ZA200400677B - Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin K inhibitory activity for the treatment of inflammations and other diseases. - Google Patents
Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin K inhibitory activity for the treatment of inflammations and other diseases. Download PDFInfo
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- ZA200400677B ZA200400677B ZA200400677A ZA200400677A ZA200400677B ZA 200400677 B ZA200400677 B ZA 200400677B ZA 200400677 A ZA200400677 A ZA 200400677A ZA 200400677 A ZA200400677 A ZA 200400677A ZA 200400677 B ZA200400677 B ZA 200400677B
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- ZA
- South Africa
- Prior art keywords
- lower alkyl
- heterocyclyl
- defined above
- aryl
- formula
- Prior art date
Links
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 7
- 102000004171 Cathepsin K Human genes 0.000 title claims description 6
- 108090000625 Cathepsin K Proteins 0.000 title claims description 6
- 201000010099 disease Diseases 0.000 title claims description 6
- 206010061218 Inflammation Diseases 0.000 title description 3
- 238000011282 treatment Methods 0.000 title description 3
- MRINWLDDTZFLSW-UHFFFAOYSA-N 4-aminopyrimidine-2-carbonitrile Chemical group NC1=CC=NC(C#N)=N1 MRINWLDDTZFLSW-UHFFFAOYSA-N 0.000 title description 2
- 239000002852 cysteine proteinase inhibitor Substances 0.000 title description 2
- 230000004054 inflammatory process Effects 0.000 title description 2
- 230000002401 inhibitory effect Effects 0.000 title description 2
- -1 R6 is H Chemical group 0.000 claims description 76
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 18
- 229910020008 S(O) Inorganic materials 0.000 claims description 17
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 16
- 150000002148 esters Chemical class 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000005843 halogen group Chemical group 0.000 claims description 12
- 125000000623 heterocyclic group Chemical group 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 8
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 229910052717 sulfur Inorganic materials 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 2
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000005257 alkyl acyl group Chemical group 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000005251 aryl acyl group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 238000011321 prophylaxis Methods 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 229920006395 saturated elastomer Polymers 0.000 claims description 2
- 125000003003 spiro group Chemical group 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 4
- 238000000034 method Methods 0.000 claims 4
- 239000002243 precursor Substances 0.000 claims 4
- 238000007333 cyanation reaction Methods 0.000 claims 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 150000001412 amines Chemical class 0.000 claims 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 1
- 230000008878 coupling Effects 0.000 claims 1
- 238000010168 coupling process Methods 0.000 claims 1
- 238000005859 coupling reaction Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- 230000001225 therapeutic effect Effects 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 description 11
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 7
- 102000005600 Cathepsins Human genes 0.000 description 3
- 108010084457 Cathepsins Proteins 0.000 description 3
- 125000003302 alkenyloxy group Chemical group 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical class C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical class C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical class C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical class C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 150000001345 alkine derivatives Chemical class 0.000 description 2
- 125000005530 alkylenedioxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 125000005133 alkynyloxy group Chemical group 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000000842 isoxazolyl group Chemical group 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 125000003226 pyrazolyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000168 pyrrolyl group Chemical group 0.000 description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 2
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 125000000335 thiazolyl group Chemical group 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000001425 triazolyl group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical class C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 1
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000006497 3-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1[H])C([H])([H])* 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- 101000941450 Lasioglossum laticeps Lasioglossin-1 Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical class C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- ATTZFSUZZUNHBP-UHFFFAOYSA-N Piperonyl sulfoxide Chemical compound CCCCCCCCS(=O)C(C)CC1=CC=C2OCOC2=C1 ATTZFSUZZUNHBP-UHFFFAOYSA-N 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical group CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical class C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical class C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 206010052779 Transplant rejections Diseases 0.000 description 1
- 206010064390 Tumour invasion Diseases 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004619 benzopyranyl group Chemical group O1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000004600 benzothiopyranyl group Chemical group S1C(C=CC2=C1C=CC=C2)* 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 230000009400 cancer invasion Effects 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- 230000001687 destabilization Effects 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical compound O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 description 1
- 229940091173 hydantoin Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000555 isopropenyl group Chemical group [H]\C([H])=C(\*)C([H])([H])[H] 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 230000002132 lysosomal effect Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 125000006353 oxyethylene group Chemical group 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- CYJAWBVQRMVFEO-UHFFFAOYSA-N piperazine-2,6-dione Chemical compound O=C1CNCC(=O)N1 CYJAWBVQRMVFEO-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical class COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003235 pyrrolidines Chemical class 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 125000001174 sulfone group Chemical group 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
CYSTEINE PROTEASE INHIBITORS WITH 2-CYANO-4-AMINO-PYRIMIDINE STRUCTURE AND
CATHEPSIN K INHIBITORY ACTIVITY FOR THE TREATMENT OF INFLAMMATIONS AND OTHER
DISEASES. . This invention relates to inhibitors of cysteine proteases, in particular to heteroaryl nitrile cathepsin K inhibitors and to their pharmaceutical use for the treatment or prophylaxis of diseases or medical conditions in which cathepsin K is implicated.
Cathepsin K is a member of the family of lysosomal cysteine cathepsin enzymes, e.g. cathepsins B, K, L and S, which are implicated in various disorders including inflammation, rheumatoid arthritis, osteoarthritis, osteoporosis, tumors (especially tumor invasion and tumor metastasis), coronary disease, atherosclerosis (including atherosclerotic plaque rupture and destabilization), autoimmune diseases, respiratory diseases, infectious diseases and immunologically mediated diseases (including transplant rejection).
Accordingly the present invention provides a compound of formula I, or a pharmaceutically acceptable salt or ester thereof
R
RA To
LL I i) N Ly
R2 wherein
Ris H, -R4, -OR4 or NR3R4, wherein R3 is H, lower alkyl or C3 to Cg cycloalkyl, and
R4 is lower alkyl or Cj to Cy cycloalkyl, and wherein R3 and R4 are independently, optionally substituted by halo, hydroxy, lower ) alkoxy, CN, NO», or optionally mono- or di-lower alkyl substituted amino;
R1 is -CO-NR5R6, -NH-CO-RS5, -CH,-NH-C(O)-RS5, -CO-RS, -S(0)-R5, -S(0)>-R5,-
CH,-CO-RS5 or -CH;-NR5R6, wherein
RS is aryl, aryl-lower alkyl, C3-Cjocycloalkyl, C3-Cjocycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl, i
R6 is H, aryl, aryl-lower alkyl, aryl-lower-alkenyl, C;-Cjgcycloalkyl, C3-Cjocycloalkyl- lower alkyl, heterocyclyl or heterocyclyl-lower alkyl, or . wherein RS and R6 together with the nitrogen atom to which they attached are joined to form an N-heterocyclyl group, wherein N-heterocyclyl denotes a saturated, partially unsaturated or aromatic nitrogen containing heterocyclic moiety attached via a nitrogen atom thereof having from 3 to 8 ring atoms optionally containing a further 1, 2 or 3 heteroatoms selected from N, NR7, O,
S, S(O) or S(O), wherein R7 is H or optionally substituted (lower alkyl, carboxy. acyl (including both lower alkyl acyl, e.g. formyl, acetyl or propionyl, or aryl acyl, e.g. benzoyl), amido, aryl, S(O) or S(O),), and wherein the N-heterocyclyl is optionally fused in a bicyclic structure, e.g. with a benzene or pyridine ring, and wherein the N- heterocyclyl is optionally linked in a spiro structure with a 3 to 8 membered cycloalkyl or heterocyclic ring wherein the heterocyclic ring has from 3 to 10 ring members and contains from 1 to 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O); wherein R6 is as defined above), and wherein heterocyclyl denotes a ring having from 3 to 10 ring members and containing from 1 to 3 heteroatoms selected from N, NR7, O, S, S(O) or S(O), wherein R7 is as defined above), and wherein R5 and R6 are independently, optionally substituted by one or more groups, e.g. 1-3 groups, selected from halo, hydroxy, oxo, lower alkoxy, CN or NO,, or optionally substituted (optionally mono- or di-lower alkyl substituted amino, lower-alkoxy, aryl, aryl-lower alkyl, N-heterocyclyl or N-heterocyclyl-lower alkyl (wherein the optional substitution comprises from 1 to 3 substituents selected from halo, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, lower alkoxy-carbonyl, CN, NO, N-heterocyclyl or N- heterocyclyl-lower alkyl, or optionally mono- or di-lower alkyl substituted amino; .
R2 is is independently H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, Cs-
Ciocycloalkyl, C3-Cjocycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl), ’ and wherein R2 is optionally substituted by halo, hydroxy, oxo, lower alkoxy, CN, NO,, or optionally mono- or di-lower alkyl substituted amino. . Above and elsewhere in the present description the following terms have the following meanings.
Halo or halogen denote I, Br, Cl or F.
The term “lower” referred to above and hereinafter in connection with organic radicals or compounds respectively defines such as branched or unbranched with up to and including 7, preferably up to and including 5 and advantageously one, two or three carbon atoms.
A lower alkyl group is branched or unbranched and contains 1 to 7 carbon atoms, preferably 1-5 carbon atoms. Lower alkyl represents; for example, methyl, ethyl, propyl, butyl, isopropyl isobutyl, tertiary butyl or neopentyl (2,2 ~-dimethylpropyl).
Halo-substituted lower alkyl is C|-C;lower alkyl substituted by up to 6 halo atoms.
A lower alkoxy group is branched or unbranched and contains 1 to 7 carbon atoms, preferably 1-4 carbon atoms. Lower alkoxy represents for example methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or tertiary butoxy.
A lower alkene, alkenyl or alkenyloxy group is branched or unbranched and contains 2 to 7 carbon atoms, preferably 2-4 carbon atoms and contains at least one carbon-carbon double bond. Lower alkene lower alkenyl or lower alkenyloxy represents for example vinyl, prop-1-enyl, allyl, butenyl, isopropenyl or isobutenyl and the oxy equivalents thereof.
A lower alkyne, alkynyl or alkynyloxy group is branched or unbranched and contains 2 to 7 carbon atoms, preferably 2-4 carbon atoms and contains at least one carbon-carbon triple bond. Lower alkyne or alkynyl represents for example ethynyl, prop-1-ynyl, propargyl, butynyl, isopropynyl or isobutynyl and the oxy equivalents thereof.
In the present description, oxygen containing substituents, e.g. alkoxy, alkenyloxy, . alkynyloxy, carbonyl, etc. encompass their sulphur containing homologues, e.g. thioalkoxy, thioalkenyloxy, thioalkynyloxy, thiocarbonyl, sulphone, sulphoxide etc. ; Aryl represents carbocyclic or heterocyclic aryl.
Carbocyclic aryl represents monocyclic, bicyclic or tricyclic aryl, for example phenyl or phenyl mono-, di- or tri-substituted by one, two or three radicals selected from , lower alkyl, lower alkoxy, aryl, hydroxy, halogen, cyano, trifluoromethyl, lower alkylenedioxy and oxy-C,-Cs-alkylene and other substituents, for instance as described in . the examples; or 1- or 2-naphthyl; or 1- or 2-phenanthrenyl. Lower alkylenedioxy is a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. methylenedioxy or ethylenedioxy. Oxy-C,-Cs-alkylene is also a divalent substituent attached to two adjacent carbon atoms of phenyl, e.g. oxyethylene or oxypropylene. An example for oxy-
C,-Cs-alkylene-phenyl is 2,3-dihydrobenzofuran-5-yl.
Preferred as carbocyclic aryl is naphthyl, phenyl or phenyl optionally substituted, for instance, as described in the examples, e.g. mono- or disubstituted by lower alkoxy, phenyl, halogen, lower alkyl or trifluoromethyl.
Heterocyclic aryl represents monocyclic or bicyclic heteroaryl, for example pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any said radical substituted, especially mono- or di-substituted as defined above.
Preferably, heterocyclic aryl is pyridyl, indolyl, quinolinyl, pyrrolyl, thiazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any said radical substituted, especially mono- or di-substituted as defined above.
Cycloalkyl represents a saturated cyclic hydrocarbon optionally substituted by lower alkyl which contains 3 to 10 ring carbons and is advantageously cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl optionally substituted by lower alkyl.
N-heterocyclyl is as defined above. Preferred N-heterocyclic substituents are optionally substituted pyrrolidine, pyrrole, diazole, triazole, tetrazole, imidazole, oxazole, thiazole, pyridine, pyrimidine, triazine, piperidine, piperazine, morpholine, phthalimde, hydantoin, oxazolidinone or 2,6-dioxo-piperazine and, for example, as hereinafter . described in the examples. .
In a further embodiment the invention provides a compound of formula Ila, or . a pharmaceutically acceptable salt or ester thereof
Re" HN SN Ila
R2 N wherein R2 is as defined above and R5”’ and R6™’ are as defined above for R5 and R6 respectively.
R2 is preferably R2’ which is lower alkyl, e.g. straight chain or more preferably branched-chain C;-Cs alkyl, e.g. especially 2-ethylbutyl, isobutyl, or 2,2-dimethylpropyl; or C3-Cgcycloalkyl, especially cyclopropyl, cyclopentyl or cyclohexyl.
R5”’ and R6’’ may be such that R5”” and R6™’ together with the nitrogen atom to which they are joined to form an N-heterocyclyl group
R5” is preferably optionally substituted (aryl-lower-alkyl, heterocyclyl-aryl, N- heterocyclyl-aryl or aryl-N-heterocyclyl (where N-heterocyclyl is as defined above).
RS” is preferably optionally substituted by from 1-4 substituents selected from halo, hydroxy, nitro, cyano, lower-alkyl, lower-alkoxy or lower-alkoxy-lower-akyl.
For example, R5”’ is 4-methoxy-benzyl, 3-methoxy-benzyl, 4-(4-methyl-piperazin- 1-yD)-benzyl, 4-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-benzyl, 1-methyl-1-phenyl-ethyl, 2-(4- methoxy-phenyl)-1,1-dimethyl-ethyl, 2-(4-fluoro-phenyl)-1,1-dimethyl-ethyl, 4-(4- methyl-piperazin-1-yl)-phenyl]-ethyl, 2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]}-1,1- dimethyl-ethyl, 2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl]-phenyl}-1,1-dimethyl-ethyl, 2- {3-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl}-1,1-dimethyl-ethyl, 2-[3-(4-ethyl- piperazin-1-yl)-phenyl]-1,1-dimethyl-ethyl, 2-[3-(4-isopropyl-piperazin-1-yl)-phenyl]- 1,1-dimethyl-ethyl, 1,1-dimethyl-2-(3-pyrrolidin-1-yl-phenyl)-ethyl, 2-{3-[4-(2-methoxy- ethyl)-piperazin-1-yl]-phenyl}-1,1-dimethyl-ethyl, 2-(4-methoxy-phenyl)-ethyl . 2-[4-(4-methyl-piperazin- 1-yl)-phenyl]-ethyl, 2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]- ethyl, 2-{4-[4-(2-methoxy-ethyl)-piperazin-1-yl}-phenyl}-ethyl, 2-(3-methoxy-phenyl)- ) ethyl, 2-[3-(4-methyl-piperazin-1-yl)-phenyl]-ethyl, 2-[4-(4-isopropyl-piperazin-1-yl)- phenyl]-ethyl, 2-pyrrol-1-yl-ethyl, 3-piperidin-1-yl-propyl
2-(4-methoxy-phenyl)-2-methyl-propyl, 2-methyl-2-[4~(4-methyl-piperazin-1-yl)-phenyl]- propyl, 2-[4-(4-isopropyl-piperazin-1-yl)-phenyl]-2-methyl-propyl, 2-{4-[4-(2-ethoxy- i ethyl)-piperazin-1-yl]-phenyl} -2-methyl-propyl, 2- {4-[pyrimidin-1-yl]-phenyl}-2-methyl- propyl, 4-(3-methoxy-phenyl)-piperazin-1-yl-methyl, 4-(4-methoxy-phenyl)-piperazin-1- . yl-methyl, 1-methyl-1-(1-phenyl-cyclopropyl)-ethyl,
For example, R5”’ and R6™ together with the nitrogen atom to which they are joined to form an N-heterocyclyl group is 4-(2-pyridin-4-yl-ethyl)-piperazin-1-yl, [4-(2-pyridin-2- yl-ethyl)-piperazin-1-yl, 4-pyridin-4-ylmethyl-piperazin-1-yl, 4-(2-piperidin-1-yl-ethyl)- piperazin-1-yl, 4-(2-pyrrolidin- 1-yl-ethyl)-piperazin- 1-yl, 4-(2-Diethylamino-ethyl)- piperazin-1-yl, 4-(3-Diethylamino-propyl)-piperazin-1-yl, 4-(1-methyl-piperidin-4-yl)- piperazin-1-yl, 4-pyrrolidin-1-yl-piperidin-1-yl, 4-(2-methoxy-ethyl)-piperazin-1-yl
In a preferred embodiment the invention provides a compound of formula II, or a oo pharmaceutically acceptable salt or ester thereof
O
H
HN SN un ho N
R wherein R2 is as defined above and R5’ is as defined above for R5.
R2 is preferably R2’ which is lower alkyl, e.g. straight chain or more preferably branched-chain C;-Cs alkyl, e.g. especially 2-ethylbutyl, isobutyl, or 2,2-dimethylpropyl; or C3-Cgeycloalkyl, especially cyclopropyl, cyclopentyl or cyclohexyl.
R5’ is preferably optionally substituted (aryl-lower-alkyl, heterocyclyl-aryl, N- heterocyclyl-aryl or aryl-N-heterocyclyl (where N-heterocyclyl is as defined above).
R5’ is preferably optionally substituted by from 1-4 substituents selected from halo, ; hydroxy, nitro, cyano, lower-alkyl, lower-alkoxy, lower-alkoxy-carbonyl or lower-alkoxy- lower-akyl. :
For example, R5’ is 4-methoxy-phenyl, 4-(1-propyl-piperidin-4-yl)-phenyl, 4-(4- ) methyl-piperazin-1-yl)-phenyl, 4-[1-(2-methoxy-ethyl)-piperidin-4-yl}-phenyl, 4-(4- propyl-piperazin-1-yl)-phenyl, 3-[4-(4-methyl-piperazin-1-yl)-phenyl]-propionyl, 3-[3-(4- ) methyl-piperazin-1-yl)-phenyl]-propionyl, 4-(4-ethyl-piperazin-1-yl)-phenyl, 4-(4- isopropyl-piperazin- 1-yl)-phenyl, 4-[4-(2-ethoxy-ethyl)-piperazin-1-yl}-phenyl, 4-[4-(2- methoxy-ethyl)-piperazin-1-yl]-phenyl, 4-piperazin-1-yl-phenyl, 4-[4-(carboxylic acid tert-butyl ester) piperazino-1-yl-J-phenyl, 3-[4-(carboxylic acid tert-butyl ester) piperazino-1-yl-]-phenyl, 3-(4-methyl-piperazin-1-yl)-phenyl, 3-(4-ethyl-piperazin-1-yl)- phenyl, 3-(4-isopropyl-piperazin-1-yl)-phenyl, 3-[4-(2-methoxy-ethyl)-piperazin-1-yl}- phenyl, 3-[4-(2-ethoxy-ethyl)-piperazin-1-yl]-phenyl, 3-(2-pyrrolidin-1-yl-ethoxy)-phenyl, 3-(2-dimethylamino-ethoxy)-4-methoxy-phenyl, 4-dimethylaminomethyl-phenyl, 4-(4- methyl-piperazin-1-ylmethyl)-phenyl, 4-[1-(2-methoxy-ethyl)-piperidin-4-ylmethyl]- phenyl, 4-methoxy-3-(2-piperidin-1-yl-ethoxy)-phenyl, 3-[4-(4-ethyl-piperazin-1-yl)- phenyl]-2,2-dimethyl-propionyl, 3-[4-(4-propyl-piperazin-1-yl)-phenyl]-propionyl, 3-(4- pyrrolidin-1-yl-phenyl)-propionyl, 3-[3-(4-ethyl-piperazin-1-yl)-phenyl]-2,2-dimethyl- propionyl, 3-{3-{4-(2-methoxy-ethyl)-piperazin- 1-yl]-phenyl}-2,2-dimethyl-propionyl, 3- {3-[4-(2-ethoxy-ethyl)-piperazin-1-yl}-phenyl} -2,2-dimethyl-propionyl, 3-(3-pyrrolidin- 1-yl-phenyl)-propionyl, 2-[4-(4-methyl-piperazin-1-yl}-phenyl]-isobutyl, 2-(4-methoxy- * phenyl)-acetyl, 2-(3-methoxy-phenyl)-acetyl, 2-[4-(4-methyl-piperazin-1-yl)-phenyl}- acetyl, 2-[4-(4-ethyl-piperazin-1-yl)-phenyl]-acetyl, 2-[4-(4-isopropyl-piperazin-1-yl)- phenyl]-acetyl, 2-(4-pyrrolidin-1-yl-phenyl)-acetyl, 2-[4-(2-diethylamino-ethylamino)- phenyl]-isobutyl, 2-(4-pyrrolidin-1-yl-phenyl)-isobutyl.
In a further preferred embodiment the invention provides a compound of formula
IIT or a pharmaceutically acceptable salt or ester thereof 0
A i) . i N SY
R2
Claims (16)
1. A compound of formula I, or a pharmaceutically acceptable salt or ester thereof . R HN Poe SN R2 wherein Ris H, -R4, -OR4 or NR3R4, wherein R3 is H, lower alkyl or C; to Cj cycloalkyl, and R4 is lower alkyl or C; to Cy cycloalkyl, Co wherein R3 and R4 are independently, optionally substituted by halo, hydroxy, lower alkoxy, CN, NO, or optionally mono- or di-lower alkyl substituted amino; R1 is —CO-NRS5R6, -NH-CO-RS, -CH,-NH-C(O)-R5, -CO-RS, -S(O)-R5, -S(O),- RS5,-CH2-CO-R5 or -CH;-NR5R6, wherein R5 is aryl, aryl-lower alkyl, C3-Cjocycloalkyl, Cs-C,cycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl, R6 is H, aryl, aryl-lower alkyl, aryl-lower-alkenyl, C3-Cjocycloalkyl, Cs- Cjocycloalkyl-lower alkyl, heterocyclyl or heterocyclyl-lower alkyl, or wherein R5 and R6 together with the nitrogen atom to which they attached are joined to form an N-heterocyclyl group, wherein N-heterocyclyl denotes a saturated, partially unsaturated or aromatic nitrogen containing heterocyclic moiety attached via a nitrogen atom thereof having from 3 to 8 ring atoms optionally containing a further 1, 2 or 3 heteroatoms selected
. from N, NR7, O, S, S(O) or S(O), wherein R7 is H or optionally substituted (lower ) alkyl, carboxy, acyl (including both lower alkyl acyl, e.g. formyl, acetyl or ’ propionyl, or aryl acyl, e.g. benzoyl), amido, aryl, S(O) or S(O);), and wherein the N-heterocyclyl is optionally fused in a bicyclic structure, e.g. with a benzene or pyridine ring, and wherein the N-heterocyclyl is optionally linked in a spiro structure with a 3 to 8 membered cycloalkyl or heterocyclic ring wherein the } heterocyclic ring has from 3 to 10 ring members and contains from 1 to 3 heteroatoms selected from N, NR6, O, S, S(O) or S(O); wherein R6 is as defined above), and wherein heterocyclyl denotes a ring having from 3 to 10 ring members and containing from 1 to 3 heteroatoms selected from N, NR7, O, S, S(O) or S(O), wherein R7 is as defined above), and wherein R5 and R6 are independently, optionally substituted by one or more groups, e.g. 1-3 groups, selected from halo, hydroxy, oxo, lower alkoxy, CN or NO, or optionally substituted (optionally mono- or di-lower alkyl substituted amino, lower alkoxy, aryl, aryl-lower alkyl, N-heterocyclyl or N-heterocyclyl-lower alkyl (wherein the optional substitution comprises from 1 to 3 substituents selected from halo, hydroxy, lower alkoxy, lower alkoxy-lower alkyl, lower alkoxy-carbonyl CN, NO, optionally mono- or di-lower alkyl substituted amino, N-heterocyclyl or N-heterocyclyl-lower alkyl or optionally mono- or di-lower alkyl substituted amino; R2 is is independently H, or optionally substituted (lower alkyl, aryl, aryl-lower alkyl, C3-C cycloalkyl, Cs-Cocycloalkyl-lower alkyl, heterocyclyl or heterocyclyl- lower alkyl), and wherein R2 is optionally substituted by halo, hydroxy, oxo, lower alkoxy, CN, NO, or optionally mono- or di-lower alkyl substituted amino.
2. A compound according to claim 1 of formula II, or a pharmaceutically acceptable salt or ester thereof Oo es HN SN n Re N wherein R2 is as defined above and R5’ is as defined above for RS in claim 1.
/
A
3. A compound according to claim 1 of formula Ila, or a pharmaceutically acceptable ‘ salt or ester thereof R m a IIa 6 HN PN SN R2 wherein R2 is as defined above and R5™ and R6™” is as defined above for RS and R6 respectivly in claim 1.
4. A compound according to claim 1 of formula III or a pharmaceutically acceptable salt or ester thereof Oo R [1] . N | ~ N A mt Hn N SY R2 wherein R2 is as defined above and R5” is as defined above for RS in claim 1.
5. A compound according to claim 1, or a pharmaceutically acceptable salt or ester thereof, selected from any one of the Examples.
6. A compound according to claim 1 for use as a pharmaceutical.
7. A pharmaceutical composition comprising a compound according to claim 1 as an . active ingredient.
¥ - »
8. A compound according to claim 1 for treating a patient suffering from or susceptible to a disease or medical condition in which cathepsin K is implicated.
9. The use of a compound according to claim 1 for the preparation of a medicament for therapeutic or prophylactic treatment of a disease or medical condition in which cathepsin K is implicated.
10. A process for the preparation of a compound of Formula II or a pharmaceutically acceptable salt or ester thereof Oo R MN all I a x BQ HN N C SN R2 wherein R2 and R5’ are as defined above, comprising cyanation of a 2-chloro precursor of formula IV O Det NS HI Ci Iv R2 wherein R2 and R5’ are as defined above, and thereafter, if desired, converting the product obtained into a further compound of formula II, or into a salt or ester thereof
11 A process for the preparation of a compound of Formula ha or a pharmaceutically acceptable salt or ester thereof 56 AMENDED SHEET
Bb bs oN ZN IIa , Rs" ~ Me HN N Cx
NN . R2 wherein R2, R5°’ and R6™ are as defined above, comprising cyanation of a 2-chloro precursor of formula IVa R LIL] ONT YON Rg" ~ BR
Lo. N Cl IVa R2 wherein R2, R5°’ and R6”’ are as defined above, and thereafier, if desired, converting the product obtained into a further compound of formula Ila, or into a salt or ester thereof.
12. A process for the preparation of a compound of Formula III or a pharmaceutically acceptable salt or ester thereof 0) R ” A mI i) N NY R2 wherein R2 and R5” are as defined above, comprising either cyanation of a 2-chloro precursor of formula V 0] R ” ’ PY v i) N Cl . R2 or coupling of a carboxylic acid precursor of formula VI with a corresponding amine of formula vil Q R " va SNH, + HO HN N AF R2 wherein the R2 and R5” are as defined above, and thereafter, if desired, converting the product obtained into a further compound of formula Ill, or into a salt or ester thereof.
13. A compound according to claim 1, substantially as herein described and exemplified.
14. A pharmaceutical composition according to claim 7, substantially as herein described and exemplified.
15. The use according to claim 9, substantially as herein described and exemplified.
16. A process according to any one of claims 10-12, substantially as herein described and exemplified. 58 AMENDED SHEET
Applications Claiming Priority (1)
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GBGB0121026.9A GB0121026D0 (en) | 2001-08-30 | 2001-08-30 | Organic compounds |
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ZA200400677B true ZA200400677B (en) | 2004-12-08 |
Family
ID=9921227
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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ZA200400677A ZA200400677B (en) | 2001-08-30 | 2004-01-28 | Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin K inhibitory activity for the treatment of inflammations and other diseases. |
Country Status (4)
Country | Link |
---|---|
EC (1) | ECSP044989A (en) |
GB (1) | GB0121026D0 (en) |
NO (1) | NO20040858L (en) |
ZA (1) | ZA200400677B (en) |
-
2001
- 2001-08-30 GB GBGB0121026.9A patent/GB0121026D0/en not_active Ceased
-
2004
- 2004-01-28 ZA ZA200400677A patent/ZA200400677B/en unknown
- 2004-02-26 EC EC2004004989A patent/ECSP044989A/en unknown
- 2004-02-26 NO NO20040858A patent/NO20040858L/en not_active Application Discontinuation
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NO20040858L (en) | 2004-05-21 |
ECSP044989A (en) | 2004-04-28 |
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