Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-04-06
2002-03-12
Bernhardt, Emily (Department: 1611)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S382000
Reexamination Certificate
active
06355800
ABSTRACT:
TECHNICAL FIELD
The present invention relates to a new industrial process excellent in yield and purity for producing aminopiperazine derivatives and pharmaceutically acceptable salts thereof in a less number of steps with a synthetic pathway without proceeding via nitroso compounds, and is useful in a pharmaceutical field.
BACKGROUND TECHNOLOGY AND PROBLEM
The process for preparing aminopiperazine derivatives of the present invention is described in an international patent application (international publication number WO91/01979) published based on the Patent Cooperation Treaty. By the said process, however, isolation and purification of intermediate products are not necessarily easy owing to water-solubility thereof or the like, so mass production of the aminopiperzine derivatives was difficult.
Additionally, the process for preparing aminopiperazine derivatives of the present invention is described in an international patent application (international publication number WO95/00502) published based on the Patent Cooperation Treaty. However, said process had many problems as an industrial synthetic process because of a large number of steps (6 steps), use of a large amount of methylene chloride as a solvent for extraction, occurrence of carcinogenic nitroso compounds as intermediates, and the necessity for reduction reaction with metallic zinc.
CONSTITUTION OF INVENTION
One object of the present invention is to provide new processes for preparing the aminopiperazine derivatives and pharmaceutically acceptable salts thereof which possess the potentiation of the cholinergic activity and are useful for treating disorders in the central nervous system, especially for treating amnesia, dementia, senile dementia, and the like in human being.
According to the present invention, the aminopiperazine derivatives of the object compound (I) or pharmaceutically acceptable salts thereof can be prepared by the following processes.
wherein R
1
is lower alkyl, aryl, ar(lower)alkoxy or heterocyclic group, each of which may be substituted with halogen, and R
2
is cyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may be substituted with halogen.
wherein R
1
is lower alkyl, aryl, ar(lower)alkoxy or heterocyclic group, each of which may be substituted with halogen, and R
2
is cyclo(lower)alkyl, aryl or ar(lower)alkyl, each of which may be substituted with halogen.
In the above and subsequent descriptions of the present specification, suitable examples of the various definitions to be included within the scope of the invention are explained in detail as follows.
The term “lower” is intended to mean 1 to 6 carbon atom(s), unless otherwise indicated.
Suitable “lower alkyl” may include a straight or branched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like, in which the preferable one is methyl.
Suitable “aryl” may include phenyl, naphthyl, tolyl, xylyl, mesityl, cumenyl, and the like, in which the preferable one is phenyl or naphthyl.
Suitable “ar(lower)alkoxy” may include benzyloxy, phenethyloxy, phenylpropoxy, benzhydryloxy, trityloxy, and the like.
Suitable “heterocyclic group” may include saturated or unsaturated monocyclic group containing at least one hetero-atom such as nitrogen, oxygen and sulfur atom.
Preferable “heterocyclic group” thus defined may be unsaturated 3 to 8-membered (more preferably 5 or 6-membered) heteromonocyclic group containing 1 to 4 nitrogen atom(s), for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridyl N-oxide, dihydropyridyl, tetrahydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, triazolyl, tetrazinyl, tetrazolyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atom(s), for example, idolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, oxazolyl, isoxazolyl, oxadiazolyl, etc.;
saturated 3 to 8-membered heteromonocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, morpholino, sydnonyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s) and 1 to 3 nitrogen atom(s), for example, benzoxazolyl, benzoxadiazolyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, thiazolyl, isothiazolyl, thiadiazolyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing 1 to 2 sulfur atom(s), for example, thienyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s) and 1 to 3 nitrogen atom(s), for example, benzothiazolyl, benzothiadiazolyl, etc.;
unsaturated 3 to 8-membered heteromonocyclic group containing an oxygen atom, for example, furyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atom(s), for example, benzothienyl, etc.;
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atom(s), for example, benzofuranyl, etc., and the like.
Suitable “cyclo(lower)alkyl” may include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
Suitable “ar(lower)alkyl” may include benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, and the like.
“Lower alkyl”, “aryl”, “ar(lower)alkoxy”, “heterocyclic group”, “cyclo(lower)alkyl” and “ar(lower)alkyl” described above may be substituted with halogen [e.g. fluoro, chloro, bromo and iodo].
Pharmaceutically acceptable salts of the object compound(I) are conventional non-toxic salts and may include an acid addition salt such as an inorganic acid addition salt (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), an organic acid addition salt (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonate, toluensulfonate etc.); a salt with an amino acid (e.g. aspartic acid salt, glutamic acid salt, etc.); and the like.
The processes for preparing the object compound(I) are explained in detail in the following.
PROCESS 1
The compound(I) or a salt thereof can be prepared by reacting the compound(III) or a salt thereof with the compound(II) or its reactive derivative at the carboxy group or a salt thereof.
Suitable salts of the compound(III) can be reffered to the ones as exemplified for the compound(I).
Suitable reactive derivative at the carboxy group of the compound (II) may include an ester, an acid halide, an acid anhydride, and the like. Suitable examples of the reactive derivatives may be an acid halide (e.g. acid chloride, acid bromide, etc.); a symmetrical acid anhydride; a mixed acid anhydride with an acid such as aliphatic carboxylic acid (e.g. acetic acid, pivalic acid, etc.), substituted phosphoric acid (e.g. dialkylphosphoric acid, diphenylphosphoric acid, etc.); an ester such as substituted or unsubstituted lower alkyl ester (e.g. methyl ester, ethyl ester, propyl ester, hexyl ester, trichloromethyl ester, etc.), substituted or unsubstituted ar(lower)alkyl ester (e.g.benzyl ester, benzhydryl ester, p-chlorobenzyl ester, etc.), substituted or unsubstituted aryl ester (e.g. phenyl ester, tolyl ester, 4-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, naphtyl ester, etc.), or an ester with N,N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxy-6-chloro-1H-benzotriazole. These reactive derivatives can optionally be selected from them according to the kind of the compound (II) to be used.
In this reaction, compound (III) or a salt thereof is reacted with compound (II) or a reactive derivative at the carboxy group or a salt thereof, to form a mixed acid anhydride of compounds (III) and (II), which is then is decarbonated to form compound (I).
In this reaction, however, compound (III) may be decarbonated depending on reaction conditions to form the following compound:
, with which compound (II) or a reactive derivative at the carboxy group or a salt thereof reacts, thus giving compound (I). This reaction is also encompassed by the process of this i
Baba Yukihisa
Furutera Tetsuo
Hashimoto Norio
Kagara Kooji
Kanda Atsushi
Bernhardt Emily
Fujisawa Pharmaceutical Co. Ltd.
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