Process for the preparation of indolizine derivatives

Details Process for the preparation of indolizine derivatives Process for the preparation of indolizine derivatives

1996-05-06

1998-07-14

Dees, Jose G.

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

546121, 546200, 546201, 540547, 544125, 544362, 5483121, 548453, 548467, 548518, 549399, 549403, 549404, 549406, 549415, C07D22104, C07D47104, C07D20902

Patent

active

057806330

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/US94/01465 filed Sep. 6, 1994.
The present invention relates to a new process for the preparation of indolizine derivatives which have pharmacological activities such as inhibitory activity on testosterone 5.alpha.-reductase and the like.
The process of the present invention is characterized by reacting a compound of the formula: ##STR2## wherein R.sup.2 is hydrogen, lower alkyl or halogen, R.sup.3 is aryl or ar(lower)alkyl, each of which may have suitable substituent(s), substituted carbamoyl(lower)alkyl, or a group of the formula: ##STR3## in which ##STR4## is heterocyclic group containing nitrogen atom, and n is 0 or 1, ##STR5## in which R.sup.4 is hydrogen or lower alkyl, and R.sup.5 is hydrogen, lower alkyl or Y--Z--R.sup.3, ##STR6## in which R.sup.6 is hydrogen, lower alkyl, ar(lower)alkyl which may have suitable substituent(s) or amino protective group, ##STR7## wherein R.sup.1 is carboxy or protected carboxy, R.sup.11 is hydrogen or lower alkyl, and ##STR8## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.11, A, Q, X, Y and Z are each as defined above,
The process of the present invention is very useful for industrially preparing the indolizine derivatives.
Suitable salts of the compounds (I), (II) and (III) are conventional non-toxic, pharmaceutically acceptable salt and may include a salt with a base or an acid addition salt such as a salt with an inorganic base, for example, an alkali metal salt (e.g. sodium salt, potassium salt, cesium salt, etc.), an alkaline earth metal salt (e.g. calcium salt, magnesium salt, etc.), an ammonium salt; a salt with an organic base, for example, an organic amine salt (e.g. triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.), etc.; an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.); an organic carboxylic or sulfonic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, etc.); a salt with a basic or acidic amino acid (e.g. arginine, aspartic acid, glutamic acid, etc.); and the like, and the preferable example thereof is an acid addition salt.
In the above and subsequent descriptions of the present specification, suitable examples and illustrations of the various definitions which the present invention include within the scope thereof are explained in detail as follows.
The term "lower" is intended to mean 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, unless otherwise indicated.
Suitable "lower alkyl" may include straight or branched one, having 1 to 10 carbon atom(s), such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and the like, preferably one having 1 to 6 carbon atoms, and more preferably one having 1 to 4 carbon atoms.
The term "halogen" means fluoro, chloro, bromo and iodo.
Suitable "lower alkylene" means straight or branched bivalent lower alkane such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, and the like, which may be substituted by oxo.
Suitable "acid residue" may include halogen (e.g. fluoro, chloro, bromo, iodo), acyloxy (e.g. acetoxy, tosyloxy, mesyloxy, etc.) and the like.
Suitable "lower alkenylene" may include one having 2 to 6 carbon atoms such as vinylene, propenylene, and the like.
Suitable "aryl which may have suitable substituent(s)" may include a conventional group such as aryl (e.g. phenyl, naphthyl, etc.), substituted aryl, for example, lower alkylaryl (e.g. tolyl, xylyl, mesityl, cumenyl, isobutylphenyl, etc.), haloaryl (e.g. chlorophenyl, etc.), and the like.
"Ar(lower)alkyl" in the "ar(lower)alkyl which may have suitable substituent(s)" means straight or branched C.sub.1 -C.sub.10 alkyl substituted by aryl group(s), and suitable "ar(lower)alkyl which may have suitable substituent(s)" may include a conventional group such as ar(lower)alkyl (e.g. trityl, benzhydryl, benz

REFERENCES:
"Indolizine Analogues of Indometaacin," C. Casagrande et al., Il Farmaco, vol. 26, No. 12 (Dec., 1971), pp. 1059-1073.
"Formation of Indolizines via Pyridinium 3-Carbomethoxyallylides", Y. Tamura et al., Chem. Pharm. Bull., vol. 20, No. 5, pp. 1058-1061 (1972).
"Methods for Construction of Indolizine Nucleus," T. Uchida et al., Synthesis, No. 4 (Apr., 1976) pp.209-236.

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