WO1999029309A2 - 2,2'-bi-1h-pyrrole derivatives useful in the treatment of leukemia brought on by htlv-i - Google Patents

2,2'-bi-1h-pyrrole derivatives useful in the treatment of leukemia brought on by htlv-i Download PDF

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Publication number
WO1999029309A2
WO1999029309A2 PCT/EP1998/007774 EP9807774W WO9929309A2 WO 1999029309 A2 WO1999029309 A2 WO 1999029309A2 EP 9807774 W EP9807774 W EP 9807774W WO 9929309 A2 WO9929309 A2 WO 9929309A2
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methyl
pyrrole
ylidene
pyrrol
methoxy
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PCT/EP1998/007774
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French (fr)
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WO1999029309A3 (en
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Francesco Colotta
Mario Ferrari
Maria Chiara Fornasiero
Paola Gnocchi
Anna Maria Isetta
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Pharmacia & Upjohn S.P.A.
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Priority to EP98965212A priority Critical patent/EP0975338A2/en
Priority to JP52997999A priority patent/JP2001511191A/en
Publication of WO1999029309A2 publication Critical patent/WO1999029309A2/en
Publication of WO1999029309A3 publication Critical patent/WO1999029309A3/en

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    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • 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
    • A61K31/4025—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 not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A61K31/403—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 condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

  • the present invention relates to the use of 2, 2 ' -bi-lH- pyrrole compounds in the treatment of adult-T-cell leukemia ly ⁇ phoma, in particular adult-T-cell leukemia-lymphoma, brought on by infection with HTLV-I in mammals, including humans .
  • ATL is an aggressive malignancy of mature activated T cells, associated with human T-cell lymphotropic virus type I infection (HTLV-1) .
  • the virus encodes regulatory proteins which induce malignant transformation of the T-lymphocytes . These proteins increase expression of cell protooncogenes as well as of lymphokines, among other IL-2, and of IL-2R.
  • IL-2 induces autocrine proliferation of T lymphocytes, which is probably the main cause of their transformation and propagation at least in the early phase of the disease.
  • ATL has a poor prognosis with a mean survival time of 6-24 months, due mainly to its resistance to conventional chemotherapy.
  • the present invention provides the use of a compound which is a 2, 2 ' -bi-lH-pyrrole of formula (I)
  • R. is hydrogen, phenyl, C 1 -C 20 alkyl or C 2 -C 20 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, alkoxy, hydroxy, aryl and aryloxy;
  • R. is hydrogen, alkoxy) carbonyl
  • R. is halogen, hydroxy or C ⁇ C ⁇ alkoxy unsubstituted or substituted by phenyl;
  • R is hydrogen, C 1 -C 6 alkyl or phenyl; each of R 5 and R 6) which are the same or different, independently represents hydrogen, C 2 -C 20 alkanoyl, C 3 -C 20 alkenoyl, phenyl, C 1 -C 20 alkyl or C 2 -C 20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C- . -Cg alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (Cj .
  • R c and R d which are the same or different, independently is hydrogen or alkyl or R c and R d , taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring; or two of R 4 , R « and R s taken together form C,-C 12 poly ethylene chain, which is unsubstituted or substituted by C ⁇ -C ⁇ alkyl, C -C alkenyl or C ⁇ -C ⁇ , alkylidene wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by halogen, alkoxy, hydroxy, cyano, carboxy, alkoxy) carbonyl, ary
  • the present invention provides a use as defined above, wherein the medicament is for use in treating the progression of adult-T-cell leukemia-lymphoma, in particular brought on by infection with HTLV-I and in ameliorating clinical symptoms of such proliferative disorder.
  • the invention also provides a method of treating a mammal, including a human subject, suffering from adult-T-cell leukemia- lymphoma, in particular brought on by infection with HTLV-I, which comprises administering to said mammal an effective amount of a compound as defined above.
  • a mammal including a human subject, suffering from adult-T-cell leukemia- lymphoma, in particular brought on by infection with HTLV-I, which comprises administering to said mammal an effective amount of a compound as defined above.
  • R 1( R 2 , R 3 , R 4 , R 5 and R 6 are as defined above, * as described in WO 95/17381.
  • a halogen atom is preferably chlorine or fluorine.
  • alkyl, alkoxy, alkenyl, alkanoyl, alkenoyl, alkadienoyl and alkylidene groups may be branched or straight chain groups .
  • An aryl group as a substituent as well as a moiety in an aryloxy, aralkyl or arylcarbamoyl group is, e.g., an aromatic
  • C 6 -C 20 mono- or poly-nuclear moiety typically phenyl, unsubstituted or substituted by one or two substituents independently chosen from halogen, hydroxy, alkyl and C L - C 6 alkoxy.
  • an aralkyl group is e.g. benzyl or phenethyl, in which the phenyl ring is optionally substituted by one or two substituents independently chosen from halogen, hydroxy, C x -
  • a C 4 -C 12 polymethylene chain is e.g. a C 4 -C 9 polymethylene chain .
  • a C 3 -C 4 or C 3 -C e alkenyl group is preferably an allyl group.
  • Ci-Cg alkyl group is preferably a C ⁇ - j alkyl group, in particular a methyl or ethyl group.
  • a alkyl group is preferably a C ⁇ - j alkyl group, in particular a methyl or ethyl group.
  • An unsubstituted C ⁇ -C ⁇ alkoxy group is preferably a C,_-C 4 alkoxy or alkoxy group, typically methoxy, ethoxy, propoxy, butoxy and undecyloxy.
  • Ci-Cj alkoxy group substituted by phenyl is preferably a phenyl-C 1 -C 4 alkoxy group, typically benzyloxy or phenylethoxy .
  • a C 1 -C 20 alkyl group is preferably a C 5 -C 14 alkyl group , in particular an undecyl group .
  • a C 2 -C 20 alkenyl group is preferably a C 5 -C 14 alkenyl group , in particular an undecenyl group .
  • a C 2 -C 20 alkanoyl group is preferably a C 5 -C 14 alkanoyl group , in particular an undecanoyl group .
  • a C 3 -C 20 alkenoyl group is preferably a C 5 -C 14 alkenoyl group, in particular an undecenoyl group.
  • a alkylidene group is preferably a alkylidene group, in particular a C 4 -C 5 alkylidene group.
  • a C 2 -C 12 alkenyl group is preferably a C 3 -C 6 alkenyl group.
  • Examples of pharmaceutically acceptable salts of a compound of formula (I) 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, dibenzylamine, methylbenzylamine, di- (2-ethyl-hexyl) -amine, piperidine, N- ethylpiperidine, N,N-diethylaminoethylamine, N- ethylmorpholine, ⁇ -phenethylamine, N-benzyl- ⁇ -phenethylamine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines, as well as the salts with inorganic, e.g. hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric,
  • Preferred compounds of the present invention are those wherein, in formula (I) , R x is hydrogen or CJ -C,., alkyl; R 2 and R s are hydrogen,*
  • R 3 is hydroxy or d-C ⁇ alkoxy unsubstituted or substituted by phenyl ;
  • R 4 is hydrogen or C x -C 4 alkyl
  • R 6 is hydrogen, C ⁇ -C ⁇ alkyl or C 2 -C 14 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by halogen, C x -C 4 alkoxy, hydroxy, phenyl, phenoxy or cyano; or R 5 and R 6 , taken together, form a C 4 -C 12 polymethylene chain, which is unsubstituted or substituted by C,_-C 6 alkyl, C 3 - C 6 alkenyl or C.-Cg alkylidene wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by halogen, C,_-C 4 alkoxy, hydroxy, cyano, phenoxy or phenyl .
  • 2 ' -bi-lH-pyrrole compounds are the following:
  • Such therapeutic activity of the compounds of the invention is proven for instance by the fact that they have been found to be active in inhibiting selectively the IL-2 induced activation and expansion of murine and human T-cells, showing thus a pharmacological profile consistent with the therapy of the IL-2 dependent ATL.
  • Th 2 murine cells D10-G4.1 (ATCC TIB 224) are IL-2 dependent for their growth. They are cultured in complete RPMI 1640 medium enriched with rhIL-2 (6 ng/ml) and ConA (6 ng/ml) .
  • D 10 cells are washed twice with complete medium, resuspended at 10 5 cells/ml in the same medium and triplicately distributed (10 4 cells/well) in flat bottomed 96 well plates. 50 ml of rhIL-2 and 50 ml of the test compound at different concentrations are simultaneously added to the cells. The cultures are then incubated at 37°C in a humidified 5% C0 2 incubator for 48h, the last 18 h in the presence of 0.2 mCi of 3 H-TdR.
  • one or more compound of formula (I) in treating a adult-T-cell leukemia-lymphoma can be administered alone or in association with an anti-tumor agent.
  • a single compound of formula (I) is used.
  • a further object of the present invention is to provide a combined method of treatment of adult-T-cell leukemia-lymphoma in mammals, including humans, in need thereof, said method comprising administering thereto a compound of formula (I) , or a pharmaceutically acceptable salt thereof, and an anti- umor agent, in amounts and close enough together in time sufficient to produce a therapeutically useful effect.
  • the present invention also provides a product containing a compound of formula (I) , or a pharmaceutically acceptable salt thereof, and an anti-tumor agent as a combined preparation for simultaneous, separate or sequential use in adult-T-cell leukemia-lymphoma therapy.
  • anti-tumor agent'' is meant to comprise both a single anti-neoplastic agent and ""cocktails' 1 , i.e. a mixture of such drugs according to clinical practice.
  • An anti-neoplastic agent can be for example an agent selected from the group consisting of an antineoplastic vinca alkaloid, an antineoplastic antibiotic, an antineoplastic antimetabolite, an antineoplastic platinum coordination complex, an antineoplastic taxane compound, an antineoplastic ceramide compound, an antineoplastic distamycin compound, an antineoplastic epidophyllotoxin compound and an antineoplastic topoisomerase I inhibitor.
  • Examples of specific antineoplastic agents, according to the invention, which are administered with a compound of formula (I), are: vincristine, vinblastine, etoposide, tallimustine- amidoxime, 3- (l-methyl-4- (1-methyl-4- (l-methyl-4- (4,N,N- bis (2-chloroethyl) aminobenzene-1-carboxamido) pyrrole-2- carboxamido) pyrrole-2 -carboxamido) pyrrole-2- carboxamido) proprionamidoxime, (2S-RR-4E) -1, 3-dihydroxy-2- tetradecanoylamido-4-octadecene, paditaxel, docetaxel, 7- epitaxol, 7-epitaxotere, epirubicin, doxorubicin, cyclophosphamide, idarubicin, 4 ' -iodoxorubicin, daunorubicin,
  • a compound of the invention to be administered to a patient suffering from adult-T-cell leukemia-lymphoma, in particular brought on by infection with HTLV-I, will vary with the precise nature of the conditions being treated and the recipient of the treatment .
  • PNU 156804 is in the range of about 0.03 to about 1.5 mg/kg, preferably about 0.06 mg/kg to about 0.7 mg/kg when given i.v. whereas the dose of the same compound for oral administration in adult humans is in general from about 0.3 mg/kg/day to about 15 mg/kg/day.
  • the dosage of a compound of formula (I) and of an antitumor agent, in case of combined therapy, to be used is, of course, dependent on various factors such as the organism to be treated (e.g., human or animal, age, weight, general state of health) , the severity of the symptoms, the disorder to the accompanying treatment with other pharmaceuticals, or the frequency of the treatmen .
  • the dosages are in general administered several times per day and preferably once to three times per day.
  • the effective amounts of the antitumor agent are in general those commonly used in therapy, as known to those skilled in the art. However, the amounts of the individual active compounds should be within the range given above, e.g. within the tolerable, efficacious dosage range for the organism to be treated.
  • Object of the present invention is also to provide a pharmaceutical composition having activity against adult-T- cell leukemia-lymphoma, in particular brought on by infections with HTLV-I, comprising a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptbale carrier or diluent.
  • compositions according to the invention will of course depend upon the desired route of administration.
  • compositions may be formulated in the conventional manner with the usual ingredients.
  • the active agents of the invention may be administered in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatine capsules, syrups, drops or suppositories.
  • the pharmaceutical compositions, containing the active agents of this invention are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for instance silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatine, methylcellulose, carboxymethylcellulose, gum-arabic, tragacanth, polyvinylpyrrolidone,* disaggregating agents, such as starches, alginic acid, alginates, sodium starch glycolate,* effervescing mixture; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, lauryl- sulphates and in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations .
  • Said pharmaceutical preparations may be manufactured in known manner, for example by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol .
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol .
  • the suspensions or solutions for intramuscular injections may contain together with the active agent 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 .
  • a pharmaceutically acceptable carrier e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride .
  • the solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic solutions .
  • the suppositories may contain together with the active agent a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • a pharmaceutically acceptable carrier e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
  • composition for 200 capsules each dosed at 0.5 g and containing 50 mg of the active substance can be prepared.
  • This formulation is encapsulated in two-piece hard gelatin capsules and dosed at 0.5 g for each capsule .

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Abstract

The use of a compound which is a 2,2'-bi-1H-pyrrole of formula (I) wherein R1 is hydrogen, phenyl, C1-C20 alkyl or C2-C20 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents; R2 is hydrogen, C1-C6 alkyl, cyano, carboxy or (C1-C6 alkoxy)carbonyl; R3 is halogen, hydroxy or C1-C11 alkoxy unsubstituted or substituted by phenyl; R4 represent hydrogen, C1-C6 alkyl or phenyl; each of R5 and R6, which are the same or different, independently represents hydrogen, C2-C20 alkanoyl, C3-C20 alkenoyl, phenyl, C1-C20 alkyl or C2-C20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and the alkenyl groups are unsubstituted or substituted by 1 to 3 substituents; or two of R4, R5 and R6 taken together form a C4-C12 polymethylene chain, which is unsubstituted or substituted by C1-C12 alkyl, C2-C12 alkenyl or C1-C12 alkylidene; or pharmaceutically acceptable salt thereof; in the preparation of a medicament for use in the treatment of adult-T-cell leukemia-lymphoma, in particular brought on by infection with HTLV-I.

Description

2,2' -BI-1H-PYRROLE DERIVATIVES USEFUL IN THE TREATMENT OF LEUKEMIA BROUGHT ON BY .HTLV-I
The present invention relates to the use of 2, 2 ' -bi-lH- pyrrole compounds in the treatment of adult-T-cell leukemia lyτphoma, in particular adult-T-cell leukemia-lymphoma, brought on by infection with HTLV-I in mammals, including humans .
Background of the invention
Adult T-cell leukemia-lymphoma (ATL) is an aggressive malignancy of mature activated T cells, associated with human T-cell lymphotropic virus type I infection (HTLV-1) . The virus encodes regulatory proteins which induce malignant transformation of the T-lymphocytes . These proteins increase expression of cell protooncogenes as well as of lymphokines, among other IL-2, and of IL-2R. IL-2 induces autocrine proliferation of T lymphocytes, which is probably the main cause of their transformation and propagation at least in the early phase of the disease. ATL has a poor prognosis with a mean survival time of 6-24 months, due mainly to its resistance to conventional chemotherapy. Recent advances in the treatment of ATL were obtained applying an IL-2R-directed therapy using a humanized monoclonal antibody capable of blocking the interaction of IL-2 with its receptor. This result is in keeping with the concept that IL-2 has a pathogenetic/exacerbating role in this malignancy and focuses on the efficacy of a therapy preventing the IL-2 proliferative effects for T-lymphocytes . The present inventor has discovered that such 2,2'-bi-lH- pyrrole compounds are active in treating such proliferative disorder . Description of the invention
The present invention provides the use of a compound which is a 2, 2 ' -bi-lH-pyrrole of formula (I)
Figure imgf000004_0001
wherein
R. is hydrogen, phenyl, C1-C20 alkyl or C2-C20 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen,
Figure imgf000004_0002
alkoxy, hydroxy, aryl and aryloxy;
R. is hydrogen,
Figure imgf000004_0003
alkoxy) carbonyl ;
R. is halogen, hydroxy or C^C^ alkoxy unsubstituted or substituted by phenyl;
R is hydrogen, C1-C6 alkyl or phenyl; each of R5 and R6) which are the same or different, independently represents hydrogen, C2-C20 alkanoyl, C3-C20 alkenoyl, phenyl, C1-C20 alkyl or C2-C20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C-.-Cg alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (Cj.-C6 alkoxy) carbonyl , (C3-C4 alkenyl) carbamoyl , aralkyl- carba oyl, arylcarbamoyl and -CO RcRd in which each of Rc and Rd, which are the same or different, independently is hydrogen or
Figure imgf000004_0004
alkyl or Rc and Rd, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring; or two of R4 , R« and Rs taken together form C,-C 12 poly ethylene chain, which is unsubstituted or substituted by C^-C^ alkyl, C -C alkenyl or C^-C^, alkylidene wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by halogen,
Figure imgf000005_0001
alkoxy, hydroxy, cyano, carboxy,
Figure imgf000005_0002
alkoxy) carbonyl, aryloxy or aryl; the remaining one being hydrogen or C^C^ alkyl; or a pharmaceutically acceptable salt thereof; in the preparation of a medicament for use in the treatment of adult-T-cell leukemia- lymphoma, in particular brought on by infection with HTLV-I.
Accordingly, the present invention provides a use as defined above, wherein the medicament is for use in treating the progression of adult-T-cell leukemia-lymphoma, in particular brought on by infection with HTLV-I and in ameliorating clinical symptoms of such proliferative disorder. The invention also provides a method of treating a mammal, including a human subject, suffering from adult-T-cell leukemia- lymphoma, in particular brought on by infection with HTLV-I, which comprises administering to said mammal an effective amount of a compound as defined above. Thus the conditions of such patient can be improved.
The compounds of the invention can be represented also by the following tautomeric formula (la)
Figure imgf000005_0003
wherein R1( R2, R3, R4, R5 and R6 are as defined above,* as described in WO 95/17381.
In a compound of formula (I) the substituents have preferably the following meanings . A halogen atom is preferably chlorine or fluorine.
The alkyl, alkoxy, alkenyl, alkanoyl, alkenoyl, alkadienoyl and alkylidene groups may be branched or straight chain groups . An aryl group as a substituent as well as a moiety in an aryloxy, aralkyl or arylcarbamoyl group is, e.g., an aromatic
C6-C20 mono- or poly-nuclear moiety, typically phenyl, unsubstituted or substituted by one or two substituents independently chosen from halogen, hydroxy,
Figure imgf000006_0001
alkyl and CL- C6 alkoxy.
Accordingly an aralkyl group is e.g. benzyl or phenethyl, in which the phenyl ring is optionally substituted by one or two substituents independently chosen from halogen, hydroxy, Cx-
C6 alkyl and
Figure imgf000006_0002
alkoxy. A C4-C12 polymethylene chain is e.g. a C4-C9 polymethylene chain .
A C3-C4 or C3-Ce alkenyl group is preferably an allyl group.
A Ci-Cg alkyl group is preferably a C^- j alkyl group, in particular a methyl or ethyl group. A
Figure imgf000006_0003
alkyl group.
An unsubstituted C^-C^ alkoxy group is preferably a C,_-C4 alkoxy or
Figure imgf000006_0004
alkoxy group, typically methoxy, ethoxy, propoxy, butoxy and undecyloxy.
A Ci-Cj alkoxy group substituted by phenyl is preferably a phenyl-C1-C4 alkoxy group, typically benzyloxy or phenylethoxy .
A C1-C20 alkyl group is preferably a C5-C14 alkyl group , in particular an undecyl group .
A C2-C20 alkenyl group is preferably a C5-C14 alkenyl group , in particular an undecenyl group .
A C2-C20 alkanoyl group is preferably a C5-C14 alkanoyl group , in particular an undecanoyl group .
A C3-C20 alkenoyl group is preferably a C5-C14 alkenoyl group, in particular an undecenoyl group. A alkylidene group is preferably a
Figure imgf000007_0001
alkylidene group, in particular a C4-C5 alkylidene group.
A C2-C12 alkenyl group is preferably a C3-C6 alkenyl group.
A
Figure imgf000007_0002
alkoxy) carbonyl group.
Examples of pharmaceutically acceptable salts of a compound of formula (I) 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, dibenzylamine, methylbenzylamine, di- (2-ethyl-hexyl) -amine, piperidine, N- ethylpiperidine, N,N-diethylaminoethylamine, N- ethylmorpholine, β-phenethylamine, N-benzyl-β-phenethylamine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines, as well as the salts with inorganic, e.g. hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulphonic and ethanesulphonic acids .
Preferred compounds of the present invention are those wherein, in formula (I) , Rx is hydrogen or CJ -C,., alkyl; R2 and Rs are hydrogen,*
R3 is hydroxy or d-C^ alkoxy unsubstituted or substituted by phenyl ;
R4 is hydrogen or Cx-C4 alkyl;
R6 is hydrogen, C^-C^ alkyl or C2-C14 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by halogen, Cx-C4 alkoxy, hydroxy, phenyl, phenoxy or cyano; or R5 and R6, taken together, form a C4-C12 polymethylene chain, which is unsubstituted or substituted by C,_-C6 alkyl, C3- C6 alkenyl or C.-Cg alkylidene wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by halogen, C,_-C4 alkoxy, hydroxy, cyano, phenoxy or phenyl .
Specific examples of compounds of formula (I) are the following:
4-methoxy-5- { [5- (undec-10-en-l-yl) -2H-pyrrol-2-ylidene] methyl} -2,2' -bi-lH-pyrrole;
4-ethoxy-5- [ (5-decyl-2H-pyrrol-2-ylidene) methyl] -2,2' -bi-lH- pyrrole ; 4 -ethoxy-5- [ (5 -dodecyl -2H-pyrrol -2 -ylidene) methyl] -2 , 2 ' -bi-
1H- pyrrole ;
4-ethoxy-5- [ (3, 5-nonamethylene-2H-pyrrol-2-ylidene)methyl] -
2,2' -bi-lH-pyrrole;
4-ethoxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene) methyl] -2,2' -bi- lH-pyrrole; m.p. 94-96°C*;
4-propoxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene) -methyl] -2,2' -bi- lH-pyrrole; m.p. 73-77°C*;
4-butoxy-5- [ (5-undecyl-2H-pyrrol-2 -ylidene) methyl] -2,2' -bi- lH-pyrrole,* m.p. 81-83°C*; 4-ethoxy-5- [ (5-methyl-2H-pyrrol-2 -ylidene) methyl] -2,2' -bi-lH- pyrrole,* m.p. 200° (dec)*;
4-methoxy-5- [ (5-decyl-2H-pyrrol-2-ylidene) methyl] -2,2' -bi-lH- pyrrole; m.p. 100-116°C* ;
4-methoxy-5- [ (5-pentadecyl-2H-pyrrol-2-ylidene) methyl] -2,2'- bi-lH-pyrrole; m.p. 100-104°C*;
4-methoxy-5- [ (5-heptyl-2H-pyrrol-2-ylidene)methyl] -2,2' -bi- lH-pyrrole; m.p. 140-145°C*;
4-methoxy-5- [ (5-phenethyl-2H-pyrrol-2-ylidene) methyl] -2,2' - bi-lH-pyrrole,- m.p. 170°C dec* ; 4-methoxy-5-{[5- (5-carboxy-pent-1-yl) -2H-pyrrol-2-ylidene] methyl}-2,2' -bi-lH-pyrrole; m.p. 157-165°C*;
4-methoxy-5-{ [5- (5 -carboxy-pent-1-yl) -2H-pyrrol-2-ylidene] methyl}-2,2 ' -bi-lH-pyrrole methylester; m.p. 138-140°C* ; 4-methoxy-5- [4,5,6, 7 -tetrahydro-2H-indol-2-ylidene)methyl] -
2,2 ■ -bi-lH-pyrrole; m.p. 212°C*;
4-methoxy-5- [ (4-hexyl-4, 5,6, 7-tetrahydro-2H-indol-2- ylidene) methyl] -2,2 ' -bi-lH-pyrrole; m.p. 181-184°C*; 4-ethoxy-5-{[5- (undec-10-en-l-yl) -2H-pyrrol-2-ylidene] methyl}-
2,2' -bi-lH-pyrrole; m.p. 80-97°C*;
4-methoxy-5- [ (4-ethyl-3 , 5-dimethyl-2H-pyrrol-2-ylidene) methyl] -2,2' -bi-lH-pyrrole;
4-methoxy-5- [ (4-hexyl-5-methyl-2H-pyrrol-2-ylidene)methyl] - 2, 2 ' -bi-lH-pyrrole;
4-methoxy-5- [ (5-methyl-4-undecyl-2H-pyrrol-2 -ylidene) methyl] -
2,2' -bi-lH-pyrrole;
4-methoxy-5- [ (5-nonyl-2H-pyrrol-2-ylidene) methyl] -2,2' -bi-lH- pyrrole ; 4-methoxy-5- [ (5-methyl-4-pentyl-2H-pyrrol-2-ylidene)methyl] -
2,2' -bi-lH-pyrrole;
4-isopropoxy-5- [ (5-undecyl-2H-pyrrol-2 -ylidene) methyl] -2,2'- bi-lH-pyrrole ,*
4-amyloxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene)methyl] -2,2' -bi- lH-pyrrole;
4-undecyloxy-5- [ (5 -undecyl-2H-pyrrol-2 -ylidene) methyl] -2,2'- bi-lH-pyrrole;
4-benzyloxy-5- [ (5-undecyl-2H-pyrrol-2 -ylidene) methyl] -2,2'- bi-lH-pyrrole; m.p. 90-93°C*,- 4-benzyloxy-5- [ (2H-pyrrol-2-ylidene) methyl] -2,2' -bi-lH- pyrrole; m.p. 200-202°C*;
4-undecyloxy-5- [ (2H-pyrrol-2 -ylidene) methyl] -2,2'-bi-lH- pyrrole;
4-methoxy-5- [ (5-tridecyl-2H-pyrrol-2-ylidene)methyl] -2,2' -bi- lH-pyrrole; m.p. 80-100°C*;
4-ethoxy-5- [ (5-tridecyl-2H-pyrrol-2-ylidene)methyl] -2,2' -bi- lH-pyrrole; m.p. 88-93°C*;
4-buthoxy-5- [ (5-tridecyl-2H-pyrrol -2 -ylidene) methyl] -2,2' -bi-
1H-pyrrole; 4-benzyloxy-5- [ (5-tridecyl-2H-pyrrol-2-ylidene)methyl] -2,2'- bi-lH-pyrrole;
4-methoxy-5- [ [5- (5-phenoxy-pent-l-yl) -2H-pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole; m.p. 126-129°C*,* 4-ethoxy-5- [ [5- (5-phenoxy-pent-l-yl) -2H-pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole; m.p. 110-120°C*;
4-buthoxy-5- [ [5- (5-phenoxy-pent-l-yl) -2H-pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole;
4-benzyloxy-5- [ [5- (5-phenoxy-pent-l-yl) -2H-pyrrol-2-ylidene] methyl] -2, 2' -bi-lH-pyrrole;
4-methoxy-5- [ [5- (6-fluoro-hex-1-yl) -2H-pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole; m.p. 115-124°C*;
4-methoxy-5- [ [5- (6-hydoxy-hex-l-yl) -2H-pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole; m.p. 118-121°C* ;
4-methoxy-5- [ [5- (5-morpholinecarboxamido-pent-l-yl) -2H- pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole
NMR ( CDC1J d ppm: 1.2-1.8 (m, 6H) ; 2.2 (m, 2H) ; 2.8 (m, 2H) ;
3.4-3.5 (m, 8H) ; 4 (s, 3H) ; 6.2 (m, 2H) ; 6.8 (m, 1H) , 7.1 (s, 1H) ; 7.4-7.6 (m, 3H) ; 12.2-12.4 (bs, 1H) ; 12.5-12.8 (two bs,
2H) ; * ; and
4-methoxy-5- [ [5- (7-cyano-hept-l-yl) -2H-pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole NMR (CDC13) d ppm: 1.3-1.8 (m, 10H) ,* 2.3 (m, 2H) ; 3 (m, 2H) ;
4.04 (s, 3H) ; 6.1 (d, 1H) ; 6.2 (dd, 1H) , 6.4 (m, 1H) ; 6.8 (m,
1H) ; 6.9 (m, 1H) ; 7.03 (s, 1H) ; 7.25 (m, 1H) 12.6-12.7 (two bs, 2H; 12.9 (bs, 1H) ; *; and the pharmaceutically acceptable salts thereof . The symbol * means determined as hydrochloride .
More preferred 2 , 2 ' -bi-lH-pyrrole compounds are the following:
4-ethoxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene) methyl] -2,2' -bi- lH-pyrrole ;
4-methoxy-5- [ (5-tridecyl-2H-pyrrol-2-ylidene) methyl] -2,2' -bi- 1H-pyrrole;
4-ethoxy-5- [ (5-tridecyl-2H-pyrrol-2-ylidene) methyl] -2,2' -bi- lH-pyrrole;
4-buthoxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene)methyl] -2,2' -bi- lH-pyrrole; and
4-benzyloxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene)methyl] -2,2'- bi-lH-pyrrole,- and the pharmaceutically acceptable salts thereof .
Pharmacology
The 2, 2 ' -bi-lH-pyrrole compounds of formula (I) and the pharmaceutically acceptable salts thereof, hereafter referred to as ""the compounds of the invention'1 or ""the active agents'1, have been found to be active in treating adult-T- cell leukemia in mammals, including humans, in particular adult-T-cell leukemia brought on by infection with HTLV-I. Such therapeutic activity of the compounds of the invention is proven for instance by the fact that they have been found to be active in inhibiting selectively the IL-2 induced activation and expansion of murine and human T-cells, showing thus a pharmacological profile consistent with the therapy of the IL-2 dependent ATL.
Inhibition of IL-2 proliferation induced activity
The Th2 murine cells D10-G4.1 (ATCC TIB 224) are IL-2 dependent for their growth. They are cultured in complete RPMI 1640 medium enriched with rhIL-2 (6 ng/ml) and ConA (6 ng/ml) .
For testing the inhibitory effects of the compounds of the invention on IL-2 activity, D 10 cells are washed twice with complete medium, resuspended at 105 cells/ml in the same medium and triplicately distributed (104 cells/well) in flat bottomed 96 well plates. 50 ml of rhIL-2 and 50 ml of the test compound at different concentrations are simultaneously added to the cells. The cultures are then incubated at 37°C in a humidified 5% C02 incubator for 48h, the last 18 h in the presence of 0.2 mCi of 3H-TdR.
Uptake of 3H-TdR in the cells (cpm) is taken as a measure of cell proliferation.
For instance for the representative compound of the invention 4-benzyloxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene)methyl] -2,2'- bi-lH-pyrrole (internal code PNU 156804) the following activity data were obtained.
Figure imgf000012_0001
* .mean cpm from triplicate wells (SE)
In treating a adult-T-cell leukemia-lymphoma one or more compound of formula (I) , as defined above, can be administered alone or in association with an anti-tumor agent. Preferably a single compound of formula (I) is used.
Accordingly, a further object of the present invention is to provide a combined method of treatment of adult-T-cell leukemia-lymphoma in mammals, including humans, in need thereof, said method comprising administering thereto a compound of formula (I) , or a pharmaceutically acceptable salt thereof, and an anti- umor agent, in amounts and close enough together in time sufficient to produce a therapeutically useful effect.
The present invention also provides a product containing a compound of formula (I) , or a pharmaceutically acceptable salt thereof, and an anti-tumor agent as a combined preparation for simultaneous, separate or sequential use in adult-T-cell leukemia-lymphoma therapy.
The term ""anti-tumor agent'' is meant to comprise both a single anti-neoplastic agent and ""cocktails'1, i.e. a mixture of such drugs according to clinical practice.
An anti-neoplastic agent can be for example an agent selected from the group consisting of an antineoplastic vinca alkaloid, an antineoplastic antibiotic, an antineoplastic antimetabolite, an antineoplastic platinum coordination complex, an antineoplastic taxane compound, an antineoplastic ceramide compound, an antineoplastic distamycin compound, an antineoplastic epidophyllotoxin compound and an antineoplastic topoisomerase I inhibitor. Examples of specific antineoplastic agents, according to the invention, which are administered with a compound of formula (I), are: vincristine, vinblastine, etoposide, tallimustine- amidoxime, 3- (l-methyl-4- (1-methyl-4- (l-methyl-4- (4,N,N- bis (2-chloroethyl) aminobenzene-1-carboxamido) pyrrole-2- carboxamido) pyrrole-2 -carboxamido) pyrrole-2- carboxamido) proprionamidoxime, (2S-RR-4E) -1, 3-dihydroxy-2- tetradecanoylamido-4-octadecene, paditaxel, docetaxel, 7- epitaxol, 7-epitaxotere, epirubicin, doxorubicin, cyclophosphamide, idarubicin, 4 ' -iodoxorubicin, daunorubicin, actinomicin D, bleomycin, plycamicin, mitomycin, camptothecin, 9-aminocamptothecin, camptothecin 11 (CPT 11) , topotecan, metotrexate, cytarabine, azauridine, azarabine, fluorodeoxyuridine, deoxycoformycin, mercaptopurine , cisplatin and carboplatin. In particular they are epirubicin, doxorubicin, cyclophosphamide, 9-aminocamptothecin and camptothecin 11. The dosage of a compound of the invention to be administered to a patient suffering from adult-T-cell leukemia-lymphoma, in particular brought on by infection with HTLV-I, will vary with the precise nature of the conditions being treated and the recipient of the treatment .
A therapeutically effective dosage of the compounds of formula (I), for example the compound 4-benzyloxy-5- [ (5- undecyl-2H-pyrrol-2-ylidene] -2,2' -bi-lH-pyrrole hydrochloride
(PNU 156804), is in the range of about 0.03 to about 1.5 mg/kg, preferably about 0.06 mg/kg to about 0.7 mg/kg when given i.v. whereas the dose of the same compound for oral administration in adult humans is in general from about 0.3 mg/kg/day to about 15 mg/kg/day.
The dosage of a compound of formula (I) and of an antitumor agent, in case of combined therapy, to be used is, of course, dependent on various factors such as the organism to be treated (e.g., human or animal, age, weight, general state of health) , the severity of the symptoms, the disorder to the accompanying treatment with other pharmaceuticals, or the frequency of the treatmen . The dosages are in general administered several times per day and preferably once to three times per day. The effective amounts of the antitumor agent are in general those commonly used in therapy, as known to those skilled in the art. However, the amounts of the individual active compounds should be within the range given above, e.g. within the tolerable, efficacious dosage range for the organism to be treated. The oral route is employed, in general, for all conditions requiring the compounds of the invention. Preference is given to intravenous injection or infusion for the acute treatments. For maintenance regimens the oral or parenteral , e.g. intramuscular or subcutaneous, route is preferred. Object of the present invention is also to provide a pharmaceutical composition having activity against adult-T- cell leukemia-lymphoma, in particular brought on by infections with HTLV-I, comprising a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof, as an active ingredient, and a pharmaceutically acceptbale carrier or diluent.
The nature of the pharmaceutical preparations and compositions according to the invention will of course depend upon the desired route of administration.
The compositions may be formulated in the conventional manner with the usual ingredients. For example, the active agents of the invention, may be administered in the form of aqueous or oily solutions or suspensions, tablets, pills, gelatine capsules, syrups, drops or suppositories.
Thus, for oral administration, the pharmaceutical compositions, containing the active agents of this invention, are preferably tablets, pills or gelatine capsules which contain the active substance together with diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose; lubricants, for instance silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; or they may also contain binders, such as starches, gelatine, methylcellulose, carboxymethylcellulose, gum-arabic, tragacanth, polyvinylpyrrolidone,* disaggregating agents, such as starches, alginic acid, alginates, sodium starch glycolate,* effervescing mixture; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, lauryl- sulphates and in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations .
Said pharmaceutical preparations may be manufactured in known manner, for example by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral administration may be e.g. syrups, emulsions and suspensions.
The syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol .
The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol .
The suspensions or solutions for intramuscular injections may contain together with the active agent a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride .
The solutions for intravenous injections or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile aqueous isotonic solutions .
The suppositories may contain together with the active agent a pharmaceutically acceptable carrier, e.g. cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty acid ester surfactant or lecithin.
The following examples illustrate but do not limit the present invention.
Formulation Example 1 Capsules, each dosed at 0.5 g and containing 50 mg of the active substance can be prepared. Composition for 200 capsules:
4-benzyloxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene) methyl] - 2,2' -bi-lH-pyrrole hydrochloride (PNU 156804) 10 g Lactose 80 g
Corn starch 5 g
Magnesium stearate 5 g
This formulation is encapsulated in two-piece hard gelatin capsules and dosed at 0.5 g for each capsule .

Claims

1. Use of a compound which is a 2, 2 ' -bi-lH-pyrrole of formula (I)
Figure imgf000017_0001
wherein
R is hydrogen, phenyl, Cx-C20 alkyl or C2-C20 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, lkoxy, hydroxy, aryl and aryloxy;
R2 is hydrogen,
Figure imgf000017_0002
alkyl, cyano, carboxy or (C,.-Cg alkoxy) carbonyl ; R3 is halogen, hydroxy or C^-C^ alkoxy unsubstituted or substituted by phenyl ; R4 is hydrogen,
Figure imgf000017_0003
alkyl or phenyl; each of R5 and R5, which are the same or different, independently represents hydrogen, C2-C20 alkanoyl, C3-C20 alkenoyl, phenyl, d-C^ alkyl or C2-C20 alkenyl, wherein the alkanoyl , alkenoyl , alkyl and alkenyl groups are unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen,
Figure imgf000017_0004
alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy,
Figure imgf000017_0005
alkoxy) carbonyl , (C3-C4 alkenyl) carbamoyl, aralkyl- carbamoyl, arylcarbamoyl and -C0NRcRd in which each of Rc and Rd, which are the same or different, independently is hydrogen or
Figure imgf000017_0006
alkyl or Rc and Rd, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring,* or two of R4 R, and R6 taken together form a C4-CL polymethylene chain, which is unsubstituted or substituted by Cx-C12 alkyl, C2-C12 alkenyl or d-C^ alkylidene, wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by halogen,
Figure imgf000018_0001
alkoxy, hydroxy, cyano, carboxy, (Cx-C6 alkoxy) carbonyl , aryloxy or aryl ; the remaining one being hydrogen or d-C^ alkyl; or a pharmaceutically acceptable salt thereof; in the preparation of a medicament for use in the treatment of adult-T-cell leukemia-lymphoma .
2. Use according to claim 1 wherein the medicament is for the treatment of adult-T-cell leukemia-lymphoma brought on by infection with HTLV-I.
3. Use according to claim 1 wherein the medicament is for use in treating the progression of adult-T-cell leukemia- lymphoma and in ameliorating clinical symptoms of such proliferative disorder.
4. Use according to claim 1 wherein, in formula (I),
Rx is hydrogen or C,_-C20 alkyl;
R, and Rs are hydrogen,*
R3 is hydroxy or Cj^-C^ alkoxy unsubstituted or substituted by phenyl ; R4 is hydrogen or C^C. alkyl; and
R5 is hydrogen, C^C^ alkyl or C2-C14 alkenyl, wherein the alkyl and alkenyl groups are unsubstituted or substituted by halogen, d-Q alkoxy, hydroxy, phenyl, phenoxy or cyano ; or R5 and R6, taken together, form a C4-C12 polymethylene chain, which is unsubstituted or substituted by C,_-C6 alkyl, C3-C6 alkenyl
Figure imgf000018_0002
alkylidene wherein the alkyl, alkenyl and alkylidene groups are in turn unsubstituted or substituted by halogen, Cx-C4 alkoxy, hydroxy, cyano, phenoxy or phenyl .
5. Use according to claim 1 wherein the said compound is
4-methoxy-5-{ [5- (undec-10-en-l-yl) -2H-pyrrol-2-ylidene] methyl} -2, 2' -bi-lH-pyrrole;
4-ethoxy-5- [ (5-decyl-2H-pyrrol-2-ylidene) methyl] -2,2' -bi-lH- pyrrole ;
4-ethoxy-5- [ (5-dodecyl-2H-pyrrol-2-ylidene)methyl] -2,2' -bi- lH-pyrrole; 4-ethoxy-5- [ (3, 5-nonamethylene-2H-pyrrol-2 -ylidene) methyl] -
2,2' -bi-lH-pyrrole ;
4-ethoxy-5- [ (5-undecyl-2H-pyrrol-2 -ylidene) methyl] -2,2' -bi- lH-pyrrole;
4-propoxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene) -methyl] -2,2' -bi- lH-pyrrole;
4-butoxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene) methyl] -2,2' -bi-
1H-pyrrole;
4-ethoxy-5- [ (5-methyl-2H-pyrrol-2-ylidene)methyl] -2,2' -bi-lH- pyrrole; 4-methoxy-5- [ (5-decyl-2H-pyrrol-2-ylidene)methyl] -2,2' -bi-lH- pyrrole ;
4-methoxy-5- [ (5-pentadecyl-2H-pyrrol-2-ylidene) methyl] -2,2' - bi-lH-pyrrole;
4-methoxy-5- [ (5-heptyl-2H-pyrrol-2-ylidene)methyl] -2,2' -bi- lH-pyrrole;
4-methoxy-5- [ ( 5 -phenethyl-2H-pyrrol- 2 -ylidene) methyl] -2,2' - bi-lH-pyrrole;
4-methoxy-5-{ [5- (5-carboxy-pent-l-yl) -2H-pyrrol- 2 -ylidene] methyl}- 2, 2 ' -bi-lH-pyrrole; 4-methoxy-5-{[5- (5-carboxy-pent-l-yl) -2H-pyrrol- 2 -ylidene] methyl}- 2 , 2 ' -bi-lH-pyrrole methylester ,*
4-methoxy-5- [4,5,6, 7-tetrahydro-2H-indol-2-ylidene)methyl] -
2,2' -bi-lH-pyrrole; 4-methoxy-5- [ (4-hexyl-4, 5,6, 7-tetrahydro-2H-indol-2- ylidene) methyl] -2,2' -bi-lH-pyrrole;
4-ethoxy-5-{[5- (undec-10-en-l-yl) -2H-pyrrol-2-ylidene] methyl}-
2,2 ' -bi-lH-pyrrole,- 4-methoxy-5- [ (4-ethyl-3 , 5-dimethyl-2H-pyrrol-2-ylidene) methyl] -2 , 2 ' -bi-lH-pyrrole;
4-methoxy-5- [ (4-hexyl-5-methyl-2H-pyrrol-2-ylidene)methyl] -
2,2' -bi-lH-pyrrole ;
4-methoxy-5- [ (5-methyl-4-undecyl-2H-pyrrol-2-ylidene)methyl] - 2, 2 ' -bi-lH-pyrrole;
4-methoxy-5- [ (5-nonyl-2H-pyrrol-2-ylidene)methyl] -2,2 ' -bi-lH- pyrrole,*
4-methoxy-5- [ (5-methyl-4-pentyl-2H-pyrrol-2-ylidene) methyl] -
2,2' -bi-lH-pyrrole; 4-isopropoxy-5- [ ( 5 -undecyl-2H-pyrrol- 2 -ylidene) methyl] -2,2'- bi-lH-pyrrole;
4-amyloxy-5- [ (5-undecyl-2H-pyrrol-2-ylidene) methyl] -2,2'-bi- lH-pyrrole;
4-undecyloxy-5- [ (5-undecyl-2H-pyrrol -2 -ylidene) methyl] -2,2'- bi-lH-pyrrole,*
4-benzyloxy-5- [ ( 5 -undecyl-2H-pyrrol- 2 -ylidene) methyl] -2,2'- bi-lH-pyrrole;
4-benzyloxy-5- [ (2H-pyrrol- 2 -ylidene) methyl] -2,2' -bi-lH- pyrrole ; 4-undecyloxy-5- [ (2H-pyrrol-2 -ylidene) methyl] -2,2' -bi-lH- pyrrole;
4-methoxy-5- [ (5-tridecyl-2H-pyrrol-2 -ylidene) methyl] -2,2' -bi- lH-pyrrole;
4-ethoxy-5- [ (5 -tridecyl-2H-pyrrol-2 -ylidene) methyl] -2,2' -bi- lH-pyrrole ;
4-buthoxy-5- [ (5-tridecyl-2H-pyrrol-2-ylidene)methyl] -2,2' -bi-
1H- pyrrole ;
4-benzyloxy-5- [ (5-tridecyl-2H-pyrrol-2-ylidene)methyl] -2,2'- bi-lH-pyrrole; 4-methoxy-5- [ [5- (5-phenoxy-pent-l-yl) -2H-pyrrol-2-ylidene] methyl] -2 , 2 ' -bi-lH-pyrrole;
4-ethoxy-5- [ [5- (5-phenoxy-pent-l-yl) -2H-pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole; 4-buthoxy-5- [ [5- (5-phenoxy-pent-l-yl) -2H-pyrrol-2-ylidene] methyl] -2,2" -bi-lH-pyrrole;
4-benzyloxy-5- [ [5- (5-phenoxy-pent-l-yl) -2H-pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole;
4-methoxy-5- [ [5- (6-fluoro-hex-1-yl) -2H-pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole;
4-methoxy-5- [ [5- (6-hydoxy-hex-l-yl) -2H-pyrrol-2-ylidene] methyl] -2,2 ' -bi-lH-pyrrole;
4-methoxy-5- [ [5- (5-morpholinecarboxamido-pent-l-yl) -2H- pyrrol-2-ylidene] methyl] -2,2' -bi-lH-pyrrole; or 4-methoxy-5- [ [5- (7-cyano-hept-l-yl) -2H-pyrrol-2-ylidene] methyl] -2, 2 ' -bi-lH-pyrrole; or a pharmaceutically acceptable salt thereof .
6. A method of treating a mammal, including a human subject, suffering from adult-T-cell leukemia-lymphoma, which comprises administering to said mammal an effective amount of a compound as defined in claim 1.
7. A pharmaceutical composition having activity against adult-T-cell leukemia-lymphoma, comprising a compound as defined in claim 1 as an active ingredient and a pharmaceutically acceptable carrier or diluent .
8. A combined method of treatment of adult-T-cell leukemia-lymphoma in mammals, including humans, in need thereof, said method comprising administering thereto a compound of formula (I) , or a pharmaceutically acceptable salt thereof, as defined in claim 1, and an anti-tumor agent, in amounts and close enough together in time sufficient to produce a therapeutically useful effect.
9. A combined method of treatment according to claim 7, wherein the antitumor agent is selected from the group consisting of an antineoplastic vinca alkaloid, an antineoplastic antibiotic, an antineoplastic antimetabolite, an antineoplastic platinum coordination complex, an antineoplastic taxane compound, an antineoplastic ceramide compound, an antineoplastic distamycin compound, an antineoplastic epidophyllotoxin compound and an antineoplastic topoisomerase I inhibitor.
10. A product containing a compound as defined in claim 1, and an anti-tumor agent as a combined preparation for simultaneous, separate or sequential use in adult-T-cell leukemia-lymphoma therapy.
11. A product according to claim 9, wherein the antitumor agent is selected from the group consisting of an antineoplastic vinca alkaloid, an antineoplastic antibiotic, an antineoplastic antimetabolite, an antineoplastic platinum coordination complex, an antineoplastic taxane compound, an antineoplastic ceramide compound, an antineoplastic distamycin compound, an antineoplastic epidophyllotoxin compound and an antineoplastic topoisomerase I inhibitor.
PCT/EP1998/007774 1997-12-10 1998-11-30 2,2'-bi-1h-pyrrole derivatives useful in the treatment of leukemia brought on by htlv-i WO1999029309A2 (en)

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Cited By (7)

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US6407244B1 (en) 2000-01-26 2002-06-18 Gemin X Biotechnologies Inc. Pyrrole-type compounds, compositions, and methods for treating cancer or viral diseases
US6602879B2 (en) 2000-01-26 2003-08-05 Gemin X Biotechnologies Inc. Pyrrole-type compounds, compositions, and methods for treating cancer or viral diseases
US7491745B2 (en) 2000-01-26 2009-02-17 Gemin X Pharmaceuticals Canada Inc. Pyrrole-Type compounds, compositions and methods for treating cancer or viral disease
US7144912B2 (en) 2001-07-18 2006-12-05 Gemin X Biotechnologies Inc. Pyrrole-type compounds, compositions, and methods for treating cancer, treating viral diseases and causing immunosuppression
WO2006056399A2 (en) * 2004-11-24 2006-06-01 Novartis Ag Combinations of jak inhibitors and at least one of bcr-abl, flt-3, fak or raf kinase inhibitors
WO2006056399A3 (en) * 2004-11-24 2006-08-31 Novartis Ag Combinations of jak inhibitors and at least one of bcr-abl, flt-3, fak or raf kinase inhibitors
CN103387529A (en) * 2013-07-30 2013-11-13 中国农业科学院烟草研究所 Anti-TMV (Tobacco Mosaic Virus) tripyrrole ring compound and preparation method and application thereof

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