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1. A process for preparing the compounds of formula (I), hence comprehensive of the compounds of formula (Ia) or (Ib) wherein R is hydrogen or an optionally substituted group selected from amino, straight or branched C1-C6 alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl; X is a single bond or a divalent radical selected from —NR′—, —CONR′—, —NH—CO—NH—, —O—, —S— or —SO2—, wherein R′ is hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl or, together with the nitrogen atom to which they are bonded, R and R′ may form a 5 to 6 membered heteroaryl or heterocyclyl group optionally containing one additional heteroatom selected among N, O or S; R1, bonded to any one of the nitrogen atoms of the pyrazole ring as per formulae (Ia) or (Ib), represents a hydrogen atom or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, in formula (Ib), R1 is a divalent —(CH2)n—NH— group being linked to R2, wherein n is 2 or 3; R2 is a group selected from —NR″R′″, —N(OH)R″, —OR″ or -R″, wherein R″ and R′″ are, each independently, hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C6 cycloalkyl or cycloalkyl-alkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl or, together with the nitrogen atom to which they are bonded, R″ and R′″ may form a 5 to 6 membered heteroaryl or heterocyclyl group, optionally containing one additional heteroatom selected among N, O or S; A is a divalent group selected from —CH2—, —(CH2)2—, —CH2—C(CH3)2—, —C(CH3)2—CH2— or —CH=CH—; or the pharmaceutically acceptable salts thereof, which process comprises: (1) when A is a —(CH2)2— group: st.1) reacting 2—ethoxy—2—cyclohexen—1 —one with diethyl oxalate, in the presence of lithium (bis-trimethylsilyl)amide [LiN(TMS)2], so as to obtain a compound of formula (II) and treating it with a hydrazine derivative of formula (III) R1—NHNH2 (III) wherein R1 is as above defined, according to any one of the operative conditions set forth in the following steps (st.2a), (st.2b) or (st.2c): st.2a) in the presence of a lower alcohol so as to obtain a mixture of the compounds of formula (IVa) and (IVb) wherein R1 is as above defined, and separating their mixture into the single compounds (IVa) and (IVb); st.2b) in the presence of acetic acid so as to obtain a compound of formula (IVa); st.2c) by alkylating a compound of formula (IVa), being obtained in step (st.2a) or (st.2b) and wherein R1 is hydrogen, with the compounds of formula (IVc)
R1 Y (IVc) wherein Y is a suitable leaving group selected from mesyl, tosyl and halogen, and R1 is as defined above but not hydrogen, as to obtain a mixture of compounds of formula (IVa) and (IVb) wherein R1 is as above defined and separating their mixture into the compounds (IVa) and (IVb); st.3) reacting the compound of formula (IVa) prepared according to any one of steps (st.2a), (st.2b) or (st.2c), or of formula (IVb) prepared according to steps (st.2a) or (st.2c), with dimethylformamide-di-tert-butylacetale so as to obtain a compound of formula (Va) or (Vb) wherein R1 is as above defined; and reacting the compound of formula (Va) or (Vb) according to any one of the alternative steps (st.4a), (st.4b) or (st.4c); st.4a) with guanidine so as to obtain a compound of formula (Ia) or (Ib) wherein R—X— is amino, R2 is ethoxy, and R1 is as above defined; st.4b) with a guanidine derivative of formula (VI)
R—NH—C(=NH)NH2 (VI) wherein R is hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, so as to obtain a compound of formula (Ia) or (Ib) wherein R and R1 are as above defined, X is —NH—, and R2 is ethoxy; st.4c) with an alkylisothiourea of formula (VII)
R—S— C(=NH)NH2 (VII) wherein R is hydrogen or an optionally substituted group selected from straight or branched C1-C6 alkyl, C3-C10cycloalkyl, aryl, arylalkyl, heterocyclyl or heterocyclylalkyl, so as to obtain a compound of formula (Ia) or (Ib) wherein R and R1 are as above defined, X is —S— and R2 is ethoxy; st.4d) with methylisourea so as to obtain a compound of formula (Ia) or (Ib) wherein R1 is as above defined, R is methyl, X is —O— and R2 is ethoxy; (2) when A is a —C(CH3)2—CH2— group: st.5) reacting 2—methoxy—4,4—dimethyl—2—cyclohexen—1 — one with diethyl oxalate, in the presence of [LiN(TMS)2], so as to obtain a compound of formula (VIII) st.6) reacting the compound of formula (VIII) with a hydrazine derivative of formula (III) R1—NHNH2, according to any one of previous steps (st.2a) or (st.2b) so as to obtain the compound of formula (IXa) or (IXb) wherein R1 is as above defined; st.7) reacting the compound of formula (IXa) or (IXb) with ethyl formate under basic conditions, so as to obtain the compound of formula (Xa) or (Xb) st.8) reacting the compound of formula (Xa) or (Xb) with a guanidine derivative of formula (VI), so as to obtain a compound of formula (Ia) or (Ib) wherein R and R1 are as above defined, X is —NH—, and R2 is ethoxy; (3) when A is a —CH2—C(CH3)2— group: st.9) reacting 2—methoxy—5,5—dimethyl—2—cyclohexen—1 —one with diethyl oxalate in the presence of sodium hydride, so as to obtain the compound of formula (XI) st.10) reacting the compound of formula (XI) with a hydrazine derivative of formula (III), R1— NHNH2 , according to any one of previous steps (st.2a) or (st.2b) so as to obtain the compound of formula (XIIa) or (XIIb) wherein R1 is as above defined; st.11) reacting the compound of formula (XIIa) or (XIIb) with dimethylformamide-di-tert-butylacetale so as to obtain a compound of formula (XIIIa) or (XIIIb) st.12) reacting the compound of formula (XIIIa) or (XIIIb) with a guanidine derivative of formula (VI), so as to obtain a compound of formula (Ia) or (Ib) wherein R and R1 are as above defined, X is —NH—, and R2 is ethoxy; (4) when, in formula (Ib), R1 is directly linked to R2 so as to yield a tetra-cyclic ring structure: st.13) reacting a compound of formula (IVa) or (IVb) wherein R1 is hydrogen, obtained according to any one of previous steps st.2a) and (st.2b) of the process, with triphenylmethyl chloride so as to obtain a compound of formula (XIV) wherein Tr stands for trityl (triphenylmethyl); st.14) reacting the compound of formula (XIV) with dimethylformamide-di-tert butylacetale, as set forth in step (st.3), so as to obtain a compound of formula (XV) st.15) reacting the compound of formula (XV) with a suitable guanidine derivative of formula (VI), R—NH—C(=NH)NH2, as set forth in step (st.4b), so as to obtain a compound of formula (Ia) or (Ib) wherein R is as above defined, X is NH, R1 is trityl and R2 is ethoxy; st.16) reacting the above compound of formula (Ia) or (Ib) under acidic conditions, so as to obtain the corresponding compound of formula (Ia) or (Ib) wherein R1 is hydrogen; st.17) reacting the above compound of formula (Ia) or (Ib) with a suitable alkylating agent of formula (XVI) in the presence of litium tert-butylate Br—(CH2)n—NH—BOC (XVI) wherein n is 2 or 3, so as to obtain a compound of formula (Ib) wherein n and R are as above defined; st.18) reacting the above compound of formula (Ib) under acidic conditions, so as to convert the tert-butoxycarbonylamino group into amino (deprotection) and reacting it with cesium carbonate (CsCO3) so as to obtain any one of the two compounds of formula (Id) wherein R is as above defined; (5) when R2 is a bulky group: st.19) reacting 2—ethoxy—2—cyclohexenone with dimethylformamide-di-tert-butylacetale, as reported in step (st.3), so as to obtain a compound of formula (XVII) st.20) reacting the compound of formula (XVII) with a derivative of formula (VII), according to step (st.4c), so as to obtain a compound of formula (XVIII) wherein R is as above defined; and subsequently treating it under acidic conditions so as to obtain a compound of formula (XIX) st.21) reacting the compound of formula (XIX) with a compound of formula (XX) wherein R2 is a bulky group, so as to obtain a compound of formula (XXI) st.22) reacting the compound of formula (XXI) with a hydrazine derivative of formula (III), as per step (st.1) of the process, so as to obtain a compound of formula (Ia) or (Ib) wherein R and R1 are as above defined, X is —S— and R2 is a bulky group. |
