2-substituted phenyl-5, 7-dehydrocarbyl-3, 7-dihydropyrrolo [2, 3-d] pyrimidin-4-one derivatives, the preparation and the pharmaceutical use thereof

A process for preparing a compound of general formula I comprising a compound of the general formula I:

• wherein R1 is H;
• C1˜C4 branched or straight chain alkyl;
• C1˜C4 halogenated branched or straight chain alkyl;
• C2˜C6 alkenyl;
• C2˜C4 alkynyl;
• pyridyl, pyrimidinyl, imidazolyl;
• except H, the above substituents may be optionally substituted with one or more following groups:
• halogen, cyano, nitro, hydroxyl, carboxyl, guanidino, C1˜C4 alkyl, C1˜C4 alkoxyl, C1˜C4 alkanoyl, C3˜C5 cycloalkyl, substituted phenyl, substituted heterocyclic group, CONR5R6, NR5R6, CO2R7, NHSO2R8 or SO2NR9R10;
• R2 is H;
• C1˜C3 branched or straight chain alkyl;
• C1˜C3 halogenated branched or straight chain alkyl;
• C2˜C6 alkenyl;
• C2˜C4 alkynyl;
• substituted phenyl;
• except H, the above substituents may be optionally substituted with one or more following groups:
• halogen, cyano-, nitro, hydroxyl, carboxyl, guanidino-, C1˜C4 alkyl, C1˜C4 alkoxyl, C1˜C4 alkanoyl, C3˜C5 cycloalkyl, substituted heterocyclic group, CONR6R7, NR6R7, CO2R8, NHSO2R9 or SO2NR10R11;
• R3 is H;
• C1˜C6 branched or straight chain alkyl which may be optionally substituted with C3˜C6 cycloalkyl or C1˜C4 alkoxyl;
• C2˜C4 alkenyl;
• C2˜C4 alkynyl;
• R4 is H;
• C1˜C6 branched or straight chain alkyl which may be optionally substituted with C3˜C6 cycloalkyl or C1˜C4 alkoxyl;
• C2˜C4 alkenyl;
• C2˜C4 alkynyl;
• R5 is H;
• C1˜C4 branched or straight chain alkyl which may be optionally substituted with OH, NR6R7, CN, CONR6R7 or CO2R8;
• C2˜C4 alkenyl which may be optionally substituted with CN, CONR6R7 or CO2R8;
• C2˜C4 alkoxyl optionally substituted with NR6R7;
• (C2˜C3 alkoxyl) C1˜C2 branched or straight chain alkyl optionally substituted with OH or NR6R7;
• CONR6R7;
• CO2R8;
• halogen;
• NR6R7;
• NHSO2NR6R7;
• NHSO2R9;
• SO2NR10R11;
• or phenyl, pyridyl, pyrimidinyl, imidazolyl, oxazolyl, thiazolyl, thienyl, or triazolyl, either of which is optionally substituted with methyl;
• R6 and R7 are each independently H or C1˜C4 branched or straight chain alkyl;
• or R6 and R7 together with their attached nitrogen atom form pyrrolinyl, piperidyl, morpholinyl, 4-N(R12)-piperazinyl or imidazolyl, either of which is optionally substituted with methyl or hydroxyl;
• R8 is H;
• C1˜C6 branched or straight chain alkyl optionally substituted with C1˜C4 alkoxyl, C1˜C4 alkylamino, dialkylamino;
• substituted phenyl and substituted heterocyclic group in which the substitute(s) on the ring of substituted phenyl and substituted heterocyclic group are defined as the above;
• R9 is C1˜C3 alkyl optionally substituted with NR6R7;
• R10 and R11 are each independently H or C1˜C12 branched or straight chain alkyl;
• C1˜C3 halogenated branched or straight chain alkyl;
• C2˜C6 alkenyl;
• C2˜C6 alkynyl or C3˜C6 cycloalkyl;
• or R10 and R11 take together to form a pyrrolinyl, pyrrolinone group, piperidyl, morpholinyl, 4-N(R13)-piperazinyl;
• or R10 and R11 together with their attached nitrogen atom form a pyrrolinyl, pyrrolinone group, piperidyl, morpholinyl, 4-N(R13)-piperazinyl which are optionally substituted with OH, CN, CO2R8, C1˜C4 branched or straight chain alkyl, C1˜C3 alkoxyl, NR14R15 or CONR14R15;
• substituted phenyl, substituted heterocyclic group, or C1˜C6 branched or straight chain alkyl substituted with substituted phenyl or substituted heterocyclic group, the said groups are optionally further substituted with OH, CO2R8, NR14R15, CONR14R15, or linked together with another substituted phenyl or substituted heterocyclic group by a carbonyl group;
• R12 is H;
• C1˜C6 branched or straight chain alkyl which may be optionally substituted with phenyl, C2˜C3 alkyl substituted by hydroxyl, or C1˜C4 alkoxyl;
• C1˜C3 fluoroalkyl;
• C2˜C6 alkenyl;
• C2˜C6 alkynyl;
• or C3˜C6 cycloalkyl;
• R13 is H;
• C1˜C6 branched or straight chain alkyl;
• C2˜C6 branched or straight chain alkyl substituted with C1˜C3 alkoxyl;
• C2˜C6 branched or straight chain alkyl substituted with hydroxyl;
• C2˜C6 branched or straight chain alkyl substituted with NR14R15;
• C2˜C6 branched or straight chain alkyl substituted with phenyl;
• C1˜C6 branched or straight chain alkyl substituted with CONR14R15;
• C2˜C6 branched or straight chain hydrocarbyl substituted with CO2R8;
• C2˜C6 branched or straight chain hydrocarbyl having substituted phenyl or substituted heterocyclic group as substituent;
• CO2R8, CONR14R15, CSNR14R15 or C(NH)NR14R15;
• C1˜C3 halogenated branched or straight chain alkyl;
• C2˜C6 alkenyl;
• C2˜C6 alkynyl or C3˜C6 cylcloalkyl;
• or polyethylene glycol group (n=2˜20), which is optionally substituted with C1˜C6 alkyl on its terminal;
• R14 and R15 are each independently H;
• C1˜C4 branched or straight chain alkyl;
• C2˜C4 branched or straight chain alkyl substituted with C1˜C3 alkoxyl;
• or C2˜C4 branched or straight chain alkyl substituted with hydroxyl;
• or R14 and R15 together with their attached nitrogen atom form a pyrrolinyl, pyrrolinone group, piperidyl or morpholinyl;
• and
• the substituted phenyl refers to a phenyl which is substituted with one or more groups selected from C1˜C4 alkoxyl, halogen, cyano-, CF3, OCF3, C1˜C4 branched or straight chain alkyl on the phenyl ring;
• The substituted heterocyclic group refers to hexatomic rings containing one or two nitrogen atoms, and the oxides thereof;
• pentatomic rings containing two or three hetero-atom selected a group consisted of nitrogen, oxygen, and sulfur atoms;
• the substituting groups on the heterocyclic ring are C1˜C4 branched or straight chain alkyl, C1˜C4 alkoxyl, amino, as well as C1˜C4 branched or straight chain alkyl amino, C1˜C4 alkoxylamino group;
• or their pharmaceutically acceptable salts,
• the process comprising
• reacting compound IE with compound IF:
• in an inert solvent in the presence of an organic base as a catalyst as well as acid neutralizer at −20° C. to 80° C., to obtain compound ID:
• wherein compound IA may be prepared by heating compound ID in an acidic aqueous solution:
• wherein R1, R2, R3, R4 and R5 are defined as the above,
• carrying out a cyclization reaction of compound IA by heating and refluxing in an appropriate solution under acidic, basic or neutral condition to obtain compound of formula I:
• wherein R1, R2, R3, R4 and R5 are defined as the above;
• or,
• compound of formula I is obtained directly by cyclization of the corresponding compound ID under conditions as follows:
• a) heating to 100-300° C. in mixture of phosphorus pentoxide, water and tertiary amine, or,
• b) reacting at room temperature or reacting by heating in basic hydrogen peroxide aqueous solution, or,
• c) reacting at room temperature or reacting by heating under acidic hydrous or anhydrous condition;
• or,
• specific example of compounds of general formula I wherein R5 is SO2NR11R12 may be prepared by processes as follows:
• compound IC is obtained by reaction between compound IF and compound IE wherein R5 is H;
• wherein R1, R2, R3 and R4 are defined as the above,
• then compound IB is obtained by reacting compound IC with chlorosulfonic acid alone or in dichloromethane, chloroform, and other inert or polar non-proton solvents
• wherein R1, R2, R3 and R4 are as previously defined,
• and then acylation reaction occurs between compound IB and proper amines in dichloromethane, chloroform, tertiary amine or other inert or polar non-proton solvents at −78° C. to 100° C. to obtain compound of formula I wherein R5 is SO2NR1“R12, wherein R1” and R12 are defined as claim 1;
• or,
• compound IG
• wherein R1, R2, R3, R4 and R5 are defined as claim 1, reacts with compound IH in the solvents of polar non-proton solvents in the presence of the base as catalyst to obtain compound of formula I, wherein X represents Cl, Br or I, R3 is defined as claim 1;
• and
• optionally, converting the compounds of the formula I into the corresponding salts thereof by reacting with pharmaceutically acceptable acids.