ZA200206404B - Novel compounds. - Google Patents
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- ZA200206404B ZA200206404B ZA200206404A ZA200206404A ZA200206404B ZA 200206404 B ZA200206404 B ZA 200206404B ZA 200206404 A ZA200206404 A ZA 200206404A ZA 200206404 A ZA200206404 A ZA 200206404A ZA 200206404 B ZA200206404 B ZA 200206404B
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- 150000001875 compounds Chemical class 0.000 title claims description 43
- 125000000217 alkyl group Chemical group 0.000 claims description 89
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 73
- -1 nitro, carboxyl Chemical group 0.000 claims description 69
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 62
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 40
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 29
- 150000002367 halogens Chemical class 0.000 claims description 29
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 25
- 239000012453 solvate Substances 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 23
- 229920006395 saturated elastomer Polymers 0.000 claims description 22
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 21
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 21
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 21
- 125000001424 substituent group Chemical group 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 18
- 229910052799 carbon Inorganic materials 0.000 claims description 15
- 125000000623 heterocyclic group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000001188 haloalkyl group Chemical group 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 12
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 125000004414 alkyl thio group Chemical group 0.000 claims description 11
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 11
- 239000005864 Sulphur Substances 0.000 claims description 10
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 238000002360 preparation method Methods 0.000 claims description 5
- 208000006673 asthma Diseases 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims 26
- 239000000126 substance Substances 0.000 claims 23
- 238000004519 manufacturing process Methods 0.000 claims 8
- 102000009410 Chemokine receptor Human genes 0.000 claims 2
- 108050000299 Chemokine receptor Proteins 0.000 claims 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 claims 2
- 239000002671 adjuvant Substances 0.000 claims 2
- 230000009286 beneficial effect Effects 0.000 claims 2
- 239000003085 diluting agent Substances 0.000 claims 2
- 230000000694 effects Effects 0.000 claims 2
- 208000027866 inflammatory disease Diseases 0.000 claims 2
- 201000006417 multiple sclerosis Diseases 0.000 claims 2
- VBTPAYQPEMGVLO-UHFFFAOYSA-N 1-[7-[3-(8-chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]indol-1-yl]ethanone Chemical compound N1C2=CC=C(Cl)C=C2C(C2)=C1CCN2CC(O)COC1=C2N(C(=O)C)C=CC2=CC=C1 VBTPAYQPEMGVLO-UHFFFAOYSA-N 0.000 claims 1
- 230000003213 activating effect Effects 0.000 claims 1
- 125000001207 fluorophenyl group Chemical group 0.000 claims 1
- 125000000593 indol-1-yl group Chemical group [H]C1=C([H])C([H])=C2N([*])C([H])=C([H])C2=C1[H] 0.000 claims 1
- NQXKGNVOZPLZFD-UHFFFAOYSA-N n-[2-[3-(8-chloro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-4-methylphenyl]acetamide Chemical compound CC(=O)NC1=CC=C(C)C=C1OCC(O)CN1CC(C2=CC(Cl)=CC=C2N2)=C2CC1 NQXKGNVOZPLZFD-UHFFFAOYSA-N 0.000 claims 1
- JQSHSKZXGCZOMY-UHFFFAOYSA-N n-[2-[3-(8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-2-hydroxypropoxy]-4-methylphenyl]acetamide Chemical compound CC(=O)NC1=CC=C(C)C=C1OCC(O)CN1CC(C2=CC(F)=CC=C2N2)=C2CC1 JQSHSKZXGCZOMY-UHFFFAOYSA-N 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 11
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 11
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 11
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 11
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 11
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 10
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 7
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 7
- 229910052801 chlorine Inorganic materials 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 6
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 5
- 229910052794 bromium Inorganic materials 0.000 description 5
- 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 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 4
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 4
- 102000019034 Chemokines Human genes 0.000 description 3
- 108010012236 Chemokines Proteins 0.000 description 3
- OABOXRPGTFRBFZ-IMJSIDKUSA-N Cys-Cys Chemical compound SC[C@H](N)C(=O)N[C@@H](CS)C(O)=O OABOXRPGTFRBFZ-IMJSIDKUSA-N 0.000 description 3
- 108010004073 cysteinylcysteine Proteins 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000006252 n-propylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 3
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- 102000004890 Interleukin-8 Human genes 0.000 description 2
- 108090001007 Interleukin-8 Proteins 0.000 description 2
- 102100036154 Platelet basic protein Human genes 0.000 description 2
- 239000002975 chemoattractant Substances 0.000 description 2
- 108010035886 connective tissue-activating peptide Proteins 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 125000004705 ethylthio group Chemical group C(C)S* 0.000 description 2
- 125000002541 furyl group Chemical group 0.000 description 2
- 125000002883 imidazolyl group Chemical group 0.000 description 2
- 125000001041 indolyl group Chemical group 0.000 description 2
- XKTZWUACRZHVAN-VADRZIEHSA-N interleukin-8 Chemical compound C([C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](NC(C)=O)CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCSC)C(=O)N1[C@H](CCC1)C(=O)N1[C@H](CCC1)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC=1C=CC(O)=CC=1)C(=O)N[C@H](CO)C(=O)N1[C@H](CCC1)C(N)=O)C1=CC=CC=C1 XKTZWUACRZHVAN-VADRZIEHSA-N 0.000 description 2
- 229940096397 interleukin-8 Drugs 0.000 description 2
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 2
- 125000006606 n-butoxy group Chemical group 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 125000003386 piperidinyl group Chemical group 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 2
- 229940076279 serotonin Drugs 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 102100022718 Atypical chemokine receptor 2 Human genes 0.000 description 1
- 102100031172 C-C chemokine receptor type 1 Human genes 0.000 description 1
- 101710149814 C-C chemokine receptor type 1 Proteins 0.000 description 1
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 1
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 1
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 description 1
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 description 1
- 102100037853 C-C chemokine receptor type 4 Human genes 0.000 description 1
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 1
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 1
- 102100036305 C-C chemokine receptor type 8 Human genes 0.000 description 1
- 102100025074 C-C chemokine receptor-like 2 Human genes 0.000 description 1
- 102100021943 C-C motif chemokine 2 Human genes 0.000 description 1
- 101710155857 C-C motif chemokine 2 Proteins 0.000 description 1
- 102100032366 C-C motif chemokine 7 Human genes 0.000 description 1
- 101710155834 C-C motif chemokine 7 Proteins 0.000 description 1
- 102100034871 C-C motif chemokine 8 Human genes 0.000 description 1
- 101710155833 C-C motif chemokine 8 Proteins 0.000 description 1
- 102100036166 C-X-C chemokine receptor type 1 Human genes 0.000 description 1
- 102100028989 C-X-C chemokine receptor type 2 Human genes 0.000 description 1
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 description 1
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 description 1
- 102000001902 CC Chemokines Human genes 0.000 description 1
- 108010040471 CC Chemokines Proteins 0.000 description 1
- 108050006947 CXC Chemokine Proteins 0.000 description 1
- 102000019388 CXC chemokine Human genes 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 102100023688 Eotaxin Human genes 0.000 description 1
- 101710139422 Eotaxin Proteins 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- 101000678892 Homo sapiens Atypical chemokine receptor 2 Proteins 0.000 description 1
- 101000777558 Homo sapiens C-C chemokine receptor type 10 Proteins 0.000 description 1
- 101000716068 Homo sapiens C-C chemokine receptor type 6 Proteins 0.000 description 1
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 1
- 101000716063 Homo sapiens C-C chemokine receptor type 8 Proteins 0.000 description 1
- 101000947174 Homo sapiens C-X-C chemokine receptor type 1 Proteins 0.000 description 1
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 description 1
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 description 1
- 108010018951 Interleukin-8B Receptors Proteins 0.000 description 1
- 102000009571 Macrophage Inflammatory Proteins Human genes 0.000 description 1
- 108010009474 Macrophage Inflammatory Proteins Proteins 0.000 description 1
- 102000014962 Monocyte Chemoattractant Proteins Human genes 0.000 description 1
- 108010064136 Monocyte Chemoattractant Proteins Proteins 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- OKTJSMMVPCPJKN-YPZZEJLDSA-N carbon-10 atom Chemical group [10C] OKTJSMMVPCPJKN-YPZZEJLDSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- AEUKDPKXTPNBNY-XEYRWQBLSA-N mcp 2 Chemical compound C([C@@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)C1=CC=CC=C1 AEUKDPKXTPNBNY-XEYRWQBLSA-N 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Description
NOVEL COMPOUNDS
The present invention relates to novel compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. ~US 5789402 describes certain indole deriatives which are said to be useful for the treatment of diseases which are caused or affected by disorders of the serotonin-affected neurological systems, particularly those relating to the serotonin 1, receptor and those relating to the uptake of serotonin.
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune . pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basis of a single amino acid insertion between the
NH-proximal pair of cysteine residues and sequence similarity.
The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and 2s MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1a and 1p (MIP-1o and MIP-18).
Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2,
CCR2A, CCR2B, CCR3, CCR4, CCRS5, CCR6, CCR7, CCR8, CCR9Y, CCR10, CXCR1,
CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug © development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those previously mentioned.
LY
In accordance with the present invention, there is therefore provided a compound of general formula
RY OH a
R Np2
RT-R" R 4 6
R R 0) wherein,
R represents either a group 3
Xs 2 1
A SIGE
1- z or a group
H
N
1
N-_ . mis 0, 1,2 or 3; each R! independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C5-Cg cycloalkyl, C;-C¢ alkoxy, C;-Cg alkoxycarbonyl, C;-Cg haloalkyl,
C;-Cg haloalkoxy, NRR?, C5-C¢ cycloalkylamino, C,-Cgq alkylthio, C;-Cg alkylcarbonyl, C;-Cg alkylcarbonylamino, sulphonamido (-SO,NH,), . C;-Cg alkylsulphonyl, -C(O)NR''R", -NR'>C(0)-(NH),R"*, phenyl, or C;-Cg alkyl optionally substituted by carboxyl or C,-Cg4 alkoxycarbonyl; pisOorl;
X represents an oxygen or sulphur atom or a CH,, CH(CH3;), OCH,, CH,0, CH,NH, ‘ NH or carbonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen or sulphur atom or a CH,O, CH,NH or NH group, then
Y represents a CH group; z! represents a bond or a group (CHy), where q is 1 or 2; z> represents a bond or a group CH,, with the proviso that Zz! and Z? do not both simultaneously represent a bond;
Q represents an oxygen or sulphur atom or a group CH, or NH;
R? represents a group 0 i ) aod
R HN \ N \ 3 24 2S 4
O en, o ® So, os: . nis 0,1 or2; each R® independently represents a C-Cg alkyl, C;-Cq4 alkoxycarbonyl, -CH,OH or ’ 15 carboxyl group;
RY, R’, R® and R” each independently represent a hydrogen atom or a C,-Cg4 alkyl ) group, or R*, rR’, R® and R’ together represent a C;-C, alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle,
or rR’, R® and R’ each represent a hydrogen atom and rR and RE together with the carbon : atoms to which they are attached form a 5- to 6-membered saturated carbocycle;
R® represents a hydrogen atom, a C;-Cg alkyl group or is linked to R* as defined ’ above; :
R® and R'? each independently represent a hydrogen atom or a C-Cg alkyl group, or
R’ and R'® together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;
RY and R'? each independently represent a hydrogen atom or a C;-Cg alkyl group optionally substituted by C,-Cg alkoxycarbonyl; rR represents a hydrogen atom or a C;-Cg alkyl group; rR" represents a hydrogen atom, or a C;-Cg alkyl group optionally substituted by carboxyl, C;-C¢ alkoxy or C,-Cg4 alkoxycarbonyl;
RY represents carboxyl, C;-Cg alkylcarbonyl, C,-Cg alkoxycarbonyl,
C;-Cy alkoxycarbonylC;-Cg alkyl or a group -NR' 'R'®, -NHSO,CH;, -NHC(O)CH,, is -C(ONR'R'®, .NHC(O)NR!'R'®, -0C(O)NR''R, -OCH,C(O)NR!'RS,
NHC(O)OR!” or -OR'""; tis0,1, 2 or 3; each R'® independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C;3-Cg cycloalkyl, C;-Cg4 alkoxy, C;-Cg4 alkoxycarbonyl, C;-Cg haloalkyl, 2 C-Cg haloalkoxy, -NR°R, C3-Cg cycloalkylamino, C;-Cg alkylthio,
C;-Cs alkylcarbonyl, C;-Cg¢ alkylcarbonylamino, sulphonamido (-SO,NH)),
C,-Cg alkylsulphonyl, -C(O)NR*'R?, -NR**C(O)(NH),R**, phenyl, or C;-Cg alkyl optionally substituted by carboxyl or C,-Cg alkoxycarbonyl;
R'7 and R'® each independently represent (i) a hydrogen atom, (ii) a 5-to 6- 2s membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at } least one substituent selected from halogen, methyl and trifluoromethyl, or (iii) a C4-Cg alkyl group optionally substituted by at least one substituent selected from halogen, trifluoromethyl, carboxyl, C;-Cg alkoxycarbonyl and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one . substituent selected from halogen, methyl and trifluoromethyl, or
R' and R'® together with the nitrogen atom to which they are attached form a 4-to 7- ’ membered saturated heterocycle; 5 rR! represents a hydrogen atom, or a C{-Cg alkyl group optionally substituted by carboxyl or C;-Cg4 alkoxycarbonyl;
R'7" is defined as for R*” above except that R!” does not represent a hydrogen atom;
R' and R?® each independently represent a hydrogen atom or a C;-Cg alkyl group, or
RY and R® together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;
R?! and R?? each independently represent a hydrogen atom or a C;-Cg alkyl group optionally substituted by C;-C4 alkoxycarbonyl; visOorl; rR? represents a hydrogen atom or a C;-Cg alkyl group; and rR* represents a hydrogen atom, or a C;-C¢ alkyl group optionally substituted by carboxyl, C;-Cg4 alkoxy or C;-Cg4 alkoxycarbonyl; provided that when X is an oxygen atom or a group CH,, Y is CH, 7! and 7? each represent a group CH, and Q is an oxygen atom, then R? is other than an unsubstituted indolyl group; } ora pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, an alkyl substituent group or an alkyl moiety in a substituent group may be linear or branched. 25s In one aspect of the present invention, there is provided a compound of general formula
RA OH
. Se
R* i R° : @) wherein,
R represents a group
Xe. ~~ (R), wT 1§ i 2 mis 0, 1,2 or 3; each R' independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C3-Cq4 cycloalkyl, C,-Cg¢ alkoxy, C;-Cg4 alkoxycarbonyl, C;-C¢ haloalkyl,
C;-Cg haloalkoxy, NR°RY, C3-Cq4 cycloalkylamino, C;-Cg4 alkylthio,
C,-Cg alkylcarbonyl, C,-Cg4 alkylcarbonylamino, sulphonamido, C,-Cg alkylsulphonyl, 0 -CONR"R", NR” C(0)-(NH),R", phenyl, or C;-C alkyl optionally substituted by carboxyl or C;-Cg4 alkoxycarbonyl; pisOor 1; -
X represents an oxygen or sulphur atom or a CH,, CH(CH3), OCH,, CH,0, CH,NH,
NH or carbonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen or sulphur atom or a CH,O, CH,NH or NH group, then
Y represents a CH group;
Zz! represents a bond or a group (CH,), where q is 1 or 2; z? represents a bond or a group CH,, with the proviso that 2! and Z? do not both simultaneously represent a bond;
Q represents an oxygen or sulphur atom or a group CH, or NH; ) Rr? represents a group
R'S
O- R"),
8 nis 0, 1 or 2; each rR? independently represents a C;-Cg alkyl, C;-Cq alkoxycarbonyl, -CH,OH or ' carboxy! group;
RY, Rr, R® and R’ each independently represent a hydrogen atom or a C;-Cg alkyl group, or RY rR’, RS and Rr’ together represent a C,-C, alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or Rr’, RS and R’ each represent a hydrogen atom and R*and R® to gether with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle;
R® represents a hydrogen atom, a C;-Cg alkyl group or is linked to R* as defined above;
R’ and R!? each independently represent a hydrogen atom or a C;-Cg alkyl group, or
R® and R' to gether with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;
R'! and R™ each independently represent a hydrogen atom or a C;-Cg alkyl group optionally substituted by C;-Cg4 alkoxycarbonyl;
Rr? represents a hydrogen atom or a C;-Cg4 alkyl group;
RM represents a hydrogen atom, or a C,-Cq alkyl group optionally substituted by carboxyl, C;-Cg alkoxy or C,-Cg alkoxycarbonyl;
RY represents carboxyl, C;-Cs alkylcarbonyl, C,-Cg¢ alkoxycarbonyl,
C,-Cg alkoxycarbonylC;-C¢ alkyl or a group NRRE, -NHSO,CH3;, -NHC(O)CHs, -c(ONR!'R!®, -NHC(O)NR''R!®, -OC(O)NR''R'}, -OCH,C(O)NR!"R®®,
NHC(O)OR!" or -OR!"; tis 0,1,2 or 3; each R'® independently represents halogen, cyano, nitro, carboxyl, hydroxyl, ’ C;3-Cg cycloalkyl, C¢-Cg4 alkoxy, C;-Cg4 alkoxycarbonyl, C-Cg¢ haloalkyl,
C,-Cg haloalkoxy, NRPR%, C3-Cg cycloalkylamino, C;-Cg alkylthio,
C,-C alkylcarbonyl, C;-Cg alkylcarbonylamino, sulphonamido (-SO,NH,),
C,-Cg alkylsulphonyl, -C(O)NR*'R*2, -NR*C(O)(NH),R**, phenyl, or C;-Cg alkyl 30° optionally substituted by carboxyl or C;-Cg4 alkoxycarbonyl;
R'7 and R!® each independently represent (i) a hydrogen atom, (ii) a 5-to 6- . membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or 5s (iii) a C;-Cg alkyl group optionally substituted by at least one substituent selected from halogen, trifluoromethyl, carboxyl, C;-C alkoxycarbonyl and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or
R" and RS together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle; rR represents a hydrogen atom, or a C,-Cg alkyl group optionally substituted by carboxyl or C;-Cg4 alkoxycarbonyl;
R'7" is defined as for R' above except that R'”" does not represent a hydrogen atom;
R' and R? each independently represent a hydrogen atom or a C;-Cg alkyl group, or
R!® and R% together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;
R*! and R?? each independently represent a hydrogen atom or a C;-Cg alkyl group optionally substituted by C;-C¢ alkoxycarbonyl; visOorl; x rR* represents a hydrogen atom or a C-Cg alkyl group; and rR* represents a hydrogen atom, or a C;-C¢ alkyl group optionally substituted by carboxyl, C;-Cg¢ alkoxy or C;-Cg4 alkoxycarbonyl; or a pharmaceutically acceptable salt or solvate thereof. ’ In another aspect of the invention, there is provided a compound of general formula
RS OH
Os pe
R R
R" R° a wherein, : R represents a group
X_ ~~ (R), of J § 7
FUN : mis0,1,2o0r3; each R! independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C3-Cg cycloalkyl, C;-Cq¢ alkoxy, C;-Cg4 alkoxycarbonyl, C;-C¢ haloalkyl,
C;-Cg haloalkoxy, -NR’R'®, C3-Cg cycloalkylamino, C;-Cg alkylthio,
C,-Cg alkylcarbonyl, C;-Cg4 alkylcarbonylamino, sulphonamido, C;-Cg4 alkylsulphonyl, -C(O)NR!'R??, NR"C(0)-NH),R, phenyl, or C;-Cg alkyl optionally substituted by carboxyl or C{-Cg alkoxycarbonyl; pisQorl; .
X represents an oxygen or sulphur atom or a CH,, CH(CH3), OCH,, CH,O, CH,NH,
NH or carbonyl group and Y represents a nitrogen atom or a CH or C(OH) group, provided that when X represents an oxygen or sulphur atom or a CH,O, CH,NH or NH group, then
Y represents a CH group; z! represents a bond or a group (CHj), where q is 1 or 2; 7? represents a bond or a group CH», with the proviso that Zz! and Z? do not both simultaneously represent a bond;
Q represents an oxygen or sulphur atom or a group CH, or NH;
Rr? represents a group
Oo
I
YC
0)
EN o ® I, or. A : * HC N nis 0, 1 or 2; : each R® independently represents a C;-Cg alkyl, C;-C¢ alkoxycarbonyl, -CH,OH or 5s carboxyl group;
RY, R>, RS and R each independently represent a hydrogen atom or a C;-Cg alkyl group, or RY, Rr’, R® and R’ together represent a C;-C, alkylene chain linking the two carbon atoms fo which they are attached to form a 4- to 7-membered saturated carbocycle, or rR’, RS and R” each represent a hydrogen atom and R* and R® together with the carbon 10 atoms to which they are attached form a 5- to 6-membered saturated carbocycle;
R® represents a hydrogen atom, a C;-Cg alkyl group or is linked to R* as defined above;
R® and R' each independently represent a hydrogen atom or a C;-Cg4 alkyl group, or
R® and RC together with the nitrogen atom to which they are attached form a 4- to 7- 1s membered saturated heterocycle;
R'! and R'? each independently represent a hydrogen atom or a C;-Cg alkyl group : optionally substituted by C;-Cg¢ alkoxycarbonyl; rR! represents a hydrogen atom or a C,-Cg alkyl group; and rH represents a hydrogen atom, or a C;-Cg alkyl group optionally substituted by : carboxyl, C,-Cg alkoxy or C;-Cg4 alkoxycarbonyl; provided that when X is an oxygen atom or a group CH,, Y is CH, 7! and 72 each represent a group CH, and Q is an oxygen atom, then R? is other than an unsubstituted indolyl group; or a pharmaceutically acceptable salt or solvate thereof.
In a further aspect of the invention, there is provided a compound of general formula
R_ OH a
SP pg?
R" FR a" wherein,
R represents a group
Ne wt TT) ~ 5 is mis 0, 1,2 or 3; each R! independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C3-Cg cycloalkyl, C1-Cg4 alkoxy, Cy-Cg alkoxycarbonyl, C;-Cg¢ haloalkyl,
C,-Cg haloalkoxy, -NR’R'?, C;-C, cycloalkylamino, C;-Cg alkylthio,
C1-Cs alkylcarbonyl, C;-Cg¢ alkylcarbonylamino, sulphonamido, C;-Cg4 alkylsulphonyl, -C(O)NR'R!?, NR ’C(0)-(NH),R™, phenyl, or C;-Cg alkyl optionally substituted by carboxyl or C;-Cg alkoxycarbonyl; pisOorl; . Q represents an oxygen or sulphur atom or a group CH, or NH;
R? represents a group o
R'" HN \ N 3 ' 16
X
HN” “CH, Jy
HN CH,
O
PI] or © HC N
H : . rR? R’, R® and R7 each independently represent a hydrogen atom or a C;-Cg alkyl group, or rR, R>, RS and R7 together represent a C,-Cy alkylene chain linking the two 5s carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or Rr, R® and R” each represent a hydrogen atom and R* and R® to gether with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle;
R® represents a hydrogen atom, a C{-Cg alkyl group or is linked to R* as defined above;
R® and R'? each independently represent a hydrogen atom or a C;-Cg alkyl group, or
R’ and RY together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle;
R' and R!? each independently represent a hydrogen atom or a C;-Cg4 alkyl group optionally substituted by C;-Cg alkoxycarbonyl;
RY represents a hydrogen atom or a C;-Cg alkyl group; rR represents a hydrogen atom, or a C-Cg alkyl group optionally substituted by carboxyl, C;-Cg alkoxy or C;-C alkoxycarbonyl;
RY represents carboxyl, C;-Cg alkylcarbonyl, C;-C¢ alkoxycarbonyl,
C,-Cg alkoxycarbonylC;-Cg alkyl or a group -NR''R'®, -NHSO,CH;, -NHC(O)CH,,
-C(ONR'R'®, -NHC(O)NR''R®, -0C(O)NR'7RY, -OCH,C(O)NR!"RYS, : -NHC(O)0R!” or -OR'""; tis 0,1,2 or 3; each R'® independently represents halogen, cyano, nitro, carboxyl, hydroxyl,
C3-Cg cycloalkyl, C;-Cg alkoxy, C;-Cgq alkoxycarbonyl, C;-C4 haloalkyl,
C 1-Cg haloalkoxy, NRYRZ, C3-C¢ cycloalkylamino, C;-Cg alkylthio,
C;-C¢ alkylcarbonyl, C;-Cg alkylcarbonylamino, sulphonamido (-SO,NH,),
C,-Cy alkylsulphonyl, -C(O)NR*'R*%, -NR**C(O)(NH),R**, phenyl, or C;-Cj alkyl optionally substituted by carboxyl or C;-Cg4 alkoxycarbonyl;
RY and R'® each independently represent (i) a hydrogen atom, (ii) a 5- to 6- membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or (iii) a C4-Cg¢ alkyl group optionally substituted by at least one substituent selected from halogen, trifluoromethyl, carboxyl, C;-Cg4 alkoxycarbonyl and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or 3 and R*® together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle; rR represents a hydrogen atom, or a C;-Cg alkyl group optionally substituted by carboxyl or C;-Cg¢ alkoxycarbonyl;
R'7" is defined as for R'” above except that R'” does not represent a hydrogen atom;
R* and R% each independently represent a hydrogen atom or a Cy-Cg alkyl group, or 2s RY and rR? together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle; } R?! and R? each independently represent a hydrogen atom or a C4-Cg alkyl group optionally substituted by C;-C¢ alkoxycarbonyl; visOorl; rR® represents a hydrogen atom or a C;-Cg alkyl group; and rR* represents a hydrogen atom, or a C;-Cg alkyl group optionally substituted by . carboxyl, C;-Cg alkoxy or C{-Cg4 alkoxycarbonyl; or a pharmaceutically acceptable salt or solvate thereof.
The integer m is preferably 0, 1 or 2.
Each R! independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C;-Cg4 cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C;-Cg, preferably C;-Cy, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C;-Cg, preferably C;-C4, alkoxycarbonyl (e.g. methoxycarbonyl or oo ethoxycarbonyl), C;-Cg, preferably C;-Cy, haloalkyl (e.g. trifluoromethyl),
C,-Cs, preferably C,-Cy, haloalkoxy (e.g. trifluoromethoxy), NRRY,
C3-Cg cycloalkylamino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), C;-Cg, preferably C;-Cy, alkylthio (e.g. methylthio or ethylthio),
Cy-Cq, preferably C,-C,, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C;-Cg, preferably C;-Cj4, alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino), sulphonamido,
C;-Cs, preferably C;-Cy, alkylsulphonyl (e.g. methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), -C(O)NR R12 NR c(0)-(NH),R™, phenyl, or
C;-Cg, preferably C;-Cy, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or C;-Cg, preferably
C;-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl).
Most preferably, each R' independently represents halogen (particularly chlorine or ) fluorine), cyano, nitro, C-Cg alkoxy (especially methoxy), C;-Cg¢ alkylcarbonyl (especially methylcarbonyl) or C;-Cg alkylcarbonylamino (particularly methylcarbonylamino).
Preferably X represents an oxygen atom or a CH,, OCH,, CH,0, NH or carbonyl group.
Preferably Y represents a nitrogen atom or CH group. 5s Preferred combinations of X - Y include O - CH, OCH, - CH, NH - CH, CH,0 - CH,
CH; -N, C(O)-N and CH,-CH.
Preferred combinations of Y, z! and 7° include: om | bs | cm (CE;
Q preferably represents an oxygen atom. “Each rR? independently represents a C;-Ce, preferably C;-Cy4, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), C,-C, preferably
C;-C4, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), -CH,OH or carboxyl group. It is preferred that R> represents a methyl, methoxycarbonyl, ethoxycarbonyl, -CH,OH or carboxyl group.
RY, R>, R® and R” each independently represent a hydrogen atom or a C;-Cg, preferably
Cy-Cy, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl . or n-hexyl), or RY, rR’, R® and R’ together represent a C;-C, alkylene chain linking the two carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle (e.g. cyclohexyl or preferably cyclopentyl), or Rr’, R® and R7 each represent a hydrogen atom and R* and R® together with the carbon atoms to which they are attached form a 5- to ‘ 6-membered saturated carbocycle (preferably cyclopentyl).
R® represents a hydrogen atom, a C;-Cg, preferably C;-Cy, alkyl: group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) or is linked to R* as defined above.
R® and R'? cach independently represent a hydrogen atom or a C;-Cg, preferably
C,-Cy4, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl), or R’ and R'° together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl).
R'! and R'? each independently represent a hydrogen atom or a C;-Cyg, preferably
C;-Cy, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by a C;-Cg, preferably C;-Cj, alkoxycarbonyl substituent group. rR? represents a hydrogen atom or a C;-Cg, preferably C,-C,, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl). rR!" represents a hydrogen atom, or a C;-Cy, preferably C;-Cy, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-penty! or n-hexyl) optionally substituted by carboxyl, C,~Cy, preferably C;-C,, alkoxy or C;-Cg, preferably
C;-C4, alkoxycarbonyl. . rR represents carboxyl, C;-Cg, preferably C;-C,, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C;-Cy, preferably C;-C,, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), C;-Cg4 alkoxycarbonylC;-Cg alkyl, preferably
C;-C4 alkoxycarbonylC,;-C, alkyl (e.g. methoxycarbonylmethyl or methoxycarbonylethyl), or a group -NR!R'8, -NHSO,CH;, -NHC(O)CH,, -C(ONR!R!, -NHC(O)NR!'R™, -0C(O)NR''R'®, .0CH,C(O)NR''RY, -NHC(O)OR!” or -OR!”".
Itis preferred that RY represents C;-Cy alkoxy (especially methoxy), C;-C, alkylcarbonyl (especially methylcarbonyl or ethylcarbonyl), C;-C,4 alkoxycarbonylC,-C, alkyl (particularly methoxycarbonylmethyl or methoxycarbonylethyl), -NHC(O)CHj, -C(O)NR''R'® NHSO,CH; or -NHC(O)NR!'R!®, jo EachR'® independently represents halogen (e.g. chlorine, fluorine, bromine or iodine), cyano, nitro, carboxyl, hydroxyl, C;-C¢ cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), C;-Cg, preferably C,-Cy, alkoxy (e.g. methoxy, ethoxy, n-propoxy or n-butoxy), C;-Cg, preferably C,-C,, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl), C;-Cg, preferably C;-C,, haloalkyl (e.g. trifluoromethyl),
Cy-Cq, preferably C,-C,, haloalkoxy (e.g. trifluoromethoxy), NRPR?,
C3-C¢ cycloalkylamino (e.g. cyclopropylamino, cyclobutylamino, cyclopentylamino or cyclohexylamino), C;-Cg, preferably C,-Cy, alkylthio (e.g. methylthio or ethylthio),
C,-Cq, preferably C-C,, alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, n-pentylcarbonyl or n-hexylcarbonyl), C1-Cg, preferably C1-Cy, alkylcarbonylamino (e.g. methylcarbonylamino or ethylcarbonylamino), sulphonamido,
C,-Cg, preferably C,-C,, alkylsulphony! (e.g. methylsulphonyl, ethylsulphonyl, n-propylsulphonyl, isopropylsulphonyl, n-butylsulphonyl, n-pentylsulphonyl or n-hexylsulphonyl), -C(O)NR*'R?, NRZC(0)-(NH),R*, phenyl, or
Cy-Cg, preferably Cy-Cy, alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by carboxyl or C;-Cg, preferably
C;-C,, alkoxycarbonyl (e.g. methoxycarbonyl or ethoxycarbonyl).
Preferably, each R16 dependently represents halogen (particularly chlorine or fluorine), . hydroxyl, cyano, C;-C, alkoxy (especially methoxy), C;-C, alkoxycarbonyl (especially methoxycarbonyl), C;-C, haloalkyl (especially trifluoromethyl), C;-C, alkylcarbonyl ' (particularly methylcarbonyl), phenyl or C;-C, alkyl (e.g. methyl or tert-butyl).
R'7 and R® each independently represent (i) a hydrogen atom, (ii) a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom (e.g. one, two or three heteroatoms independently) chosen from nitrogen, oxygen and sulphur (such as cyclopentyl, cyclohexyl, pyrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl or furanyl), the ring being optionally substituted with at least one substituent (e.g. one, two or three substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), methyl and trifluoromethyl, or (iii) a Cy-Cg, preferably C;-Cy, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally substituted by at least one substituent (e.g. one, two or three substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), trifluoromethyl, carboxyl,
C,-Cg, preferably C,-C,, alkoxycarbonyl, especially methoxycarbonyl, and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom (e.g. one, two or three heteroatoms independently) chosen from nitrogen, oxygen and sulphur (such as cyclopentyl, cyclohexyl, pyrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thienyl or furanyl), the ring being optionally substituted with at least one substituent (e.g. one, two or three substituents independently) selected from halogen (e.g. fluorine, chlorine, bromine or iodine), methyl and trifluoromethyl, or ss R7andR'® together with the nitrogen atom to which they are attached form a 4- to 7- ' membered saturated heterocycle (preferably pyrrolidinyl or piperidinyl). rR! represents a hydrogen atom ora C;-Cs, preferably C;-C,, alkyl group (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl or n-hexyl) optionally
Claims (32)
1. A compound of general formula RA OH R QA 2 R® R’ R 4 6 R R an wherein, R represents a group H N 1 N-_ mis0,1,2or3; each R independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C5-Cg cycloalkyl, C;-Cg alkoxy, C;-C¢ alkoxycarbonyl, C,-Cg haloalkyl, C,-Cg haloalkoxy, -NR’R'?, C;-C¢ cycloalkylamino, C;-Cg alkylthio, a C;-C¢ alkylcarbonyl, C;-Cg¢ alkylcarbonylamino, sulphonamido, C;-Cg alkylsulphonyl, - is -C(ONR'R", -NR"C(0)-(NH),R'*, phenyl, or C,-Cj alkyl optionally substituted by carboxyl or C{-Cyg alkoxycarbonyl; pisOorl; Q represents an oxygen or sulphur atom or a group CH; or NH; - p2 R” represents a group oO . no—X . 3 R' HN NT ) 16 Big HN~ “CH, 1 HN CH, 0 PIS or * HC N
H . 1:3 RS, RS and R’ each independently represent a hydrogen atom or a C,-Cg alkyl group, or RY, R>, R® and R’ together represent a C;-C, alkylene chain linking the two s carbon atoms to which they are attached to form a 4- to 7-membered saturated carbocycle, or rR’, RS and R each represent a hydrogen atom and R* and R® together with the carbon atoms to which they are attached form a 5- to 6-membered saturated carbocycle; R® represents a hydrogen atom, a C;-Cg alkyl group or is linked to R? as defined above; R® and R'? each independently represent a hydrogen atom or a C,-Cg alkyl group, or R’ and RY to gether with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle; R!! and R'? each independently represent a hydrogen atom or a C;-Cg alkyl group optionally substituted by C;-Cg alkoxycarbonyl; : 15 rR! represents a hydrogen atom or a C,-Cgq alkyl group; rR! represents a hydrogen atom, or a C;-Cg alkyl group optionally substituted by carboxyl, C;-C¢ alkoxy or C;-Cg4 alkoxycarbonyl; RY represents carboxyl, C;-Cg alkylcarbonyl, C;-C¢ alkoxycarbonyl, CC alkoxycarbonylC;-Cg alkyl or a group -NR' 'R'®, -NHSO,CHs, -NHC(O)CHs,
-C(ONR'R'®, NHC(O)NR!R'®, -0C(O)NR''R'®, -OCH,C(O)NR''R'S, : -NHC(O)OR'” or -OR!" tis 0, 1,2 or 3; each R'® independently represents halogen, cyano, nitro, carboxyl, hydroxyl, C3-Cg cycloalkyl, C;-Cg4 alkoxy, C;-Cg alkoxycarbonyl, C,-Cg haloalkyl,
C;-C¢ haloalkoxy, NRPR%, C;-Cg cycloalkylamino, C;-Cg alkylthio,
C,-Cg alkylcarbonyl, C,-Cg alkylcarbonylamino, sulphonamido (-SO,NH;),
C,-C alkylsulphonyl, -C(O)NR*'R?, -NRZC(O)(NH),R**, phenyl, or C;-Cg alkyl optionally substituted by carboxyl or C;-C¢ alkoxycarbonyl;
R'7 and R'® each independently represent (i) a hydrogen atom, (ii) a 5- to 6- membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or (iii) a C;-Cg alkyl group optionally substituted by at least one substituent selected from halogen, trifluoromethyl, carboxyl, C;-Cg4 alkoxycarbonyl and a 5- to 6-membered saturated or unsaturated ring which may comprise at least one heteroatom chosen from nitrogen, oxygen and sulphur, the ring being optionally substituted with at least one substituent selected from halogen, methyl and trifluoromethyl, or
RY and R'® to gether with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle; RY represents a hydrogen atom, or a C-Cg alkyl group optionally substituted by carboxyl or C;-Cg¢ alkoxycarbonyl; R'7" is defined as for R’ above except that R!7" does not represent a hydrogen atom; RY and R% each independently represent a hydrogen atom or a C;-Cg alkyl group, or 5 RY and R® together with the nitrogen atom to which they are attached form a 4- to 7- membered saturated heterocycle; ] R* and R? each independently represent a hydrogen atom or a C;-C4 alkyl group . optionally substituted by C;-Cg4 alkoxycarbonyl; visOorl; ] rR® represents a hydrogen atom or a C;-Cg alkyl group; and r* represents a hydrogen atom, or a C;-Cg alkyl group optionally substituted by . carboxyl, C,-Cg alkoxy or C;-Cg¢ alkoxycarbonyl; or a pharmaceutically acceptable salt or solvate thereof.
2. A compound according to claim 1, wherein Q represents an oxygen atom.
3. A compound according to claim 1 or 2, wherein Rr? represents a group RS 16 EE )
4. A compound according to claim 3, wherein RY represents C;-C, alkoxy, C,-C, alkylcarbonyl, C;-Cj alkoxycarbonylC,-Cy alkyl, -NHC(O)CH;, -C(O)NR RS, NHSO,CH; or -NHC(O)NR''RS.
5. A compound according to claim 3 or 4, wherein each R16 independently represents halogen, cyano, hydroxyl, C;-C, alkoxy, C;-C4 alkoxycarbonyl, C;-Cy4 haloalkyl, C,-C, alkylcarbonyl, phenyl or C;-C, alkyl
6. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as defined in claim 1 being selected from: N-{5-Chloro-2-[3-(8-chloro-1,3,4,5-tetrahydro-pyrido[4,3-bJindol-2-yl)-2-hydroxy- propoxy]-phenyl}-acetamide, . N-{3-Acetyl-2-[3-(8-chloro-1,3,4,5-tetrahydro-pyrido[4,3-bJindol-2-yl)-2-hydroxy- propoxy]-5-methyl-phenyl}-acetamide, ) 25 N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4- methyl-phenyl}-acetamide,
N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-bJindol-2-y1)-2-hydroxy-propoxy]-5- . fluoro-phenyl}-acetamide, 1-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-y1)-3-(1H-indol-7-yloxy)-propan- 2-0l, 1-{7-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy] - indol-1-yl}-ethanone, N-{4-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-y1)-2-hydroxy-propoxy]- biphenyl-3-yl}-acetamide, N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-b]Jindol-2-y1)-2-hydroxy-propoxy]-4- fluoro-phenyl}-acetamide, N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido{4,3-bJindol-2-y1)-2-hydroxy-propoxy}-5- methyl-phenyl}-acetamide, N-{2-[3-(8-Chloro-1,3,4,5-tetrahydro-pyrido[4,3-bJindol-2-y1)-2-hydroxy-propoxy]- phenyl}-acetamide, : N-{5-Chloro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-bJindol-2-yl)-2-hydroxy- propoxy]-phenyl}-acetamide, N-{3-Acetyl-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido{4,3-bJindol-2-yl)-2-hydroxy- propoxy]-5-methyl-phenyl}-acetamide, N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-2-hydroxy-propoxy]-4- methyl-phenyl}-acetamide, N-{5-Fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-blindol-2-yl)-2-hydroxy- propoxy]-phenyl }-acetamide, 1-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-bJindol-2-yl)-3-(1H-indol-7-yloxy)-propan- 2-0l, 1-{7-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-bJindol-2-y1)-2-hydroxy-propoxy]- ’ indol-1-yl}-ethanone, N-{4-[3~(8-Fluoro-1,3,4,5-tetrahydro-pyrido[4,3-bJindol-2-yl)-2-hydroxy-propoxy]- biphenyl-3-yl}-acetamide, N-{4-Fluoro-2-[3-(8-fluoro-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-y1)-2-hydroxy- propoxy]-phenyl}-acetamide,
N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido{4,3-bJindol-2-y1)-2-hydroxy-propoxy]-5- . methyl-phenyl}-acetamide, and N-{2-[3-(8-Fluoro-1,3,4,5-tetrahydro-pyrido [4,3-bJindol-2-y1)-2-hydroxy-propoxyl- phenyl} -acetamide. : :
7. A process for the preparation of a compound of formula (I'"') as defined in claim 1 which comprises, (a) reacting a compound of general formula R-H am wherein R is as defined in formula (I), with a compound of general formula o.__R RR (ur) wherein Q, RZ, RY, R’, RS, R’ and R® are as defined in formula (I); or (b) reacting a compound of general formula RU o ROR qm) wherein R, RY R>, RS, R’ and R® are as defined in formula (I'"), with a compound of general formula Ll-Q-r? (vm wherein L' represents a hydrogen atom or an activating group and Q and R? are as defined in formula (I"™); and optionally thereafter converting the compound of formula (I) to a further compound 25s of formula (I'"); and, if desired, forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
- 8. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
9. A process for the preparation of a pharmaceutical composition as claimed in claim 8 which comprises mixing a compound of formula (I""), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 with a pharmaceutically acceptable adjuvant, diluent or carrier.
10. A compound of formula (I'""), or a pharmaceutically-acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 for use in therapy.
11. Use of a compound of formula (I"), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in therapy.
12. Use of a compound of formula (I'""), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial. -
13. Use of a compound of formula (I'""), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use 2s in treating rheumatoid arthritis.
14. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate i thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in treating chronic obstructive pulmonary disease.
} 169 PCT/SE01/00405
15. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in treating asthma.
16. Use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for use in treating multiple sclerosis.
17. Use of a compound of formula (I”), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for treating an inflammatory disease in a patient suffering from, or at risk of, said disease.
18. Use of a compound of formula (I”), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6 in the manufacture of a medicament for treating an airways disease in a patient suffering from, or at risk of, said disease.
19. A substance or composition for use in a method for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial, said substance or composition comprising a compound of formula (I"), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6, and said method comprising administering said substance or composition.
20. A substance or composition for use in a method of treating rheumatoid arthritis, said substance or composition comprising a compound of formula (I**), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6, and said method comprising administering said substance or composition.
21. A substance or composition for use in a method of treating chronic obstructive pulmonary disease, said substance or composition comprising a compound of formula (I"), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6, and said method comprising administering said substance or composition.
22. A substance or composition for use in a method of treating asthma, said substance or composition comprising a compound of formula (I"”"), or a pharmaceutically acceptable salt or AMENDED SHEET
170 PCT/SE01/00405 solvate thereof, as claimed in any one of claims 1 to 6, and said method comprising administering said substance or composition.
23. A substance or composition for use in a method of treating multiple sclerosis, said substance or composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6, and said method comprising administering said substance or composition.
24. A substance or composition for use in a method of treating an inflammatory disease in a patient suffering from, or at risk of, said disease, said substance or composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6, and said method comprising administering to the patient a therapeutically effective amount of said substance or composition.
25. A substance or composition for use in a method of treating an airways disease in a patient suffering from, or at risk of, said disease, said substance or composition comprising 4 compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as claimed in any one of claims 1 to 6, and said method comprising administering to the patient a therapeutically effective amount of said substance or composition.
26. A compound according to any one of claims 1 to 6 or 10, substantially as herein described and illustrated.
27. A process according to claim 7, substantially as herein described and illustrated.
28. A composition according to claim 8, substantially as herein described and illustrated.
29. A process according to claim 9, substantially as herein described and illustrated.
30. Use according to any one of claims 11 to 18, substantially as herein described and illustrated.
31. A substance or composition for use in a method of treatment, according to claim 10, or any one of claims 19 to 25, substantially as herein described and illustrated. AMENDED SHEET
171 PCT/SE01/00405
32. A new compound, a new process for the preparation of a compound, a new composition, a new process for the preparation of a composition, a new use of a compound as claimed in any one of claims 1 to 6, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE0000620A SE0000620D0 (en) | 2000-02-25 | 2000-02-25 | Novel compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200206404B true ZA200206404B (en) | 2003-11-12 |
Family
ID=20278589
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200206402A ZA200206402B (en) | 2000-02-25 | 2002-08-12 | Novel compounds. |
| ZA200206404A ZA200206404B (en) | 2000-02-25 | 2002-08-12 | Novel compounds. |
| ZA200206665A ZA200206665B (en) | 2000-02-25 | 2002-08-20 | Novel Compounds. |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200206402A ZA200206402B (en) | 2000-02-25 | 2002-08-12 | Novel compounds. |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200206665A ZA200206665B (en) | 2000-02-25 | 2002-08-20 | Novel Compounds. |
Country Status (2)
| Country | Link |
|---|---|
| SE (1) | SE0000620D0 (en) |
| ZA (3) | ZA200206402B (en) |
-
2000
- 2000-02-25 SE SE0000620A patent/SE0000620D0/en unknown
-
2002
- 2002-08-12 ZA ZA200206402A patent/ZA200206402B/en unknown
- 2002-08-12 ZA ZA200206404A patent/ZA200206404B/en unknown
- 2002-08-20 ZA ZA200206665A patent/ZA200206665B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200206402B (en) | 2003-11-12 |
| ZA200206665B (en) | 2003-11-20 |
| SE0000620D0 (en) | 2000-02-25 |
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