Benzyloxy prodigiosine compounds

Details Benzyloxy prodigiosine compounds Benzyloxy prodigiosine compounds

1999-10-07

2002-04-09

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C548S518000

Reexamination Certificate

active

06369096

ABSTRACT:

The present invention relates to novel benzyloxy prodigiosine compounds, to a process for their preparation, to pharmaceutical compositions containing them and to their use as therapeutic agents, in particular as immunomodulating agents.
International application WO 95/17381 discloses 2,2′-bi-1H-pyrrole compounds endowed with high in vitro immunosuppressive activity. However such compounds, similarly to other known prodigiosine compounds, are characterized by high lipophylicity, low aqueous solubility and consequently low bioavailability.
Moreover, the task to combine in the same prodigiosine molecule a high immunosuppressive activity and adequate hydrosolubility cannot be achieved by merely introducing hydrophilic groups into the structure of in vitro active immunosuppressants, as in most cases this strategy results in a significant loss of immunosuppressive activity. In fact, as known in the art, the therapeutic efficacy of all drugs is thoroughly influenced by different parameters that can affect their bioavailability. Object of the present invention is to provide novel prodigiosine compounds endowed with improved bioavailability.
The present invention is based on the discovery that a sub-genus of compounds disclosed in WO 95/17381, besides possessing good bioavailability, have in vivo high immunosuppressive activity.
Object of the present invention are novel compounds which are 2-(1H-pyrrol-2-yl)-5[(2H-pyrrol-2-ylidene)methyl]-1H-pyrroles i.e. prodigiosine compounds, having the following formula (I)
wherein
R1 is hydrogen or a C
1
-C
5
alkyl; and
R2 is C
1
-C
5
alkyl;
or pharmaceutically acceptable salts thereof.
The present invention includes within its scope all possible isomers, stereoisomers and optical isomers and their mixtures, and the metabolites and the metabolic precursors or bioprecursors of the compounds of formula (I).
The compounds of the invention can be represented also by the following tautomeric formula (Ia)
wherein R1 and R2 are as defined above.
Accordingly, the chemical compounds provided by the present invention are named throughout the description of the invention according to the chemical nomenclature provided for the compounds of either formula (I) or (Ia), on the basis of the structural evidence validated by people skilled in the art.
The alkyl groups may be branched or straight chain groups.
R1 as alkyl group is preferably methyl or ethyl.
R2 is preferably a methyl, ethyl, propyl, isopropyl, butyl or pentyl group.
Examples of pharmaceutically acceptable salts of the compounds of the invention are the salts with inorganic, e.g. hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, methanesulphonic and ethanesulfonic acids.
As stated above, the present invention also includes within its scope pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above, but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
Preferred compounds of the invention are those wherein, in formula (I),
R1 is hydrogen or methyl;
R2 is a C
1
-C
5
alkyl.
Examples of particularly preferred compounds of the invention are:
4-benzyloxy-5-[(5-methyl-2H-pyrrol-2-ylidene)methyl]-2,2′-bi-1H-pyrrole;
4-benzyloxy-5-[(5-ethyl-2H-pyrrol-2-ylidene)methyl]-2,2′-bi-1H-pyrrole;
4-benzyloxy-5-[(5-propyl-2H-pyrrol-2-ylidene)methyl]-2,2′-bi-1H-pyrrole;
4-benzyloxy-5-[(5-isopropyl-2H-pyrrol-2-ylidene)methyl]-2,2′-bi-1H-pyrrole;
4-benzyloxy-5-[(5-butyl-2H-pyrrol-2-ylidene)methyl]-2,2′-bi-1H-pyrrole;
4-benzyloxy-5-[(5-pentyl-2H-pyrrol-2-ylidene)methyl]-2,2′-bi-1H-pyrrole;
5′-methyl-4-benzyloxy-5-[(5-methyl-2H-pyrrol-2-ylidene)methyl]-2,2′-bi-1H-pyrrole;
5′-methyl-4-benzyloxy-5-[(5-ethyl-2H-pyrrol-2-ylidene)methyl]-2,2′-bi-1H-pyrrole;
and the pharmaceutically acceptable salts thereof, in particular the hydrochlorides, hydrobromides and methanesulphonates.
A further object of the present invention is to provide a compound of formula (I), as defined above, for use in a method of treatment of the human or animal body by therapy, in particular as an immunomodulating agent, especially as an immunosuppressive agent.
Object of the present invention is also to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and as an active principle a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof.
The present invention also provides a method of treating a mammal, including humans, in need of an immunomodulating agent, said method comprising administering to said mammal an effective amount of a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof can be obtained by an analogy process.
According to a preferred embodiment of the invention a compound of formula (I) and the salts thereof can be prepared by a process comprising reacting a compound of formula (II)
wherein
R2 is as defined above and X is a leaving group, with a compound of formula (III)
wherein
R1 is as defined above and R7 is hydrogen or a lower alkyl chain;
and, if desired, salifying a compound of formula (I) and/or, if desired, converting a salt of a compound of formula (I) into a free compound and/or, if desired, separating a mixture of isomers of a compound of formula (I) into the single isomers.
When R7 is a lower alkyl chain, it is preferably a C
1
-C
4
alkyl chain, for instance methyl, ethyl or isopropyl. In a compound of general formula (II), the leaving group X can be for instance a trifluoromethane-sulphonate group or a halogen such as chlorine, bromine or iodine.
The reaction between a compound of formula (II) and a compound of formula (III) may be carried out in a suitable organic solvent such as tetrahydrofurane, dioxane, dimethoxyethane, DMF, toluene, methanol, ethanol, water or mixtures thereof, in the presence of a suitable palladium (0) catalyst, in the presence of a basic agent, such as K
2
CO
3
, Na
2
CO
3
, NaHCO
3
, K
3
PO
4
, NaOAc, KOH, NaOH, Ba (OH)
2
, EtONa, Bu
4
NF, Et
3
N, at a temperature varying between about 60° C. and about 120° C., for a time of about 1 hour to about 3 days.
A wide range of palladium (0) catalysts can be used such as for instance Pd(PPh
3
)
4
, PdCl
2
(PPh
3
)
2
, Pd(OAc)
2
plus PPh
3
or other ligands as described for example in Chem. Rev. 95, 2457 (1995).
Optionally, salt such as LiCl, LiBr, KCl, KBr can be added to stabilize the catalyst.
According to a preferred embodiment of the invention, when in a compound of formula (II) the leaving group X is trifluoromethanesulfonate, a preferred catalyst is Pd(PPh
3
)
4
in the presence of sodium or potassium carbonate, and the reaction can be performed in dioxane or toluene, at a temperature varying between about 65° C. and about 90° C., for a time from about 5 hours to about 24 hours.
Also the optional salification of a compound of formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried out by conventional methods. For example, the separation of optical isomers may be carried out by salification with an optically active base or acid and by subsequent fractional crystallization of the diastereoisomeric salts, followed by recovering of the optically active isomeric acids or, respectively, bases.
A compound of formula (II) can be obtained from a compound of formula (IV)
wherein
R2 is as defined above, by means of an opportune reagent such as for instance trifluoromethane-sulfonic anhydride or a halogenating agent such as POCl
3
, POBr
3
, POCl(OEt)
2
/TMSI in an inert organic solvent such as dichloromethane, dichloroethane, acetonitrile, optionally

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