Xanthine phosphodiesterase V inhibitors

A method for producing a compound having the formula (I), comprising:

• (i) reacting a compound having the formula (III) with an alkyl halide in the presence of a base to form a compound having the formula (IV):
• 226
• where,
• (a) R1 is a hydrogen atom or a C1-15 alkyl group, branched or straight chain, with or without one or more substituents, a C2-15 alkenyl group, branched or straight chain, with or without one or more substituents, a C2-15 alkynyl group, branched or straight chain, with or without one or more substituents, a C3-15 cycloalkyl group, with or without one or more substituents, an arylalkyl group, with or without one or more substituents, an aryl group, with or without one or more substituents, a heteroaryl group, with or without one or more substituents, —OR5, —COOR5, —C(O)R5 or —C(O)N(R5)2, where R5 is a hydrogen atom or a hydrocarbon radical, branched or straight-chain, with or without one or more substituents;
• (b) L is R2 or a protected form of R2;
• and
• (c) Ph is a phenyl group;
• (ii) debenzylating and then alkylating the compound having the formula (IV) with an alkyl halide having the formula XCH2R3 to form the compound having the formula (V):
• 227
• where,
• X is a halogen atom and
• R3 is an aryl group, with or without one or more substituents, a heteroaryl group, with or without one or more substituents, or a heterocyclic group having 1 to 3 heteroatoms fused to a 5- or 6-membered aryl ring, with or without one or more substituents, with the proviso that R3 is not an aryl group substituted at its para position with a —Y-aryl group, where Y is a carbon-carbon single bond, —CO—, —O—, —S—, —N(R21)—, —CON(R22)—, —N(R22)CO—, —OCH2—, —CH2O—, —SCH2—, —CH2S—, —NHC(R23) (R24)—, —NR23SO2—, —SO2NR23—, —C(R23) (R24)NH—, —CH═CH—, —CF═CF—, —CH═CF—, —CF═CH—, —CH2CH2—, —CF2CF2—,
• 228
• where,
• R21 is a hydrogen atom or a —CO(C1-4 alkyl), C1-6 alkyl, allyl, C3-6 cycloalkyl, phenyl or benzyl group;
• R22 is a hydrogen atom or a C1-6 alkyl group;
• R23 is a hydrogen atom or a C1-5 alkyl, aryl or —CH2-aryl group;
• R24 is a hydrogen atom or a C1-4 alkyl group;
• R25 is a hydrogen atom or a C1-8 alkyl, C1-8 perfluoroalkyl;
• C3-6 cycloalkyl, phenyl or benzyl group;
• R26 is a hydrogen atom or a C1-6 alkyl, C3-6 cycloalkyl, phenyl or benzyl group;
• R27 is —NR23R24, —OR24, —NHCONH2, —NHCSNH2,
• 229
• and
• R28 and R29 are, independently of one another, each a C1-4 alkyl group, or R28 and R29, taken together with each other, are a —(CH2)q group, where q is 2 or 3;
• wherein, R21 through R29 are optionally substituted with one or more substituents;
• and
• (iii) deprotonating and then halogenating the compound having the formula (V) to form a compound having the formula (VI):
• 230
• where,
• Hal is a halogen atom;
• (iv) reacting the compound having the formula (VI) with an amine having the formula R4NH2 to form a compound having the formula (VII):
• 231
• where,
• R4 is a C3-15 cycloalkyl group, with or without one or more substituents, a C3-15 cycloalkenyl group, with or without one or more substituents, or a heterocycloalkyl group of 3 to 15 members, with or without one or more substituents;
• and
• (v) removing the protecting portion of L, when L is the protected form of R2, on the compound having the formula (VII) to form the compound having the formula (I):
• 232
• where,
• R2 is defined the same as R1 above, with the proviso that at least one of R1 and R2 is not a hydrogen atom;
• wherein, the one or more substituents for all the groups are chemically-compatible and are, independently of one another, each an:
• alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, arylalkyl, alkylaryl, aryl, heteroaryl, heterocycloalkyl, hydroxyalkyl, arylalkyl, aminoalkyl, haloalkyl, thioalkyl, alkylthioalkyl, carboxyalkyl, imidazolylalkyl, indolylalkyl, mono-, di- and trihaloalkyl, mono-, di- and trihaloalkoxy, amino, alkylamino, dialkylamino, alkoxy, hydroxy, halo, nitro, oximino, —COOR50, —COR50, —SO0-2R50, —SO2NR50R51, NR52SO2R50, ═C(R50R51), ═N—OR50, ═N—CN, ═C(halo)2, ═S, ═O, —CON(R50R51), —OCOR50, —OCON(R50R51), —N(R52)CO(R50), —N(R52)COOR50 or —N(R52)CON(R50R51) group, where:
• R50, R51 and R52 are, independently of one another, each a hydrogen atom or a C1-6 alkyl, C3-6 cycloalkyl, C4-6 heterocycloalkyl, heteroaryl and aryl group, or R50 and R51 are joined together to form a carbocyclic or heterocyclic ring system, or R50, R51 and R52 are, independently of one another, each:
• 233
• where,
• R40 and R41 are, independently of one another, each a hydrogen atom or an alkyl, cycloalkyl, heterocycloalkyl, halo, aryl, imidazolylalkyl, indolylalkyl, heteroaryl, arylalkyl, arylalkoxy, heteroarylalkyl, heteroarylalkoxy, aminoalkyl, haloalkyl, mono-, di- or trihaloalkyl, mono-, di- or trihaloalkoxy, nitro, cyano, alkoxy, hydroxy, amino, phosphino, phosphate, alkylamino, dialkylamino, formyl, alkylthio, trialkylsilyl, alkylsulfonyl, arylsulfonyl, alkylsulfinyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxyalkyl, morpholino, thioalkyl, alkylthioalkyl, carboxyalkyl, oximino, —COOR50, —COR50, —SO0-2R50, —SO2NR50R51, —NR52SO2R50, —CON(R50R51), —OCON(R50R51), —N(R52)CO(R50), —N(R52)COOR50, —N(R52)CON(R50R51) or —OCONR50 group, where, R50, R51 and R52 are defined the same as above;
• R42 is a hydrogen atom or an alkyl, alkenyl, arylalkyl or acyl group;
• and
• R43 is a hydrogen atom or an alkyl or aryl group;
• where, R40 through R43 and R50 through R52 are, independently of one another, each optionally substituted with any one of the groups defined above for the one or more substituents.