 , 2-pyrrole ) carbonylimino ) )bis (2,6-naphthalendisulfonic acid) tetrasodium salt; 7 ,7 ' - (carbony1-bis ( imino-N-methyl-4 , 2-pyrrolecarbony1-imino(N-methyl-4 , 2-pyrrole ) carbonylimino ) )bis ( 1 , 5-naphthalendisulfonic acid) tetrasodium salt; 7,7' -(carbonyl-bis( imino-N-methyl-4 , 2-pyrrolecarbonyl-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(N-methyl-4 , 2-pyrrole ) carbonylimino) )bis (2,3-naphthalendisulfonic acid) tetrasodium salt; 8,8' -(carbonyl-bis( imino-N-methyl-4 , 2-pyrrolecarbonyl- imino(N-methyl-4 , 2-pyrrole ) carbonylimino ) ) bis ( 1 , 6 naphthalendisulfonic acid) tetrasodium saltier' -(carbonyl-bis( imino-N-methyl-4 , 2-pyrrolecarbonyl imino(N-methyl- 4 , 2-pyrrole ) carbonylimino ) )bis ( 2 , 6 naphthalendisulfonic acid) tetrasodium salt; 8 , 8 ' - (carbony1-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino(N-methyl-4 , 2-pyrrole ) carbonylimino) )bis ( 2 , 5 naphthalendisulfonic acid) tetrasodium salt; 8,8' - (carbony1-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl imino(N-methyl-4 , 2-pyrrole ) carbonylimino ) )bis ( 3 , 6 naphthalendisulfonic acid) tetrasodium salt; 8,8' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino ( N-met yl- 4 , 2-pyrrole Jcarbonylimino) )bis( 2,3,5-naphthalentrisulfonic acid) hexasodium salt, 8 , 8 ' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino ( -methy1-4 , 2-pyrrole )carbonylimino) )bis (1,4,6-naphthalentrisulfonic acid) hexasodium salt; 8,8' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino(N-methyl-4 , 2-pyrrole )carbonylimino) )bis( 2 ,4,6-naphthalentrisulfonic acid) hexasodium salt; 7,7' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-iraino ( -methyl - 4 , 2 -pyrrole ) carbonylimino ) )bis( 1-naphthalensulfonic acid) disodium salt; 7 ,7 ' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino ( -methy 1- 4 , 2 -pyrrole ) carbonylimino ) )bis( 2-naphthalensulfonic acid) disodium salt; 7 ,7 ' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino ( N-methy 1- 4 , 2 -pyrrole ) carbonylimino ) ) bis ( 3-naphthalensulfonic acid) disodium salt; 7 ,7 ' - ( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-iraino ( N-me thyl- 4 , 2 -pyrrole ) carbonylimino ) ) bis ( 4-naphthalensulfonic acid) disodium salt; 7,7' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino ( -methyl - 4 , 2-pyrrole ) carbonylimino) )bis ( 1 , 4 , 6-naphthalentrisulfonic acid) hexasodium salt; 7,7' -(carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl- imino ( N-methy1 -4,2-pyrrole ) carbonylimino) )bis ( 1 , 3 , 6- naphthalentrisulfonic acid) hexasodium salt; 7 ,7 ' - ( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl- imino ( N-methy1- 4 , 2-pyrrole ) carbonylimino ) )bis (2,4,6-naphthalentrisulfonic acid) hexasodium salt; and 7,7' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino ( -methy1 - 4 , 2-pyrrole ) carbonylimino ) ) bis (2,3,5-naphthalentrisulfonic acid) hexasodium salt.

EXAMPLE 2 8,8' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrolecarbonyl-imino(N-methyl-4 , 2-pyrrole ) carbonylimino ) ) -bis (3,5-naphthalenedisulfonic acid) .

A solution of 8,8' -( carbonyl-bis ( imino-N-methyl-4, 2-pyrrolecarbonyl-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-pyrrolecarbonyl-imino(N-methyl-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. 109235/2

Claims (4)

1. CLAIMS Use of a compound of formula 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 apceptable salt thereof ; in the preparation of a pharmaceutical composition for use in the treatment of lentivirus infection, substantially as described in the specification.

2. Use according to claim 1 wherein the lentivirus is a human immunodeficiency virus.

3. Use according to claim 1 wherein m and n are each 2.

4. Use according to any one of claims 1 to 3 wherein the compound is: 7,7' -(carbonyl-bis( imino-N-methyl-4 , 2-pyrrole carbonylimino(N-methyl-4 , 2-pyrrole ) carbonyl iraino) )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-pyrrole carbonyl imino ( N-methyl-4 , 2-pyrrole ) carbonyl-imino) )bis (1,3, 6-naphthalentrisulfonic acid) ; 7,7' -( carbonyl-bis( imino-N-methyl-4 , 2-pyrrole-carbonylimino ( N-methyl-4 , 2-pyrrole ) carbonyl-imino) )bis ( 1 , 3-naphthalendisulfonic acid) ; 7,7' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole-carbonyl imino (N-methyl-4 , 2-pyrrole ) carbonyl-imino) )bis ( 2 , 4-naphthalendisulfonic acid) ; 8 , 8 ' - ( carbonyl-bis( imino-N-methyl-4 , 2-pyrrole carbonylimino(N-methyl-4 , 2-pyrrole ) carbonyl imino) )bis ( 2 , 4-naphthalendisulfonic acid) ; 8,8' - (carbonyl-bis( imino-N-methyl-4 , 2-pyrrole carbonyl imino (N-methyl-4 , 2-pyrrole ) carbonyl imino) )bis (1,3, 5-naphthalentrisulfonic acid) ; 8,8' - (carbonyl-bis( imino-N-methyl-4 , 2-pyrrole carbony limino (N-methyl- 4 , 2-pyrrole ) carbonyl imino) )bis ( 5-naphthalensulfonic acid) ; 8,8' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole carbonyl imino ( -methyl-4 , 2-pyrrole ) carbonyl imino) )bis ( 1 , 3-naphthalendisulfonic acid) ; 8,8' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole carbonyl imino ( N-methyl- 4 , 2-pyrrole ) carbonyl imino) )bis( 3 , 5-naphthalendisulfonic acid) ; 8,8' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole' c arbonyl imino ( -methyl- 4 , 2-pyrrole ) carbonyl imino) )bis ( 1 , 5-naphthalendisulfonic acid) ; 8,8' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole-carbonylimino(N-methyl-4 , 2 -pyrrole ) carbonyl-imino) )bis ( 3-naphthalensulfonic acid) ; 8,8' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole-carbonyl imino (N-methyl- 4 , 2-pyrrole ) carbonyl-imino) )bis( 1-naphthalensulfonic acid) ; 2,2' - (carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole c arbonyl imino (N-methyl-4 , 2-pyrrole ) carbonyl imino) )bis( 1 , 5-naphthalendisulfonic acid) ; 7 ,7 ' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole carbony limino (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-c a rbonyl imino (N-methyl- 4 , 2-pyrrole ) carbonylimino ) ) bis ( 2 , 3-naphthalendisulfonic acid) ; 8,8' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole-carbonyl imino (N-methyl-4 , 2-pyrrole ) carbonylimino) )bis( 1 , 6-naphthalendisulfonic acid) ; 8.8 ' - ( carbonyl-bis ( imino-N-methyl-4 , 2 -pyrrole-carbony1 imino (N-methyl-4 , 2 -pyrrole ) carbonylimino) )bis( 2 , 6-naphthalendisulfonic acid); 8,8' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole-carbonyl imino (N-methyl-4 , 2-pyrrole ) carbonylimino) ) bis ( 2 , 5-naphthalendisulfonic acid) ; 8 , 8 ' - ( carbonyl-bis ( imino-N-methyl-4 , 2 -pyrrole-carbony 1 imino ( -methyl-4 , 2-pyrrole ) carbonylimino) ) bis ( 3 , 6-naphthalendisulfonic acid) ; 8 , 8 ' - ( carbonyl-bis ( imino-N-methy1- 4 , 2 -pyrrole carbonylimino(N-methyl-4 , 2-pyrrole ) carbonyl imino) )bis( 2 , 3 , 5-naphthalentrisulfonic acid) ; 8,8' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole carbonyl imino (N-methy1-4 , 2-pyrrole ) carbonyl imino ) ) bis ( 1 , 4 , 6-naphthalentrisulfonic acid) ; 8,8' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole c arbony 1 imino (N-methyl- 4 , 2-pyrrole ) carbonyl imino) ) bis (2,4, 6-naphthalentrisulfonic acid); 7,7 ' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole carbonyl imino (N-methy1-4 , 2-pyrrole ) carbonyl' imino) )bis ( 1-naphthalensulfonic acid) ; 7,7' -( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole' carbonyl imino ( N-methyl- 4 , 2-pyrrole ) carbonyl' imino) ) bis ( 2-naphthalensulfonic acid); 7 ,7 ' -( carbonyl-bis ( imino-N-methyl-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 carbony 1 imino ( -methy1-4 , 2-pyrrole ) carbonyl imino) ) bis ( 4-naphthalensulfonic acid) ; 7 ,7 ' - ( carbonyl-bis ( imino-N-methyl-4 , 2-pyrrole carbonylimino(N-methyl-4 , 2-pyr ole ) carbonyl imino) )bis (1,4, 6-naphthalentrisulfonic acid) ; - 37 - 109235/2 7 , 7 ' - ( carbonyl-bis ( imino-N-methy1 - 4 , 2 -pyrrole-carbonylimino(N-raethyl-4 , 2 -pyrrole ) carbonyl- imino ) ) bis ( 1 , 3 , 6-naphthalentrisulfonic acid ) ; 7 , 7 ' - ( carbonyl-bis ( imino-N-methy1- 4 , 2-pyrrole-carbonylimino( N-methyl- 4 , 2 -pyrrole ) carbonyl-imino ) ) bis ( 2 , 4 , 6-naphthalentrisulfonic acid); or 7 , 7 ' - ( carbonyl-bis ( imino-N-methy1 - 4 , 2 -pyrrole -carbonylimino( -methy1-4 , 2 -pyrrole ) carbonyl-imino) )bis( 2,3, 5-naphthalentrisulfonic acid) ; or a pharmaceutically acceptable salt thereof. A use according to any one of claims 1 to 4 wherein the pharmaceutically acceptable salt is the sodium or potassium salt. Use according to any one of claims 1 to 5 wherein the pharmaceutical composition 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. 109235/3 - 38 - 7: Pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 and 3 to 5 and a second active agent selected from an agent that affects reverse transcriptase, an antimicrobial agent and an antitumor agent or a mixture of two or more thereof as a combined preparation for simultaneous, separate or sequential use in the treatment of a human patient suffering from lentivirus infection. 8. A pharmaceutical composition comprising a compound of formula (I) in claim 1 for use in the treatment of lentivirus infection. 9. A compound of formula (I) in claim 1 for the treatment of lentivirus infectio . For the Applicajits, REINHOLI TOHN AND PARTNERS