Organic compounds -- part of the class 532-570 series – Organic compounds – Four or more ring nitrogens in the bicyclo ring system
Patent
1997-10-15
1998-12-08
McKane, Joseph K.
Organic compounds -- part of the class 532-570 series
Organic compounds
Four or more ring nitrogens in the bicyclo ring system
548518, 548519, C07D41304
Patent
active
058471278
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP97/00368 filed Jan. 22, 1997.
FIELD OF THE INVENTION
The present invention relates to a new process for the preparation of (I): ##STR1## wherein R1 represents hydrogen, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkyl and alkenyl groups may be unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl and aryloxy; -C.sub.6 alkoxy) carbonyl; substituted by phenyl; alkanoyl, C.sub.3 -C.sub.20 alkenoyl, phenyl, C.sub.1 -C.sub.20 alkyl or C.sub.2 -C.sub.20 alkenyl, wherein the alkanoyl, alkenoyl, alkyl and the alkenyl groups may be unsubstituted or substituted by 1 to 3 substituents chosen independently from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, aryl, aryloxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy) carbonyl, (C.sub.3 -C.sub.4 alkenyl) carbamoyl, aralkylcarbamoyl, arylcarbamoyl and -CONRcRd in which each of Rc and Rd independently is hydrogen or C.sub.1 -C.sub.6 alkyl or Rc and Rd, taken together with the nitrogen atom to which they are linked, form a morpholino or piperidino ring; polymethylene chain, which can be unsubstituted or substituted by a C.sub.1 -C.sub.2 alkyl, by a C.sub.2 -C.sub.12 alkenyl or by a C.sub.1 -C.sub.12 alkylidene group, wherein the alkyl, alkenyl and alkylidene groups may be in turn unsubstituted or substituted by a substituent chosen from halogen, C.sub.1 -C.sub.6 alkoxy, hydroxy, cyano, carboxy, (C.sub.1 -C.sub.6 alkoxy)carbonyl, aryloxy and aryl; the remaining one being hydrogen or C.sub.1 -C.sub.12 alkyl; and the pharmaceutically acceptable salts thereof.
Several naturally occurring compounds having a 2,2'-bipyrrolyl-pyrromethene skeleton have been reported in literature: J. Antibiotics 24, 636 (1971); Mar. Biol. 34, 223 (1976); Can. J. Microbiol. 22, 658 (1976); Can. J. Chem. 56, 1155 (1978); Tetrahedron Letters 24, 2797 (1983); J. Antibiotics 38, 128 (1985), J. Gen. Microbiol. 132, 1899 (1986); J. Antibiotics 28, 194 (1975); Nature 213, 903 (1967); Tetrahedron Letters 24, 2701 (1983).
Most of the above references relates to compounds, generally known as `prodigiosins`, having antibiotic and cytotoxic properties.
More recently an immunosuppressive activity has been disclosed for some of them: J. Antibiotics 39, 1155 (1986); J6 1280 429-A; JO 2250 828-A; and for the synthetic ones WO 95/17381.
Most of the compounds known from such publications fall within the scope of formula (I) as defined above.
BACKGROUND OF THE INVENTION
Although some total synthesis of prodigiosins have been reported in the past years (Rapoport H., Holden K. J., J. Am. Chem. Soc. 84, 635 (1962); Boger D. L., Patel M., J. Org. Chem. 53, 1405 (1988); Wasserman H. H., Lombardo L. J., Tetrahedron Lett. 30, 1725 (1989); Wasserman H. H., Keith D. D., Nadelson J. Tetrahedron 32, 1867 (1976); Doria et al. WO 95/17381), most of prodigiosin derivatives known so far comes from natural source extraction.
The known synthetic methods for the preparations of prodigiosins in particular rely on: substituted pyrrole (III) in acidic media: ##STR2## wherein R1, R2, R3, R4, R5, R6 are as defined above; or substituted pyrrole aldehyde (V): ##STR3## wherein R1, R2, R3, R4, R5, R6 are as defined above.
Details of process-variants a) and b) can be found for instance in WO95/17381. However, in both processes the following main drawbacks can be noticed: time consuming and involves several steps (from 9 to 14).
That makes the above-mentioned process not suitable to be scaled up. On the other hand, in view of the valuable biological properties of the compounds of formula (I), in particular of the immunomodulating compounds known from WO95/17381 encompassed therein, there is a need in this field of a process suitable for a large scale industrial production.
SUMMARY OF THE INVENTION
The present invention provides a new process for preparing a prodigiosin derivative of formula (I) as defined above, as shown in following Scheme 1 : ##STR4## wherein R1, R2, R3, R4, R5, R6 are as defined above, R7
REFERENCES:
CA 13265-13268: Porphyrins. III. Preliminary studies on the synthesis of porphyrin a. Badger et al, 1964.
Journal of the Chemical Society. Porphyrins. Part I. Intramolecular Hydrogen Bonding in Pyrromethenes and Porphyrins. Badger et al, 1962.
Ceriani Lucio
D'Alessio Roberto
Rossi Arsenia
Tibolla Marcellino
McKane Joseph K.
Pharmacia & Upjohn S.p.A.
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