Novel heterocyclic compounds, their preparation, pharmaceutical compositions containing them and their use in medicine

A process for the preparation of a compound of formula (I) as claimed in claim 1,

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• their derivatives, their analogs, their tautomeric forms, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, their pharmaceutically acceptable solvates, wherein one or more groups R1, R2, R3, R4 may be same or different and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C1-C12)alkyl, linear or branched (C2-C12)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, ar(C1-C12)alkoxy, heterocyclyl, heteroaryl, heterocyclyl(C1-C12)alkyl, heteroar(C1-C12)alkyl, heteroaryloxy, heteroar(C1-C12)alkoxy, heterocyclyloxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, heterocyclyloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, (C1-C12)alkylthio, thio(C1-C12)alkyl, arylthio, (C1-C12)alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, alkyl hydrazino, alkoxyamino, hydroxylamino, derivatives of sulfenyl and sulfonyl groups, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives;
• or the adjacent groups R2 and R3 together may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, or S;
• n is an integer ranging from 1 to 8;
• W represents O, S or NR9 where R9 represents hydrogen, (C1-C2)alkyl or aryl;
• Ar represents a substituted or unsubstituted divalent single or fused aromatic, heteroaromatic or heterocyclic group;
• R5 and R6 represent both hydrogen or together represent a bond;
• R5 and R6 may also represent a hydroxy, (C1-C12)alkyl, (C1-C12)alkoxy, halogen, acyl, substituted or unsubstituted aralkyl group;
• X represents O or S;
• R7 represents hydrogen, perfluoro(C1-C12)alkyl, substituted or unsubstituted groups selected from (C1-C12)alkyl, cyclo(C1-C12)alkyl, aryl, ar(C1-C12)alkyl, heteroaryl, heteroar(C1-C12)alkyl, heterocyclyl, alkoxyalkyl, aryloxyalkyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkyloxycarbonyl, alkylaminocarbonyl, arylaminocarbonyl, acyl groups;
• Y represents O or S;
• Z represents oxygen, sulfur or NR10, where R10 represents hydrogen or substituted or unsubstituted groups selected from (C1-C12)alkyl, aryl, ar(C1-C12)alkyl, hydroxy(C1-C12)alkyl, amino(C1-C12)alkyl, heteroaryl, heteroar(C1-C12)alkyl groups;
• R8 represents hydrogen, substituted or unsubstituted groups selected from (C1-C12)alkyl, aryl, ar(C1-C12)alkyl, heteroaryl, heteroar(C1-C12)alkyl, heterocyclyl, heterocyclylalkyl, hydroxyalkyl, alkoxyalkyl, alkylaminoalkyl groups;
• R10 and R8 together may form a 5 or 6 membered substituted or unsubstituted cyclic ring structure containing carbon atoms or containing one or more heteroatoms selected from O, N and S, which comprises:
• a. reacting a compound of formula (1a), where all symbols are as defined above,
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• with a compound of formula (1b) which may be racemic or chiral, where all symbols are as defined earlier to yield a compound of general formula (I);
• b. reacting a compound of formula (1c), as described in claim 40,
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• with a compound of formula (1d) which may be racemic or chiral, where all symbols are as defined earlier to yield a compound of general formula (I);
• c. reacting the compound of formula (1e), as described in claim 42
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• with a compound of general formula (1d) which may be racemic or chiral, where W is particularly O or S and all other symbols as defined earlier;
• d. reacting a compound of formula (1f), as described in claim 44
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• where all the symbols are as defined earlier with an alcohol of formula (1g) wherein R7 and X are as defined, to produce a compound of formula (I), wherein all symbols are as defined earlier and R6 represents H;
• e. reacting a compound of general formula (1h), as described in claim 38
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• where all the symbols are as defined earlier, with a compound of formula (1i) which may be chiral or racemic, where R represents (C1-C8) alkyl and other symbols are as defined earlier and to afford a compound of formula (I) where R5 and R6 together form a bond and other symbols are as defined earlier and;
• and
• f. reacting a compound of general formula (1h), as described in claim 38
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• where all the symbols are as defined earlier, with a compound of formula (1i) which may be chiral or racemic, where all the symbols are as defined earlier and R represents (C1-C8) alkyl to afford a compound of formula (I) wherein all symbols are as defined earlier and R5 and R6 together form a bond which is reduction of the double bond formed together by R1and R6.

The compound compound of formula (1h),

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• wherein one or more groups R1, R2, R3, R4 may be same or different and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C1-C12)alkyl, linear or branched (C2-C12)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, ar(C1-C12)alkoxy, heterocyclyl, heteroaryl, heterocyclyl(C1-C12)alkyl, heteroar(C1-C12)alkyl, heteroaryloxy, heteroar(C1-C12)alkoxy, heterocyclyloxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, heterocyclyloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, (C1-C12)alkylthio, thio(C1-C12)alkyl, arylthio, (C1-C12)alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, alkyl hydrazino, alkoxyamino, hydroxylamino, derivatives of sulfenyl and sulfonyl groups, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives;
• or the adjacent groups R2 and R3 together may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, or S;
• n is an integer ranging from 1 to 8;
• W represents O, S or NR9 where R9 represents hydrogen, (C1-C12)alkyl or aryl;
• Ar represents a substituted or unsubstituted divalent single or fused aromatic, heteroaromatic or heterocyclic group.

A process for the preparation of compound of formula (1h),

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• wherein one or more groups R1, R2, R 3, R4 may be same or different and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C1-C12)alkyl, linear or branched (C2-C12)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, ar(C1-C12)alkoxy, heterocyclyl, heteroaryl, heterocyclyl(C1-C12)alkyl, heteroar(C1-C12)alkyl, heteroaryloxy, heteroar(C1-C12)alkoxy, heterocyclyloxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocyclylalkoxycarbonyl, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, heterocyclyloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, (C1-C12)alkylthio, thio(C1-C2)alkyl, arylthio, (C1-C12)alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, alkyl hydrazino, alkoxyamino, hydroxylamino, derivatives of sulfenyl and sulfonyl groups, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives;
• or the adjacent groups R2 and R3 together may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, or S;
• n is an integer ranging from 1 to 8;
• W represents O, S or NR9 where R9 represents hydrogen, (C1-C12)alkyl or aryl;
• Ar represents a substituted or unsubstituted divalent single or fused aromatic, heteroaromatic or heterocyclic group, which comprises,
• a. reacting a compound of the general formula (1c) as described in claim 40,
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• with a compound of general formula (1j), where Ar is as defined earlier;
• b. reacting a compound of the formula (1e) as described in claim 42,
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• with compound of the formula (1k), where L2 is a halogen atom such as fluorine, chlorine, bromine or iodine and Ar is as defined earlier.

The intermediate of formula (1c),

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• wherein one or more groups R1, R2, R3, R4 may be same or different and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C1-C12)alkyl, linear or branched (C2-C12)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, ar(C1-C12)alkoxy, heterocyclyl, heteroaryl, heterocyclyl(C3-C7)alkyl, heteroar(C1-C12)alkyl, heteroaryloxy, heteroar(C1-C12)alkoxy, heterocyclyloxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocycloalkoxycarbonyl, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, heterocyclyloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, (C1-C12,)alkylthio, thio(C1-C12)alkyl, arylthio, (C1-C12)alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, alkyl hydrazino, alkoxyamino, hydroxylamino, derivatives of sulfenyl and sulfonyl groups, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives;
• or the adjacent groups R2 and R3 together may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, or S;
• n is an integer ranging from 1 to 8;
• and L1 is either a halogen atom such as chlorine, bromine or iodine or a leaving group such as methanesulfonate, trifluoromethanesulfonate and p-toluenesulfonate groups.

A process for intermediate of formula (1c),

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• wherein one or more groups R1, R2, R3, R4 may be same or different and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C1-C12)alkyl, linear or branched (C2-C12)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, ar(C1-C12)alkoxy, heterocyclyl, heteroaryl, heterocyclyl(C3-C7)alkyl, heteroar(C1-C12)alkyl, heteroaryloxy, heteroar(C1-C12)alkoxy, heterocyclyloxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocycloalkoxycarbonyl, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, heterocyclyloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, (C1-C12)alkylthio, thio(C1-C12)alkyl, arylthio, (C1-C12)alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, alkyl hydrazino, alkoxyamino, hydroxylamino, derivatives of sulfenyl and sulfonyl groups, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives;
• or the adjacent groups R2 and R3 together may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, or S;
• n is an integer ranging from 1 to 8;
• and L1 is either a halogen atom such as chlorine, bromine or iodine or a leaving group such as methanesulfonate, trifluoromethanesulfonate and p-toluenesulfonate groups, which comprises,
• a. reacting the compound of formula (1a), where R1, R2, R3, R4 are as defined earlier
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• with a compound of formula (1m) where L1 is either a halogen atom such as chlorine, bromine or iodine or a leaving group such as methanesulfonate, trifluoromethanesulfonate and p-toluenesulfonate groups and all symbols are as defined earlier, to yield the compound of formula (1c);
• and
• b. reacting the compound of formula (1n) where R1, R2, R3 and R4 are as defined earlier,
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• with a compound of formula (1o) where L1 and L2 is either a halogen atom such as chlorine, bromine or iodine or a leaving group such as methanesulfonate, trifluoromethanesulfonate and p-toluenesulfonate groups and n is as defined earlier, to yield the compound of formula (1c).

A process to prepare intermediate of formula (1e),

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• wherein one or more groups R1, R2, R3, R4 may be same or different and represent hydrogen, halogen, perhaloalkyl, hydroxy, thio, amino, nitro, cyano, formyl, amidino, guanidino, substituted or unsubstituted groups selected from linear or branched (C1-C12)alkyl, linear or branched (C2-C12)alkenyl, (C3-C7)cycloalkyl, (C3-C7)cycloalkenyl, bicycloalkyl, bicycloalkenyl, (C1-C12)alkoxy, cyclo(C3-C7)alkoxy, aryl, aryloxy, aralkyl, ar(C1-C12)alkoxy, heterocyclyl, heteroaryl, heterocyclyl(C3-C7)alkyl, heteroar(C1-C12)alkyl, heteroaryloxy, heteroar(C1-C12)alkoxy, heterocyclyloxy, heterocyclylalkyloxy, acyl, acyloxy, acylamino, monoalkylamino, dialkylamino, arylamino, aralkylamino, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, heterocycloalkoxycarbonyl, heteroaryloxycarbonyl, heteroaralkoxycarbonyl, heterocyclyloxycarbonyl, hydroxyalkyl, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, (C1-C12)alkylthio, thio(C1-C12)alkyl, arylthio, (C1-C12)alkoxycarbonylamino, aryloxycarbonylamino, aralkyloxycarbonylamino, aminocarbonylamino, alkylaminocarbonylamino, alkylamidino, alkylguanidino, dialkylguanidino, hydrazino, alkyl hydrazino, alkoxyamino, hydroxylamino, derivatives of sulfenyl and sulfonyl groups, carboxylic acid and its derivatives, sulfonic acid and its derivatives, phosphonic acid and its derivatives;
• or the adjacent groups R2 and R3 together may form a five or a six membered ring, optionally containing one or more double bonds and optionally containing one or more heteroatoms selected from O, N, or S;
• n is an integer ranging from 1 to 8, which comprises,
• a. reacting the compound of formula (1a) where R1, R2, R3 and R4 are as defined earlier,
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• with a compound of formula (1l) where all symbols are as defined earlier, to give compound of formula (1e);
• b. reacting the compound of general formula (1n) where R1, R2, R3 and R4 are as defined earlier,
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• with a compound of formula (1p) where all symbols are as defined earlier, to give compound of formula (1e);
• and
• c. reducing the compound of general formula (1q), wherein R1-R4 are as defined earlier
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• to give compounds of formula (1e), where W is O.