NOVEL COMPOUNDS FOR MEDICAL USE AS PEPTIDASE EFFECTORS

التفاصيل البيبلوغرافية
العنوان: NOVEL COMPOUNDS FOR MEDICAL USE AS PEPTIDASE EFFECTORS
Document Number: 20120028995
تاريخ النشر: February 2, 2012
Appl. No: 13/185993
Application Filed: July 19, 2011
مستخلص: The invention relates to compounds of general formula (I) as set forth in the claims as well as to the use of the compounds of the general formula (1) in the medical field, specifically for use in the suppression of DNA synthesis and inflammatory cytokine production as well as in the stimulation of anti-inflammatory cytokine production in vitro and in vivo. This abstract is neither intended to define the invention disclosed in this specification nor intended to limit the scope of the invention in any way.
Inventors: ANSORGE, Siegfried (Hohenwarthe, DE); BANK, Ute (Stassfurt, DE); HEIMBURG, Anke (Magdeburg, DE); JULIUS, Heiko (Magdeburg, DE); NORDHOFF, Karsten (Magdeburg, DE); TAEGER, Michael (Heinrichsberg, DE)
Assignees: IMTM GMBH (Magdeburg, DE)
Claim: 1. A compound of general formula (I), including an acid addition salt thereof with an organic or inorganic acid: [chemical expression included] wherein the residues R1, R2, R3 and R4 may be the same or different and are independently selected from —H; -halogen; alkyl having from about 1 to about 25 carbon atoms, which alkyl may be straight chain or branched, saturated or once, twice or more times unsaturated, unsubstituted or substituted with any of the residues R1, R2, R3 and/or R4, and/or uninterrupted or interrupted by any of the residues —O—, —NH—, —NRS—, —S—; >C(═O), —C(═O)O—, —O—C(═O)—, —C(═O)NH—, —C(═O)NR5-, —NHC(═O)—, —NR5(C═O)—, >C(═S), —C(═S)O—, —O—C(═S)—, —C(═S)NH—, —C(═S)NR5-, —NHC(═S)—, —NR5(C═S)—, —PH—, —PR5-, >P(═O)H2, >P(═O)H, >P(═O)R5, >P(═O)(OH), >P(═O)OR5; cycloalkyl having from 3 to about 9 ring members, which cycloalkyl may be saturated or once, twice or more times unsaturated, unsubstituted or substituted with any of the residues R1, R2, R3 and/or R4, and/or may comprise one or several heteroatoms within the ring structure, which heretoatoms may be selected from −O—, unsubstituted or alkyl-substituted —N<, —S— and —P<; aryl having from about 3 to about 9 ring members, which aryl may be un-substituted or substituted with any of the residues R1, R2, R3 and/or R4, and/or may comprise one or several heteroatoms within the ring structure, which heteroatoms may be selected from —O—, unsubstituted or alkyl-substituted —N<, —S— and —P<; which cycloalkyl and/or aryl groups may form non-fused ring systems or ring systems comprising one, two or more fused rings selected from cycloalkyl, heterocycloalkyl, aryl or heteroaryl rings; —OH, —OR5, —NH2, —NHR5, —NR5R6, —C(═O)H, —C(═O)R5, —C(═O)OH, —C(═O)OR5, —C(═O)NH2, —C(═O)NHR5, —C(═O)NR5R6, —NH—C(═O)H, —NR5(C═O)H, —NH—C(═O)R5, —NR5(C═O)R5, —C(═S)OH, —C(═S)OR5, —C(═S)NH2, —C(═S)NHR5, —C(═S)NR5R6, —O—C(═O)H, —OC(═O)R5, —NH(C═O)R5, —NR5(C═O)R6, —C(═O)(NHOH), —C(C═O)(NR5OH), —C(C═O)(NR5OR6), —C(C═O)NHOR5, —PH2, —PHR5, —PR5R6, —P(═O)H2, —P(═O)R5H, —P(═O)R5R6, —P(═O)(OH)2, —P(═O)R5OH, —P(═O)OR5OR6; wherein R5 and R6 may be the same or different and may be selected from the group of residues set forth above by R1, R2, R3 and R4; E may represent a group selected from —O—, —S—, —NH— or —NR7-, wherein R7 is a group which may be selected from the group of residues set forth above by R1, R2, R3 and R4; Y may represent a group selected from —O—, —NH—, —NR8-, —S—, —CH2—, —CHR8- and —CR8R9-, wherein R8 and R9 may be the same or different and may be selected from the group of residues set forth above by R1, R2, R3 and R4; B may represent a group of general formula (IIa) or (IIb) [chemical expression included] wherein Cy1 may represent fused or non-fused, aromatic or non aromatic homo- or heterocyclic systems having from about 3 to about 9 ring members, and, in the case of a condensed system, from about 3 to about 9 ring members in each partial ring which, in the case of non aromatic moieties, may be saturated or once, twice or more times unsaturated, and Cy1 may be unsubstituted or substituted with any of the residues R1, R2, R3 and/or R4, and/or may comprise one or several heteroatoms within the ring structure, which heteroatoms may be selected from —O—, unsubstituted or alkyl-substituted —N<, —S— and —P<; aryl having from about 3 to about 9 ring members, and, in the case of a fused system, from about 3 to about 9 ring members in each partial ring, which aryl may be unsubstituted or substituted with any of the residues R1, R2, R3 and/or R4, and/or may comprise one or several heteroatoms within the ring structure, which heteroatoms may be selected from —O—, unsubstituted or alkyl-substituted —N<, —S— and —P<; which cycloalkyl and/or aryl groups may form non-fused ring systems or ring systems comprising one, two or more fused rings selected from cycloalkyl, heretocycloalkyl, aryl or heteroaryl rings; X may represent a single bond, —O—, —S—, —NH—, —NR10-, —CH2—, —CHR10-, —CR10R11-, >C(═O), >C(═S), >C(═NH), >C(═NR10), —C(═O)O—, —C(═S)O—, —C(═NH)NH—, —C(═O)NH—, —C(═O)NR10-, —O(C═O)—, —NH(C═O)—, —NR10(C═O)—, —O(C═S)—, —NH(C═S)—, or —NR10(C═S)—, wherein R10 and R11 may be the same or different and may be selected from the group of residues set forth above by R1, R2, R3 and R4; k and l may be the same or different and represent zero (0) or may be integers of from 1 to about 5; C may represent a group of general formula (III): [chemical expression included] wherein m may be the same or different and represent zero (0) or may be an integer of from 1 to about 5; the sequence A-L1-J-L2 as a whole may be a single bond, or A may be absent or may be selected from the group of residues set forth for R1 above, with the proviso that the carbon chain may have from about 1 to about 10 carbon atoms; and J may be absent or may be selected from the group of alkylene having from about 1 to about 10 carbon atoms, which alkylene may be straight chain or branched, saturated or once, twice or more times unsaturated, unsubstituted or substituted with any of the residues R1, R2, R3 and/or R4, and/or uninterrupted or interrupted by any of the residues —O—, —NH—, —NR5-, —S—; >C(═O), —C(═O)O—, —O—C(═O)—, —C(═O)NH—, —C(═O)NR5-, —NHC(═O)—, —NR5(C═O)—, >C(═S), —C(═S)O—, —O—C(═S)—, —C(═S)NH— —C(═S)NR5-, —NHC(═S)—, —NR5(C═O)—, —PH—, —PR5-, >P(═O)H2, >P(═O)H, >P(═O)R5, >P(═O)(OH), >P(═O)OR5; cycloalkylene having from 3 to about 9 ring members, which cycloalkylene may be saturated or once, twice or more times unsaturated, unsubstituted or substituted with any of the residues R1, R2, R3 and/or R4, and/or may comprise one or several heteroatoms within the ring structure, which heteroatoms may be selected from —O—, unsubstituted or alkyl-substituted —N<, —S— and —P<; arylene having from about 3 to about 9 ring members, which arylene may be unsubstituted or substituted with any of the residues R1, R2, R3 and/or R4, and/or may comprise one or several heteroatoms within the ring structure, which heteroatoms may be selected from —O—, unsubstituted or alkyl-substituted —N<, —S— and —P<; which cycloalkylene and/or arylene groups may form non-fused ring systems or ring systems comprising one, two or more fused rings selected from cycloalkyl, heretocycloalkyl, aryl or heteroaryl rings; —NH—, —NRS—, —C(═O)—, —C(═O)O—, —C(═O)R5-, —C(═O)NH—, —C(═O)NR5-, —NH—C(═O)—, —NR5-C(═O)—, —C(═S)O—, —C(═S)R5-, —C(═S)NH—, —C(═S)NHR5-, —C(═S)NR5- —NH—C(═O)—, —NRS—C(═O)—, —C(═O)(NHO)—, —C(═O)(NR5O)—, —PH—, —PRS—, —P(═O)H—, —P(═O)R5- —P(═O)(OH)—, —P(═O)OR5—; wherein R5 and R6 may be the same or different and may be selected from the group of residues set forth above by R1, R2, R3 and R4; L1 and L2 may be the same or different and may represent a single bond or may represent moieties independently selected from —CH2—, —O—, >C═O, —NH—, —NR12-, —S—, >C═S, —SO2—, —C(═O)—O—, —C(═S)—O—, —C(═O)—S—, —C(═S)—S—, —C(═O)NH—, —C(═O)NR14-, —C(═S)NH—, —C(═S)NR14-, —C(═NH)—, —C(═NH)—NH—, —C(═NH)—NR14-, —C(═NR1)-NR14-, wherein R12, R13 and R14 may be the same or different and may be selected from the group of residues set forth above by R1, R2, R3 and R4; and D represents any of the structures of formula (IVa) or (IVb): [chemical expression included] wherein Cy2 is homo- or heterocyclic, non-aromatic or aromatic, non-fused or once or twice fused, annelated structural element and binds directly to the rest of the structure, which, in the case of heteroaromatic residues, may contain the groups —N═, —NH—, —NR1-, —S—, —O—, —S(═O)—, —S(═O)2—, —P═, —PH—, —PR15-, —P(═O)—, —OP(═O)— and —P(═O)O— as ring members, where carbon or a heteroatom moiety may be the connecting unit to structural part C (IVa) and =A2 (IVb), respectively, wherein, in the case of non-aromatic moieties Cy2, the ring structures making up Cy2 may be saturated, may be partially unsaturated, may be unsubstituted or substituted once, twice or more times at any chemically possible position by any of the substituents defined above as substituents for cycloaliphatic and aromatic residues, and Cy2 may comprise from about 3 to about 9 ring members, and, in the case of a fused system, from about 3 to about 9 ring members in each partial ring; and A2 may represent a group selected from ═C, ═CH, ═CR16, —O—, —S—, —NH— and —NR16-, wherein R15 and R16 may be the same or different and may be selected from the group of residues set forth above by R1, R2, R3 and R4.
Claim: 2. The compounds of claim 1, namely a compound selected from the compounds set forth below: [table included]
Claim: 3. The compound of claim 1, wherein the compound acts as dual inhibitor or central pore binding ligand of at least one of a dipeptidyl peptidase IV or a peptidase with analogous enzymatic effect, and an alanyl aminopeptidase N (APN) or a peptidase with analogous enzymatic effect, or acts as a solitary inhibitor or central pore binding ligand of at least one of a dipeptidyl peptidase IVor a peptidase with analogous enzymatic effect, and an alanyl aminopeptidase N (APN) or a peptidase with analogous enzymatic effect.
Claim: 4. A method of suppressing DNA synthesis and inflammatory cytokine production as well as stimulating anti-inflammatory cytokine production in vitro and in vivo, wherein the method comprises employing the compound of claim 1.
Claim: 5. A method of substantially preventing or of treating in a subject in need thereof at least one of an autoimmune disease, a disease with exceeding immune response and/or inflammatory genesis, including arteriosclerosis, neuronal diseases, cerebral damages, skin diseases, tumour diseases, transplant rejection, Graft-versus-Host Diseases (GvHD) and virus- or bacteria-caused diseases, wherein the method comprises administering to the subject an effective amount of a compound of claim 1.
Claim: 6. The method of claim 5, wherein the disease or condition is at least one of multiple sclerosis, morbus Crohn, colitis ulcerosa, diabetes mellitus Typ 1, rheumatoid arthritis, arteriosclerosis, arterial inflammation, stent-restenosis, another autoimmune disease, and an inflammatory disease.
Claim: 7. The method of claim 5, wherein the disease or condition is at least one of a tumor and a metastase.
Claim: 8. The method of claim 5, wherein the disease or condition is at least one of a skin- or mucosa-related disease, psoriasis, acne, a dermatological disease with hyper-proliferation and modified conditions of differentiation of fibroblasts, a benign fibrosing and sclerosing skin disease, and a malign fibroblastic condition of hyper-proliferation.
Claim: 9. The method of claim 5, wherein the disease or condition is asthma bronchiale or another allergic disease or chronic obstructive pulmonary disease (COPD)
Claim: 10. The method of claim 5, wherein the disease or condition is at least one of an acute neuronal disease, ischemia-caused cerebral damage after an ischemia- or haemorrhagic apoplexia, cranio-cerebral injury, cardiac arrest, heart attack or as a consequence of cardio surgical intervention, a chronic neuronal disease, for example Morbus Alzheimer, Pick disease, progressive supra-nuclear palsy, corticobasal degeneration, frontotemporal dementia, Morbus Parkinson, particularly parkinsonism coupled to chromosome number 17, Morbus Huntington, a prion-caused condition or disease, and amyotrophic lateral sclerosis.
Claim: 11. The method of claim 5, wherein the disease or condition is a rejection of at least one of allogene or xenogene transplanted organs, tissues and cells such as bone marrow, kidney-, heart-, liver- pancreas-, skin- or stem cells, and stents, joint implants (knee joint implants, hip joint implants), bone implants, cardiac pace makers or other implants, vessel balloons, and Graft-versus-Host Diseases (GvHD).
Claim: 12. The method of claim 5, wherein the disease or condition is at least one of an inflammatory infectious disease such as malaria, severe acute respiratory syndrome (SARS), and sepsis or a sepsis-like condition.
Claim: 13. The compound of claim 1 in combination with one or more substances selected from pharmaceutically acceptable carriers, auxiliary substances, and adjuvants.
Claim: 14. A pharmaceutical preparation, wherein the preparation comprises at least one compound of claim 1, optionally in combination with one or more substances selected from pharmaceutically acceptable carriers, auxiliary substances, and adjuvants.
Claim: 15. The pharmaceutical preparation of claim 14, wherein the preparation comprises at least one further pharmaceutically effective compound.
Claim: 16. A cosmetic preparation, wherein the preparation comprises at least one compound of claim 1, optionally in combination with one or more substances selected from cosmetically acceptable carriers, auxiliary substances, and adjuvants.
Current U.S. Class: 5142/631
Current International Class: 61; 07; 61; 07; 61; 07; 61; 07; 61; 07; 61; 07; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 61; 12; 07
رقم الانضمام: edspap.20120028995
قاعدة البيانات: USPTO Patent Applications