AU670194B2

AU670194B2 - Biologically active ureido derivatives useful in the treatment of lentivirus-induced disease

Info

Publication number: AU670194B2
Application number: AU65371/94A
Authority: AU
Inventors: Giovanni Biasoli; Marina Ciomei; Maria Cristina Geroni; Maria Grandi; Nicola Mongelli
Original assignee: Farmitalia Carlo Erba SRL; Carlo Erba SpA
Current assignee: Pfizer Italia SRL
Priority date: 1993-04-16
Filing date: 1994-03-29
Publication date: 1996-07-04
Anticipated expiration: 2014-03-29
Also published as: NO944809D0; NO944809L; KR950701812A; RU94046312A; HU9500120D0; WO1994023718A1; IL109235A; CA2137148A1; RU2142798C1; EP0646004A1; NO307126B1; PL306798A1; JPH07508044A; GB9307948D0; IL109235A0; HUT71838A; AU6537194A; UA42693C2; CZ282988B6; TW308593B

Description

_I I I_ L WO 94/23718 PCT/EP94/00984 1 "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 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 is a 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.

I ~L WO 94/23718 PCT/EP94/00984 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.

WO 91/10649 provides ureido derivatives of poly-4amino-2-carboxyl-l-methylpyrrole compounds which have angiogenesis inhibitor activity and TNF-a 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-c 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.

I WO 94/23718 PCT/EP94/00984 3 Accordingly the present invention provides the use of a compound of formula (I)

NH

0 N NH-R (I) m n 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 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 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 __ReL_ I WO 94/23718 PCT/EP94/00984 4 of lentivirus-induced disease in a human patient suffering from lentivirus infection.

The substituted naphthyl group is preferably a 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 3- and 5- or 1, 3- and 6positions. When it is substituted by 2 acid groups the sulfonic acid substituents are preferably in the 1- and 1- and 3- and 5- or 3- and 6-positions. When it is substituted by one acid group the sulfonic acid substituent is preferably in the 3- or The invention also includes within its scope all the possible isomers, stereoisomers and their mixtures and the metabolites and the metabolic precursors or bioprecursors of the compounds of formula As already said, the invention includes within its scope also the pharmaceutically acceptable salts of the compounds of formula 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-methylglucamine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N-ethylpiperidine, N,N-diethylaminoethyl- WO 94/23718 PCT/EP94/00984 5 amine, N-ethylmorpholine, B-phenethylamine, N-benzyl- -B-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 bioprecursors (otherwise known as pro-drugs) of the compounds of formula i.e. compounds which have a different formula to formula above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula Preferred compounds of formula 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-methyl-4,2-pyrrole)carbonylimino))bis(3,5- -naphthalendisulfonic acid); 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))bis(3,6naphthalendisulfonic acid); 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))bis(1,3,5naphthalentrisulfonic acid); WO 94/23718 PCT/EI'94/00984 8,81 -(carboriyl-bis iiino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,3,6naphthalentrisulfonic acid); 7,7' -(carbonyl-bis irino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,3naphthalendisulfonic acid); 7,7' -(carbonyl-bis imino-N-methyl-4 ,2-pyrrolecarbonylirino(N-methyl-4,2-pyrrole)carbony Iimino) )bis(2,4naphthalendisulfonic acid);I 8,8' -(carbonyl-bis (imino-N-rnethyl-4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,4naphthalendisulfonic acid); 8,8' -(carbonyl-bis irino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,3,5naphthalentrisulfonic acid); 8,8' -(carbonyl-bis imino-N-methyl-4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylinino))bis(5naphthalensulfonic acid); 8,81 -(carbonyl-bis imino-N-methyl-4 ,2-pyrrolecarbonylirino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,3naphthalendisulfonic acid); 8,8' -(carbonyl-bis (imino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) naphthalendisulfonic acid); 8,8'-(carbonyl-bis( imino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylinino) )bis( WO 94/23718 WO 9423718PCTIEP94/00984 -7 -naphthalendisulfonic acid); 8,8' -(carbonyl-bis irino-N-methyl-4, 2-pyrrolecarbonylimi no me thy1-42-pyrrole)carbonylimiino) )bis(3naphthalensulfonic acid); 8,81 -(carbonyl-bis irino-N-rnethyl-4 ,2-pyrrolecarbonylimi no(N -me thy 1- 4, 2-pyrrole) carbonylimino) )bis(lnaphthalensulfonic acid); 2,2 carbonyl-bis (imino-N-methyl-4 ,2-pyrrolecarbonylimino (N-rethyl- 4, 2-pyrrole) carboriylimino) bis (1,5 naphthalendisulfonic acid); 7,7' (carbonyl-bis imino-N-rnethyl- 4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,6naphthalendisulfonic acid); 7,7' (carbonyl-bis imino-N-rnethyl-4 2-pyrrolecarbonylirino(N-rethyl-4,2-pyrrole)carbonylimino) )bis(2,6naphthalendisulfonic acid); 7,7 (carbonyl-bis (imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) naphthalendisulfonic acid); 7,7 (carbonyl-bis (irnino-N-methyl-4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) naphthalendisulfonic acid); 7,7' (carbonyl-bis imino-N-rnethyl-4 2-pyrrolecarbonylimino(N-rethyl-4,2-pyrrole)carbonylimino) )bis(2,3naphthalendisulfonic acid); 8,8' (carbonyl-bis imino-N-methyl-4 2-pyrrolecarbonyl- WO 94/23718 WO 9423718PCT/EP94/00984 8- -imino(N-rnethyl-4,2-pyrrole)carboy 2 imilo) )bis(1,6naphthalendisulfonic acid); 8, 81-(carbonyl-bis (imino-N-methyl-4, 2-pyrrolecarbonylixino(N-methyl-4,2-pyrrole)carboflylimiflo))bis(2, 6 naphthalendisulfonic acid); 8,8'-(carbonyl-bis(imino-N-methyl-4 ,2-pyrrolecarbonylimino(N-rnethyl-4,2-pyrroe)carboyJ~lifno) naphthalendisulfonic acid); 88 -(carbonyl-bis imino-N-methyl-4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbolimilo) )bis( 3,6naphthalendisulfonic acid); 8,8' -(carbonyl-bis( imino-N-methyl-4 ,2-pyrrolecarbonylirnino(N-methyl-4,2-pyrrole)carbonylimilo) )bis(2,3,5naphthalentrisulfonic acid); 8,8' -(carbonyl-bis (imino-N-methyl-4,2-pyrrolecarbOflyliniino(N-methyl-4,2-pyrrole)carbonylimilo) )bis(1,4,6naphthalentrisulfonic acid); 8,8' -(carbonyl-bis imino-N-rnethyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimilo) )bis(2,4,6naphthalentrisulfonic acid); 7,7 carbonyl-bis (imino-N-rnethyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carboiylimiflo))bis(l1 naphthalensulfonic acid); 7,7' -(carbonyl-bis irino-N-rnethyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimiflo))bis(2naphthalensulfonic acid); WO 94/23718 PCT/FP94/00984 9423 18PTE9/0 7,7 -(carbonyl-bis (imino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) )bis(3naphthalensulfonic acid); 7,7' -(carbonyl-bis (imino-N-methyl-4 ,2-pyrrolecarbonyliiino (N -me thyl1-4, ,2-pyrrole) carbonylimino) )bis(4naphthalensulfonic acid); 7,7 carbonyl-bis (imino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) )bis(1,4,6naphthalentrisulfonic acid); 7,7' -(carbonyl-bis (irino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methiyl-4,2-pyrrole)carbonylimino) )bis(1,3,6naphthalentrisulfonic acid); 7,7' carbonyl-bis (imino-N-methyl- 4 ,2-pyrrolecarbonylirino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,4,6naphthalentrisulfonic acid); 7,7' -(carbonyl-bis Cirino-N-methyl-4 ,2-pyrrolecarbonylimino(N-rnethyl-4,2-pyrrole)carbonylimino) )bis(2,3,5naphthalentrisulfonic acid); and the pharmaceutically acceptable salts thereof, in particular the sodium or potassium salt.

The compounds of formula 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).

WO 94/23718 PCT/EP94/00984 10 For instance the representative compounds of the invention 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))bis(1,3,5naphthalentrisulfonic acid) hexasodium salt; 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))bis(3,5naphthalendisulfonic acid) tetrasodium salt; and 7,7'-(carbonyl-bis(imino-N-methyl- 4 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))bis(1,3naphthalendisulfonic 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 WO 94/23718 PCT/EP94/00984 11 syndrome 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 or pharmaceutically acceptable salts thereof can be administered by usual routes, for example, parenterally, e.g. by intravenous injection or infusion, intramuscularly, subcutaneously, topically br 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 for example 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino)bis(1,3,5naphthalentrisulfonic 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 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 WO 94/23718 PCT/EP94/00984 12 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 WO 91/23718 PCT/EP94/(0984 13 instance, lecithin, polysorbates, laurylsul ;es; 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 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 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 WO 94/23718 PCT/EP94/00984 14 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. 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 arninoglycoside (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 WO 94/23718 PCT/EP94/00984 15 response to changes in conditions and/or in light of other clinical conditions.

The compounds of formula and the pharmaceutically acceptable salts thereof can be obtained according to WO 91/10649, for instance by reacting a compound of formula (II) H2N

NH

N

0

N(II)

I 0 CH- n-1 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 thus obtained; and/or, if desired, obtaining a free compound of formula 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 WO 94/23718 I'CT[EP94/00984 16 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 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 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, hexamethylphosphotriamide, dimethylacetamide or, preferably, dimethylformamide, or their aqueous mixtures, or in water/ dioxane or water/toluene mixtures, in the presence of either an organic base such as triethylamine or diisopropylethylamine, or an inorganic base such as sodium bicarbonate or sodium acetate. The reaction temperature WO 94/23718 I'CT/EP94/00984 17 may vary from about -10 0 C to about 50°C and the reaction time from about 1 to about 12 hours.

The compounds of formula 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 compdund 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 into a free product and the conversion of a compound of formula into a pharmaceutically acceptable salt t ereof.

WO 94/23718 PCT/EP94/00984 18 The following examples further illustrate the present invention: EXAMPLE 1 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))bis(3,5naphthalendisulfonic acid) tetrasodium salt.

To a solution of 8-(amino-N-methyl-4,'2-pyrrolecarbonylimino(N-methyl-.4,2-pyrrole)carbonylimino)) naphthalendisulfonic acid) disodium salt hydrochloride (1256 mg, 2 mmols) in water (60 ml) and dioxane ml), NaOH 1N (2 ml) and sodium acetate (328 mg, 4 mmols) was added under stirring.

The whole was cooled to 5 0 C with an ice bath, then a solution of bis(trichloromethyl)carbonate (149 mg, 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-d 6 6 3.85 6.83 (lH,d,J=1.8); 7.06 7.26 7.38 (1H,d,J=1.08); WO 94/23718 WO 94/3718 CT[LP94/00984 19 7.50 (1H,d,J=7.8); (1H,dd,J=1.7,J=8.9); 8,25 (lH,bs); 9.91 (lH,bs); (lH,bs); 7 .72 7 .98 9.19 10.03 U.V. rim X max (E 1 310 (431); 231 (1027) F.A.B. M.S. m/z :1209, MW+H; 640; 618; 614; 592.

By proceeding analogously, the following compounds can be prepared: 7,7' -(carbonyl-bis (imino-N-methyl-4 ?--yrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) naphthalendisulfonic acid) tetrasodium salt; N.M.R. (DI4SO-d, 6 5 3.85 3.90 6.81 6.90 (lH,d,J=1.8); 7.12 7.32 7.70 (lH,dd,J=1.6, 7.80 (1H,d, 8.11 8.15 (1H, bs), 8.58 8.78 (lH,d, J=1.7); 10,05 (1H,bs); 10.94 (1H,bs); WO 94/237 18 PTE9/08 IICTIEI'94/00984 20 F.A.B. M.S. m/z: 1209, 1187, M'-Ne+H; U.V. (H 2 0) run max (E 1% :321 (416); 231 (721); 7,7 1 -(carbonyl-bis imino-N-methyl-4 ,2-pyrrolecarbonylimino(N-rethyl-4,2-pyrrole)carbonylimino) )bis(3,6naphthalendisulfonic acid) tetrasodium salt; N.M.R. 8 3.85 3.93 6.81 6.91 (1H,d,J=1.8); 7.08 7.51 7.68 (lH,dd,J=1.6, 7.78 8.04 8.12 (1H,bs); 8.23 (lH,s); 8.89 10',02 (1H,bs); 10,98 (1H,bs); F.A.B. M.S. m/z: 1209, 1187, M'-Ne+H; U.V. (H, 2 0) rn max (E 1% 323,4 (540); 227,7 (732); 7,7 carbonyl-bis (imino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino))bis(1,3,5naphthalentrisulfonic acid) hexasodium salt; WO 94/23718 WO 94/3718 CTIP94/00984 21 N.M.R. 5 3.85 (3H,s); (lH,d,J=1.8); 7 .22 (1H,d (lH,d,J=1.8); 8.30 (lH,bs); (1H,bs) 9.07 (lH,bs); 10,20 3.89 6.78 7.08 (1H,dJ=1.8); 7.35 (1H,d,J=1.9); 8.36 (1H,bs); 9.00 (1H, d,J=1.6) 9. 82 (lH,bs); U.V. (H 2 0) rm Xmax (E 1% 320 (374); 254 (444); 8,8' -(carbonyl-bis (imino-N-methyl- 4 ,2 -pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbolyliio) )bis(1,3,6naphthalentrisulfonic acid); hexasodium salt; N.M.R. 8 3.84 3.88 6.81 7.07 (lli,d,J=1.8); 7.11 7.42 7.87 (lH,d,J=1.9); 7.87 8.06 8.12 (1H,bs); 8,33 9.93 (1H,bs); 12.1.9 (1H,bs); U.V. rim max (E 1 320 (374); 254 (444); 7,7' -(carbonyl-bis (imino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carboflylimilo) )bis(1,3naphthalendisulfonic acid) tetrapotassiun salt; WO 94/23718 I'CT/EP94/00984 22 I.R. (KiBr) cm-' 3450 1650; 1580; 1530; 1190; 1030 N.M.R. (DMSO-d 6 8 3.84 3.87 6.80 (1H,d) 7. 05 (1H,d; 7. 18 (1H,d) 7.33 7.86 (2H,m);8.00 8.16 (1H,bs); 8.21 8,95 (1H,bs); 9,86 (1H,bs); 10.21*(1H,bs); U.V. rm :X max (E 1 316.8 (371); 248.95 (444) F.A.B. D4.J. m/z :1273 1311 7,71 -(carbonyl-bis imino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2,4naphthalendisulfonic acid) tetrasodium salt; N.M.R. 5 3.85 3.89 6.81 7.06 (1H,d,J=1.7); 7.22 7.33 7.33 (1H,d,J=1.7); 7.38 (1H,dd,J=2.0,3=9.5); 7.92 (1H,bs); 8.10 8.20 (1H,bs); 8,32 8,69 9.88 (1H,bs); 10.08 (lH,bs); WO 94/23718 WO 94/3718 CT[E P94/00984 23 8, 8 (carbonyl-bis imino-N-rnethyl- 4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonyliio) )bis(2, 4naphthalendisulfonic acid) tetrasodiun salt; N.M.R. 8 3.85 6.81 (1H,d,J 1.7 Hz); 7.06 (1H,d,J 1+Hz); 7.25 (1H,d,J 1.7 Hz); 7.34 (lH,d,J 1.7 Hz); 7.4 7.6 8.14 (1H,bs);8.25 8.73 (1H,dd,j 13 Hz, J =8,3 Hz); 9.92 (1H,bs); 10.07 (1H,bs); U.V. (H, 2 0) Dn X max (E 1 307 (435); 231 (932) F.A.B. rn/z 1209 1231 8,8' -(cari-ony1-bis iiino-b4-rethyl-4, 2-pyrrolecarbonylimino(N-raethyl-4,2-pyrrole)carbonylimino) )bis(1,3,5naphth-alentrisulfonic acid) hexasodiun salt; WO 94/23718 24 I.R. (KBr) cm-' 3440 b, 1640, 1590, 1190, 1030 N.M4.R. (DMSO-d,): 8 3.80 3.83 6.80 7.06 7.40 (1H,d); 7.88 7.99 (1H,d);8.02 (1H,bs); 8.57 9.33 (1H,d); 9.91 (1H,bs); 12.29 (1H,bs).

U.V. rn X max (E 1% 311 t266); 233 (551) m/z 1411, M--H;1389, M--Na; 8,8 (carbonyl-bis (imino-N-rnethyl- 4, 2-pyrrolecarbonylimino (N -mnethy 1- 4, 2-pyrrole) carbonylinino) naphthalensulfonic acid) disodiun salt; N.M.R. (DI4SO-d,,): 8 3.85 6.84 (lH,d,J=1.8j; 7.05 (1H,d,J=1.8tp; 7.25 7.35 (1H,d,J=1.8); 7.46-7.56 7.92-8.00 8.15 (lH,bs); 8,87 (1H,m); 9,89 (1H,bs); 10.03 (1H,bs); U.V. m max (E 1% 310 (531); 227 (1043) F.A.B. M.S. m/z 1027 (M'+Ne);512; WO 94/23718 WO 94/2718 P '94/00984 25 8, 81-(carbonyl-bis (irnino-N-methyl-4, 2-pyrrolecarbonylimino(N-rethyl-4,2-pyrrole)carbonylimino) )bis(1,3naphthalendi.--iulfonic acid) tetrasodiwn salt; N.M.R. 8 3.84 3.86 6.82.

7.08 (2H,bs); 7.41 1H,d,J=1.8); 7.50 (1H,t,J=7.0); 7.78 (1H,dJ=7.0); 8.02 8.11 8.53 (1H,d,J=2.02); 9~.93 (1H,bs); 12.2.

(2.H,bs); U.V.(H20 run I ma (E1% 390 43;296

U.V.(H

2 0 nin X ma (Ecm) 390 (4);2,6 735 F.A.B. M.S. m/z :1209, 1231,MW+Ne; 1187, M'-Ne+H; 1129; 640; 618; 614; 592; 2,2'-(carbony2.-bis( imino-N-methyl-4, 2-pyrrolecarbonylimino(N-niethyl-4,2-pyrrole)carbony.iino) naphthalendisulfonic acid) tetrasodiun salt; N.M.R. (DM 8 0-dG): 3.85 (3H, 3.91 6.90 (1H, d, 6.98 (1H, d, 7.09 (iH, d, 7.35 (1H, dd, J=7, 7.47 (1Hi, d, 7.9 (iH, d, 9.15 WO 94/23718 WO 94/3718 CT[EP94/00984 26 (1Hi, bs); 8.67-8.82 (2H, ad, 8.99 (1H, d, 9.98 (1H, bs); 12.64 (1H, bs).

F.A.B. m/z 1207, 1185, [r4-233V; 1105 (M-SONa)-.

U.V. rim :X max 298; (El 1% 522; 1cm 8,8 '-(carbonyl-bis irino-N-rnethyl-4 ,2-pyrrolecarbonylimino(N-rethyl-4,2-pyrrole)carbonylimino) naphthalendisulfonic acid) tetrasodium salt; I.R. (KBr) cnV 1 3440 b, 1660, 1640, 1585, 1180, 1030.

N.M.R. (DMSO-de): 8 3.84 3.85 (311,s); 6.80 lH,d); 7.07 (211,m); 7.41 211,m); 7.92 (2H,dd); 8.12 (1.12 (1H,s); 8,27 (1H,dd); 9.07 (1H,dd); 9.90 (lH,bs); 12.27 (lH,bs).

U.V. (1120) 1'im )max (E 1 316 (331); 229 (478) F.A.B. m/z 1209, 1231, M'+23; 1128, 8,8' -(carbonyl-bis( iwr.no-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) )bis(3naphthalensultonic acid) disodium salt; WO 94/23718 WO 94/3718 CT/EP94/00984 27 I.R. (KBr)cm-': 3430 b, 1640, 1585, 1200, 1030 8 3.84 (61i,s); 6.86 7.05 7.24 7.35 (1H,d) 7.54 (2H,m) 7.70 (1H,dd) 7.90 8.15 8.15 (1H,d); 8.95 (lH,bs); 9.94 (1H,bs); 10.03 (1H,bs).

U.V. rim Xmax (E 1 1 304 (366); 226 (1002) F.A.B. M.S. :m/z 1005, MW+H; 1027, MV+2Na; 8,8' -(carbonyl-bis( imino-N-methyl-4 ,2-pyrrolecarbonylirino (N-methyl- 4, 2-pyrrole)carbonylimino) )bis (1naphthalensulfonic acid) disodiun salt; N.M.R. (DMSO-ds): 8 3.84 3.85 6.82 7.06(1H,d,J=1.8); 7.09 7.39-7.54 (3H,xn); 7.74 (1H,dd,J=1.3,J.,.3, 7.93-8.02 8.13 (1H,bs); 8.26 (lH,dd,J=1.5,J=7.3); 9.93 (lh,bs); 12.20 (1H,bs); F.A.B. M.S. m/z 1005, 1027,14'+Ne; U.V. (1120) rm :X max (E1% 312 (490); 224 (831); WO 94/23718 PCT/EP94/00984 28 (carbonyl-bis (imino-N-rnethyl- 4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)car bony limino) )bis(1,6naphthalendisulfonic acid) tetrasodium salt; 7,71 (carbonyl-bis (imino-N-methyl-4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylinino) )bis(2,6naphthalendisulfonic acid) tetrasodiun salt; 7 ,71 -(carbonyl-bis (imino-N--methyl-4 ,2-pyrrolecarbonylinino(N-rrethyl-4,2-pyrrole)carbonylinino) naphthalendisulfonic acid.) tetrasodium salt; 7,7'-(carbonyl-bis(imino-N-methyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) )bis(2, naphthalendisulfonic acid) tetrasodium salt; 7,7' carbonyl-bis ixino-N-methyl- 4, 2-pyrrolecarbonylimino (N-rethyl- 4, 2-pyrrole) carbonylimino) bis (2,3 naphthalendisulfonic acid) tetrasodiun salt; 8,8'1 (carbonyl-bis (imino-N-methyl- 4, 2-pyrrolecarbonylirino(N-rethyl-4,2-pyrrole)carbonylimino) )bis(1,6naphthalendisulfonic acid) tetrasodiun salt; ,81 (carbonyl-bis ixino-N-methyl- 4, 2-pyrrolecarbonylimino (N-methy1- 4, 2-pyrro le) carbony limino) bi s(2,6 naphthalendisulfonic acid) tetrasodiun salt; 8, 8' (carbonyl-bis imino-N-methyl- 4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) naphthalendisulfonic acid) tetrasodium salt; 8,8'1 (carbonyl-bis irino-N-Tnethyl- 4, 2-pyrrolecarbonylimino(N-rethyl-4,2-pyrrole)carbonylimino) )bis(3,6- WO 94/23718 WO 94/3718 CTIEP941/00984 29 naphthaleridisulfonic acid) tetrasodiun salt; 8, 8' (carbonyl-bis imino-N-methyl-4, 2-pyrrolecarbonlylimino (N -me thy1- 4,2-pyrrole) carbonylimino) )bis (2,3,5naphthalentrisulfonic acid) hexasodium salt, 8,8'1 -(carbonyl-bis irino-N-rnethyl-4, 2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonyliiru:no) )bis(1,4,6naphthalentrisulfonic acid) hexasodium salt; 8,8' -(carbonyl-bis( imino-bN-methyl-4 ,2-pyrrolecarbonylimino (N-rnethyl- 4, 2-pyrrole) carbonylimino) )bis 4,6naphthalentrisulfonic acid) hexasodium salt; 7,7' (carbonyl-bis imino-N-methyl- 4, 2-pyrrolecarbonylimino(N-methyl-4 ,2-pyrrole)carbonylinino) )bis(1naphthalensulfonic acid) disodiun salt; 7,7'1 (carbonyl-bis imino-N-methyl- 4, 2-pyrrolecarbonylimino (N -me thy1- 4, ,2-pyrrole) carbonylinino) bis (2 naphthalensulfonic acid) disodium salt; 7,7' (carbonyl-bis imino-N-rnethyl- 4, 2-pyrrolecarbonylim ino (N -methy1- 4, 2-pyrro le)carbonylinino) )bis (3 naphthalensulfonic acid) disodiun salt; 7,7' (carbohyl-bis irino-N-methyl- 4, 2-pyrrolecarbonylirino(N-methyl-4,2-pyrrole)carbonylimino))bis(4naphthalensulfonic acid) disodium salt; 7,7' (carbonyl-bis imino-N-methyl- 4, 2-pyrrolecarbonylimino (N -methyl 2-pyrrole) carbonylimino) bis 6naphthalentrisulfonic acid) hexasodiun salt; 7,7' (carbonyl-bis irino-N-methyl-4, 2-pyrrolecarbonyl- WO 94/23718 WO 9/23 18PCTIE P94/00984 30 irnino(N-methyl-4,2-pyrrole)carbonylimilo) )bis(1,3,6naphthalentrisulfonic acid) hexasodiun salt; 7,7' -(carbonyl-bis (imino-N-rnethyl-4, 2-pyrrolecarbonylimino(N-rnethyl-4 ,2-pyrrole)carbonylimino) )bis(2,4,6naphthalentrisulfonic acid) hexasodiun salt; and 7,7' -(carbonyl-bis imino-N-methyl-4 ,2-pyrrolecarbonylirnino(N-rethyl-4,2-pyrrole)carbonylimino) )bis(2,3,5naphthalentrisulfonic acid) hexasodium salt.

EXAM~PLE 2 8,8' -(carbonyl-bis (iinino-N-rnethyl-4 ,2-pyrrolecarbonylimino(N-methyl-4,2-pyrrole)carbonylimino) naphthalenedisulfonic acid).

A solution of 8,8' -(carbonyl-bis( irino-N-rethyl-4,2pyrrolecarbonj l-imino(t4-methyl-4,2-pyrrole)carbonylirnino) )-bis 5-naphthalenedisulfonic acid) tetrasodium salt (400 mg) in water (10 ml), is chromatographed on an Axberlite 1R-120(H) column (20 ml), with water as eluent.

The solution is evaporated to dryness in vacuum, 210 affording 0.3 g of the title compound.

WO 94/23718 P'CT/EP94/00984 31 EXAM4PLE 3 Intramuscular injection 40 mg/mi.

An injectable pharmaceutical preparation can be manufactured by dissolving 40 g of 8,8'-(carbonylbis(imino-N-methyl-4 ,2-pyrrolecarbonyl-imino(N-methyl- 4, 2-pyrrole)carbonylimino) )-bis( 3, disulfonic acid) tetrasodiun salt in water for injection (1000 ml) and sealing ampoules of 1-10 ml.

Claims

1. A method of treatment of lentivirus infection in a mammal said method comprising administering to said mammal an effective amount of a compound formula (I) NH-R a o r 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.

2. The method according to claim 1 wherein the lentrivirus is a human immunodeficiency virus and the mammal is a human.

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

4. The method according to any one of claims 1 to 3 wherein the compound is: staflryankalkeepspecl65371 94 18496 I r WO 94/23718 WO~~~IM 4/31 T1P94/00984 33 7,71 -(carbonyl-bis( ixino-N-methyl-4 2-pyrrole- carbonylimino(N-methyl-4 ,2-pyrrole)carbonyl- imino) )bis(3,5-naphthalendisulfonic acid); 7,71 -(carbonyl-bis( imino-N-methyl-4 ,2-pyrrole- carbonylimino(N-rnethyl-4,2-pyrrole)carbonyl- imino) )bis( 3,6-naphthalendisulfonic acid); 7,71 (carbonyl-bis inino-N-methyl- 4, 2-pyrrole- carbonylirnino(N-methyl-4 ,2-pyrrole)carbonyl- iinino) )bis( 1,3, 5-naphthalentrisulfonic acid); 8,8'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl- imino) )bis( 1,3, 6-naphthaler~trisulfonic acid); 7,7' (carbonyl-bis imino-N-methyl- 4, 2 -pyrrole- carbonyl1intino (N-methyl- 4, 2-pyrrole) carbonyl- iminio) )bis( 1, 3-naphthalendisulfonic acid); 7,7' -(carbonyl-bis( imino-N-methyl-4 2-pyrrole- carbonylimino(4-rethyl-4, 2-pyrrole) carbonyl- ixuino) )bis 4-naphthalendisulfonic acid); 8,81 -(carbonyl-bis( iiino-N-methyl-4 2-pyrrole- carbonyliniino(N-methyl-4,2-pyrrole)carbonyl- imino) )bis 4-naphthalendisulfonic acid); 8,8' -(carbonyl-bis( imino-N-methyl-4 2-pyrrole- carbonylimino(N-niethyl-4,2-pyrrole)carbonyl- irnino) )bis(1,3,5-naphthalentrisulfonic acid); WO 94/23718 I'CT[EP94/00984 34 8,81 -(carboriyl-bis(irino-N-rethyl-4, 2-pyrrole- c arbonylimino(N-methyl-4, 2-pyrrole) carbonyl- imino) )bis(5-naphthalensulfonic acid); 8,8' carbonyl-bis (imino-N'-methyl- 4, 2-pyrrole- c arbonylimi no(N -me thy 1-4, 2-pyrrole) carbonyl- imino) )bis(1,3-naphthalendisulfonic acid); 8,8' -(carbonyl-bis( imino-N-methyl-4, 2-pyrrole- carbonylinino(N-znethyl-4, 2-pyrrole)carbonyl- iniino) )bis( 3, 5-naphthalendisulfonic acid); 8,81 -(carbonyl-bis(imino-N-methyl-4, 2-pyrrole- carbonyliinino(N-methyl-4 ,2-pyrrole)carbonyl- imino) )bis( 1, 5-naphthalendisulfonic acid); 8,8' -(carbonyl-bis( irino-N-methyl-4, 2-pyrrole- carbonylimino(N-methyl-4 *,2-pyrrole)carbonyl- irnino) )bis(3-naphthalensulfonic acid); s8 1 (carbonyl-bis(imino-N-methyl-4,Z--pyrrole- carbonylinino(N-niethyl-4 ,2-pyrrole) carbonyl- ixuino) )bis(l-naphthalensulfonic acid); 2,2 (carbonyl-bis(imino-N -me thy 1-4, 2-pyrrole- carbonylimino(b4-methyl-4 ,2-pyrrole)carbonyl- imino)~)bis( 1, 5-naphthalendisulfonic acid); 7,7' (carbonyl-bis irino-N-methyl- 4, 2-pyrrole- carbonylimino(N-methyl-4,2-pyrrole)carbonyl- irnino) )bis( 1, 6-naphthalendisulfonic acid); WO 94/23718 IICTtEP94/00984 35 7,7' -(carbonyl-bis(irino-N-methyl-4,2-pyrrole- carbonylimino (N-nethyl-4 2-pyrrole) carbonyl- imino) )bis( 2, 6-naphthalendisulfonic acid); 7,71 -(carbonyl-bis( izino-N-mei::hyl-4 ,2-pyrrole- carbonylimino (-rnethyl-4 ,2-pyrrole) carbonyl- imino) )bis( 1, 5-naphthalendisifonic acid); 7,7' -(carbonyl-bis( imirno-t4-rethyl-4, 2-pyrrole- car bony 1imino (N-mevhyl- 4, 2-pyrrole) carbonyl- imino) )bis(2,5-naphthalendisulfonic acid); 7,7'-(carbonyl-bis(imino-N-methyl-4,2-pyrrole- carbonylimino (N-methyl-4, 2-pyrrole )carbonyl- irnino) )bis( 2, 3-naphthalendisulfonic acid); 8,8' (carbonyl-bis (imino-N-nethyl-4, 2-pyrrole- carbonylimino(N-methyl-4, 2-pyrrole) carbonyl- imino) )bis( 1, 6-naphthalendisulfonic acid); 8,81 -(carbonyl-bis(ixnino-N-rethyl-4,2-pyrrole- carbonylimino(N-methyl-4, 2-pyrrole)carbonyl- iinino) )bis( 2, 6-naphthalendisulfonic. acid); 8, 8'1 (carbonyl-bis imino-N-methyl- 4, 2-pyrrole- c arbo.nyl imino (N-methyl- 4, 2-pyrrole) carbonyl- iinino) )bis( 2, 5-naphthalendisulfonic acid); 8,8 (carbonyl-bis (imino-N-methyl-4, 2-pyrrole- c arbonylimino (N-tnethyl- 4, 2-pyrrole) carbonyl- irnino) )bist 3, 6-naphthalendisulfonic acid); WO 94/23718 I'CT/EP94/00984 36 8,8' -(carbonyl-bis(imino-N-rnethyl-4,2-pyrrole- c a rbony limrino(N-rnethy 1-4, 2-pyrrole) ca~bonyl- imino) )bis(2,3,5-naphthalentrisUlfonic acid); 8,8 (carbonyl-bis(imino-N-methyl-4, 2-pyrrole- c arbonylimino (N-methyl-4,2-pyrrole) carbonyl- imino) )bis(1, 4,6-naphthalentrisulfonic acid); 8,81 -(carbonyl-bis(imino-N-rnethyl-4, 2-pyrrole- car bony Iinino (N-methyl- 4, 2-pyrrole) carbonyl- imino) )bis(2,4,6-naphthalentrisulfonic acid); 7,7'-(carbonyl-bis(inino-N-rethyl-4,2-pyrrole- carbonylimino(N-methyl-4, 2-pyrrole )carbonyl- imino) )bis(l-naphthalensulfonic acid); 7,7'-(carbonyl-bis(irino-Nmethyl-4,2-pyrrole- carbonylimino(N-nethyl-4 ,2-pyrrole) carbonyl- imino) )bis(2-naphthalensulfonic acid); 7,7' (carbonyl-bis( imino-N-methyl-4, 2-pyrrole- carbonylirnino(N-methyl-4, 2-pyrrole) carbonyl- imino) )bis(3-naphthalensulfonic acid); 7,7 (carbonyl-bis(irnino-N -me thy 1-4, 2-pyrrole- carbanylimino (N-rnethyl- 4, 2-pyrrole) carbonyl- iniino) )bis(4-naphthalensulfonic acid); 7,7' -(carbonyl-bis( imino-N-methyl-4 ,2-pyrrole- carbonylinino (N-methyl-4 ,2-pyrrole) carbonyl- iniino) )bis(1., 4,6-naphthalentrisIfonic acid); 37 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- carbonylimino(N-methyl-4,2-pyrrole)carbonyl- imino))bis(2,3,5-naphthalentrisulfonic acid); or a pharmaceutically acceptable salt thereof.

The method according to any one of claims 1 to 4 wherein the pharmaceutically acceptable salt is the sodium or potassium salt.

6. The method according to any one of claims 1 to wherein said manmadl is a human who is seropositive for a lentrivirus disease, stressed or pathological as a result of infection with a lentrivirus or who is suffering from lentrivirus-induced disease wherein said method results in the amelioration of symptoms associated with said seropositive condition, stress, pathology or disease. e

7. The method of any one of claims 1 to 6 wherein a compound of formula or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 and 3 to and a second active agent is administered as a combined preparation either simultaneously, separately or sequentially. DATED THIS 9TH DAY OF MAY 1996. FARMITALIA CARLO ERBA S.R.L. By its Patent Attorneys: GRIFFITH HACK CO Fellows Institute of Patent Attorneys of Australia statfryankaJkop/specU5371 94 18496 n C' INTI'IRNATIONAL SEARCH RPORT INTERNATIONAL SEARCI O International application No. PCT/EP 94/00984 A. CLASSIFICATION OF SUBJECI' MAT'TERl IPC 5 A61K31/40 According to Intemational Patent Classificaton (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) IPC 5 A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the internatonal search n smn: of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category' Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X WO,A,91 10649 (FARMITALIA CARLO ERBA SRL) 1-7 July 1991 cited in the application see page 11, line 4 line 31; claims see page 14 Y JOURNAL OF EXPERIMENTAL PATHOLOGY 1-7 vol. 5, no. 3 1990 pages 111 122 LAU ET AL 'The Role of Interferon and Tumor Necrosis Factor in the Pathogenesis of AIDS' see page 117, paragraph 2 see conclusion Further documents are listed in the continuation of box C. l Patent family members are listed 1i annex. Special categories of cited documents later document published after the international filing date document defining the general state of the art which is not r p yate and ot in confict witho the aplerlyion but considered to be of partcular relevance iton earlier document but published on or after the international "X document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on priority claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referrng to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published prior to the international filing date but in the art. later than the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 19 July 1994 40 oD Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk Tel. (+31-70) 340-2040, Tx. 31 651 epo nl, Uib P Fax: 31-70) 340-3016 Ui P Form PCT/ISA/210 (second sheet) (July 1992) page 1 of 2 r 13 I tNTERN ATI'INAI, SEA RCII R10EPOR'r International application No. PCT/EP 94/00984 C.(Continuation) DOCUMENTS CONSIDERED TO BE1 RELEVANT Category fCitation of document, wvith indication, where appropriate, of thc rclevant pastages Relvant to claim No. Y A AIDS RESEARC'H AND HUMAN RETROVIRUSES vol.

8, no 1992 pages 191 197 POLI ET AL 'The Effect of Cytokines and Pharmacologic Agents on Chronic HIV infection' see page 192, column 2, line 24 line 31 WO,A,92 13838 (SYNPHAR LABORATORIES, INC) August 1992 see claims 1,19 Form, PCTISA/1 0 (continuation of second sheet) (July 1992) page 2 of 2 I NTICIN ATIONAI, Ski'A 14CI ,foflatuon oil patet family members REPORTF International opilcation No. PCT/EP 94/00984 Patent document I Publication IPatent family I Publication cited in search report date member(s) date W0-A-9110649 25-07-91 AU-B- 647446 24-03-94 AU-A- 7059991 05-08-91 CN-A- 1053230 24-07-91 EP-A- 0462258 27-12-91 JP-T- 4504426 06-08-92 US-A- 5260329 09-11-93 WO-A-9213838 20-08-92 AU-A- 1224392 07-09-92 ronn PCT/ISA1310 (patent family annex) (July 1993)