ZA200102185B - Benzamide derivatives and their use as cytokine inhibitors. - Google Patents
Benzamide derivatives and their use as cytokine inhibitors. Download PDFInfo
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- ZA200102185B ZA200102185B ZA200102185A ZA200102185A ZA200102185B ZA 200102185 B ZA200102185 B ZA 200102185B ZA 200102185 A ZA200102185 A ZA 200102185A ZA 200102185 A ZA200102185 A ZA 200102185A ZA 200102185 B ZA200102185 B ZA 200102185B
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- South Africa
- Prior art keywords
- alkyl
- alkylamino
- alkoxy
- amino
- alkanoylamino
- Prior art date
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- 108090000695 Cytokines Proteins 0.000 title claims description 20
- 102000004127 Cytokines Human genes 0.000 title claims description 20
- 239000003112 inhibitor Substances 0.000 title description 6
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- 125000003282 alkyl amino group Chemical group 0.000 claims description 183
- -1 cyano, mercapto, nitro, amino, carboxy, carbamoyl Chemical group 0.000 claims description 135
- 125000003545 alkoxy group Chemical group 0.000 claims description 107
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 82
- 125000001424 substituent group Chemical group 0.000 claims description 38
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 28
- 150000001408 amides Chemical class 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims description 17
- 125000001072 heteroaryl group Chemical group 0.000 claims description 16
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 14
- 238000004519 manufacturing process Methods 0.000 claims description 12
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- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 8
- 125000005224 heteroarylcarbonylamino group Chemical group 0.000 claims description 8
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 8
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
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- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 4
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- 239000000203 mixture Substances 0.000 claims 7
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- 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 claims 4
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 4
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims 4
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Description
BENZAMIDE DERIVATIVES AND THEIR USE AS CYTOKINE INHIBITORS
This invention concerns certain amide derivatives which are useful as inhibitors of cytokine mediated disease. The invention also concerns processes for the manufacture of the ] 5 amide derivatives of the invention, pharmaceutical compositions containing them and their use in therapeutic methods, for example by virtue of inhibition of cytokine mediated disease.
The amide derivatives disclosed in the present invention are inhibitors of the production of cytokines such as Tumour Necrosis Factor (hereinafter TNF), for example
TNFa. and various members of the interleukin (hereinafter IL) family, for example IL-1, IL-6 and IL-8. Accordingly the compounds of the invention will be useful in the treatment of diseases or medical conditions in which excessive production of cytokines occurs, for example excessive production of TNFa or IL-1. It is known that cytokines are produced by a wide variety of cells such as monocytes and macrophages and that they give rise to a variety of physiological effects which are believed to be important in disease or medical conditions such as inflammation and immunoregulation. For example, TNFa and IL-1 have been implicated in the cell signalling cascade which is believed to contribute to the pathology of disease states such as inflammatory and allergic diseases and cytokine-induced toxicity. It is also known that, in certain cellular systems, TNFa production precedes and mediates the production of other. cytokines such as IL-1.
Abnormal levels of cytokines have also been implicated in. for example, the production of physiologically-active eicosanoids such as the prostaglandins and leukotrienes, the stimulation of the release of proteolytic enzymes such as collagenase, the activation of the immune system, for example by stimulation of T-helper cells, the activation of osteoclast activity leading to the resorption of calcium, the stimulation of the release of proteoglycans from, for example, cartilage, the stimulation of cell proliferation and to angiogenesis. a Cytokines are also believed to be implicated in the production and development of disease states such as inflammatory and allergic diseases, for example inflammation of the
E joints (especially rheumatoid arthritis, osteoarthritis and gout), inflammation of the gastrointestinal tract (especially inflammatory bowel disease, ulcerative colitis, Crohn’s disease and gastritis), skin disease (especially psoriasis. eczema and dermatitis) and - respiratory disease (especially asthma. bronchitis. allergic rhinitis and adult respiratory distress syndrome), and in the production and development of various cardiovascular and cerebrovascular disorders such as congestive heart disease, myocardial infarction, the formation of atherosclerotic plaques, hypertension, platelet aggregation, angina, stroke, reperfusion injury, vascular injury including restenosis and peripheral vascular disease, and, for example, various disorders of bone metabolism such as osteoporosis (including senile and postmenopausal osteoporosis), Paget's disease, bone metastases, hypercalcaemia, hyperparathyroidism, osteosclerosis, osteoperosis and periodontitis, and the abnormal changes in bone metabolism which may accompany rheumatoid arthritis and osteoarthritis. Excessive cytokine production has also been implicated in mediating certain complications of bacterial, fungal and/or viral infections such as endotoxic shock, septic shock and toxic shock syndrome and in mediating certain complications of CNS surgery or injury such as neurotrauma and ischaemic stroke. Excessive cytokine production has also been implicated in mediating or exacerbating the development of diseases involving cartilage or muscle resorption, pulmonary fibrosis, cirrhosis, renal fibrosis, the cachexia found in certain chronic diseases such as malignant disease and acquired immune deficiency syndrome (AIDS), tumour invasiveness and tumour metastasis and multiple sclerosis.
Evidence of the central role played by TNFa in the cell signalling cascade which gives rise to rheumatoid arthritis is provided by the efficacy in clinical studies of antibodies of
TNFa (The Lancet, 1994, 344, 1125 and British Journal of Rheumatology, 1995, 34, 334).
Thus cytokines such as TNFa and IL-1 are believed to be important mediators of a considerable range of diseases and medical conditions. Accordingly it is expected that inhibition of the production of and/or effects of these cytokines will be of benefit in the prophylaxis, control or treatment of such diseases and medical conditions.
Without wishing to imply that the compounds disclosed in the present invention possess pharmacological activity only by virtue of an effect on a single biological process, it \ is believed that the compounds inhibit the effects of cytokines by virtue of inhibition of the enzyme p38 kinase. p38 kinase, otherwise known as cytokine suppressive binding protein . (hereinafter CSBP) and reactivating kinase (hereinafter RK), is a member of the mitogen- activated protein (hereinafter MAP) kinase family of enzymes which is known to be activated by physiological stress such as that induced by ionising radiation, cytotoxic agents, and toxins, for example endotoxins such as bacterial lipopolysaccharide, and by a variety of agents
: such as the cytokines, for example TNFa and IL-1. It is known that p38 kinase phosphorylates certain intracellular proteins which are involved in the cascade of enzymatic steps which leads to the biosynthesis and excretion of cytokines such as TNFa and IL-1.
Known inhibitors of p38 kinase have been reviewed by G J Hanson in Expert Opinions on
Therapeutic Patents, 1997, 7, 729-733. p38 kinase is known to exist in isoforms identified as p38a and p38f.
The compounds disclosed in the present invention are inhibitors of the production of cytokines such as TNF, in particular of TNFa, and various interleukins, in particular IL-1.
According to one aspect of the present invention there is provided a compound of the
Formula (Rp 5 F (R?), pat ‘ : Re H &F 0 ) N= 2
H (CH,),—Q I wherein R’ is (1-6C)alkyl or halogeno; “mis0,1,2o0r3;
R'is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsuiphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]Jamino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl,
N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (1-6C)alkanoylamino,
N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonyiamino, . N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino- . (1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl- (1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy,
(1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl- (1-6C)alkoxy, N.N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, halogeno- (2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1 -6C)alkoxy-(2-6C)alkylamino, cyano-(1-6C)alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbony!- - (1-6C)alkylamino, carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino,
N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]Jamino-(2-6C)alkylamino,
N-(1-6C)alkyl-halogeno-(1-6C)alkylamino, N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,
N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino, N-(1-6C)alkyl-cyano-(1-6C)alkylamino,
N-(1-6C)alkyl-carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-(1 -6C)alkoxycarbonyl- (1-6C)alkylamino, N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino, N-(1 -6C)alkyl-
N-(1-6C)alkylcarbamoyi-(1-6C)alkylamino, N-(1-6C)alkyl-N,N-di-[(1 -6C)alkyl]carbamoy!l- (1-6C)alkylamino, N-(1 -6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino- (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (1-6C)alkoxy- (2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino, carbamoyl-(2-6C)alkanoylamino,
N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino, N,N-di-[(1 -6C)alkyljcarbamoyl- (2-6C)alkanoylamino, amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino or di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, or R' is aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy, arylamino,
N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino, aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino, . N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1 -6C)alkylamino, N-(1-6C)alkyl-heteroaryl- (1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino,
N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyl- (1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1 -6C)alkoxy, heterocyclylamino, N-(1-6C)alkyl- heterocyclylamino, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino,
N-heterocyclylsulphamoy! or heterocyclyl-(2-6C)alkanoylamino, and wherein any aryl, heteroaryl or heterocyclyl group in a R' substituent may optionally bear 1 or 2 substituents selected from hydroxy. halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]jcarbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkylJamino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, ~ (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alky!, (1-6C)alkylamino- (1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl; pis0,1or2;
R? is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, (1-6C)alkoxycarbonyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino or di-[(1-6C)alkyl}amino;
R* is amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, amino-(1-6C)alkyl, (1-6C)alkylamino- (1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy, (1-6C)alkylamino- 4 (2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, amino-(2-6C)alkylamino, . 15 (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]Jamino-(2-6C)alkylamino,
N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, . N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino or di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, or R* is heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino,
N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroaryl-(1-6C)alkylamino-(1-6C)alkyl,
N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl, heterocyclyl- (1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy, heterocyclylamino, N-(1-6C)alkyl- heterocyclylamino, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, : N-heterocyclylsulphamoyl, heterocyclyl-(2-6C)alkanoylamino, heterocyclyl-(1-6C)alkoxy- (1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl or N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino-(1-6C)alkyl, and wherein any of the R* substituents defined hereinbefore which comprises a CH, group which is attached to 2 carbon atoms or a CH, group which is attached to a carbon atom may optionally bear on each said CH, or CH, group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl, and wherein any aryl, heteroaryl or heterocyclyl group in a R* substituent may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyi, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl; qis0, 1,2, 3 or 4; and
Q’ is heteroaryl, heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino,
N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl- (1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino,
N-heteroarylsulphamoy! or heteroaryl-(2-6C)alkanoylamino and Q” is optionally substituted with 1, 2 or 3 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkyny], (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl,
N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,
N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino, N-(1-6C)alkyl- (1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy- (1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl, carbamoy!-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,
N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl- (1-6C)alkoxy, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl}amino-(2-6C)alkoxy, halogeno- (2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)alkoxy-(2-6C)alkylamino, cyano-
(1-6C)alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino, carbamoyl-(1-6C)alkylamino, N~(1-6C)alkylcarbamoyl-(1-6C)alkylamino,
N,N-di-[(1-6C)alkyl]carbamoyl-~(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino. di-[(1-6C)alkylJamino-(2-6C)alkylamino,
N-(1-6C)alkyl-halogeno-(1-6C)alkylamino, N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino, ~
N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino, N-(1-6C)alkyl-cyano-(1-6C)alkylamino,
N-(1-6C)alkyl-carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonyl- (1-6C)alkylamino, N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino, N-(1-6C)alky!-
N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoy!- (1-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino- (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (1-6C)alkoxy- (2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino, iv (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino, carbamoyl-(2-6C)alkanoylamino, d 15 N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino, N,N-di-[(1-6C)alkyl]carbamoyI- (2-6C)alkanoylamino, amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino, di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, * aryloxy, arylamino, N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl- : * (1-6C)alkylamino, aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryl- (2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl. heteroaryloxy, heteroaryl- (1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino,
N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroaryl-(1-6C)alkylamino-(1-6C)alkyl,
N-(1-6C)alkyl-heteroaryi-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl, heterocyclyl- : (1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy, heterocyclylamino, N-(1 -6C)alkyl- heterocyclylamino, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino,
N-heterocyclylsulphamoyl, heterocyclyl-(2-6C)alkanoylamino, heterocyclyl-(1-6C)alkoxy- (1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl and N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino-(1-6C)alkyl,
Claims (20)
1. An amide derivative of the Formula I (Rm o R (R23), ~ R4 H Oo N= 2 S H (CH), —Q I wherein R’ is (1-6C)alkyl or halogeno; mis0,1,2o0r3; R'is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyi, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, (2-6C)alkanoyloxy, (1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl, N,N-di-[(1-6C)alkyl]sulphamoyl, (1-6C)alkanesulphonylamino, N-(1-6C)alkyl-(1-6C)alkanesulphonylamino, halogeno-(1-6C)alky!l, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino- (1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl- (1-6C)alkyl, carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyi-(1-6C)alky], N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkyl, halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy, (1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbamoyl-(1-6C)alkoxy, N-(1-6C)alkyicarbamoyl- (1-6C)alkoxy, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy,
. (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, halogeno- (2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1 -6C)alkoxy-(2-6C)alkylamino, - cyano-(1-6C)alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl- (1-6C)alkylamino, carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyljamino-(2-6C)alkylamino, N-(1-6C)alkyl-halogeno-(1-6C)alkylamino, N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,
N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino, N-(1-6C)alkyl-cyano-(1-6C)alkylamino,
+ N-(1-6C)alkyl-carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonyl- (1-6C)alkylamino, N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl- N-(1-6C)alkylcarbamoyl-(1-6C)alkvlamino, N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyl-
(1-6Cjalkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylaniino- (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (1-6C)alkoxy-
(2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino, carbamoy!-(2-6C)alkanoylamino,
N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino, N,N-di-[(1-6C)alkyl]carbamoyl- (2-6C)alkanoylamino, amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino or di-[(1-6C)alkyl]amino-(2-6C)alkanoylamino, or R' is aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino, aryl-(1-6C)alkylamino, N-(1-6C)alkyl-aryl-(1-6C)alkylamino,
aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryl-(2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl- (1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heterocyclyl, heterocyclyl-
(1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy. heterocyclylamino, N-(1-6C)alkyl- heterocyclylamino, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino, heterocyclylcarbonylamino, heterocyclyisulphonylamino, N-heterocyclylsulphamoyl or heterocyclyl-(2-6C)alkanoylamino, and wherein any aryl, heteroaryl or heterocyclyl group in a R' substituent may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl,
“ N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoy]l. (2-6C)alkanoy!, amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino- (1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl; pis0,1or2;
R’ is hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, - (1-6C)alkoxycarbonyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-6C)alkylamino or di-[(1-6C)alkyl]Jamino; R* is amino, (1-6C)alkylamino, di-[(1-6C)alkyl}amino, amino-(1-6C)alkyl, (1-6C)alkylamino- (1-6C)alkyl, di-[(1-6C)alkyllamino-(1-6C)alkyl, amino-(2-6C)alkoxy, (1-6C)alkylamino- ~ (2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino, amino-(2-6C)alkanoylamino,
(1-6C)alkylamino-(2-6C)alkanoyviamino or di-{(1-6C)alkyl]amino-(2-6C)alkanoylamino, or Ris heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino,
heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroaryl-(1-6C)alkylamino-(1-6C)alkyl, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl, heterocyclyl- (1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy, heterocyclylamino, N-(1-6C)alkyl- heterocyclylamino, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino,
N-heterocyclylsulphamoyl, heterocyclyl-(2-6C)alkanoylamino, heterocyclyl-(1-6C)alkoxy- (1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl or N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino-(1-6C)alkyl, and wherein any of the R* substituents defined hereinbefore which comprises a CH, group which is attached to 2 carbon atoms or a CH, group which is attached to a carbon atom may optionally bear on each said CH, or CH, group a substituent selected from hydroxy, amino,
\ (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl]amino and heterocyclyl, and wherein any aryl, heteroaryl! or heterocyclyl group in a R* substituent may optionally bear . 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkylJamino, halogeno-(1-6C)alkyl,
hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, + (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, aryl and aryl-(1-6C)alkyl; qis0,1,2,3 0r4; and Q’ is heteroaryl, heteroaryloxy, heteroaryl-(1-6C)alkoxy, heteroarylamino,
__ _..5 N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino, N-(1-6C)alkyl-heteroaryl- = (1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl or heteroaryl-(2-6C)alkanoylamino and Q’ is optionally substituted with 1, 2 or 3 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylthio, (1-6C)alkylsulphinyl, (1-6C)alkylsulphonyl, (1-6C)alkylamino, di-[(1-6C)alkylJamino, (1-6C)alkoxycarbonyl, : N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]carbamoyl, (2-6C)alkanoy]l, (2-6C)alkanoyloxy, (1-6C)alkanoylamino, N-(1-6C)alkylsulphamoyl,
- N,N-di-[(1-6C)alkyl]sulphamoy]l, (1-6C)alkanesulphonylamino, N-(1-6C)alkyl-
Eo “ 15 (1-6C)alkanesulphonylamino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy- (1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl,
SS di-[(1-6C)alkyl}amino-(1-6C)alkyl, carboxy-(1-6C)alkyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl,
Lk carbamoyl-(1-6C)alkyl, N-(1-6C)alkylcarbamoyl-(1-6C)alkyl,
- - N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alky!, halogeno-(2-6C)alkoxy, hydroxy-(2-6C)alkoxy,
(1-6C)alkoxy-(2-6C)alkoxy, cyano-(1-6C)alkoxy, carboxy-(1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkoxy, carbamoyl-(1-6C)alkoxy, N-(1-6C)alkylcarbamoyl- (1-6C)alkoxy, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkoxy, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, halogeno- (2-6C)alkylamino, hydroxy-(2-6C)alkylamino, (1-6C)alkoxy-(2-6C)alkylamino, cyano-
(1-6C)alkylamino, carboxy-(1-6C)alkylamino, (1-6C)alkoxycarbonyl-(1-6C)alkylamino,
\ carbamoyl-(1-6C)alkylamino, N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino, N,N-di-[(1-6C)alkyl]carbamoyl-(1-6C)alkylamino, amino-(2-6C)alkylamino, E (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, N-(1-6C)alkyl-halogeno-(1-6C)alkylamino, N-(1-6C)alkyl-hydroxy-(2-6C)alkylamino,
N-(1-6C)alkyl-(1-6C)alkoxy-(2-6C)alkylamino, N-(1-6C)alkyl-cyano-(1-6C)alkylamino,
N-(1-6C)alkyl-carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkoxycarbonyl-
(1-6C)alkylamino, N-(1-6C)alkyl-carbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl- N-(1-6C)alkylcarbamoyl-(1-6C)alkylamino, N-(1-6C)alkyl-N,N-di-[(1-6C)alkyl]carbamoyi- (1-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino- (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]amino-(2-6C)alkylamino,
halogeno-(2-6C)alkanoylamino, hydroxy-(2-6C)alkanoylamino, (1-6C)alkoxy- - (2-6C)alkanoylamino, cyano-(2-6C)alkanoylamino, carboxy-(2-6C)alkanoylamino, (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino, carbamoyl-(2-6C)alkanoylamino, N-(1-6C)alkylcarbamoyl-(2-6C)alkanoylamino, N,N-di-[(1-6C)alkyl]carbamoyl- (2-6C)alkanoylamino, amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino,
di-[(1-6C)alkyi]amino-(2-6C)alkanoylamino, aryl, aryl-(1-6C)alkyl, aryl-(1-6C)alkoxy, aryloxy, arylamino, N-(1-6C)alkyl-arylamino, ary!-(1-6C)alkylamino, N-(1-6C)alkyl-aryl- (1-6C)alkylamino, aroylamino, arylsulphonylamino, N-arylsulphamoyl, aryl- (2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryloxy, heteroaryl- (1-6C)alkoxy, heteroarylamino, N-(1-6C)alkyl-heteroarylamino, heteroaryl-(1-6C)alkylamino,
N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino, heteroarylcarbonylamino, heteroarylsulphonylamino, N-heteroarylsulphamoyl, heteroaryl-(2-6C)alkanoylamino, heteroaryl-(1-6C)alkoxy-(1-6C)alkyl, heteroary!l-(1-6C)alkylamino-(1-6C)alky!, N-(1-6C)alkyl-heteroaryl-(1-6C)alkylamino-(1-6C)alkyl, heterocyclyl, heterocyclyl- (1-6C)alkyl, heterocyclyloxy, heterocyclyl-(1-6C)alkoxy, heterocyclytamino, N-(1-6C)alkyl-
heterocyclylamino, heterocyclyl-(1-6C)alkylamino, N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino, heterocyclylcarbonylamino, heterocyclylsulphonylamino, N-heterocyclylsulphamoyl, heterocyclyl-(2-6C)alkanoylamino, heterocyclyl-(1-6C)alkoxy- (1-6C)alkyl, heterocyclyl-(1-6C)alkylamino-(1-6C)alkyl and N-(1-6C)alkyl-heterocyclyl- (1-6C)alkylamino-(1-6C)alkyl,
and wherein any of the substituents on Q* defined hereinbefore which comprises a CH, group . which is attached to 2 carbon atoms or a CH, group which is attached to a carbon atom may optionally bear on each said CH, or CH, group a substituent selected from hydroxy, amino, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alky!]amino and heterocyclyl, and wherein any aryl, heteroaryl or heterocyclyl group in a substituent on Q* may optionally bear 1 or 2 substituents selected from hydroxy, halogeno, (1-6C)alkyl, (1-6C)alkoxy, carboxy, (1-6C)alkoxycarbonyl, N-(1-6C)alkylcarbamoyl, N,N-di-[(1-6C)alkyl]Jcarbamoyl,
(2-6C)alkanoyl, amino, (1-6C)alkylamino, di-[(1-6C)alkyl}Jamino, halogeno-(1-6C)alkyl, hydroxy-(1-6C)alkyl, (1-6C)alkoxy-(1-6C)alkyl, cyano-(1-6C)alkyl, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkylJamino-(1-6C)alkyl, aryl and aryl-(1-6C)alky]; S or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof.
2. B An amide derivative of the Formula I according to claim 1 wherein Q’ is a heteroaromatic 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring with up to five ring heteroatoms selected from oxygen, nitrogen and sulphur which bears a basic substituent selected from amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, amino-(1-6C)alkyl, (1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy, (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyl]amino-(2-6C)alkoxy, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino-(2-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino-(2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]Jamino-(2-6C)alkylamino, amino-(2-6C)alkanoylamino, (1-6C)alkylamino-(2-6C)alkanoylamino, di-{(1-6C)alkyl]amino-(2-6C)alkanoylamino, heteroaryl, heteroaryl-(1-6C)alkyl, heteroaryl-(1-6C)alkoxy, heterocyclyl, heterocyclyl-(1-6C)alkyl and heterocyclyl-(1-6C)alkoxy, and wherein any heteroary! or heterocyclyl group in a basic substituent on Q* may optionally bear 1 or 2 substituents selected from halogeno, (1-6C)alkyl, (2-6C)alkanoyl, amino, (1-6C)alkylamino and di-[(1-6C)alkyl]amino.
3. An amide derivative of the Formula [ according to claim 1 wherein Q’ is a heteroaromatic S- or 6-membered monocyclic ring, a 9- or 10-membered bicyclic ring or a 13- or 14-membered tricyclic ring each with up to five ring heteroatoms : selected from oxygen, nitrogen and sulphur which optionally bears 1, 2 or 3 substituents selected from hydroxy, halogeno, trifluoromethyl, cyano, nitro, amino, carboxy, (1-6C)alkyl, . (1-6C)alkoxy, (1-3C)alkylenedioxy, (1-6C)alkylamino, di-[(1-6C)alkyi]amino and (1-6C)alkoxycarbonyl. 4, An amide derivative of the Formula I according to claim 1 wherein R* is amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, amino-(1-6C)alkyl,
(1-6C)alkylamino-(1-6C)alkyl, di-[(1-6C)alkyl]amino-(1-6C)alkyl, amino-(2-6C)alkoxy, ~ (1-6C)alkylamino-(2-6C)alkoxy, di-[(1-6C)alkyljamino-(2-6C)alkoxy, amino- (2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino, di-[(1-6C)alkyl]amino- (2-6C)alkylamino, N-(1-6C)alkyl-amino-(2-6C)alkylamino, N-(1-6C)alkyl-(1-6C)alkylamino- (2-6C)alkylamino, N-(1-6C)alkyl-di-[(1-6C)alkyl]Jamino-(2-6C)alkylamino, pyridyl, - imidazolyl, pyridyl-(1-6C)alkyl, imidazolyl-(1-6C)alkyl, pyridyl-(1-6C)alkoxy, imidazolyl- (1-6C)alkoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-(1-6C)alkylpiperazinyl, homopiperazinyl, 4-(1-6C)alkylthomopiperazinyl, 4-(2-6C)alkanoylpiperazinyl, pyrrolidinyl- (1-6C)alkyl, piperidinyl-(1-6C)alkyl, morpholinyl-(1-6C)alkyl, piperazinyl-(1-6C)alkyl, 4-(1-6C)alkylpiperazinyl-(1-6C)alkyl, homopiperazinyl-(1-6C)alkyl, 4-(1-6C)alkylhomopiperazinyl-(1-6C)aikyl, 4-(2-6C)alkanoylpiperazinyl-(1-6C)alkyl, pyrrolidinyloxy, piperidinyloxy, 1-(1-6C)alkylpiperidinyloxy, pyrrolidinyl-(2-6C)alkoxy, piperidinyl-(2-6C)alkoxy, morpholinyl-(2-6C)alkoxy, piperazinyl-(2-6C)alkoxy, 4-(1-6C)alkylpiperazinyl-(2-6C)alkoxy or 4-(2-6C)alkanoylpiperazinyl-(2-6C)alkoxy.
5. An amide derivative of the Formula I according to claim 1 wherein R’ is methyl, ethyl, chloro or bromo; misQorl; R' is hydroxy, fluoro, chloro, bromo, trifluoromethyl, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylamino, ethylamino, dimethylamino or diethylamino; pis 0; R* is amino, methylamino, ethylamino, dimethylamino, diethylamino, methylaminomethyl, cthylaminomethyl, dimethylaminomethyl, diethylaminomethy!, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, B 3-dimethylaminopropoxy, 3-diethylaminopropoxy, pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, 4-acetylpiperazinylmethyl, piperidinyloxy, 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy, 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy,
3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy or 3-(4-acetylpiperazinyl)propoxy; q is 0; and _ 5 Q’is furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, ~ pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothiophenyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl which optionally bears I or 2 substituents selected from hydroxy, fluoro, chloro, trifluoromethyl, cyano, amino, methyl, 10 ethyl, methoxy, ethoxy, methylenedioxy, methylamino, ethylamino, dimethylamino, diethylamino, aminomethyl, methylaminomethyl, ethylaminomethyl, dimethylaminomethyl, diethylaminomethyl, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methoxyethoxy, 2-ethoxyethoxy, 3-methoxypropoxy, 3-ethoxypropoxy, 2-aminoethoxy, 3-aminopropoxy, 2-methylaminoethoxy, 2-ethylaminoethoxy, 3-methylaminopropoxy, 3-ethylaminopropoxy, 15 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, pyridyl, pyridylmethyl, pyridylmethoxy, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, 4-methylpiperazinyl, 4-acetylpiperazinyl, pyrrolidinylmethyl, piperidinylmethyl, morpholinylmethyl, piperazinylmethyl, 4-methylpiperazinylmethyl, . 4-acetylpiperazinylmethyl, piperidinyloxy, 1-methylpiperidinyloxy, 2-(pyrrolidinyl)ethoxy, 20 3-(pyrrolidinyl)propoxy, 2-(piperidinyl)ethoxy, 3-(piperidinyl)propoxy, 2-(morpholinyl)ethoxy, 3-(morpholinyl)propoxy, 2-(piperazinyl)ethoxy, 3-(piperazinyl)propoxy, 2-(4-methylpiperazinyl)ethoxy, 3-(4-methylpiperazinyl)propoxy, 2-(4-acetylpiperazinyl)ethoxy and 3-(4-acetylpiperazinyl)propoxy; or a pharmaceutically-acceptable salt thereof. 25
6. An amide derivative of the Formula I according to claim 1 wherein R’ is methyl; - mis 0 orm is 1 and R' is hydroxy, fluoro, chloro, amino, methyl, methoxy, methylamino or dimethylamino; eachofpandqisO;
R* is located at the 3- or 4-position and is selected from dimethylaminomethyl,
- diethylaminomethyl, 2-dimethylaminoethoxy, 2-diethylaminoethoxy, 3-dimethylaminopropoxy, 3-diethylaminopropoxy, 3-dimethylamino-2-hydroxypropoxy, 3-diethylamino-2-hydroxypropoxy, 2-aminoethylamino, 3-aminopropylamino,
4-aminobutylamino, 3-methylaminopropylamino, 2-dimethylaminoethylamino, = 2-diethylaminoethylamino, 3-dimethylaminopropylamino, 4-dimethylaminobutylamino, 3-amino-2-hydroxypropylamino, 3-dimethylamino-2-hydroxypropylamino, N-(2-dimethylaminoethyl)-N-methylamino, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl,
4-ethylpiperazin-1-yl, 4-(2-hydroxyethyl)piperazin-1-yl, 4-methylhomopiperazin-1-yl, piperazin-1-yimethyl, 4-methylpiperazin-1-ylmethyl, 4-methylhomopiperazin-1-yimethyl, morpholinomethyl, 3-aminopyrrolidin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, 4-(2-hydroxyethyl)piperazin-1-ylmethyl, piperidin-4-yloxy, I-methylpiperidin-4-yloxy, 1-benzylpiperidin-4-yloxy, 2-pyrrolidin-1-ylethoxy, 3-pyrrolidin-1-ylpropoxy,
2-piperidinoethoxy, 3-piperidinopropoxy, 2-morpholinoethoxy, 3-morpholinopropoxy, 2-piperazin-1-ylethoxy, 3-piperazin-1-ylpropoxy, 2-(4-methylpiperazin-1-yl)ethoxy, 3-(4-methylpiperazin-1-yl)propoxy, 2-hydroxy-3-pyrrolidin-1-ylpropoxy, 2-hydroxy- 3-piperidinopropoxy, 2-hydroxy-3-morpholinopropoxy, piperidin-4-ylamino, 1-methylpiperidin-4-ylamino, 1-benzylpiperidin-4-ylamino, 2-pyrrolidin-1-ylethylamino,
3-pyrrolidin-1ylpropylamino, 2-morpholinoethylamino, 3-morpholinopropylamino, 2-piperidinoethylamino, 3-piperidinopropylamino, 2-piperazin-1-ylethylamino, 3-piperazin-1-ylpropylamino, 2-(4-methylpiperazin-1-yl)ethylamino, 3-(4-methylpiperazin-1-yl)propylamino, 2-(1-methylpyrrolidin-2-yl)ethylamino, 3-(1-methylpyrrolidin-2-yl)propylamino, 2-dimethylaminoethylaminomethyl,
3-dimethylaminopropylaminomethyl, 3-dimethylamino-2,2-dimethylpropylaminomethyl,
RB 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 3-pyrrolidin-1-ylpropylaminomethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 2-piperazin- 1-ylethylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl and 2-pyridylmethoxy; and Q? is 2-pyridyl, 3-pyridyl or 4-pyridyl which bears a substituent selected from pyrrolidin-1-yl, 3-hydroxypyrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, morpholino,
piperidino, 4-hydroxypiperidin-1-yl and piperazin-1-yl;
or a pharmaceutically-acceptable salt thereof.
7. An amide derivative of the Formula I according to claim 1 wherein R’ is methyl; 5S misOormis1andR!'is nitro or amino; . oT } eachof pand q is 0; R* is located at the 3- or 4-position and is selected from diethylaminomethyl, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, homopiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, 3-aminopyrrolidin- 1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, 4-(2-hydroxyethyl)piperazin-1-ylmethyl, pyrrolidin-3-yloxy, N-methylpyrrolidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin- 4-yloxy, N-ethylpiperidin-4-yloxy, N-isopropylpiperidin-4-yloxy, homopiperidin-4-yloxy, : 15 N-methylhomopiperidin-4-yloxy, 3-pyrrolidin-1-ylpropylaminomethyl, 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethyl, pyrid-2-ylmethoxy, thiazol-4-ylmethoxy and 2-methylthiazol-4-ylmethoxy; and Q? is 2-pyridyl, 3-pyridyl or 4-pyridyl which bears a substituent selected from pyrrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, morpholino and piperidino, and wherein any of the 4 last- named substituents may optionally bear 1 or 2 methyl groups, or Q? is 2- or 4-dibenzofuranyl; or a pharmaceutically-acceptable salt thereof.
8. An amide derivative of the Formula I according to claim 1 wherein R? is methyl; R mis Oormis 1 and R'is nitro or amino; each of pand q is 0; R‘ is located at the 3- or 4-position and is selected from diethylaminomethyl, N-(3-dimethylaminopropyl)-N-methylamino, pyrrolidin-1-yl, morpholino, piperidino, piperazin-1-yl, 4-methylpiperazin-1-yl, 4-methylhomopiperazin-1-yl, pyrrolidin-1-ylmethyl, piperidinomethyl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl,
homopiperazin-1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, 3-aminopyrrolidin- 1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, 4-(2-hydroxyethyl)piperazin-1-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, 3-pyrrolidin-1-ylpropylaminomethyl, 2-(1-methylpyrrolidin-2-ylethyl)aminomethyl, 2-morpholinoethylaminomethyl, 3-morpholinopropylaminomethyl, 3-(4-methylpiperazin-1-ylpropyl)aminomethy! or = pyrid-2-ylmethoxy; and Q? is 2-pyridyl, 3-pyridyl or 4-pyridyl which bears a substituent selected from pyrrolidin-1-yl, 2-hydroxymethylpyrrolidin-1-yl, morpholino and piperidino; or a pharmaceutically-acceptable salt thereof.
9. An amide derivative of the Formula I according to claim 1 wherein R’ is methyl; each of m, p and q is 0; R* is located at the 3- or 4-position and is selected from diethylaminomethyl, 4-methylpiperazin-1-yl, morpholinomethyl, piperazin-1-ylmethyl, 4-methylpiperazin- 1-ylmethyl, 4-methylhomopiperazin-1-ylmethyl, 3-hydroxypyrrolidin-1-ylmethyl, pyrrolidin-3-yloxy, piperidin-4-yloxy, N-methylpiperidin-4-yloxy, N-isopropylpiperidin- 4-yloxy, N-methylhomopiperidin-4-yloxy, 2-(N-methylpyrrolidin-2-yl)ethoxy, 3-dimethylamino-2,2-dimethylpropylaminomethyl N-(3-dimethylaminopropyl)- N-methylaminomethyl, 3-morpholinopropylaminomethyl and 2-methylthiazol-4-ylmethoxy; and Q’ is 4-pyridyl which bears a substituent selected from morpholino, piperidino, 3-methylpiperidin-1-yl and homopiperidin-1-yl, or Q? is 4-dibenzofuranyl; or a pharmaceutically-acceptable salt thereof.
10. An amide derivative of the Formula I according to claim 1 selected from :- K N-{4-methyl-3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]phenyl} furan-2-carboxamide, N-{4-methyl-3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]phenyl}isoxazole- 5-carboxamide, N-[3-(4-diethylaminomethylbenzamido)-4-methylphenyl]-2-morpholinopyridine- 4-carboxamide,
N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}- 2-pyrrolidin-1-ylpyridine-4-carboxamide, N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl} -2-morpholinopyridine- 4-carboxamide,
__ ... .. _ 5 N-{3-[3-(4-methylhomopiperazin-1-ylmethyl)benzamido]-4-methylphenyl}- ~~ 2-morpholinopyridine-4-carboxamide, N-{3-{4-(4-methylhomopiperazin-1-ylmethyl)benzamido]-4-methylphenyl}- 2-morpholinopyridine-4-carboxamide, N-[3-(3-piperazin-1-ylmethylbenzamido)-4-methylphenyl]-2-morpholinopyridine- 4-carboxamide, N-{3-[4-(3-hydroxypyrrolidin-1-ylmethyl)benzamido]-4-methylphenyl}- 2-morpholinopyridine-4-carboxamide, N-{3-[3-(3-pyrrolidin-1-ylpropylaminomethyl)benzamido]-4-methylphenyl}- 2-morpholinopyridine-4-carboxamide,
. 15 N-{3-[4-(3-morpholinopropylaminomethyl)benzamido]-4-methylphenyl}- 2-morpholinopyridine-4-carboxamide, N-[3-(3-diethylaminomethylbenzamido)-4-methylphenyl]-2-morpholinopyridine- 4-carboxamide, N-[3-(4-diethylaminomethylbenzamido)-4-methylphenyl]-5-morpholinopyridine- 3-carboxamide, N-[3-(4-diethylaminomethylbenzamido)-4-methylphenyl}-2-piperidinopyridine- 4-carboxamide, N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}-2-(3-methylpiperidin- 1-yl)pyridine-4-carboxamide, N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido}-4-methylphenyl}-2-homopiperidin- 1-ylpyridine-4-carboxamide, N-[4-methyl-3-(4-morpholinomethylbenzamido)phenyl]-2-morpholinopyridine- - 4-carboxamide, N-{3-[3-(3-dimethylamino-2,2-dimethylpropylaminomethyl)benzamido}-4-methylphenyl}- 2-morpholinopyridine-4-carboxamide,
N-{3-[4-(3-dimethylamino-2,2-dimethylpropylaminomethyl)benzamido]-4-methylpheny!}- 2-morpholinopyridine-4-carboxamide, N-(3-{4-[N-(3-dimethylaminopropyl)-N-methylaminomethyl]benzamido } -4-methylphenyl)- 2-morpholinopyridine-4-carboxamide, N-[4-methyl-3-(3-piperidin-4-yloxybenzamido)phenyl]-2-morpholinopyridine- = 4-carboxamide, N-[4-methyl-3-(3-pyrrolidin-3-yloxybenzamido)phenyl]-2-morpholinopyridine- 4-carboxamide, N-{3-[3-(N-methylhomopiperidin-4-yloxy)benzamido]-4-methylphenyl}- 2-morpholinopyridine-4-carboxamide, N-(3-{3-[2-(N-methylpyrrolidin-2-yl)ethoxy]benzamido} -4-methylphenyl)- 2-morpholinopyridine-4-carboxamide, N-{4-methy!-3-[4-(2-methylthiazol-4-ylmethoxy)benzamido]phenyl}-2-morpholinopyridine- 4-carboxamide and N-{3-[3-(4-methylpiperazin-1-ylmethyl)benzamido]-4-methylphenyl}dibenzofuran- 4-carboxamide; or a pharmaceutically-acceptable salt thereof.
11. A process for the preparation of an amide derivative of the Formula [, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, according to claim which comprises :- (a) reacting an aniline of the Formula II (RY, o R3 CE
NH. II 2 : with an acid of the Formula III, or a reactive derivative thereof, ’s HO,C — (CHy)q — Q2 II under standard amide bond forming conditions, wherein variable groups are as defined in claim 1 and wherein any functional group is protected if necessary, and:
i) removing any protecting groups; and (1) optionally forming a pharmaceutically-acceptable salt or in-vivo-cleavable ester; (b) reacting an acid of the Formula V, or an activated derivative thereof, — RY, o | - s Re EK, \4 with an aniline of the Formula VII R3 Kr (R?), ’ HN H N 0 MCHy,— a2 vi : under standard amide bond forming conditions, wherein variable groups are as defined in claim 1 and wherein any functional group is protected, if necessary, and:
6) removing any protecting groups; and
(ii) optionally forming a pharmaceutically-acceptable salt or in-vivo-cleavable : ester;
" (c) for the preparation of a compound of the Formula I wherein R', R or a substituent on Q? is (1-6C)alkoxy or substituted (1-6C)alkoxy, (1-6C)alkylthio, (1-6C)alkylamino,
di-[(1-6C)alkyl}amino or substituted (1-6C)alkylamino, the alkylation, conveniently in the presence of a suitable base, of an amide derivative of the Formula I wherein R!, R* or a substituent on Q? is hydroxy, mercapto or amino as appropriate;
(d) for the preparation of a compound of the Formula I wherein a substituent on Qis amino, (1-6C)alkylamino, di-[(1-6C)alkyl]amino, substituted (1-6C)alkylamino, substituted
N-(1-6C)alkyl-(2-6C)alkylamino or a N-linked heterocyclyl group, the reaction, conveniently
: in the presence of a suitable base, of an amide derivative of the Formula I wherein a substituent on Q” is a suitable leaving group with an appropriate amine; (¢) for the preparation of a compound of the Formula I wherein R', R* or a substituent on Q’ is (1-6C)alkanoylamino or substituted (2-6C)alkanoylamino, the acylation of a compound
PCT/GB99/03144 of the Formula I wherein R', R* or a substituent on Q? is amino; ® for the preparation of a compound of the Formula I wherein R' or a substituent on Q? is (1-6C)alkanesulphonylamino, the reaction of a compound of the Formula I wherein R! or a substituent on Q? is amino with a (1-6C)alkanesulphonic acid, or an activated derivative thereof: or (2) for the preparation of a compound of the Formula [ wherein R' or a substituent on Q? is carboxy, carboxy-(1-6C)alkyl, carboxy-(1-6C)alkoxy, carboxy-(1-6C)alkylamino, N-(1-6C)alkyl-carboxy-(1-6C)alkylamino or carboxy-(2-6C)alkanoylamino, the cleavage of a compound of the Formula I wherein R' or a substituent on Q? is (1-6C)alkoxycarbonyl, (1-6C)alkoxycarbonyl-(1-6C)alkyl, (1 -6C)alkoxycarbonyl~( 1-6C)alkoxy, (1-6C)alkoxycarbonyl-(1-6C)alkylamino, N~(1-6C)alkyl-(1-6C)alkoxycarbonyl- (1-6C)alkylamino or (1-6C)alkoxycarbonyl-(2-6C)alkanoylamino as appropriate.
12. A pharmaceutical composition which comprises an amide derivative of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, according to claim 1 in association with a pharmaceutically-acceptable diluent or carrier.
13. The use of an amide derivative of the Formula I, or a pharmaceutically-acceptable salt or in-vivo-cleavable ester thereof, according to claim 1 in the manufacture of a medicament for use in the treatment of medical conditions mediated by cytokines.
14. A substance or composition for use in method of treatment of medical conditions mediated by cytokines, said substance or composition comprising a compound as claimed in claim 1, and said method comprising administering said substance or composition.
15. A compound according to claim 1, substantially as herein described and illustrated.
16. A process according to claim 11, substantially as herein described and illustrated. AMENDED SHEET 2002 -01- 18
- 133 - PCT/GB99/03144
17. A composition according to claim 12, substantially as herein described and illustrated.
18. Use according to claim 13, substantially as herein described and illustrated.
19. A substance or composition for use in a method of treatment according to claim 14, substantially as herein described and illustrated.
20. A new compound, a new composition, new use of a compound as claimed in claim 1, or a substance or composition for a new use in a method of treatment, substantially as herein described. AMENDED SHEET 2002 -mM- 18
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9820770.7A GB9820770D0 (en) | 1998-09-25 | 1998-09-25 | Amide derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200102185B true ZA200102185B (en) | 2002-06-18 |
Family
ID=10839368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200102185A ZA200102185B (en) | 1998-09-25 | 2001-03-15 | Benzamide derivatives and their use as cytokine inhibitors. |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB9820770D0 (en) |
| ZA (1) | ZA200102185B (en) |
-
1998
- 1998-09-25 GB GBGB9820770.7A patent/GB9820770D0/en not_active Ceased
-
2001
- 2001-03-15 ZA ZA200102185A patent/ZA200102185B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| GB9820770D0 (en) | 1998-11-18 |
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