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  New spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitorsUSPTO Application #: 20070049558Title: New spirotricyclic derivatives and their use as phosphodiesterase-7 inhibitors Abstract: in which X1, X2, X3, X4, X, Y, Z, A and Z1 are as defined in the description, methods for preparing them and their use for the treatment of disorders for which therapy by a PDE7 inhibitor is relevant.
The invention provides compounds which are PDE7 inhibitors, having the following formula (I), (II) and (III) (end of abstract)
Agent: Warner-lambert Company - Ann Arbor, MI, US Inventors: Patrick Bernardelli, Pierre Ducrot, Edwige Lorthiois, Fabrice Vergne USPTO Applicaton #: 20070049558 - Class: 514090000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai, Nitrogen Containing Hetero Ring, Hetero Ring Is Six-membered And Includes Only One Ring Nitrogen, Chalcogen In The Six-membered Hetero Ring The Patent Description & Claims data below is from USPTO Patent Application 20070049558. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] The invention relates to spirotricyclic derivatives, the process for their preparation, and their use as phosphodiesterase 7 (PDE7) inhibitors. BACKGROUND OF THE INVENTION [0002] Phosphodiesterases (PDE) play an important role in various biological processes by hydrolysing the key second messengers adenosine and guanosine 3',5'-cyclic monophosphates (cAMP and cGMP respectively) into their corresponding 5'-monophosphate nucleotides. Therefore, inhibition of PDE activity produces an increase of cAMP and cGMP intracellular levels that activate specific protein phosphorylation pathways involved in a variety of functional responses. [0003] At least eleven isoenzymes of mammalian cyclic nucleotide phosphodiesterases, numbered PDE 1 through PDE 11, have been identified on the basis of primary structure, substrate specificity or sensitivity to cofactors or inhibitory drugs. [0004] Among these phosphodiesterases, PDE7 is a cAMP-specific PDE. The biochemical and pharmacological characterization showed a high-affinity cAMP-specific PDE (Km=0.2 .mu.M), that was not affected by cGMP potent selective PDE isoenzyme inhibitors. [0005] PDE7 activity or protein has been detected in T-cell lines, B-cell lines, airway epithelial (AE) cell lines and several foetal tissues. [0006] Increasing cAMP levels by selective PDE7 inhibition appears to be a potentially promising approach to specifically block T-cell mediated immune responses. Further studies have demonstrated that elevation of intracellular cAMP levels can modulate inflammatory and immunological processes. This selective approach could presumably be devoid of the side effects associated with known selective PDE inhibitors (e.g. PDE3 or PDE4 selective inhibitors) and which limit their use. [0007] A functional role of PDE7 in T-cell activation has also been disclosed; therefore selective PDE7 inhibitors would be candidates for the treatment of T-cell-related diseases. [0008] AE cells actively participate in inflammatory airway diseases by liberating mediators such as arachidonate metabolites and cytokines. Selective inhibition of PDE7 may be a useful anti-inflammatory approach for treating AE cells related diseases. [0009] Thus, there is a need for selective PDE7 inhibitors, which are active at very low concentrations, i.e. preferably nanomolar inhibitors. [0010] WO 88/01508 discloses compounds of formula [0011] where R is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, halo, cyano, carbamoyl, alkyl carbamoyl, formyl, alkylamino or amino; [0012] X is --(CR4R5)a-NR6-(CR4R5)b-; [0013] R1, R2, R3, and R5 are hydrogen or alkyl; [0014] R4 and R6 are hydrogen, alkyl or aralkyl; a and b are 0, 1 or 2 and a+b=0, 1 or 2; [0015] R4 and R5 groups on vicinal carbon atoms may together form a carbon-carbon double bond; and geminal R4 and R5 groups may together form a spiro substitutent, --(CH2)d-, where d is 2 to 5; or a pharmaceutically acceptable salt thereof. These compounds are described as cardiotonics. [0016] WO 00/66560 discloses compounds of formula [0017] These compounds are described as progesterone receptor modulators SUMMARY OF THE INVENTION [0018] The invention provides the use of spirotricyclic derivatives, which are PDE inhibitors and more particularly PDE7 inhibitors, having the following formula (I), (II) or (III): in which, [0019] a) X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are the same or different and are selected from: [0020] N, provided that not more than two of the groups X.sub.1, X.sub.2, X.sub.3 and X.sub.4 simultaneously represent a nitrogen atom, or, [0021] C--R.sup.1, in which R.sup.1 is selected from: [0022] Q1, or [0023] lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with one or several groups Q2; [0024] the group X.sup.5--R.sup.5 in which, [0025] X.sup.5 is selected from [0026] a single bond, [0027] lower alkylene, lower alkenylene or lower alkynylene, optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, the carbon atoms of these groups being unsubstituted or substituted with one or several groups, identical or different, selected from SR.sup.6, OR.sup.6, NR.sup.6R.sup.7, .dbd.O, .dbd.S or .dbd.N--R.sup.6 in which R.sup.6 and R.sup.7 are the same or different and are selected from hydrogen or lower alkyl, and, [0028] R.sup.5 is selected from aryl, heteroaryl, cycloalkyl optionally interrupted with C(.dbd.O) or with 1, 2, or 3 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with C(.dbd.O) or with 1, 2, or 3 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, or a bicyclic group, these groups being unsubstituted or substituted with one or several groups selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3; in which Q1, Q2, Q3 are the same or different and are selected from [0029] hydrogen, halogen, CN, NO.sub.2, SO.sub.3H, P(.dbd.O)(OH).sub.2 [0030] OR.sup.2, OC(.dbd.O)R.sup.2, C(.dbd.O)OR.sup.2, SR.sup.2, S(.dbd.O)R.sup.2, C(.dbd.O)--NH--SO.sub.2--CH.sub.3, NR.sup.3R.sup.4, Q-R.sup.2, Q-NR.sup.3R.sup.4, NR.sup.2-Q-NR.sup.3R.sup.4 or NR.sup.3-Q-R.sup.2 in which Q is selected from C(.dbd.NR), C(.dbd.O), C(.dbd.S) or SO.sub.2, R is selected from hydrogen, CN, SO.sub.2NH.sub.2 or lower alkyl and R.sup.2, R.sup.3 and R.sup.4 are the same or different and are selected from: [0031] hydrogen, [0032] lower alkyl optionally interrupted with C(.dbd.O), Q4-aryl, Q4-heteroaryl, Q4-cycloalkyl optionally interrupted with C(.dbd.O) or with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, or Q4-cycloalkenyl optionally interrupted with C(.dbd.O) or with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, in which [0033] Q4 is selected from (CH.sub.2).sub.n, lower alkyl interrupted with one heteroatom selected from O, S or N, lower alkenyl or lower alkynyl, these groups being optionally substituted with lower alkyl, OR' or NR'R'' in which R' and R'' are the same or different and are selected from hydrogen or lower alkyl; [0034] n is an integer selected from 0, 1, 2, 3 or 4; [0035] these groups being unsubstituted or substituted with one or several groups selected from lower alkyl, halogen, CN, CH.sub.3, SO.sub.3H, SO.sub.2CH.sub.3, C(.dbd.O)--NH--SO.sub.2--CH.sub.3, CF.sub.3, OR.sup.6, COOR.sup.6, C(.dbd.O)R.sup.6, NR.sup.6R.sup.7, NR.sup.6C(.dbd.O)R.sup.7, C(.dbd.O)NR.sup.6R.sup.7 or SO.sub.2NR.sup.6R.sup.7, in which R.sup.6 and R.sup.7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR.sup.8 in which R and R.sup.8 are hydrogen or lower alkyl, and, [0036] R.sup.6 and R.sup.7, and/or, R.sup.3 and R.sup.4, together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S, S(.dbd.O), SO.sub.2 or N, and which may be substituted with, [0037] (CH.sub.2).sub.n-Q5, in which n is an integer selected from 0, 1, 2 and 3, and Q5 is a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or, [0038] a lower alkyl optionally substituted with OR', NR'R'', C(.dbd.O)NR'R'' or COOR' in which R' and R'' are the same or different and are selected from, [0039] H, or, [0040] lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and, [0041] R' and R'' together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N; or, [0042] when X.sub.1 and X.sub.2 both represent C--R.sup.1, the 2 substituents R.sup.1 may form together with the carbon atoms to which they are attached, a 5-membered heterocyclic ring comprising a nitrogen atom and optionally a second heteroatom selected from O, S or N; [0043] b) X is O, S or NR.sup.9, in which R.sup.9 is selected from, [0044] hydrogen, CN, OH, NH.sub.2, [0045] lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, aryl, heteroaryl, OR.sup.10, COOR.sup.10 or NR.sup.10R.sup.11 in which R.sup.10 and R.sup.11 are the same or different and are selected from hydrogen or lower alkyl; [0046] c) Y is selected from O, S or N--R.sup.12, in which R.sup.12 is selected from: [0047] hydrogen, CN, OH, NH.sub.2, [0048] lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, aryl, heteroaryl, OR.sup.10, COOR.sup.10 or NR.sup.10R.sup.11 in which R.sup.10 and R.sup.11 are the same or different and are selected from hydrogen or lower alkyl; [0049] d) Z is chosen from CH--NO.sub.2, O, S or NR.sup.13 in which R.sup.13 is selected from: [0050] hydrogen, CN, OH, NH.sub.2, aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, C(.dbd.O)R.sup.14, C(.dbd.O)NR.sup.14R.sup.15, OR.sup.14, or, [0051] lower alkyl, unsubstituted or substituted with one or several groups which are the same or different and which are selected OR.sup.14, COOR.sup.14 or NR.sup.14R.sup.15; [0052] R.sup.14 and R.sup.15 being independently selected from hydrogen or lower alkyl, or, R.sup.14 and R.sup.15, together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl, or, [0053] when Y is N--R.sup.12 and Z is N--R.sup.13, R.sup.12 and R.sup.13 may form together a --CH.dbd.N-- group or a --C.dbd.C-- group, [0054] when X is N--R.sup.9 and Z is N--R.sup.13, R.sup.9 and R.sup.13 may form together a --CH.dbd.N-- group or a --C.dbd.C-- group; [0055] e) Z.sup.1 is chosen from H, CH.sub.3 or NR.sup.16R.sup.17 in which R.sup.16 and R.sup.17 are the same or different and are selected from: [0056] hydrogen, CN, aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, C(.dbd.O)R.sup.14, C(.dbd.O)NR.sup.14R.sup.15, OR.sup.14, or, [0057] lower alkyl unsubstituted or substituted with one or several groups selected from OR.sup.14, COOR.sup.14 or NR.sup.14R.sup.15, [0058] R.sup.14 and R.sup.15 being chosen from hydrogen or lower alkyl, and, [0059] R.sup.14 and R.sup.15, and/or, R.sup.16 and R.sup.17, together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl; [0060] f) A is a cycle chosen from: in which, [0061] A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 and A.sup.6 are the same or different and are selected from O, S, C, C(.dbd.O), SO, SO.sub.2 or N--R.sup.18 in which R.sup.18 is selected from: [0062] hydrogen, aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, [0063] lower alkyl unsubstituted or substituted with aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, CN, NR.sup.19R.sup.20, C(.dbd.O)NR.sup.19R.sup.20, OR.sup.19, C(.dbd.O)R.sup.19 or C(.dbd.O)OR.sup.19 in which R.sup.19 and R.sup.20 are identical or different and are selected from hydrogen or lower alkyl; [0064] * represents the carbon atom which is shared between the cycle A and the backbone cycle containing X and/or Y; [0065] each carbon atom of the cycle A is unsubstituted or substituted with 1 or 2 groups, identical or different, selected from lower alkyl optionally substituted with OR.sup.21, NR.sup.21R.sup.22, COOR.sup.21 or CONR.sup.21R.sup.22, lower haloalkyl, [0066] CN, F, .dbd.O, SO.sub.2NR.sup.19R.sup.20, OR.sup.19, SR.sup.19, C(.dbd.O)OR.sup.19, C(.dbd.O)NR.sup.19R.sup.20 or NR.sup.19R.sup.20 in which R.sup.19 and R.sup.20 are identical or different and are selected from hydrogen or lower alkyl optionally substituted with OR.sup.21, NR.sup.21R.sup.22, [0067] COOR.sup.21 or CONR.sup.21R.sup.22 in which R.sup.21 and R.sup.22 are identical or different and are selected from hydrogen or lower alkyl, and, [0068] R.sup.19 and R.sup.20, and/or, R.sup.21 and R.sup.22, together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring; [0069] 2 atoms of the cycle A, which are not adjacent, may be linked by a 2, 3 or 4 carbon atom chain which may be interrupted with 1 heteroatom chosen from O, S or N; [0070] provided that not more than two of the groups A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 and A.sup.6 simultaneously represent a heteroatom; [0071] of their tautomeric forms, their racemic forms or their isomers and of their pharmaceutically acceptable derivatives, [0072] for the prevention or the treatment of disorders for which therapy by a PDE7 inhibitor is relevant. [0073] The invention also relates to compounds, which are PDE7 inhibitors, having the following formula (I), (II) or (III) in which, [0074] a) X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are the same or different and are selected from: [0075] N, provided that not more than two of the groups X.sub.1, X.sub.2, X.sub.3 and X.sub.4 simultaneously represent a nitrogen atom, or, [0076] C--R.sup.1, in which R.sup.1 is selected from: [0077] Q1, or [0078] lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with one or several groups Q2; [0079] the group X.sup.5--R.sup.5 in which, [0080] X.sup.5 is selected from [0081] a single bond, [0082] lower alkylene, lower alkenylene or lower alkynylene, optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, the carbon atoms of these groups being unsubstituted or substituted with one or several groups, identical or different, selected from SR.sup.6, OR.sup.6, NR.sup.6R.sup.7, .dbd.O, .dbd.S or .dbd.N--R.sup.6 in which R.sup.6 and R.sup.7 are the same or different and are selected from hydrogen or lower alkyl, and, [0083] R.sup.5 is selected from aryl, heteroaryl, cycloalkyl optionally interrupted with C(.dbd.O) or with 1, 2, or 3 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with C(.dbd.O) or with 1, 2, or 3 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, or a bicyclic group, these groups being unsubstituted or substituted with one or several groups selected from Q3, heteroaryl or lower alkyl optionally substituted with Q3; [0084] in which Q1, Q2, Q3 are the same or different and are selected from [0085] hydrogen, halogen, CN, NO.sub.2, SO.sub.3H, P(.dbd.O)(OH).sub.2 [0086] OR.sup.2, OC(.dbd.O)R.sup.2, C(.dbd.O)OR.sup.2, SR.sup.2, S(.dbd.O)R.sup.2, C(.dbd.O)--NH--SO.sub.2--CH.sub.3, NR.sup.3R.sup.4, Q-R.sup.2, Q-NR.sup.3R.sup.4, NR.sup.2-Q-NR.sup.3R.sup.4 or NR.sup.3-Q-R.sup.2 in which Q is selected from C(.dbd.NR), C(.dbd.O), C(.dbd.S) or SO.sub.2, R is selected from hydrogen, CN, SO.sub.2NH.sub.2 or lower alkyl and R.sup.2, R.sup.3 and R.sup.4 are the same or different and are selected from: [0087] hydrogen, [0088] lower alkyl optionally interrupted with C(.dbd.O), Q4-aryl, Q4-heteroaryl, Q4-cycloalkyl optionally interrupted with C(.dbd.O) or with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, or Q4-cycloalkenyl optionally interrupted with C(.dbd.O) or with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, in which [0089] Q4 is selected from (CH.sub.2).sub.n, lower alkyl interrupted with one heteroatom selected from O, S or N, lower alkenyl or lower alkynyl, these groups being optionally substituted with lower alkyl, OR' or NR'R'' in which R' and R'' are the same or different and are selected from hydrogen or lower lower alkyl; [0090] n is an integer selected from 0, 1, 2, 3 or 4; [0091] these groups being unsubstituted or substituted with one or several groups selected from lower alkyl, halogen, CN, CH.sub.3, SO.sub.3H, SO.sub.2CH.sub.3, C(.dbd.O)--NH--SO.sub.2--CH.sub.3, CF.sub.3, OR.sup.6, COOR.sup.6, C(.dbd.O)R.sup.6, NR.sup.6R.sup.7, NR.sup.6C(.dbd.O)R.sup.7, C(.dbd.O)NR.sup.6R.sup.7 or SO.sub.2NR.sup.6R.sup.7, in which R.sup.6 and R.sup.7 are the same or different and are selected from hydrogen or lower alkyl optionally substituted with one or two groups selected from OR, COOR or NRR.sup.8 in which R and R.sup.8 are hydrogen or lower alkyl, and, [0092] R.sup.6 and R.sup.7, and/or, R.sup.3 and R.sup.4, together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S, S(.dbd.O), SO.sub.2, or N, and which may be substituted with, [0093] (CH.sub.2).sub.n-Q5, in which n is an integer selected from 0, 1, 2 and 3, and Q5 is a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms selected from O, S or N and which may be substituted with a lower alkyl, or, [0094] a lower alkyl optionally substituted with OR', NR'R'', C(.dbd.O)NR'R'' or COOR' in which R' and R'' are the same or different and are selected from, [0095] H, or, [0096] lower alkyl optionally substituted with OR or COOR in which R is hydrogen or lower alkyl and, [0097] R' and R'' together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring, which may contain one or two heteroatoms selected from O, S or N; or, [0098] when X.sub.1 and X.sub.2 both represent C--R.sup.1, the 2 substituents R.sup.1 may form together with the carbon atoms to which they are attached, a 5-membered heterocyclic ring comprising a nitrogen atom and optionally a second heteroatom selected from O, S or N; [0099] b) X is O or NR.sup.9, in which R.sup.9 is selected from, [0100] hydrogen, CN, OH, NH.sub.2, [0101] lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, aryl, heteroaryl, OR.sup.10, COOR.sup.10 or NR.sup.10R.sup.11 in which R.sup.10 and R.sup.11 are the same or different and are selected from hydrogen or lower alkyl; [0102] c) Y is selected from O, S or N--R.sup.12, in which R.sup.12 is selected from: [0103] hydrogen, CN, OH, NH.sub.2, [0104] lower alkyl, lower alkenyl or lower alkynyl, these groups being unsubstituted or substituted with, cycloalkyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with 1 or 2 heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, aryl, heteroaryl, OR.sup.10, COOR.sup.10 or NR.sup.10R.sup.11 in which R.sup.10 and R.sup.11 are the same or different and are selected from hydrogen or lower alkyl; [0105] d) Z is chosen from CH--NO.sub.2, O, S or NR.sup.13 in which R.sup.13 is selected from: [0106] hydrogen, CN, OH, NH.sub.2, aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, C(.dbd.O)R.sup.14, C(.dbd.O)NR.sup.14R.sup.15, OR.sup.14, or, [0107] lower alkyl, unsubstituted or substituted with one or several groups which are the same or different and which are selected OR.sup.14, COOR.sup.10 or NR.sup.14R.sup.15; [0108] R.sup.14 and R.sup.15 being independently selected from hydrogen or lower alkyl, or, R.sup.14 and R.sup.15, together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl, or, [0109] when Y is N--R.sup.12 and Z is N--R.sup.13, may form together a --CH.dbd.N-- group or a --C.dbd.C-- group, [0110] when X is N--R.sup.9 and Z is N--R.sup.13, R.sup.9 and R.sup.13 may form together a --CH.dbd.N-- group or a --C.dbd.C-- group; [0111] e) Z.sup.1 is chosen from H, CH.sub.3 or NR.sup.16R.sup.17 in which R.sup.16 and R.sup.17 are the same or different and are selected from: [0112] hydrogen, CN, aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, C(.dbd.O)R.sup.14, C(.dbd.O)NR.sup.14R.sup.15, OR.sup.14, or, [0113] lower alkyl unsubstituted or substituted with one or several groups selected from OR.sup.14, COOR.sup.14 or NR.sup.14R.sup.15, [0114] R.sup.14 and R.sup.15 being chosen from hydrogen or lower alkyl, and, [0115] R.sup.14 and R.sup.15, and/or, R.sup.16 and R.sup.17, together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring which may contain one or two heteroatoms chosen from O, S or N, and which may be substituted with a lower alkyl; [0116] f) A is a cycle chosen from: in which, [0117] A.sup.1, A.sup.2, A.sup.4, A.sup.5 and A.sup.6 are the same or different and are selected from O, S, C, C(.dbd.O), SO, SO.sub.2 or N--R.sup.18 in which R.sup.18 is selected from: [0118] hydrogen, aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, [0119] lower alkyl unsubstituted or substituted with aryl, heteroaryl, cycloalkyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, cycloalkenyl optionally interrupted with one or several heteroatoms chosen from O, S, S(.dbd.O), SO.sub.2 or N, CN, NR.sup.19R.sup.20, C(.dbd.O)NR.sup.19R.sup.20, OR.sup.19, C(.dbd.O)R.sup.19 or C(.dbd.O)OR.sup.19 in which R.sup.19 and R.sup.20 are identical or different and are selected from hydrogen or lower alkyl; [0120] A.sup.3 is selected from O, S, C, C(.dbd.O), SO or SO.sub.2, or N--R.sup.18 when A.sup.1 and/or A.sup.2 are C(.dbd.O) or when Y is 0 or S, wherein R.sup.13 is as defined above; [0121] * represents the carbon atom which is shared between the cycle A and the backbone cycle containing X and/or Y; [0122] each carbon atom of the cycle A is unsubstituted or substituted with 1 or 2 groups, identical or different, selected from lower alkyl optionally substituted with OR.sup.21, NR.sup.21R.sup.22, COOR.sup.21 or CONR.sup.21R.sup.22, lower haloalkyl, CN, F, .dbd.O, SO.sub.2NR.sup.19R.sup.2 , OR.sup.19, SR.sup.19, C(.dbd.O)OR.sup.19, C(.dbd.O)NR.sup.19R.sup.20 or NR.sup.19R.sup.20 in which R.sup.19 and R.sup.20 are identical or different and are selected from hydrogen or lower alkyl optionally substituted with OR.sup.21, NR.sup.21R.sup.22, COOR.sup.21 or CONR.sup.21R.sup.22 in which R.sup.21 and R.sup.22 are identical or different and are selected from hydrogen or lower alkyl, and, [0123] R.sup.19 and R.sup.20, and/or, R.sup.21 and R.sup.22, together with the nitrogen atom to which they are linked, can form a 4- to 8-membered heterocyclic ring; [0124] 2 atoms of the cycle A, which are not adjacent, may be linked by a 2, 3 or 4 carbon atom chain which may be interrupted with 1 heteroatom chosen from O, S or N; [0125] provided that: [0126] not more than two of the groups A.sup.1, A.sup.2, A.sup.3, A.sup.4, A.sup.5 and A.sup.6 simultaneously represent a heteroatom; [0127] the cycle A does not contain more than 2 carbon atoms in an sp.sup.2 hybridization state; [0128] when X is O, X.sub.2 is not C--R.sup.1 in which R.sup.1 is [0129] a thienyl substituted with CN or with CN and CH.sub.3, [0130] a phenyl substituted with CN, Cl, NO.sub.2 or CN and F, [0131] Br [0132] F; [0133] or their tautomeric forms, their racemic forms or their isomers and their pharmaceutically acceptable derivatives. [0134] These compounds are selective PDE7 inhibitors. They can be used in the treatment of various diseases, such as T-cell-related diseases, autoimmune diseases, osteoarthritis, rheumatoid arthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease (COPD), asthma, cancer, acquired immune deficiency syndrome (AIDS), allergy or inflammatory bowel disease (IBD). [0135] The invention also relates to a process for preparing the above compounds. [0136] The invention further concerns the use of a compound of formula (I), (II) or (III) for the preparation of a medicament for the prevention or the treatment of disorders for which therapy by a PDE7 inhibitor is relevant. [0137] The invention also provides a method for the treatment of a disorder for which therapy by a PDE7 inhibitor is relevant, comprising administering to a mammal in need thereof an effective amount of compound of formula (I), (II) or (III). [0138] The invention also provides a method for the treatment of T-cell-related diseases, autoimmune diseases, osteoarthritis, rheumatoid arthritis, multiple sclerosis, osteoporosis, chronic obstructive pulmonary disease (COPD), asthma, cancer, acquired immune deficiency syndrome (AIDS), allergy or inflammatory bowel disease (IBD), comprising administering to a mammal in need thereof an effective amount of compound of formula (I), (II) or (III). [0139] The invention also concerns a pharmaceutical composition comprising a compound of formula (I), (II) or (III) together with a pharmaceutically acceptable carrier, excipient, diluent or delivery system. Continue reading... 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