CN1356902A - IL-8 receptor antagonists - Google Patents

IL-8 receptor antagonists Download PDF

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CN1356902A
CN1356902A CN00809095A CN00809095A CN1356902A CN 1356902 A CN1356902 A CN 1356902A CN 00809095 A CN00809095 A CN 00809095A CN 00809095 A CN00809095 A CN 00809095A CN 1356902 A CN1356902 A CN 1356902A
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alkyl
heteroaryl
aryl
alkenyl
heterocyclic radical
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K·L·威多森
G·M·本森
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SmithKline Beecham Corp
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Abstract

This invention relates to novel phenyl ureas useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

Description

The IL-8 receptor antagonist
Invention field
The present invention relates to one group of new phenylurea chemical compound, their preparation method, their application in the disease of treatment IL-8, GRO α, GRO β, GRO γ, NAP-2 and ENA-78 mediation, and the pharmaceutical composition that is used for this class treatment.
Background of invention
Interleukin 8 (IL-8) has a lot of different titles, for example chemotactic factor for neutrophil (MDNCF) of neutrophil attractant/activated protein-1 (NAP-1), monocyte derived, NAF (NAF) and T cell lymphocyte chemotactic factors.Interleukin 8 is a chemical inhibitor for neutrophil, basophilic granulocyte and a kind of T cell subsets.It is to contact generation by most of nucleated cell (comprising macrophage, fibroblast, endotheliocyte and epithelial cell) with TNF, IL-1 α L-1 β or LPS, is perhaps produced when contacting with LPS or chemotactic factor (as FMLP) by neutrophil itself.M.Baggiolini etc., Journal of Clinical Investigation (J.Clin.Invest.), 84,1045 (1989); J.Schroder etc., Journal of Immunology (J.Immunol.), 139,3474 (1987) and 144,2223 (1990); Strieter etc., science (Science) 243,1467 (1989) and journal of biological chemistry (J.Biol.Chem.), 264,10621 (1989); Cassatella etc., Journal of Immunology (J.Immunol.) 148,3216 (1992).
GRO α, GRO β, GRO γ and NAP-2 also belong to chemokine alpha family.As IL-8, these chemotactic factors also have different titles.For example, GRO α, β, γ are known as MGSA α, β and γ (melanoma growth-stimulating activity) respectively, see Richmond etc., cytophysiology magazine (J.Cell.Physiology) 129,375 (1986) and Chang etc., Journal of Immunology (J.Immunol.) 148,451 (1992).All chemotactic factors with the ELR motif that was right after before the CXC motif all combine with the IL-8 beta receptor in the α family.
IL-8, GRO α, GRO β, GRO γ, NAP-2 and ENA-78 excite many functions external.They demonstrate entirely has chemical inhibitor character to neutrophil, and IL-8 and GRO α are proved and have T-lymphocyte and basophilic granulocyte chemotactic activity.In addition, IL-8 can bring out histamine and discharge in the basophilic granulocyte of normal and atopic individuals, and the lysosomal enzyme that GRO α and IL-8 also bring out in the neutrophil discharges and the respiratory burst effect.IL-8 also demonstrates can increase the surface expression of Mac-1 (CDllb/CD18) on neutrophil under the situation that does not have the protein de novo synthesis.This has and helps strengthen the adhesion of neutrophil to vascular endothelial cell.A lot of known diseases are that infiltration with a large amount of neutrophils is a feature.Because IL-8, GRO α, GRO β, GRO γ and NAP-2 promote the accumulation and the activation of neutrophil, it is relevant with a variety of acute and chronic inflammations that these chemotactic factors have shown, comprise psoriasis and rheumatoid arthritis, Baggiolini etc., Europe biochemistry community's wall bulletin (FEBS Lett.) 307,97 (1992); Miller etc., immunology comment (Crit.Rev.Immunol.) 12,17 (1992); Oppenheim etc., (Annu.Rev.Immunol.) 9,617 (1991) commented in immunity academic year; Seitz etc., Journal of Clinical Investigation (J.Clin.Invest.) 87,463 (1991); Miller etc., U.S. respiratory tract disease comment (Am.Rev.Respir.Dis.) 146,427 (1992); Donnely etc., lancet (Lancet) 341,643 (1993).In addition, ELR chemotactic factor (chemotactic factor that contains the aminoacid ELR motif that was right after before the CXC motif) is also relevant with vascularization (angiostasis).Strieter etc., science (Science) 258,1798 (1992).
In in vitro tests, IL-8, GRO α, GRO β, GRO γ and NAP-2 are by the receptor (g protein coupled receptor family) of combination with the activation seven-transmembrane, particularly by with the combining of IL-8 receptor, especially beta-receptor, bring out neutrophil alteration of form, chemotaxis, granule and discharge and the respiratory burst effect.Thomas etc., journal of biological chemistry (J.Biol.Chem), 266,14839 (1991); With Holmes etc., science (Science) 253,1278 (1991).The development of this receptor family member's non-peptide micromolecule antagonist has precedent.About summary, roll up 33-98 page or leaf, Birkhauser Verlag, Basel, 1993 in drug research progress (Progress in DrugResearch.) the 40th referring to R.Freidinger.Therefore, the IL-8 receptor has been represented a target position likely developing new antibiotic medicine.
Two kinds of high affinity people IL-8 receptors (77% homology) are identified: IL-8R α, and it only combines with IL-8 with high affinity, and IL-8R β, and it all has high affinity for IL-8 and GRO α, GRO β, GRO γ and NAP-2.See the above-mentioned document of Holmes etc.: Murphy etc., science (Science) 253,1280 (1991); Lee etc., journal of biological chemistry (J.Biol.Chem.) 267,16283 (1992); LaRosa etc., journal of biological chemistry (J.Biol.Chem.) 267,25402 (1992); With Gayle etc., journal of biological chemistry (J.Biol.Chem.) 268,7283 (1993).
In this field, still need now to be used for the treatment of can with IL-8 α or the bonded chemical compound of beta receptor.Therefore, the generation with IL-8 increases (it causes neutrophil and T cell subsets to enter the chemotaxis of inflamed sites) diseases associated and can have benefited from those chemical compounds as the inhibitor of IL-8 receptors bind.
Brief summary of the invention
The invention provides a kind of treatment by with the method for the bonded chemokine mediated disease of IL-8 α or beta receptor, this method comprises formula (1) chemical compound or its pharmaceutically useful salt of taking effective dose.Particularly this chemotactic factor is IL-8.
The invention still further relates to the method that suppresses IL-8 and its receptors bind in the mammal that needs is arranged, this method comprises the formula of this administration effective dose (I) chemical compound.
Can be used for formula of the present invention (I) chemical compound is the compound or pharmaceutically acceptable salt thereof of following structure Wherein
X is oxygen or sulfur;
R is (CR 8R 8) rC (O) 2H, (CR 8R 8) rNH-C (O) R a, (CR 8R 8) rC (O) NR 6 'R 7 ', (CR 8R 8) rNHS (O) 2R b, (CR 8R 8) rS (O) 2NHR c, (CR 8R 8) rNHC (X 2) NHR b, or the tetrazolium basic ring;
X 2Be oxygen or sulfur;
R 1Be to be independently selected from hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, azido, (CR 8R 8) qS (O) tR 4Hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroaryl alkyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, heteroaryl C 1-4Alkoxyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocyclic radical C 2-10Alkenyl, (CR 8R 8) qNR 4R 5C 2-10Alkenyl C (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 10S (O) 3R 8(CR 8R 8) qC (O) R 11C 2-10Alkenyl C (O) R 11C 2-10Alkenyl C (O) OR 11(CR 8R 8) qC (O) OR 12(CR 8R 8) qOC (O) R 11(CR 8R 8) qNR 4C (O) R 11(CR 8R 8) qNHS (O) 2R 17(CR 8R 8) qS (O) 2NR 4R 5Perhaps two R 1Can form O-(CH altogether 2) sSaturated or the unsaturated ring of O-or 5-6 unit; The part that wherein contains aryl, heteroaryl and heterocyclic radical can randomly be substituted; Condition is that not containing pKa on 2 of benzyl ring is the dissociable hydrogen of 3-10;
N is the integer of 1-3;
M is the integer of 1-3;
Q is 0, or the integer of 1-10;
R is 0 or the integer of 1-4;
S is the integer of 1-3;
T is 0 or integer 1 or 2;
V is the integer of 1-4;
R 4And R 5Be hydrogen independently, the optional C that replaces 1-4Alkyl, the optional aryl that replaces, the optional aryl C that replaces 1-4Alkyl, the optional heteroaryl that replaces, the optional heteroaryl C that replaces 1-4Alkyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, perhaps R 4And R 5Form 5-7 unit ring with the nitrogen that they connected, this ring can randomly contain the hetero atom that another is selected from O/N/S;
R 6And R 7Be hydrogen or C independently 1-4Alkyl, perhaps R 6And R 7Form a 5-7 unit ring with the nitrogen that they connected, this ring can randomly contain the hetero atom that another is selected from oxygen, nitrogen or sulfur;
R 6 'And R 7 'Be independently selected from hydrogen, C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, heterocyclic radical C 2-4Alkenyl, condition are R 6 'And R 7 'One of be hydrogen, but be not hydrogen simultaneously;
Y is hydrogen independently, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, azido, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroaryl alkyl, heteroaryl C 1-4Alkoxyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocyclic radical C 2-10Alkenyl, (CR 8R 8) qNR 4R 5C 2-10Alkenyl C (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 10S (O) 3R 8(CR 8R 8) qC (O) R 11C 2-10Alkenyl C (O) R 11C 2-10Alkenyl C (O) OR 11C (O) R 11(CR 8R 8) qC (O) OR 12(CR 8R 8) qOC (O) R 11(CR 8R 8) qNR 4C (O) R 11(CR 8R 8) qNHS (O) 2R d(CR 8R 8) qS (O) 2NR 4R 5Perhaps two Y can form O-(CH altogether 2) sSaturated or the unsaturated ring of O-or 5-6 unit; And wherein contain aryl, heteroaryl and the heterocyclic radical part can randomly be substituted;
R 8Be independently selected from hydrogen or C 1-4Alkyl;
R 10Be C 1-10Alkyl C (O) 2R 8
R 11Be hydrogen, C 1-4Alkyl, the optional aryl that replaces, the optional aryl C that replaces 1-4Alkyl, the optional heteroaryl that replaces, the optional heteroaryl C that replaces 1-4Alkyl, the optional heterocyclic radical that replaces, or the optional heterocyclic radical C that replaces 1-4Alkyl;
R 12Be hydrogen, C 1-10Alkyl, optional aryl that replaces or the optional aralkyl that replaces;
R 13And R 14Be hydrogen independently, the optional C that replaces 1-4Alkyl, perhaps R 13With R 14In one can be the optional aryl that replaces;
R 17Be C 1-4Alkyl, aryl, aralkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl, aryl wherein, heteroaryl and heterocycle all can randomly be substituted;
R aBe alkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical, or heterocyclic radical C 1-4Alkyl, wherein all these groups all can randomly be substituted;
R bBe NR 6R 7, alkyl, aryl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, heterocyclic radical C 2-4Alkenyl, or camphoryl, wherein all these groups all can randomly be substituted;
R cBe alkyl, aryl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, or heterocyclic radical C 2-4Alkenyl, wherein all these groups all can randomly be substituted;
R dBe NR 6R 7, alkyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, the ring that wherein contains aryl, heteroaryl and heterocyclic radical can randomly be substituted;
W is
Figure A0080909500111
The ring that contains E can randomly be selected from:
Figure A0080909500121
Wherein *The junction point of number representative ring;
R 20Be W 1, the optional heteroaryl that replaces, the optional C that replaces 5-8Cycloalkyl, the optional C that replaces 1-10Alkyl, the optional C that replaces 2-10Alkenyl, or the optional C that replaces 2-10Alkynyl;
W 1Be
Figure A0080909500122
The ring that contains E ' randomly is selected from
Figure A0080909500123
*The junction point of number representative ring.Detailed Description Of The Invention
Formula (I) chemical compound also can be used for needs suppress IL-8 or with the veterinary treatment of the non-human mammal of IL-8 α and bonded other chemotactic factor of beta receptor.With regard to the therapeutic or prophylactic treatment of animal, chemokine mediated disease comprises the disease that the application mentions in the Therapeutic Method part.
In formula (I) chemical compound, R is (CR 8R 8) rC (O) 2H, (CR 8R 8) rNH-C (O) R a, (CR 8R 8) rC (O) NR 6 'R 7 ', (CR 8R 8) rNHS (O) 2R b, (CR 8R 8) rS (O) 2NHR c, (CR 8R 8) rNHC (X 2) NHR b, or the tetrazolium basic ring.These groups can be directly connected on the 3-position of ring, or through linking group (CR 8R 8) rBe connected to the 3-position of ring.
R is preferably 0 or integer 1-4, is preferably 0.
X 2Be preferably oxygen or sulfur, be preferably oxygen, wherein r is 0 or the integer of 1-4.
R 6And R 7Should be hydrogen or C independently of one another 1-4Alkyl, perhaps R 6And R 7Form 5-7 unit ring with the nitrogen that they connected, this ring can randomly contain another hetero atom that is selected from oxygen, nitrogen or sulfur.
R 6 'And R 7 'Be preferably hydrogen, C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocycle C 1-4Alkyl or heterocycle C 2-4Alkenyl, condition are R 6 'And R 7 'In one be hydrogen, and can not all be hydrogen.All these groups all can randomly be replaced 1-3 time by following group independently: halogen, nitro, halo C 1-4Alkyl is (as CF 3), C 1-4Alkyl (as methyl), C 1-4Alkoxyl (as methoxyl group), NR 9C (O) R a, C (O) NR 6R 7, S (O) 3H or C (O) OC 1-4Alkyl.
R aBe preferably alkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocycle C 1-4Alkyl, wherein all these groups all can resemble be optionally substituted with defining.
R bBe preferably NR 6R 7, alkyl, aryl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocycle C 1-4Alkyl or heterocycle C 2-4Alkenyl, or camphoryl, the part that wherein contains alkyl, aryl, heteroaryl and heterocyclic radical all can randomly be replaced 1-3 time by following group independently: halogen, nitro, halo C 1-4Alkyl is (as CF 3), C 1-4Alkyl (as methyl), C 1-4Alkoxyl (as methoxyl group), NR 9C (O) R a, C (O) NR 6R 7, S (O) 3H or C (O) OC 1-4Alkyl.R bPreferably optional phenyl, benzyl or the styryl that replaces.Work as R bWhen being heteroaryl ring, its preferably optional thiazolyl that replaces, the optional thienyl that replaces or the optional quinolyl that replaces.
R 9Be preferably hydrogen or C 1-4Alkyl is preferably hydrogen.Work as R 9Be at substituted radical NR 9C (O) R aWhen middle, R aPreferably alkyl, for example methyl.
R cBe preferably hydrogen, alkyl, aryl, aryl C 1-4Alkyl, aryl C 1-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 1-4Alkenyl, heterocyclic radical or heterocycle C 1-4Alkyl or heterocycle C 1-4Alkenyl, they all can randomly independently be replaced 1-3 time by following group: halogen, nitro, halo C 1-4Alkyl, C 1-4Alkyl, C 1-4Alkoxyl, NR 9C (O) R a, C (O) NR 6R 7, S (O) 3H or C (O) OC 1-4Alkyl.R cThe preferably optional phenyl that replaces.
W is preferably
The ring that contains E is preferably the substituent group that is selected from following group:
Figure A0080909500142
Asterisk wherein *The junction point of representative ring.
In formula (I) chemical compound, R 1Should be independently selected from: hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl is (as CF 3), C 1-10Alkyl (as methyl, ethyl, isopropyl or n-pro-pyl), C 2-10Alkenyl, C 1-10Alkoxyl (as methoxy or ethoxy), halo C 1-10Alkoxyl (as trifluoromethoxy), azido, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl (as methanol or ethanol), aryl (as phenyl or naphthyl), aryl C 1-4Alkyl (as benzyl), aryloxy group (as phenoxy group), aryl C 1-4Alkoxyl (as benzyloxy), heteroaryl, heteroaryl alkyl, heteroaryl C 1-4Alkoxyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocycle C 2-10Alkenyl, (CR 8R 8) qNR 4R 5, C 2-10Alkenyl C (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 10, S (O) 3R 8As S (O) 3H, (CR 8R 8) qC (O) R 11, C 2-10Alkenyl C (O) R 11, C 2-10Alkenyl C (O) OR 11, C (O) R 11, (CR 8R 8) qC (O) OR 12, (CR 8R 8) qOC (O) R 11, (CR 8R 8) qNR 4C (O) R 11, (CR 8R 8) qNHS (O) 2R 17, (CR 8R 8) qS (O) 2NR 4R 5, perhaps two R 1Can form O-(CH altogether 2) sSaturated or the unsaturated ring of O-or 5-6 unit.Contain aryl, heteroaryl and heterocyclic part all can resemble define below be optionally substituted.
T is preferably 0, and numerical value is 1 or 2 integer.
S is preferably integer 1-3.
Q is preferably 0, integer 1-10.
Work as R 1When forming a dioxy abutment, s is preferably 1.Work as R 1When forming other saturated or unsaturated ring, preferably form 6 yuan of rings of naphthalene nucleus system.These saturated and unsaturated ring systems can be randomly by other R as defined above 1Group replaces 1-3 time independently.
R 4And R 5Should be hydrogen independently, the optional C that replaces 1-4Alkyl, the optional aryl that replaces, the optional aryl C that replaces 1-4Alkyl, the optional heteroaryl that replaces, the optional heteroaryl C that replaces 1-4Alkyl, heterocyclic radical, or heterocycle C 1-4Alkyl, perhaps R 4And R 5Form 5-7 unit ring with the nitrogen-atoms that they connected, this ring can randomly contain another hetero atom that is selected from O/N/S.
R 8Should be independently selected from hydrogen or C 1-4Alkyl.
R 10Be preferably C 1-10Alkyl C (O) 2R 8, CH for example 2C (O) 2H or CH 2C (O) 2CH 3
R 11Should be hydrogen independently, C 1-4Alkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical, or heterocycle C 1-4Alkyl.
R 12Be preferably hydrogen, C 1-10Alkyl, the optional aryl that replaces or the optional aralkyl that replaces.
R 17Be preferably C 1-4Alkyl, aryl, aralkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocycle C 1-4Alkyl, wherein aryl, heteroaryl and heterocycle all can randomly be substituted.
R 1Preferably halogen, cyano group, nitro, CF 3, C (O) NR 4R 5, alkenyl C (O) NR 4R 5, C (O) R 4R 10, alkenyl C (O) OR 12, heteroaryl, heteroaryl alkyl, heteroaryl alkenyl or R 1S (O) NR 4R 5, preferred R 4And R 5All be hydrogen, perhaps R 4With R 5In one be phenyl.The preferred ring replacement of group is the 4-position at benzyl ring.
When R is (CR 8R 8) rOH, (CR 8R 8) rSH or (CR 8R 8) rNHS (O) 2R bThe time, R then 1Preferably be substituted, or, replaced by two on the 4-position 2 in the 4-position.R 1Substituent group is electron withdraw group preferably, for example nitro, halogen, cyano group, trifluoromethyl or C (O) NR 4R 5
When R is carboxylic acid, R then 1Preferably hydrogen, perhaps R 1Preferably be substituted, more preferably replaced by trifluoromethyl or chlorine in the 4-position.
In formula (I) chemical compound, R 13And R 14Should be hydrogen independently, optional replacement is the C of straight or branched as herein defined 1-4Alkyl, perhaps R 13With R 14In one be the optional aryl that replaces.
Work as R 13Or R 14When being the alkyl of optional replacement, its moieties can be replaced 1-3 time independently by following group: halogen, halo C 1-4Alkyl (as trifluoromethyl), hydroxyl, hydroxyl C 1-4Alkyl, C 1-4Alkoxyl (as methoxy or ethoxy), halo C 1-10Alkoxyl, S (O) tR 4, aryl, NR 4R 5, NHC (O) R 4, C (O) NR 4R 5Or C (O) OR 8
V is preferably 0 or the integer of 1-4.
Y is suitable to be independently selected from following group: hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, azido, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroaryl alkyl, heteroaryl C 1-4Alkoxyl, heterocyclic radical, heterocycle C 1-4Alkyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocycle C 2-10Alkenyl, (CR 8R 8) qNR 4R 5, C 2-10Alkenyl C (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 10, S (O) 3H, S (O) 3R 8(as S (O) 3H), (CR 8R 8) qC (O) R 11, C 2-10Alkenyl C (O) R 11, C 2-10Alkenyl C (O) OR 11, (CR 8R 8) qC (O) OR 12, (CR 8R 8) qOC (O) R 11, (CR 8R 8) qNR 4C (O) R 11, (CR 8R 8) qNHS (O) 2R d, (CR 8R 8) qS (O) 2NR 4R 5, perhaps two Y can form O-(CH altogether 2) sSaturated or the unsaturated ring of O-or 5-6 unit.The part that contains aryl, heteroaryl and heterocyclic radical all can be chosen wantonly and be substituted.
When Y formed the dioxy abutment, s was preferably 1.When Y formed another unsaturated ring, it preferably formed 6 yuan of rings of naphthalene ring system.These saturated and unsaturated rings can be randomly partly replaced 1-3 time by other Y as defined above.
R dBe preferably NR 6R 7, alkyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl or heterocyclic radical C 2-4The alkenyl part wherein contains aryl, heteroaryl and heterocyclic part and all can randomly be substituted as herein defined.
Y is halogen preferably, C 1-4Alkoxyl, the optional aryl that replaces, optional aryloxy group or the alkoxy aryl that replaces, methylene-dioxy, NR 4R 5, sulfo-C 1-4Alkyl, thioaryl, halogenated alkoxy, the optional C that replaces 1-4Alkyl or hydroxy alkyl.Y is more preferably mono-substituted halogen, dibasic halogen, mono-substituted alkoxyl, dibasic alkoxyl, methylene-dioxy, aryl or alkyl.More preferably these groups 2 of phenyl ring '-position or 2 ', 3 '-singly replacement or two replacement are gone up in position.
Though Y can be substituted on any one of 5 ring positions, when R is (CR 8R 8) rC (O) 2During H, preferred Y 2 '-position or 3 '-position on single the replacement, 4 '-preferably be not substituted.If should be replaced by two by ring, when R is (CR 8R 8) rC (O) 2During H, substituent group is preferably in monocyclic 2 ' position or 3 ' position.Though R 1With Y can be hydrogen, but preferably have at least a ring to be substituted, more preferably two rings all are substituted.
In formula (I) chemical compound, X is preferably oxygen or sulfur, is preferably oxygen.
Use asterisk *E and the E ' ring of representing its junction point can randomly exist.If it does not exist, then ring is to be illustrated the R shown in the book 1Phenyl moiety with the Y replacement.E and E ' ring can be respectively at any ring (saturated or unsaturated) by R 1Replace the replacement in unsaturated ring of only having drawn here with Y.
In formula (I) chemical compound, R 20Be W 1, the optional heteroaryl that replaces, the optional C that replaces 5-8Cycloalkyl, the optional C that replaces 1-10Alkyl, the optional C that replaces 2-10Alkenyl or the optional C that replaces 2-10Alkynyl.
Work as R 20Be the optional C that replaces 5-8During cycloalkyl, this ring can be by (Y) of above definition nReplace.
Work as R 20Be the optional C that replaces 1-10Alkyl, the optional C that replaces 2-10Alkenyl or the optional C that replaces 2-10During alkynyl, these groups can randomly independently be replaced one or many by following group: halogen, nitro, cyano group, halo C 1-10Alkyl (as trifluoromethyl), C 1-10Alkoxyl, halo C 1-10Alkoxyl, S (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryloxy, heteroaryl C 1-4Alkoxyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, heterocyclic oxy group, heterocyclic radical C 1-4Alkoxyl, NR 4R 5, C (O) NR 4R 5, C (O) NR 4R 10, S (O) 3H, S (O) 3R 8, C (O) R 11, C (O) OR 12, OC (O) R 11Or NR 4C (O) R 11
Work as R 20Be the optional C that replaces 2-10Alkenyl or the optional C that replaces 2-10During alkynyl, except above-mentioned those groups, they also can be randomly by aryl, aryl C 1-4Alkyl, heteroaryl or heteroaryl C 1-4Alkyl (ring that wherein contains aryl and heteroaryl can randomly be substituted) replaces.
W 1Be preferably
Figure A0080909500171
The ring that contains E ' can randomly be selected from:
In formula (I) chemical compound, work as R 20When being heteroaryl (HET) ring, it is preferably heteroaryl ring or ring system.If HET partly is a polycyclic system, containing heteroatomic ring does not need and urea moiety or (CR 13R 14) vPart directly connects.All rings in this ring system all can be randomly by (Y as defined above (n)) replace.The HET part is pyridine radicals preferably, and it can be 2-, 3-or 4-pyridine radicals.If this ring be one multi-ring, then preferably benzimidazole, dibenzothiophenes or indole ring.Other relevant heterocycle includes but not limited to thiophene, furan, pyrimidine, pyrroles, pyrazoles, quinoline, isoquinolin, quinazoline, pyridine, oxazole, thiazole, thiadiazoles, triazole or imidazoles.
R 20Preferably optional phenyl, pi-allyl, the C that replaces 1-10Alkyl, ethoxycarbonyl-ethyl, dimethyl-acetal, 2-methoxyl group isopropyl or 2-methoxy ethyl.
Formula (I) examples for compounds comprises:
N-(3-carboxy phenyl)-N '-(2-bromophenyl) urea
N-(3-carboxymethyl phenyl)-N '-(2-bromophenyl) urea
N-(3-carboxymethyl phenyl)-N '-(2, the 3-Dichlorobenzene base) urea
N-(3-carboxy phenyl)-N '-(2, the 3-Dichlorobenzene base) urea
N-(3-(2-carboxyethyl) phenyl)-N '-(2, the 3-Dichlorobenzene base) urea
N-(2,4-two chloro-3-carboxyls)-N '-(2-bromophenyl) urea
N-(4-chloro-3-carboxy phenyl)-N '-(2-bromophenyl) urea
N-(4-chloro-3-carboxy phenyl)-N '-(2, the 3-Dichlorobenzene base) urea; With
N-(4-chloro-3-carboxy phenyl)-N-(3-chlorphenyl) urea; Or their officinal salt.
Unless otherwise indicated, said here " can choose replacement wantonly " is meant following group: halogen, as fluorine, chlorine, bromine or iodine; Hydroxyl; The C that hydroxyl replaces 1-10Alkyl; C 1-10Alkoxyl is as methoxy or ethoxy; S (O) M 'C 1-10Alkyl, wherein m ' is 0,1 or 2, for example methyl mercapto, methylsulfinyl or methyl sulphonyl; Amino, one or dibasic amino, for example NR 4R 5Group; NHC (O) R 4C (O) NR 4R 5C (O) OH; S (O) 2NR 4R 5NHS (O) 2R 2C 1-10Alkyl, for example methyl, ethyl, propyl group, isopropyl or the tert-butyl group; Halo C 1-10Alkyl is as CF 3The optional aryl that replaces, as phenyl, or the optional aralkyl that replaces, as benzyl or phenethyl, the optional heterocyclic radical that replaces, the optional heterocyclic radical alkyl that replaces, the optional heteroaryl that replaces, the optional heteroaryl alkyl that replaces, and wherein these aryl, heteroaryl or heterocyclic radical part can be by alkyl, the C of halogen, hydroxyl, hydroxyl replacement 1-10Alkoxyl, S (O) mC 1-10Alkyl, amino, one or two C 1-4The amino that alkyl replaces is (as NR 4R 5), C 1-10Alkyl or halo C 1-10Alkyl is (as CF 3) replace 1-2 time.
R 2Be preferably C 1-4Alkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl.
Suitable officinal salt is well-known to those skilled in the art, comprise inorganic and the organic acid basic salt, hydrochloric acid for example, the basic salt of hydrobromic acid, sulphuric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.In addition, the officinal salt of formula (I) chemical compound also can form with pharmaceutically useful cation, for example, contains the situation of carboxyl in substituent group.Suitable pharmaceutically useful cation is well-known to those skilled in the art, comprises alkali metal, alkaline-earth metal, ammonium and quaternary ammonium cation.
Following noun used herein is meant:
" halogen "-all halogens, that is, and chlorine, fluorine, bromine and iodine.
" C 1-10Alkyl " or " alkyl " unless-chain length is added restriction in addition, all refer to the straight or branched group of 1-10 carbon, include but not limited to: methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl etc.
" cycloalkyl " is meant annular group, preferably has 3-8 carbon atom, includes but not limited to cyclopropyl, cyclopenta, cyclohexyl etc.
" alkenyl " all refers to the straight or branched group of 2-10 carbon atom unless chain length is added restriction in addition at all occasions, and this includes but not limited to vinyl, 1-acrylic, 2-acrylic, 2-methyl isophthalic acid-acrylic, 1-butylene base, crotyl etc.
" aryl "-phenyl and naphthyl;
" heteroaryl " (itself or in any combination, as " heteroaryloxy " or " heteroaryl alkyl ")-5-10 unit aromatic ring system, the hetero atom that contains one or more N of being selected from, O or S in wherein one or more rings, such as but not limited to: pyrroles, pyrazoles, furan, thiophene, quinoline, isoquinolin, quinazolyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazoles, triazole, imidazoles or benzimidazole.
" heterocycle " (or in any combination, for example " heterocyclic radical alkyl ")-the saturated or undersaturated 4-10 of part unit ring system itself wherein contains the hetero atom of one or more N of being selected from, O or S in one or more ring; Such as but not limited to: pyrrolidine, piperidines, piperazine, morpholine, Pentamethylene oxide. or imidazolidine.
" aralkyl " or " heteroarylalkyl " or " heterocyclic radical alkyl " except as otherwise noted, is meant the C as defined above that is connected with aryl, heteroaryl or heterocyclic moiety as defined above 1-10Alkyl.
The oxide S (O) of " sulfinyl "-corresponding sulfide, term " sulfur " refers to sulfide, and " sulfonyl " refers to the S (O) of complete oxidation 2Part.
Here said " two R wherein 1Partly (or two Y parts) can form 5 or 6 yuan saturated or unsaturated ring altogether and " are meant and form and undersaturated 6 yuan of rings of part such as C 6Cycloalkenyl group (being hexene) or C 5Naphthalene ring system or phenyl moiety that cycloalkenyl group (as the cyclopentenes ring) connects.Preparation method
Formula (I) chemical compound can use synthetic method to obtain, and the some of them method is the example explanation in following scheme.The synthetic method that provides in these schemes can be used for preparing and has different R, the R that meeting of all kinds reacts 1With formula (I) chemical compound of aromatic yl group, utilize by the optional substituent group of due care, compatible to realize with the reaction of this paper general introduction.In this situation, remove to protect the chemical compound that obtains having disclosed general characteristic subsequently.In case formed urea nuclear, then can use to be used for other chemical compound that standard method that the functional group transforms mutually prepares these chemical formulas, this is well known in the art.Though in each scheme with W and R 20Illustrate as phenyl, but this is just for the example explanation.
Required aniline (2-scheme 1) is not if there is the commercial goods, can obtain by reducing corresponding nitro.This reduction reaction can be utilized multiple Reducing agent, and for example hydrogen and palladium catalyst/carbon or stannic chloride are finished in polar solvent (as DMF or ethyl acetate).This aniline (2-scheme 1) subsequently can with commercially available isocyanates condensation in aprotic solvent (as DMF, DMSO or toluene).
Scheme 1
Figure A0080909500211
R＝CH 2CH 2COOH，COOH，CH 2COOH
a)H 2，Pd/Cb)PhCNO
Or required chemical compound can synthesize in the following manner: with this carboxylic acid protection, for example form methyl ester with Azimethylene. with condition well-known in the art.The available subsequently multiple Reducing agent of this chemical compound for example hydrogen and palladium catalyst/carbon or stannic chloride reduces in polar solvent (as DMF or ethyl acetate).In the presence of alkali (as triethylamine or bicarbonate),, form isocyanates (4-scheme 2) with phosgene equivalent such as surpalite or triphosgene condensation.This chemical compound subsequently can with required commercially available aniline reaction.Can use the standard conditions of this area then, for example metal hydroxides removes this carboxylic acid to protection, reuse acid (as HCl) acidify, the chemical compound 3 in the formation scheme 2 in polar solvent (as THF/ water). R=CH 2CH 2COOH, COOH, or CH 2COOH; Protected R is R=CH wherein 2CH 2COOMe, COOMe, or CH 2COOMea) CH 2N 2, ether b) and H 2, 5%Pd/Cc) triphosgene, Et 3Nd) PhNH 2, DMFe) LiOH, THF/H 2Of) HCl/H 2O
The officinal salt of formula (I) chemical compound can obtain in a known manner, for example in the presence of suitable solvent with an amount of acid or alkali treatment.
Another aspect of the present invention is the similarity method of preparation formula (I) chemical compound, and this method comprises makes formula (A) chemical compound
Figure A0080909500221
Wherein R, R 1Define suc as formula (I) is middle with m, react with following formula: compound:
-N (X)-(CR 13R 14) v-R 20Thereby the formula of obtaining (I) chemical compound, the X in the following formula, R 13, R 14, v and R 20Identical with the definition in the formula (I).
Or, can use formula (A1) chemical compound
Figure A0080909500222
Wherein E, R, R 1Identical with m with the definition in the formula (I), perhaps formula (A2) chemical compound
Figure A0080909500223
Wherein E, R, R 1Identical with m with the definition in the formula (I), with the following formula: compound reaction,
-N (X)-(CR 13R 14) v-R 20Production (I) chemical compound, the X in the following formula, R 13, R 14, v and R 20Identical with the definition in the formula (I).
Another aspect of the present invention is the other method of preparation formula (I) chemical compound, and this method comprises formula (B) chemical compound R wherein 1, m and R be suc as formula defining in (I); React with following formula: compound:
NH 2-(CR 13R 14) v-R 20Obtain formula (I) chemical compound, the R in the following formula 13, R 14, v and R 20With middle define identical of formula (I); In case of necessity the R group is gone protection.
With top the same, also can use formula (B1) chemical compound
Figure A0080909500232
Wherein E, R, R 1Define suc as formula (I) is middle with m, or formula (B2) chemical compound Wherein E, R, R 1Define suc as formula (I) is middle with m, react with following formula: compound:
NH 2-(CR 13R 14) v-R 20Obtain formula (I) chemical compound, the R in the following formula 13, R 14, v and R 20With middle define identical of formula (I); In case of necessity the R group is gone protection.
In an embodiment, all temperature be degree centigrade (℃).Unless otherwise indicated, mass spectrum obtains with the fast atom bombardment method on VG Zab mass spectrograph. 1H-NMR (is called later on that " NMR ") spectrum is with Bruker AM 250 or AM 400 photometers record under 250MHz or 400MHz respectively.Multiple symbolic representation is as follows: s=is unimodal, and d=is bimodal, t=three peaks, and the q=quartet, m=multiplet, br are represented wide unimodal.Sat. represent saturated solution, equiv represents the molar equivalent ratio of reagent with respect to the primary response thing.
Flash chromatography is to carry out on Merck silica gel 60 (230-400 order).Synthetic embodiment
Referring now to following examples explanation the present invention, these embodiment just for the example explanation, do not limit the scope of the present invention and be not understood as.Except as otherwise noted, all degree centigrade to provide, the solvent of use is getable highest purity to all temperature, and institute responds and all carries out under anhydrous condition under argon atmospher.
The preparation of embodiment 1N-(3-carboxy phenyl)-N '-(2-bromophenyl) urea
The 3-amino benzoic Acid (1 equivalent, 1.37g) (solution in DMF 1.98g) was handled about 2 hours with Carbimide. 2-bromophenyl ester down at about 80 ℃ by 1 equivalent.With this solution cooling, product is recrystallization purifying in dichloromethane and hexane, obtains the 1.28g title compound, is white solid.MS(ES)M-H＝333。
The preparation of embodiment 2N-(3-carboxymethyl phenyl)-N '-(2-bromophenyl) urea
The 3-aminophenyl acetic acid (1 equivalent, 0.151g) (solution in DMF 0.198g) was handled about 2 hours with Carbimide. 2-bromophenyl ester down at about 80 ℃ by 1 equivalent.With this solution cooling, product is recrystallization purifying in dichloromethane and hexane, obtains the 0.32g title compound, is white solid.MS(ES)M-H＝347。
The preparation of embodiment 3N-(3-carboxymethyl phenyl)-N '-(2, the 3-Dichlorobenzene base) urea
The 3-aminophenyl acetic acid (1 equivalent, DMF solution 151mg) 80 ℃ with Carbimide. 2,3-Dichlorobenzene base ester (188mg) handled 2 hours by 1 equivalent.With this solution cooling, product is recrystallization purifying in dichloromethane and hexane, obtains the 0.12g title compound, is white solid.MS(ES)M-H＝337。
The preparation of embodiment 4N-(3-carboxy phenyl)-N '-(2, the 3-Dichlorobenzene base) urea
The 3-amino benzoic Acid (1 equivalent, DMF solution 1.37g) 80 ℃ with Carbimide. 2,3-Dichlorobenzene base ester (1.88g) handled 2 hours by 1 equivalent.With the solution cooling, product is recrystallization purifying in dichloromethane and hexane, obtains the 1.01g title compound, is white solid.MS(ES)M-H＝323。
A) the amino dihydro cinnamon acid of 3-of the preparation of embodiment 5N-(3-(2-carboxyethyl) phenyl)-N '-(2, the 3-Dichlorobenzene base) urea
The ethyl acetate solution of 3-nitro dihydro cinnamon acid (500mg) is handled with 10%Pd/C (500mg).Charge into hydrogen in the suspension that forms and at room temperature stir and spend the night.Reactant mixture argon purge is then through diatomite filtration.Filtrate is concentrated, and residue is recrystallization in toluene and ethyl acetate. 1H NMR (DMSO) 6.95t (1H), 6.4m (3H), 2.7t (2H), 2.45t (2H) b) N-(3-(2-carboxyethyl) phenyl)-N '-(2, the 3-Dichlorobenzene base) urea
The amino dihydro cinnamon acid of 3-(1 equivalent, DMF solution 83mg) 80 ℃ with Carbimide. 2,3-Dichlorobenzene base ester (94mg) handled 2 hours by 1 equivalent.With the solution cooling, product is recrystallization purifying in dichloromethane and hexane, obtains the 0.037g title compound, is white solid. 1H?NMR(DMSO)9.45s(1H)，8.47s(1H)，8.17d(1H)，7.31m(4H)，7.24t(1H)，6.88d(1H)，2.73t(2H)，2.54t(2H)
The preparation of embodiment 6N-(2,4-two chloro-3-carboxyls)-N '-(2-bromophenyl) urea is 5-amino-2 a), the 6-dichlorobenzoic acid
5-nitro-2, the ethyl acetate solution of 6-dichlorobenzoic acid (2.0g) is handled with 10%Pd/C (1.5g).Spend the night with this suspension of hydrogen purge and stirring at room temperature.With reactant mixture usefulness argon purge and through diatomite filtration.Filtrate is concentrated, and residue is recrystallization purifying in ethyl acetate and hexane, obtains title compound (0.7g), is white solid. 1H NMR (DMSO) 7.15d (1H), 6.8d (1H), 5.74s (1H, br) b) N-(2,4-two chloro-3-carboxyls)-N '-(2-bromophenyl) urea
5-amino-2, the 6-dichlorobenzoic acid (1 equivalent, handled 2 hours with Carbimide. 2-bromophenyl ester (1 equivalent, 153 μ l) at 80 ℃ by DMF solution 250mg).With the solution cooling, product is recrystallization purifying in dichloromethane and hexane, obtains the title compound of 35mg white solid.MS(ES)M-H＝401。
The preparation of embodiment 7N-(4-chloro-3-carboxy phenyl)-N '-(2-bromophenyl) urea
5-amino-2-chlorobenzoic acid (1 equivalent, (DMF solution 1.71g) 1.98g) was handled 2 hours with Carbimide. 2-bromophenyl ester at 80 ℃ by 1 equivalent.With the solution cooling, product is recrystallization purifying in dichloromethane and hexane, obtains the title compound of 0.880g white solid.MS(ES)M-H＝367。
The preparation of embodiment 8N-(4-chloro-3-carboxy phenyl)-N '-(2, the 3-Dichlorobenzene base) urea
5-amino-2-chlorobenzoic acid (1 equivalent, (DMF solution 1.71g) 1.88g) was handled 2 hours at 80 ℃ with Carbimide. 2,3-Dichlorobenzene base ester by 1 equivalent.With the solution cooling, product is recrystallization purifying in dichloromethane and hexane, obtains the title compound of 1.57g white solid.MS(ES)M-H＝357。
The preparation of embodiment 9N-(4-chloro-3-carboxy phenyl)-N-(3-chlorphenyl) urea
5-amino-2-chlorobenzoic acid (1 equivalent, (DMF solution 1.71g) 1.53g) was handled 2 hours with Carbimide. 3-chlorphenyl ester at 80 ℃ by 1 equivalent.With the solution cooling, product is recrystallization purifying in dichloromethane and hexane, obtains the title compound of 0.66g white solid.MS(ES)M-H＝323。Therapeutic Method
Formula (I) compound or pharmaceutically acceptable salt thereof can be used for making the medicine that is used to prevent or treat people or other mammiferous disease, this disease is because described mammiferous cell, include but not limited to mononuclear cell and/or macrophage, excessive or produce the IL-8 cytokine out of control or with IL-8 α and beta receptor (being also referred to as I type or II receptor) bonded other chemotactic factor and cause or aggravate.
Therefore, the invention provides the method for a kind of treatment by chemokine mediated disease, wherein this chemotactic factor is and IL-8 α and the bonded chemotactic factor of beta receptor, and described method comprises formula (I) compound or pharmaceutically acceptable salt thereof of taking effective quantity.Specifically, this chemotactic factor is IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78.
Formula (I) chemical compound is to be enough to suppress cytokine, particularly the amount of the function of IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 is taken, thereby it is turned down the normal physiological function level biologically, perhaps be adjusted to below the normal level, so that improve morbid state in some situation.For the present invention, the abnormal level of IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 comprises: (i) free IL-8 content is more than or equal to every ml 1 pik; The bonded IL-8 of (ii) any cell, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 are higher than normal physiological level; Or the existence of IL-8, the GRO α, GRO β, GRO γ, NAP-2 or the ENA-78 that are higher than foundation level arranged in the cell or tissue that produces IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 respectively (iii).
Interleukin 8 and rhinoviral the contact can be found in following article: Turner etc., clinical infectious disease (Clin.Infect.Dis.) (1998), 26 (4), 840-846; Sanders etc., Journal of Virology (J.Virol.) (1998) 72 (2), 934-942; Sethi etc., clinical experiment immunology (Clin.Exp.Immunol.) (1997) 110 (3), 362-369; Zhu etc., U.S. physiology magazine (Am.J.Physiol.) (1997), 273 (4, Pt.1), L814-L824; Terajima etc., U.S. physiology magazine (Am.J.Physiol.) (1997), 273 (4, Pt.1), L749-L759; Grunberg etc., clinical experiment allergy (Clin.Exp.Allergy) (1997), 27 (1), 36-45; With Johnston etc., infectious disease magazine (J.Infect.Dis.) (1997), 175 (2), 323-329.
Interleukin 8 and osteoporotic the contact can be found in following article: Streckfus etc., and presbyatrics magazine (J.Gerontol.) A collects (1997), 52A (6), M343-M351; Hermann, T.WO 95/31722; With Chaudhary etc., endocrinology (Endocrinology (Baltimore)) (1992) 130 (5), 2528-34.
The principal character of these diseases is a large amount of neutrophil infiltration, T-cellular infiltration or neovascularity growths, and increase relevantly with the generation of IL-8, GRO α, GRO β, GRO γ or NAP-2, this is the reason that neutrophil enters the oriented growth of the chemotaxis of inflamed sites or endotheliocyte.(IL-1, TNF and IL-6) is different with other inflammatory cytokine, and IL-8, GRO α, GRO β, GRO γ or NAP-2 have the neutrophil of raising chemotaxis, promote enzyme to discharge (including but not limited to that elastoser discharges) and superoxides generation and activatory peculiar property.α-chemotactic factor, particularly the GRO α that works by IL-8 I type or II receptor, GRO β, GRO γ or NAP-2 can promote the neovascularization of tumor by the oriented growth that promotes endotheliocyte.Therefore, will cause the direct minimizing of neutrophil infiltration for the inhibition of inductive chemotaxis of IL-8 or activation.
Recent evidence has also shown the effect of chemotactic factor in treatment HIV infects, Littleman etc., (Nature) 381, p.661 (1996) and Koup etc., (Nature) 381, p.667 (1996) naturally naturally.
The present invention also provides the chemokine receptor anagonists chemical compound that utilizes formula (I) to prevent in the individuality of sensitivity and has treated a kind of method of (acute attack) CNS damage.
Here said CNS damage comprises opening or penetrance head trauma, and for example head trauma that causes of surgical operation, or closure head trauma is for example caused by the damage of head zone.Also comprise cerebral infarction, especially brain area in this definition.
Cerebral infarction can be defined as the focus neurological disorder that the blood supply insufficiency owing to specific brain area causes, it often is the result of embolus in the blood vessel, thrombosis or local intra-arterial atherosclerotic closure.The effect of inflammatory cytokine in this field appears, and the invention provides a kind of possible method of these damages of treatment.Adoptable Therapeutic Method for this class acute injury is less relatively.
Existing evidence has also shown the application of IL-8 inhibitor in the treatment atherosclerosis.List of references the earliest, Boisvert etc., Journal of Clinical Investigation (J.Clin.Invest.), 1998,101:353-363, show that by bone marrow transplantation stem cell (so monocyte/macrophage) goes up the IL-8 receptor and do not exist and can cause the development of the atherosis speckle of the damaged mice medium-sized artery of ldl receptor to be slowed down.Other support document is: Apostolopoulos etc., arteriosclerosis, thrombosis and blood vessel biology (Arterioscler Thromb.Vasc.Biol.) 1996,16:1007-1012; Liu etc., arteriosclerosis, thrombosis and blood vessel biology, 1997,17:317-323; Rus etc., atherosclerosis, 1996,127:263-271; Wang etc., journal of biological chemistry (J.Biol.Chem.), 1996,271:8837-8842; Yue etc., European pharmacology's magazine (Eur.J.Pharmacol.), 1993,240:81-84; Koch etc., American Journal of Pathology (Am.J.Pathol.), 1993,142:1423-1431; Lee etc., immunology wall bulletin (Immunol.Lett.), 1996,53,109-113; With Terbeltaub etc., arteriosclerosis and thrombosis (Arterioscler Thromb.), 1994,14:47-53.
TNF-α has short scorching effect, comprises a kind of cytokine of endothelial leukocyte adhesion molecule expression.Leukocyte infiltration is in ischemic brain zone, and therefore, the chemical compound of inhibition or minimizing TNF level will can be used for treating ischemic brain injury.See Liu etc., apoplexy (Stroke), Vol.25, No.7, p.1481-88 (1994), disclosure is wherein quoted as a reference in this article.
Blood vessel and clinical physiology and pharmacology's magazine (J.of.Vaisc ﹠amp at Shohami etc.; Clinical Physiology and Pharmacology) Vol 3, p.99-107 No.2 has discussed the model of closo head damage and has treated with blended 5-LO/CO medicine in (1992), and this content is here quoted as a reference.Discovery makes edema form the Therapeutic Method that reduces can improve the functional consequence of the animal of being treated.
Formula (I) chemical compound is used with IL-8 α or the bonded IL-8 of beta receptor and with the bonded amount of these receptors to be enough to suppress, and this weakens by neutrophil chemotaxis and activation and shows.Discoverable type (I) chemical compound be the bonded inhibitor of IL-8 be based on herein formula (I) chemical compound described at extracorporeal receptor in conjunction with the effect in the test.In some situations, it is the double inhibitor of reorganization I type and two kinds of IL-8 receptors of II type that formula (I) chemical compound shows.This chemical compound preferably is a kind of inhibitor of receptor, more preferably is the inhibitor of II receptor.
Here " disease or the morbid state of IL-8 mediation " are meant a kind of like this morbid state to said term, wherein IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78, or by IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78, the generation of itself, or by IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78, cause that another kind of monokine (such as but not limited to IL-1, IL-6 or TNF) discharges, and play certain effect.For example, IL-1 is dominant role therein, and its generation or action response aggravates in IL-8 or excretory morbid state is considered to the disease states mediated by IL-8.
Here said term " chemokine mediated disease or morbid state " is meant wherein the morbid state that works with IL-8 α or the bonded chemotactic factor of beta receptor, and described chemotactic factor is not limited to for example IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78.This comprise IL-8 wherein by himself generation or cause that another kind of monokine (being not limited to for example IL-1, IL-6 or TNF) discharges the morbid state that works.For example, IL-1 is dominant role therein, and its generation or action response aggravates in IL-8 or excretory morbid state is considered to the disease states mediated by IL-8.
These diseases include but not limited to: psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel, Crohn disease, ulcerative colitis, apoplexy, septic shock, endotoxin shock, gram-negative sepsis, toxicogenic shock is comprehensively demonstrate,proved, the heart and renal reperfusion injury, glomerulonephritis, thrombosis, graft versus host disease, presenile dementia, allograft rejection, malaria, restenosis (restinosis), angiogenesis, atherosclerosis, osteoporosis, gingivitis, bad hematopoietic stem cell discharges and by respiratory virus (including but not limited to rhinovirus and influenza virus), the disease that herpesvirus (including but not limited to I and II herpes simplex virus type) and hepatitis virus (including but not limited to hepatitis B and hepatitis C virus) cause.
Here said " cytokine " speech is meant any excretory polypeptide, and they influence cell function, is a kind of molecule of regulating cell interaction in immunity, inflammation or the hemopoietic response.Cytokine includes but not limited to monokine and lymphokine, no matter which kind of cell they are derived from.For example, monokine is considered to usually by mononuclear cell (for example macrophage and/or mononuclear cell) generation and excretory.But much other cell also produces monokine, for example natural killer cell, fibroblast.Basophilic granulocyte.Neutrophil, endotheliocyte, cerebral astrocytic, marrow stromal cell, epithelium keratinocyte and bone-marrow-derived lymphocyte.Lymphokine is commonly considered as being produced by lymphocyte.The example of cytokine includes but not limited to: interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF-β) and tumor necrosis factor (TNF-β).
" chemotactic factor " used herein speech, similar to above " cytokine " speech, be meant any excretory polypeptide, they influence cell function, are a kind of molecules of regulating cell interaction in immunity, inflammation or the hemopoietic response.Chemotactic factor is mainly secreted by cell transmembrane, and causes the chemotaxis and the activation of specific leukocyte and leukocyte, neutrophil, mononuclear cell, macrophage, T cell, B cell, endotheliocyte and smooth muscle cell.The example of chemotactic factor includes but not limited to: IL-8, GRO α, GRO β, GRO γ, NAP-2, ENA-78, IP-10, MIP-1 α, MIP-β, PF4 and MCP 1,2 and 3.
For formula (I) compound or pharmaceutically acceptable salt thereof is used for the treatment of, usually its pharmaceutical operation according to standard is mixed with pharmaceutical composition.Therefore, the invention still further relates to and contain effectively and formula (I) chemical compound of avirulence amount and the pharmaceutical composition of pharmaceutically suitable carrier or diluent.
Formula (I) chemical compound, its officinal salt can utilize any administration that is generally used for dispenser easily with the pharmaceutical composition that contains them, for example, oral, local, non-intestinal or suction administration.Formula (I) chemical compound can be to combine the regular dosage form administration that makes according to conventional method with formula (I) chemical compound with the pharmaceutical carrier of standard.Formula (I) chemical compound also can be united with regular dosage form with known second kind of therapeutical active compound and taken.These methods can comprise mixes each component, and granulation and compression or suitable are with the active component dissolving, to form desired preparation.Should be appreciated that the form of pharmaceutically useful carrier or diluent and characteristics are by the amount of wanting bonded active component, route of administration and the decision of other variable of knowing.Carrier with the meaning of other component compatibility of preparation on must be " acceptable ", and harmless to the pill taker.
The pharmaceutical carrier that uses can be for example solid or liquid.The typical solid carrier has lactose, Gypsum Fibrosum powder, sucrose, Talcum, gelatin, agar, pectin, arabic gum, magnesium stearate, stearic acid etc.Exemplary of liquid carriers has syrup, Oleum Arachidis hypogaeae semen, olive oil, water etc.Similarly, carrier or diluent can comprise delay releasable material well-known in the art, for example glyceryl monostearate or glycerol distearate itself or with the mixture of wax.
Can adopt medicament forms miscellaneous.For example, if use solid carrier, preparation can be placed in the hard gelatin capsule with powder or pill form by tabletting, or lozenge or lozenge.The amount of solid carrier can in very large range change, but is preferably about 25mg to about 1g.If use liquid-carrier, the form of preparation will be injection such as the ampulla or the on-aqueous liquid suspensoid of syrup, Emulsion, Perle, sterilization.
Formula (I) chemical compound can local application, promptly uses in the mode of non-whole body administration.This comprises formula (I) chemical compound is used for epidermis or oral cavity outward, and this chemical compound is placed ear, eye and nose, so this chemical compound can not enter in the blood flow in a large number.Different therewith, that the general administration is meant is oral, intravenous, intraperitoneal and intramuscular administration.
The preparation that is fit to topical comprises and is fit to see through liquid or the semi-liquid preparations that skin arrives inflamed sites, for example liniment, lotion, cream, unguentum or paste, and the drop that is fit to eye, ear and nose.For topical, active component can account for the 0.001-10% of weight of formulation, for example 1-2%.It can account for and reach 10%, but preferably is less than 5%, more preferably the 0.1-1% of weight of formulation.
Lotion of the present invention comprises and being fit to a skin or a lotion of using.Eye lotions can comprise the optional aqueous solution that contains the sterilization of antibacterial, and it can be used and prepare the preparation of drop similar methods.The lotion or the liniment that are used for skin also can contain a kind of reagent dry and cooling skin that quickens, for example alcohol or acetone, and/or wetting agent, for example oil of glycerol or picture Oleum Ricini or Oleum Arachidis hypogaeae semen and so on.
Cream of the present invention, ointment or paste are the active component semi-solid preparations of external.They can be with suitable machinery by segmenting or powdered active component is mixed with oil or non-oil base material individually or in the solution of water base or non-water-based fluid or suspension and prepared.Base material can comprise hydro carbons, as hard, soft or liquid paraffin, and glycerol, Cera Flava, metallic soap; Rubber cement; The oil of natural origin is as almond oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Ricini or olive oil; The mixture of lanoline or derivatives thereof or fatty acid (as stearic acid or oleic acid) and alcohol (as glycol) or macrogel.Can add suitable surfactant in the preparation, for example anion, cation or non-ionic surface active agent are as sorbitan ester or its polyoxyethylene deriv.Can also add suspending agent, natural gum for example, cellulose derivative or inorganic matter such as silicon dioxide (silicaeous silicas), and other component such as lanoline.
Drop of the present invention can comprise the water base of sterilization or oil base solution or suspension, it can prepare by active component is dissolved in the suitable aqueous solution, contain antibacterial and/or antifungal and/or any other suitable antiseptic in the solution, preferably contain surfactant.The solution that obtains can filter clarification subsequently, transfers in the suitable containers, and sealing then utilizes autoclaving or keeps sterilize half an hour at 98-100 ℃.Or, can utilize the filtration sterilization technology with this solution sterilization and transfer in the container.The antibacterial and the antifungal that are fit to be added in the drop are phenylmercuric nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).The solvent that is fit to preparation oil base solution comprises glycerol, Diluted Alcohol and propylene glycol.
Formula (I) chemical compound can parenterai administration, that is, and and intravenous, intramuscular, subcutaneous, intranasal, internal rectum, intravaginal or intraperitoneal administration.The parenterai administration form of usually preferred subcutaneous and intramuscular.The dosage forms of this class administration can prepare with routine techniques.Formula (I) chemical compound also can be with the suction administration, that is, and and with intranasal and oral cavity suction administration.The dosage forms of this class administration, for example aerosol preparations or metered dose inhaler can prepare with routine techniques.
For all usings method of the disclosed formula of the application (I) chemical compound, oral daily dose is preferably the about 0.01-80mg of every kg TBW.The non-intestinal daily dose of taking medicine is the about 0.001-80mg of every kg TBW.The topical daily dose is preferably 0.1-150mg, and every day, administration was 1-4 time, preferred 2 or 3 times.The daily dose of inhalation is preferably the about 0.01-1mg of every kg.One skilled in the art will realize that, the optimised quantity of the single dose of formula (I) compound or pharmaceutically acceptable salt thereof and taking medicine will be decided by at interval the nature and extent of the disease of being treated, the form of administration, approach and position, and the concrete patient who is treated, optimised quantity can be determined with routine techniques.Those skilled in the art also will appreciate that, optimized treatment course of action promptly, the medication number of times of formula (I) compound or pharmaceutically acceptable salt thereof every day and the alloted days of such medication, can utilize conventional treatment confirmed test process to determine by those skilled in the art.
Now with reference to following biological Examples explanation the present invention, they just for the example explanation, should not be counted as limitation of the scope of the invention.Biological Examples
In order to the inhibitory action of following external test determination The compounds of this invention to IL-8 and GRO-α chemotactic factor.Receptor binding assays:
[ 125I] IL-8 (people recombinate thing) is by Amersham Corp., Arlington Heights, IL obtains, given activity 2000 Ci/mmol.GRO-α is obtained by NEN-New EnglandNuclear.All other chemicals are analytical pure.(Holmes etc., science (Science), 1991,253,1278) make high-caliber recombined human IL-8 α and β receptor be expressed in Chinese hamster ovary cell respectively as previously mentioned.According to previous described scheme homogenize (Haour etc., journal of biological chemistry (J.Biol.Chem., 249, p.2195-2205 (1974)) Chinese hamster ovary film.Difference is that the homogenize buffer is changed into 10mM Tris-HCl, 1mMMgSO 4, 0.5mM EDTA (ethylenediamine tetraacetic butanoic acid), 1mM PMSF (α-tosyl fluorine), 0.5mg/L leupeptin, pH7.5.Adopt bovine serum albumin as standard, measure memebrane protein concentration with the trace test box of Pierce Co..All tests are all carried out in the mode of 96 hole micro plates.Each reactant mixture is containing 1.2mM MgSO 4, 0.1mMEDTA, 25mM NaCl and 0.03%CHAPS 20mM 1, contain in 3-two (three (methylol) methylamino) propane and the 0.4mM Tris HCl buffer (pH8.0) 125I IL-8 (0.25nM) or 125I Gro-α and 0.5 μ g/ml IL-8R α or 1.0 μ g/ml IL-8R α films.In addition, add the medicine that will test or the allied compound that are dissolved in advance among the DMSO, so that make ultimate density reach 0.01nM to 100 μ M.Add 125I-IL-8 begins test.After following 1 hour of the room temperature, plate is collected on the glass fibre filter that blocks with 1% polymine/0.5%BSA with Tontec 96 hole picker, with 25mM NaCl, 10mM TrisHCl, 1mM MgSO 4, 0.5mM EDTA, 0.03%CHAPS (pH7.4) Xian Sanci.With the filter drying, on the Betaplate liquid scintillation counter, count.Reorganization IL-8R α type or I receptor are also referred to as non-permission receptor in this article, and reorganization IL-8R α type or II receptor are known as the permission receptor.
All typical formula (I) chemical compounds of mentioning in this paper synthetic chemistry part embodiment 1-9 are all showing inhibitory action for the IL-8 receptor in the inhibiting permission model.Find following chemical compound non-activity: N-(2,4-two chloro-3-carboxyls)-N '-(2, the 3-Dichlorobenzene base) urea in this test; N-(3-carboxy phenyl)-N '-(phenyl) urea and N-(3-methyl carboxy phenyl)-N '-(phenyl) urea.The chemotaxis test
The vitro inhibition of these chemical compounds is as immunology rules (Current Protocolsin Immunology) vol 1 in the present age, supplement 1,6.12.3 described in the joint, measure in the test of neutrophil chemotaxis, the content of the document is here all quoted as a reference.By above-mentioned document the 1st volume, from human blood, separate neutrophil described in supplement 1, the 7.23.1 joint, this part content of document here is incorporated by reference in this text to be examined.Chemoattractant IL-8, GRO α, GRO β, GRO γ and NAP-2 are placed on the porous pit in one 48 hole, and (in kerve MD), concentration is between 0.1 to 100nM for Neuro Probe, Cabin John.Polycarbonate leaching film with one 5 μ m between two grooves separates.When the test The compounds of this invention, it is mixed with cell (0.001-1000mM), immediately cell is added in the groove.Under about 37 ℃ in containing 5%CO 2The humidification incubator in cultivated about 45-90 minute.When this culture period finishes, take out polycarbonate membrane, wash its end face, Diff Quick dyeing scheme (BaxterProducts, McGaw Park, IL, USA) dyeing are arranged then.Be attracted to the cell at chemotactic factor place with microscopic visual measurement counting chemistry.Usually, each 4 visual field of sample counting, with these digital averagings, the cell average that obtains having moved.Every kind of sample repeated trials three times, every kind of chemical compound repeats 4 times at least.Do not add chemical compound for some cell (positive control cell), these cells have been represented the maximum chemotactic response of cell.In the situation that needs negative control (not exciting), do not add chemokines in the kerve.Difference between positive control and the negative control has been represented the chemotactic activity of cell.The elastoser release test
Tested the ability that The compounds of this invention stops elastoser to discharge in human neutrophils.According to immunology rules (Current Protocols in Immunology) vol1 in the present age, described in the supplement 1 7.23.1 joint, by separating neutrophil in the human blood.Placing volume and be 50 μ l in each hole of 96 orifice plates is suspended in Ringer solution (NaCl 118, and KCl 4.56, NaHCO 325, KH 2PO 41.03, glucose 11.1, HEPES 5mM, pH7.4) PMN 0.88 * 10 in 6Cell.Adding volume in this plate is that the test compound (0.001-1000nM) of 50 μ l, cytochalasin B and the volume of volume 50 μ l (20 μ g/ml) are the Ringer buffer of 50 μ l.With these cells warm (37 ℃, 5%CO 2, 95%RH) 5 minutes, add IL-8, GRO α, GRO β, GRO γ or NAP-2 that ultimate density is 0.01-1000nM then.Reaction was carried out 45 minutes, with this 96 orifice plate centrifugal (800xg, 5 minutes), took out 100 μ l supernatant then.This supernatant is added in second 96 orifice plate, then add the artificial elastin laminin zymolyte that is dissolved in the phosphate buffer (MeOSuc-Ala-Aia-Pro-Val-AMC, Nova Biochem, La Jolla, CA), to ultimate density be 6 μ g/ml.Immediately plate is placed on 96 orifice plate fluorescence read the plate device (Cytofluor 2350, Millipore, Bedford, MA) in, according to methods in journal of biological chemistry (J.Biol.Chem) 254,4027 (1979) such as Nakajima to collect at interval data in 3 minutes.Calculate the elastoser amount that in PMN, discharges by the degradation rate of measuring MeOSuc-Ala-Aia-Pro-Val-AMC.TNF-α in the traumatic head injury test
The assay method that this test provides tumor necrosis factor mRNA to express in rat specific brain zone.Described expression is kowtowed hitting property traumatic brain injury (TBI) and is carried out afterwards bringing out effluent by experiment.Because the release of other cytokine in TNF-α energy inducing neural somatomedin (NGF) and the thorn activation spider cell, the variation of the gene expression of TNF-α all plays an important role in the acute and reproducibility response to the CNS wound after this wound.Can find suitable test method in WO97/35856 or WO97/49286, the disclosure content is here quoted as a reference.The CNA damage model of IL-β mRNA
This test has identified that the rat experiment effluent is kowtowed and has hit traumatic brain injury (TBI) afterwards that interleukin-1 ' beta ' (IL-1 β) mRNA expresses at the local in specific brain regions district.The result of these tests shows, after TBI, has excited the transient expression of IL-1 β mRNA in special brain zone regionally.Regionality among cytokine such as the IL-1 β changes after the wound of brain injury in pathologic or the reproducibility sequela plays a role.Can find suitable test method in WO97/35856 or WO97/49286, its content is quoted as a reference in this article.In the body-the atherosclerosis test
Be used to measure the atherosclerotic body inner model of mice and be test method based on the Paigen that revises slightly as described below etc.See Paigen B, Morrow A, Holmes PA, Mitchell D, Williams RA, the quantitative assay of the atherosis damage of mice medium-sized artery.Atherosclerosis (Atherosclerosis), 68:231-240 (1987); With Groot PHE, van Vlijmen BJM, Benson GM, Hofker MH, Schiffelers R, Vidgeon-Hart M, Havekes LM.APOE *In the 3 Leiden transgenic mices quantitative assay of atherosclerosis of aorta and with the relation of serum cholesterol.Arteriosclerosis, thrombosis and blood vessel biology (Arterioscler Thromb Vasc Biol) 16,926-933 (1996).The section of aortic sinus and dyeing
Obtain the cross section of aortic root by before described (1,2).In brief, under near the position, atrium, heart is divided into two, takes off heart bottom and aortic root and be used for analyzing.This is organized in the OCT chemical compound after the equilibrate overnight, heart is placed on the cryostat chuck (BrightInstrument Company Ltd.UK) be dipped in the OCT chemical compound, with aorta towards chuck.To organize freezing with this chuck of dry ice embedding.With direction, along the aorta direction heart is cut then by intracardiac beginning perpendicular to the aorta axle.In case confirmed after the aortic root by the outward appearance of three valve core lobe points, cut section and place on the slide glass of gelatinization by interval 10mm.The air drying of will cutting into slices 1 hour is washed in 60% isopropyl alcohol subsequently momently.,, use glycerin gelatine to be coated with coverslip, and seal section statining with oil red O with nial polish with Mayer hematoxylin counterstaining.The quantification that the aortic root medium-sized artery is atherosis
(Hitachi, Olvmpus BH-2 microscope HV-C10) is taken pictures with 4 times of object lens and video camera are housed with 10 parts of alternative aortic root sections.Obtain the polychrome of 24 bits, with being furnished with picture collection plate (Snapper, Active Imaging Ltd, Berks, U.K) personal computer (Datacell Pentium P5-133, Datacell, Berks, U.K), utilization Optimas software (version 5.1, Optimas Corp., WA U.S.A.) analyzes.These images are to obtain under the condition of identical illumination, microscope, photographing unit and personal computer.Use Optimas software, center on the damage zone setting-out with hands, atherosclerotic lesions area quantification.The setting color threshold value, its quantificational expression the area that is incarnadined in the damage zone.The cross-sectional area of damage zone and to incarnadine district's absolute value be to obtain after utilizing the image of the normal grid on the hematimeter slide glass that software is proofreaied and correct.
All publications of mentioning in this description include but not limited to patent and patent application, all quote in the present invention as a reference, are quoted as a reference just as each publication all ad hoc and individually indicates in this article comprehensively.
Above description discloses the present invention all sidedly, comprises its embodiment preferred.The correction of concrete the disclosed embodiments herein is within the scope of following claim with improving.Need not to be described in detail again, believe that those skilled in the art utilize above stated specification can use the present invention to greatest extent.Therefore, embodiment herein is interpreted as only illustrating for example, rather than limits the scope of the invention by any way.Wherein require embodiment of the present invention of proprietary property right or privilege to limit as follows.

Claims (7)

1. the method for the chemokine mediated mammalian diseases of treatment, this disease is to be selected from malaria, restenosis, vascularization, atherosclerosis, osteoporosis, gingivitis, bad hematopoietic stem cell release and the disease that is caused by respiratory virus, herpesvirus and hepatitis virus, wherein chemotactic factor combines with IL-8 α or beta receptor, and described method comprises the formula of this administration effective dose (I) compound or pharmaceutically acceptable salt thereof:
Figure A0080909500021
Wherein
X is oxygen or sulfur;
R is (CR 8R 8) rC (O) 2H, (CR 8R 8) rNH-C (O) R a, (CR 8R 8) rC (O) NR 6 'R 7 ', (CR 8R 8) rNHS (O) 2R b, (CR 8R 8) rS (O) 2NHR c, (CR 8R 8) rNHC (X 2) NHR b, or the tetrazolium basic ring;
X 2Be oxygen or sulfur;
R 1Be to be independently selected from hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, (CR 8R 8) qS (O) tR 4Hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroaryl alkyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, heteroaryl C 1-4Alkoxyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocyclic radical C 2-10Alkenyl, (CR 8R 8) qNR 4R 5C 2-10Alkenyl C (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 10S (O) 3R 8(CR 8R 8) qC (O) R 11C 2-10Alkenyl C (O) R 11C 2-10Alkenyl C (O) OR 11(CR 8R 8) qC (O) OR 12(CR 8R 8) qOC (O) R 11(CR 8R 8) qNR 4C (O) R 11(CR 8R 8) qNHS (O) 2R 17(CR 8R 8) qS (O) 2NR 4R 5Perhaps two R 1Can form O-(CH altogether 2) sSaturated or the unsaturated ring of O-or 5-6 unit; The part that wherein contains aryl, heteroaryl and heterocyclic radical can randomly be substituted;
N is the integer of 1-3;
M is the integer of 1-3;
Q is 0, or the integer of 1-10;
R is 0 or the integer of 1-4;
S is the integer of 1-3;
T is 0 or integer 1 or 2;
V is the integer of 1-4;
R 4And R 5Be hydrogen independently, the optional C that replaces 1-4Alkyl, the optional aryl that replaces, the optional aryl C that replaces 1-4Alkyl, the optional heteroaryl that replaces, the optional heteroaryl C that replaces 1-4Alkyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, perhaps R 4And R 5Form 5-7 unit ring with the nitrogen that they connected, this ring can randomly contain the hetero atom that another is selected from O/N/S;
R 6And R 7Be hydrogen or C independently 1-4Alkyl, perhaps R 6And R 7Form a 5-7 unit ring with the nitrogen that they connected, this ring can randomly contain the hetero atom that another is selected from oxygen, nitrogen or sulfur;
R 6 'And R 7 'Be independently selected from hydrogen, C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, heterocyclic radical C 2-4Alkenyl, condition are R 6 'And R 7 'One of be hydrogen, but be not hydrogen simultaneously;
Y is hydrogen independently, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, azido, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroaryl alkyl, heteroaryl C 1-4Alkoxyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocyclic radical C 2-10Alkenyl, (CR 8R 8) qNR 4R 5C 2-10Alkenyl C (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 10S (O) 3H; S (O) 3R 8(CR 8R 8) qC (O) R 11C 2-10Alkenyl C (O) R 11C 2-10Alkenyl C (O) OR 11C (O) R 11(CR 8R 8) qC (O) OR 12(CR 8R 8) qOC (O) R 11(CR 8R 8) qNR 4C (O) R 11(CR 8R 8) qNHS (O) 2R d(CR 8R 8) qS (O) 2NR 4R 5Perhaps two Y can form O-(CH altogether 2) sSaturated or the unsaturated ring of O-or 5-6 unit; And wherein contain aryl, heteroaryl and the heterocyclic radical part can randomly be substituted;
R 8Be independently selected from hydrogen or C 1-4Alkyl;
R 10Be C 1-10Alkyl C (O) 2R 8
R 11Be hydrogen, C 1-4Alkyl, the optional aryl that replaces, the optional aryl C that replaces 1-4Alkyl, the optional heteroaryl that replaces, the optional heteroaryl C that replaces 1-4Alkyl, the optional heterocyclic radical that replaces, or the optional heterocyclic radical C that replaces 1-4Alkyl;
R 12Be hydrogen, C 1-10Alkyl, optional aryl that replaces or the optional aralkyl that replaces;
R 13And R 14Be hydrogen independently, the optional C that replaces 1-4Alkyl, perhaps R 13With R 14In one can be the optional aryl that replaces;
R 17Be C 1-4Alkyl, aryl, aralkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl, aryl wherein, heteroaryl and heterocycle all can randomly be substituted;
R aBe alkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical, or heterocyclic radical C 1-4Alkyl, wherein all these groups all can randomly be substituted;
R bBe NR 6R 7, alkyl, aryl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, heterocyclic radical C 2-4Alkenyl, or camphoryl, wherein all these groups all can randomly be substituted;
R cBe alkyl, aryl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, or heterocyclic radical C 2-4Alkenyl, wherein all these groups all can be randomly by 1-3 halogen, nitro, halo C 1-4Alkyl, C 1-4Alkyl, C 1-4Alkoxyl, NR 9C (O) R a, C (O) NR 6R 7, S (O) 3H or C (O) OC 1-4Alkyl replaces independently;
R dBe NR 6R 7, alkyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, the ring that wherein contains aryl, heteroaryl and heterocyclic radical can randomly be substituted;
W is
Figure A0080909500041
The ring that contains E can randomly be selected from: Wherein *The junction point of number representative ring;
R 20Be W 1, the optional heteroaryl that replaces, the optional C that replaces 5-8Cycloalkyl, the optional C that replaces 1-10Alkyl, the optional C that replaces 2-10Alkenyl, or the optional C that replaces 2-10Alkynyl;
W 1Be
Figure A0080909500052
The ring that contains E ' randomly is selected from
Figure A0080909500053
*The junction point of number representative ring.
2. the process of claim 1 wherein that R is (CR 8R 8) rC (O) 2H.
3. the process of claim 1 wherein R 1Be halogen, cyano group, nitro, CF 3, C (O) NR 4R 5, alkenyl C (O) NR 4R 5, C (O) R 4R 10, alkenyl C (O) OR 12, heteroaryl, heteroaryl alkyl, heteroaryl alkenyl or S (O) NR 4R 5
4. the process of claim 1 wherein R 20Be W 1
5. the process of claim 1 wherein R 20It is heteroaryl.
6. the method for claim 4, wherein Y is halogen, C 1-4Alkoxyl, the optional aryl that replaces, optional alkoxy aryl, methylene-dioxy, the NR that replaces 4R 5, sulfo-C 1-4Alkyl, sulfur aryl, halogenated alkoxy, the optional C that replaces 1-4Alkyl, hydroxy alkyl.
7. the process of claim 1 wherein R 1Be substituted in 2 or 4 by the electron-withdrawing group single group, perhaps twoly be substituted in 2,4.
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