Piperazine derivatives and process for the preparation thereof

Details Piperazine derivatives and process for the preparation thereof Piperazine derivatives and process for the preparation thereof

2002-03-26

2004-01-27

Bernhardt, Emily (Department: 1624)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S356000, C544S360000, C544S363000, C544S390000, C544S357000, C544S392000

Reexamination Certificate

active

06683184

ABSTRACT:

The present invention relates to a new piperazine derivative of the general formula (I) or its pharmaceutically acceptable acid addition salt, and process for the preparation thereof.
wherein R
1
and R
2
are independently hydrogen, C
1
-C
4
alkyl, C
1
-C
4
alkylcarboxyl, C
1
-C
4
alkylcarbonyl, C
1
-C
4
alkoxy, C
1
-C
4
hydroxyalkyl, C
1
-C
4
aminoalkyl or C
1
-C
4
hydroxyiminoalkyl, or R
1
and R
2
are fused to form C
3
-C
4
unsaturated ring;
R
3
, R
4
, R
5
, R
6
, and R
7
are independently hydrogen, halogen, hydroxy, nitro, amino, C
1
-C
4
alkyl, C
1
-C
4
alkylcarboxyl, C
1
-C
4
alkylcarbonyl, C
1
-C
4
alkoxy or C
1
-C
4
thioalkoxy; R
8
is C
1
-C
4
alkyl;
Y is oxygen, sulphur, amino, subsitituted amino or C
1
-C
4
thioalkyl;
Z is C
1
-C
4
alkoxy, C
1
-C
4
alkyl, C
1
-C
4
alkylamino or C
1
-C
4
thioalkoxy;
X
1
and X
2
are independently CH or nitrogen; and
—N═C— and —C═Y— may form a single bond or a double bond provided that if —N═C— forms a single bond, —C═Y— forms a double bond, and if —C═Y— forms a single bond, —N═C— forms a double bond and R
8
is nonexistent.
In the above definitions, C
1
-C
4
alkyl means methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
C
1
-C
4
alkylcarboxyl means carboxyl esterified with a lower alkyl such as methylcarboxyl and ethylcarboxyl.
C
1
-C
4
alkylcarbonyl means carbonyl ketonized with a lower alkyl such as methylcarbonyl and ethylcarbonyl.
C
1
-C
4
alkoxy means methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy or tert-butoxy.
C
1
-C
4
thioalkoxy means methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio or tert-butylthio.
C
1
-C
4
aminoalkyl means aminomethyl, aminoethyl, aminopropyl, aminobutyl or the like.
C
1
-C
4
kydroxyalkyl means hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl or the like.
C
1
-C
4
hydroxyiminoalkyl means C
1
-C
4
alkyl substituted with hydroxyimino such as hydroxyiminoethyl.
Substituted amino means hydroxyamino, C
1
-C
4
alkylamino, C
1
-C
4
alkoxyamino or the like.
The present inventors had studied for a long time to find compounds having intensive antitumor activity. As a result, now we have finally found out the facts that the present compounds of the general formula (I) and acid addition salts thereof have not only prominent antitumor activities but very low toxicities.
Accordingly, the one object of the present invention is to provide the novel compounds of the general formula (I) and acid addition salts thereof having not only prominent antitumor activities but very low toxicities.
The other object of the present invention is to provide a process for the preparation of the compounds of general formula (I) and acid addition salts thereof.
The compounds of the present invention can be mixed with pharmaceutically acceptable vehicles by a known method to give pharmaceutical compositions and thus the pharmaceutical compositions can be used to prevent or treat with various kinds of tumors of human beings or mammals.
Therefore, another object of the present invention is to provide pharmaceutical compositions containing the compound of the general formula (I) or an acid addition salt thereof as an active ingredient.
Acids which can be reacted with the compounds of the general formula (I) to form acid addition salts are pharmaceutically acceptable inorganic or organic acids; for example, inorganic acids such as hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, nitric acid; organic acids such as formic acid, acetic acid, propionic acid, succinic acid, citric acid, maleic acid, malonic acid, glycolic acid, lactic acid; amino acids such as glycine, alanine, valine, leucine, isoleucine, serine, cysteine, cystine, asparaginic acid, glutamic acid, lysine, arginine, tyrosine, proline; sulfonic acids such as methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid; or the like.
Vehicles which can be used in the preparation of pharmaceutical compositions containing the compound of the general formula (I) as the active ingredient may include a sweetening agent, binding agent, dissolving agent, aids for dissolution, wetting agent, emulsifying agent, isotonic agent, adsorbent, degrading agent, antioxident, antiseptics, lubricating agent, filler, perfume or the like; such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, stearin, magnesium stearate, calcium stearate, magnesium aluminum silicate, starch, gelatine, tragacanth gum, glycine, silica, alginic acid, sodium alginate, methyl cellulose, sodium carboxy methyl cellulose, agar, water, ethanol, polyethylenglycol, polyvinyl pyrrolidone, sodium chloride, potassium chloride, orange essence, strawberry essence, vanilla aroma or the like.
Daily dosage of the compound of the general formula (I) may be varied depending on age, sex of a patient, degree of disease, etc. and generally 1.0 mg to 5,000 mg per day may be administered one to several times.
The compounds of the general formula (I) according to the present invention wherein —N═C— forms a single bond and —C═Y— forms a double bond, may be prepared by the following scheme I.
wherein R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, R
8
, X
1
, X
2
, Y and Z are as defined above, and Lie is a conventional leaving group such as halogen, sulfonyl or the like.
The above process comprises reacting a compound of the general formula (2) with a —C(═Y)— group-providing agent in an organic solvent to obtain a compound of the general formula (3) and successively reacting the compound of the formula (3) with a compound of the general formula (4) to give the compound of the general formula (5). Then, the compound of the formula (5) may be reacted with an alkylating agent or an arylating agent in the presence of a base to give a compound of the general formula (Ia).
The —C(═Y)— group-providing agent used in the above reaction may include 1,1-carbonyldiimidazole, 1,1-carbonylthiodiimidazole, phosgene, thiophosgene, carbonyldiphenoxide and phenylchloroformate, and it may be used in an amount of 1-1.5 equivalent, preferably 1-1.1 equivalent to the starting compound.
organic solvent such as, for example, tetrahydrofuran, dichloromethane, acetonitrile, chloroform and dimethylformamide.
And also the reaction is preferably carried out in the presence of a coupling agent such as a conventional inorganic or an organic base. Such conventional inorganic or organic bases used in the reaction may include sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine and DBU.
The reaction may be carried out at a temperature between 3° C. and boiling point of the solvent used, preferably at 50° C.-100° C. and for 5-48 hours, preferably for 10-24 hours.
The reaction of the compound (3) with the compound (4) to give the compound (5) may be carried out in the presence of a conventional organic solvent at the temperature of 50-100° C. for 5-48 hours. The compound (4) may be used by 1-1.5 equivalent.
And also the reaction is preferably carried out in the presence of a conventional inorganic or organic base, such as sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, triethylamine, pyridine, DBU or the like.
Then, the compound of the formula (5) may be reacted with an alkylating agent or an arylating agent in the presence of a conventional organic or inorganic base to give a compound of the general formula (Ia).
The alkylating agent and arylating agent used in the above step may include C
1
-C
8
alkylhalide, C
1
-C
8
alkylsulfonate, substituted or unsubstituted C
3
-C
8
cycloalkyl halide, arylhalide, and substituted or unsubstituted C
3
-C
8
cycloalkyl sulfonate.
C
1
-C
8
alkyl halide means methyl chloride, methyl bromide, methyl iodide, ethyl chloride, ethyl bromide, ethyl iodide, p

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