CN1494424A - IL-8 receptor antagonists - Google Patents

IL-8 receptor antagonists Download PDF

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CN1494424A
CN1494424A CNA008089205A CN00808920A CN1494424A CN 1494424 A CN1494424 A CN 1494424A CN A008089205 A CNA008089205 A CN A008089205A CN 00808920 A CN00808920 A CN 00808920A CN 1494424 A CN1494424 A CN 1494424A
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D·L·布赖安
�������ɭ
J·G·格莱森
��ά��ɭ
K·L·维多森
G·M·本森
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SmithKline Beecham Corp
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Abstract

This invention relates to novel compounds of Formula (I), pharmaceutical compositions and their use 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 new guanidine-containing compounds, pharmaceutical composition, its preparation method with and purposes in the disease of treatment IL-8, GRO α, GRO β, GRO γ, ENA-78 and NAP-2 mediation.
Background of invention
Interleukin 8 (IL-8) has many different titles, lure/activated protein-1 (NAP-1) such as neutrophilic granulocyte, come from monocytic neutrophilic chemotactic factor (MDNCF), the neutrophilic granulocyte activation factor (NAF) and T cell lymphocyte chemotactic factor.Interleukin 8 is the chemical inhibitor to neutrophilic granulocyte, basophil and T cell subsets, it is by comprising that the huge most nucleated cell of having a liking for cell, fibroblast, endotheliocyte and epithelial cell that are exposed to TNF, IL-1 α, IL-1 β or LPS produce, and by being exposed to LPS or being produced such as the neutrophilic granulocyte of the chemotactic factor of FMLP itself.M.Baggiolini etc., J.Clin.Invest.84,1045 (1989); J.Schroder etc., J.Immunol.139,3474 (1987) and J.Immunol.144,2223 (1990): Strieter etc., Science243,1467 (1989) and J.Biol.Chem.264,10621 (1989); Cassatella etc., 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 are also by titled with different titles, for example GRO α, β, γ are called as MGSA α, β and γ (melanoma growth-stimulating activity (Melanoma Growth StimulatingActivity)) respectively, see Richmond etc. J.Cell Physiology129,375 (1986) and Chang etc., J.Immunol148,451 (1992).All chemotactic factors that have a α family that is located immediately at the ELR motif before the CXC motif all with the combination of IL-8 beta receptor.
External, IL-8, GRO α, GRO β, GRO γ and NAP-2 have promoted many functions, and they all demonstrate the granulocytic chemical attractants characteristic of neutrality, and IL-8 and GRO α demonstrate T-lymphocyte and basophil chemotactic activity simultaneously.In addition, IL-8 can induce the basophil of normal and atopic individuality to discharge histamine.In addition, IL-8 and GRO-α can induce the lysozyme of neutrophilic granulocyte to discharge and respiratory burst.IL-8 also demonstrates has increased Mac-1 (CD11b/CD18) surface expression at neutrophilic granulocyte when not having de novo albumen synthetic.This can help to increase the adhesive attraction of neutrophilic granulocyte and vascular endothelial cell.Many known diseases are to be feature with a large amount of neutrophil infiltration.Promote gathering and activating of neutrophilic granulocyte as IL-8, GRO α, GRO β, GRO γ and NAP-2, these chemotactic factors are relevant with the very large-scale acute and chronic inflammation disease that comprises psoriasis and rheumatic arthritis, Baggiolini etc., FEBS Lett.307,97 (1992); Miller etc., Crit.Rev.Immunol.2,17 (1992); Oppenheim etc., Annu Rev. Immunol.9,617 (1991); Seitz etc., J.Clin.Invest.87,463 (1991); Miller etc., Am.Rev.Respir.Dis.146,427 (1992); Donnely etc., Lancet341,643 (1993).In addition, ELR chemotactic factor (those just in time before the CXC motif contain aminoacid ELR motif) is also relevant with antagonist, Strieter etc., Science258,1798 (1992).
External, by in conjunction with and activate the receptor of striding the G albumen coupling family of film for seven times, particularly pass through in conjunction with the IL-8 receptor, the most significant is the B receptor, IL-8, GRO α, GRO β, GRO γ and NAP-2 induce neutrophilic granulocyte alteration of form, chemotaxis, particle release and respiratory burst, Thomas etc. J.Biol.Chem.266,14839 (1991) and Holmes etc., Science253,1278 (1991).The development of this receptor family member's non-peptide micromolecule antagonist has had precedent, and its summary sees that R.Freidinger exists Progress in Drug Research, Vol.40, pp.33-98, Birkhauser Verlag, Basel1993.Therefore, the IL-8 receptor has been represented the target full of hope of novel anti-inflammatory drug development.
The feature of the human IL-8 receptor (77% homology) of two kinds of high-affinities is as follows: only with the bonded IL-8R α of IL-8 high-affinity, and the IL-8R β that IL-8 and GRO α, GRO β, GRO γ and NAP-2 is all had high-affinity.See Holmes etc., see above; Murphy etc., Science253,1280 (1991); Lee etc., J.Biol.Chem.267,16283 (1992); LaRosa etc., J.Biol.Chem.267,25402 (1992); With Gayle etc., J.Biol.Chem.268,7283 (1993).
In this field, to the treatment also need can with IL-8 α or the bonded chemical compound of beta receptor.Therefore, the chemical compound as IL-8 receptors bind inhibitor will be useful to increase (it is responsible for neutrophilic granulocyte and T cell subsets chemotactic are arrived areas of inflammation) relevant disease with the IL-8 generation.
Summary of the invention
The invention provides a kind of method for the treatment of chemokine mediated diseases, wherein, chemotactic factor and IL-8 α or beta receptor combination, and the method comprises formula (I) compound or pharmaceutically acceptable salt thereof of using effective dose.Particularly, this chemotactic factor is IL-8.
The invention still further relates to the method for needs inhibition IL-8 and its receptors bind in mammal, it comprises the chemical compound to the formula of above-mentioned administration effective dose (I).
The used formula of the present invention (I) compound or pharmaceutically acceptable salt thereof, formula (I) chemical compound has following structure:
Wherein
Z is cyano group, OR 11, C (O) NR 15R 16, R 18, C (O) R 11, C (O) OR 11, or S (O) 2R 17
R is that any functional group and pKa with dissociable hydrogen are 10 or lower;
R 1Independently be selected from hydrogen, halogen, nitro, cyano group, halogenated C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halogenated C 1-10Alkoxyl, azide, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy, aryl C 1-4Alkyl oxy, heteroaryl, heteroaryl alkyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, heteroaryl C 1-4Alkyl oxy, 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, (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 19, (CR 8R 8) qS (O) 2NR 4R 5, or two R 1Part can form O-(CH jointly 2) sO-or 5 to 6 yuan of saturated or unsaturated rings;
Q is 0 or 1～10 integer;
T is 0 or 1 or 2 integer;
S is 1～3 integer;
V is 0 or 1～4 integer;
R 4And R 5Independent is hydrogen, 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 or R 4With R 5With 5 to 7 yuan of rings of the common formation of coupled nitrogen, it can be chosen wantonly and comprise the hetero atom that another is selected from oxygen, nitrogen or sulfur;
Y independently is selected from hydrogen, halogen, nitro, cyano group, halogenated C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halogenated C 1-10Alkoxyl, azide, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy, aryl C 1-4Alkyl oxy, heteroaryl, heteroaryl alkyl, heteroaryl C 1-4Alkyl oxy, heterocyclic radical, heterocyclic radical 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, (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 d, (CR 8R 8) qS (O) 2NR 4R 5, or common O-(CH that form of two Y part 2) sO-or 5 to 6 yuan of saturated or unsaturated rings;
N is 1～3 integer;
M is 1～3 integer;
R 6And R 7Independent is hydrogen or C 1-4Alkyl; Or R 6With R 7With 5 to 7 yuan of rings of the common formation of coupled nitrogen, this ring can be chosen wantonly and comprise the hetero atom that another is selected from oxygen, nitrogen or sulfur;
R 8Independently be 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, the optional aryl that replaces or the optional aryl alkyl that replaces;
R 13And R 14Independent is hydrogen, the optional C that replaces 1-4Alkyl or R 13And R 14One of be the optional aryl that replaces;
R 15And R 16Independent hydrogen, 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, the optional heterocyclic radical that replaces, the optional heterocyclic radical C that replaces 1-4Alkyl or R 15And R 16Form 5 to 7 Yuans rings together with the nitrogen that is attached thereto, the optional hetero atom that is selected from oxygen, nitrogen or sulfur in addition that comprises of this ring;
R 17Be C 1-4Alkyl, NR 15R 16, OR 11, 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 18Be 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, the optional heterocyclic radical that replaces or the optional heterocyclic radical C that replaces 1-4Alkyl;
R 19Be C 1-4Alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl, wherein all groups can be optionally 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, wherein alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical and heterocyclic radical alkyl ring can be optionally substituted;
W is Or
Figure A0080892000112
The ring that contains E ' is selected from following ring:
Figure A0080892000113
Or
Figure A0080892000114
Asterisk * represents and encircles the point that is connected;
W 1Be
Figure A0080892000121
Or
The ring that comprises E is selected from following ring:
Figure A0080892000123
Figure A0080892000124
Or
Figure A0080892000125
Asterisk * represents and encircles the point that is connected.
Detailed Description Of The Invention
The chemical compound of formula (I) also can be used for and mammal, except the mankind, veterinary's treatment relevant, need to suppress IL-8 or with IL-8 α and bonded other chemotactic factor of beta receptor in.Treatment or prevention comprise chemokine mediated disease those diseases as partly mentioning at this paper Therapeutic Method in animal.
In formula (I) chemical compound, suitable W is
Figure A0080892000126
Or
Figure A0080892000127
The ring that contains E ' that the point of indicating by asterisk (*) is represented can be chosen existence wantonly.If there is no, then ring is the R that is expressed out 1The phenyl moiety that replaces.The E ring can be by the R in arbitrary ring 1Partly (saturated or unsaturated) replaces.This paper only provides the R on the unsaturated ring for this purpose 1Replace.
Suitable R provides any functional group of dissociable hydrogen, and its pKa is 10 or less than 10, be preferably about 3～9, more preferably from about 3～7.Such functional group include, but are not limited to hydroxyl, carboxylic acid, thiol ,-SR 2,-OR 2,-NH-C (O) Ra ,-C (O) NR 6 'R 7 ', formula-NHS (O) of replacing 2R b,-S (O) 2NHR c, NHC (X 2) NHR bSulfonamide or tetrazole radical, X wherein 2For oxygen or sulfur, be preferably oxygen.Preferably, this functional group is not a sulfonic acid, perhaps directly on aryl, heteroaryl or heterocyclic moiety ring, and perhaps as the substituent group on aryl, heteroaryl or the heterocyclic moiety ring, for example, at SR 2Or OR 2In.More preferably R is OH, SH or NHS (O) 2R b
Suitably, R 2The aryl, heteroaryl or the heterocyclic radical that be to replace, its ring has the functional group that dissociable hydrogen is provided, and pKa is 10 or less than 10.
Suitably, R 6 'And R 7 'Be 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, all these groups can be chosen wantonly independently by following groups one to three replacement: halogen; Nitro; Halogenated C 1-4Alkyl, for example CF 3C 1-4Alkyl, for example methyl; C 1-4Alkoxyl, for example methoxyl group; NR 9C (O) Ra; C (O) NR 6R 7S (O) 3H; Or C (O) OC 1-4Alkyl, prerequisite are to have only R 6 'And R 7 'One of be hydrogen, can not all be hydrogen.
Suitable, R 6And R 7Independent is hydrogen or C 1-4Alkyl, perhaps R 6And R 7Form 5～7 yuan of rings together with coupled nitrogen, the optional hetero atom that is selected from oxygen, nitrogen or sulfur that also contains of this ring.This heterocycle can be chosen place like this definition wantonly and be substituted.
Suitably, R aBe aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl, all these groups can be chosen wantonly and be substituted, as following definition.
Suitably, 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, all these groups can be chosen wantonly independently by following groups one to three replacement: halogen; Nitro; Halogenated C 1-4Alkyl, for example CF 3C 1-4Alkyl, for example methyl; C 1-4Alkoxyl, for example methoxyl group; NR 9C (O) Ra; C (O) NR 6R 7S (O) 3H; Or C (O) OC 1-4Alkyl.R bBe preferably optional phenyl, benzyl or the styryl that replaces.Work as R bWhen being heteroaryl, be preferably the optional thiazole that replaces, the optional thienyl that replaces or the optional quinoline basic ring that replaces.
Suitably, R 9Be hydrogen or C 1-4Alkyl is preferably hydrogen.Preferably, when substituent group be NR 9C (O) R aThe time, R then aBe preferably alkyl, for example methyl.
Suitably, R cBe hydrogen, alkyl, aryl, aryl C 1-4Alkyl, aryl C 1-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 1-4Alkenyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl or heterocyclic radical C 1-4Alkenyl, all these groups can be chosen wantonly independently by following groups one to three replacement: halogen, nitro, halogenated 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, wherein R 9Be hydrogen or C 1-4Alkyl.Preferably, R cBe the optional phenyl that replaces.
When R is OR 2Or SR 2During group, but one skilled in the art will recognize that aromatic ring must comprise required dissociates hydrogen.This aromatic ring also can be chosen wantonly by one to three group and replace independently, and these groups also can comprise another group that can dissociate, and it includes but not limited to halogen, nitro, halo C 1-4Alkyl, C 1-4Alkyl, C 1-4Alkoxyl, hydroxyl, SH ,-C (O) NR 6R 7,-NH-C (O) Ra ,-NHS (O) 2R b, S (O) 2NR 6R 7, C (O) OR 8Or tetrazole ring.
In formula (I) chemical compound, suitable R 1Independently be selected from hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl, for example CF3, C 1-10Alkyl, methyl for example, ethyl, isopropyl or n-pro-pyl, C 2-10Thiazolinyl, C 1-10Alkoxyl, for example methoxy or ethoxy, halo C 1-10Alkoxyl, for example trifluoromethoxy, azide, (CR 8R 8) qS (O) tR 4, wherein t be 0,1 or 2, hydroxyl, hydroxyl C 1-4Alkyl, for example methanol or ethanol, aryl, for example phenyl or naphthyl, aryl C 1-4Alkyl, for example benzyl, aryloxy, for example phenoxy group, aryl C 1-4Alkyl oxy, for example benzyl oxygen base, heteroaryl, heteroaryl alkyl, heteroaryl C 1-4Alkyl oxy, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocyclic radical 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, (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 19, (CR 8R 8) qS (O) 2NR 4R 5, or two R 1Common O-(the CH that forms of part 2) sO-or 5 to 6 yuan of saturated or unsaturated rings, and s is the integer of 1-3.The part that contains aryl, heteroaryl and heterocyclic radical can be chosen wantonly and be substituted, as give a definition.
Suitably, q is 0, or 1～10 integer.
Work as R 1When forming two oxo bridges, s is preferably 1.Work as R 1Form another saturated or undersaturated 5 to 6 yuan of whens ring, be preferably undersaturated 6 yuan of rings, form the naphthalene nucleus system.These rings can be independently by as the R of above-mentioned other 1Part replaces 1 to 3 time.
Suitably, R 4And R 5Independent is hydrogen, 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 yuan of rings together with coupled nitrogen, the optional hetero atom that is selected from O/N/S that also contains of this ring.
Suitable R 8Independently be selected from hydrogen or C 1-4Alkyl.
Suitable R 10Be C 1-10Alkyl C (O) 2R 8, CH for example 2C (O) 2H or CH 2C (O) 2CH 3
R 11Be suitable for hydrogen, C 1-4Alkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl.
Suitable R 12Be hydrogen, C 1-10Alkyl, the optional aryl that replaces or the optional aryl alkyl that replaces.
R 19Be C 1-4Alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, wherein all these groups can be chosen wantonly and be substituted;
Preferably, 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, and preferred R 4And R 5All be hydrogen or one of for phenyl.To R 1Preferred ring replacement is the 4-position at phenyl ring.
When R is OH, SH or NSO 2R bThe time, R then 1Preferably in the 3-position, the 4-position is substituted or 3, the 4-position is replaced by two.Substituent group is suitably for drawing electron group, and preferably working as R is OH, SH or NSO 2R bThe time, R 1Be nitro, halogen, cyano group, trifluoromethyl, C (O) NR 4R 5
When R is carboxylic acid, R 1Be preferably hydrogen, or R 1Preferably be substituted, more preferably replaced by trifluoromethyl or chlorine in the 4-position.
In formula (I) chemical compound, suitable R 13And R 14Independent is hydrogen, the optional C that replaces 1-4Alkyl, it can be straight or branched, perhaps R as defined herein 13And R 14One of be the optional aryl that replaces; V is 0 or 1～4 integer.
Work as R 13Or R 14During for the optional alkyl that replaces, this alkyl can be replaced by following groups one to three independently: halogen; Halogenated C 1-4Alkyl, for example trifluoromethyl; Hydroxyl; Hydroxyl C 1-4Alkyl; C 1-4Alkoxyl, for example methoxy or ethoxy; Halogenated C 1-10Alkoxyl; S (O) tR 4Aryl; NR 4R 5NHC (O) R 4C (O) NR 4R 5Or C (O) OR 8
In formula (I) chemical compound, W 1Be suitable for
Or
Figure A0080892000162
The ring that contains E that marks point of contact with asterisk (*) can be chosen existence wantonly.If it does not exist, encircle the phenyl that replaces into by Y as shown here.E ring can be replaced by the Y in any ring (saturated or unsaturated), and this paper only provides the replacement of Y on the unsaturated ring for this purpose.
Suitably, Y independently is selected from hydrogen, halogen, nitro, cyano group, halogenated C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halogenated C 1-10Alkoxyl, azide, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy, aryl C 1-4Alkyl oxy, heteroaryl, heteroaryl alkyl, heteroaryl C 1-4Alkyl oxy, 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 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, (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 5Perhaps two Y parts form O-(CH together 2) sO-or 5 to 6 yuan of saturated or undersaturated rings, the part that wherein contains aryl, heteroaryl, heterocyclic radical can be chosen wantonly as defined herein and be substituted.
If Y forms a dioxy Ji Qiao, s is preferably 1.If Y forms another saturated or undersaturated ring, it is preferably 6 yuan of rings and forms a naphthylene member ring systems.This naphthylene ring can be replaced for 1 to 3 time by other Y part of above-mentioned definition.Above-mentioned aryl, aryl alkyl, aromatic yl alkenyl, heteroaryl, heteroaryl alkyl, heteroaryl alkenyl, heterocyclic radical, heterocyclic radical alkyl and heterocyclic radical alkenyl part all can be optionally substituted as defined herein.
Suitably, 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 or heterocyclic radical C 2-4Alkenyl, wherein above-mentioned aryl, aryl alkyl, aromatic yl alkenyl, heteroaryl, heteroaryl alkyl, heteroaryl alkenyl, heterocyclic radical and heterocyclic radical alkyl and heterocyclic radical alkenyl all can be optionally substituted by this paper definition.
Y is preferably halogen, C 1-4Alkoxyl, the optional aryl that replaces, the optional aryloxy that replaces or alkoxy aryl, methylene dioxy base, NR 4R 5, sulfo-C 1-4Alkyl, thioaryl, halogenated alkoxyl, the optional C that replaces 1-4Alkyl or hydroxy alkyl.(mono-substituted halogen), the halogen dibasic (disubstituted halogen) of Y halogen list-replacement more preferably, alkoxyl mono-substituted (mono-substitutedalkoxy), alkoxyl dibasic (disubstitued alkoxy), methylene dioxy base, aryl or alkyl, more preferably these groups are single or two-replacement in 2 '-position or in 2 ', 3 '-position.
Y can be in 5 positions of ring the substituted while of any position, Y preferably 2 '-position or 3 '-position coverlet-replacements, 4 '-be preferably unsubstituted; More preferably R is OH, SH or NSO 2R bIf this ring is by dibasic, preferably working as R is OH, SH or NSO 2R bThe time, these substituent groups are preferably at monocyclic 2 ' or 3 '.At R 1When can all be hydrogen with Y, preferred is lacked a ring is substituted, and preferred two rings are substituted.
Preferably working as Z is cyano group, and W is a phenyl, and R is OH, and v is O and W 1During for phenyl, (Y) n, wherein n is 1 or 2, is not that 3 ' at phenyl ring is mono-substituted or dibasic by following groups in 3 ' of phenyl ring-5 ' position by following groups: halogen, trifluoromethyl, OCF 3, C (O) 2H, C (O) 2Alkyl, C (O) 2Aryl, C (O) amino, CN, alkyl, alkoxyl, hydroxyl, nitro, methylol, sulfonamides, amino, aryloxy, alkyl-carbonyl, aryl carbonyl, alkyl-carbonyl oxygen base or aryl carbonyl oxygen base.
In addition, preferably working as Z is cyano group, and v is 0, and W is a phenyl, and R is OH, W 1During for phenyl, Y (n), wherein n is 1, is not the aryl alkyl that 2-replaces, perhaps aromatic yl alkenyl (choose wantonly and replaced by alkyl).
In formula (I) chemical compound, Z is suitable for cyano group, OR 11, C (O) NR 15R 16, R 18, C (O) R 11, C (O) OR 11Or S (O) 2R 17
Suitably, R 15And R 16Independent is hydrogen, 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, the optional heterocyclic radical that replaces, the optional heterocyclic radical C that replaces 1-4Alkyl, or R 15And R 16With 5 to 7 yuan of rings of the common formation of coupled nitrogen, it is chosen wantonly and comprises the hetero atom that another is selected from oxygen, nitrogen or sulfur.
Suitably, R 17Be C 1-4Alkyl, NR 15R 16, OR 11, 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.
Suitably, R 18Be 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, the optional heterocyclic radical that replaces or the optional heterocyclic radical C that replaces 1-4Alkyl.
Unless stated otherwise, " the optional replacement " used herein refer to some groups like this: halogen, for example fluorine, chlorine, bromine or iodine; Hydroxyl; The C that hydroxyl replaces 1-10Alkyl; C 1-10Alkoxyl, for example methoxy or ethoxy; S (O) M 'C 1-10Alkyl, wherein m ' is 0,1 or 2, for example methyl sulfenyl, methyl sulfinyl or methyl sulphonyl; The amino of amino, list and two-replacement, for example group NR 4R 5In; NHC (O) R 4C (O) NR 4R 5C (O) OH; S (O) 2NR 4R 5NHS (O) 2R 21, C 1-10Alkyl, for example methyl, ethyl, propyl group, isopropyl or the tert-butyl group; Halogenated C 1-10Alkyl is as CF 3The optional aryl that replaces, phenyl for example, or the optional aryl alkyl that replaces, for example 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, wherein these aryl, heteroaryl or heterocyclic radical can be replaced for 1 to 2 time by following groups: alkyl, C that halogen, hydroxyl, hydroxyl replace 1-10Alkoxyl, S (O) M 'C 1-10The amino of alkyl, amino, list and two-replacement, for example group NR 4R 5In, C 1-10Alkyl or halogenated C 1-10Alkyl, for example CF 3
R 21Be suitable for C 1-4Alkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl.
Suitable officinal salt be well known to those skilled in the art those, and comprise inorganic or organic acid basic salt (basic salts), acid as: hydrochloric acid, 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 can also form with pharmaceutically useful cation, for example, if contain a carboxyl in a substituent group.Suitable pharmaceutically acceptable cation is well known to those skilled in the art, and comprises: alkali, alkaline earth, ammonium and quaternary ammonium cation.
Following term used herein is meant:
● " halogen "-all halogens, i.e. chlorine, fluorine, bromine and iodine.
● " C 1-10Alkyl " or " alkyl "-all refer to the straight or branched part of 1-10 carbon atom, unless chain length is had qualification in addition, it includes but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl etc.
● term used herein " cycloalkyl " is meant cyclic group, and preferred 3 to 8 carbon include but not limited to cyclopropyl, cyclopenta, cyclohexyl etc.
● term used herein " alkenyl " all refers to the straight or branched group of 2-10 carbon atom in all cases, unless chain length is had qualification in addition, 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 " is (in itself or any associating, such as " heteroaryl oxygen base " or " heteroaryl alkyl ")-5-10 unit aromatic ring system, wherein one or more rings contain the hetero atom of one or more N of being selected from, O or S, for example, but be not limited to pyrroles, pyrazoles, furan, thiophene, quinoline, isoquinolin, quinazoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazoles, triazole, imidazoles or benzimidazole.
● " heterocyclic radical " is (in itself or any associating, such as " heterocyclic radical alkyl ")-the saturated or undersaturated 4-10 of part unit member ring systems, wherein one or more rings contain the hetero atom of one or more N of being selected from, O or S, for example, but be not limited to pyrrolidine, piperidines, piperazine, morpholine, Pentamethylene oxide. or imidazoline.
● term used herein " aryl alkyl " or " heteroaryl alkyl " or " heterocyclic radical alkyl " do not refer to C as defined above if there is other explanation 1-10Alkyl is connected on aryl defined herein, heteroaryl or the heterocyclic radical part.
● the S of " sulfinyl "-corresponding sulfide (O) oxide, term " sulfo-" refers to sulfide, and term " sulfonyl " refers to the S (O) of complete oxidation 2Part.
● term used herein " two R wherein 1Partly (or two Y parts) can form 5 or 6 yuan of saturated or unsaturated rings jointly " finger-type becomes naphthylene member ring systems or phenyl moiety to link the undersaturated 6 yuan of rings of a part, as C 6Cycloalkenyl group, i.e. hexene or C 5The cycloalkenyl group part, cyclopentenes.
Comprising for example of formula (I) chemical compound:
N-(2-hydroxyl-4-nitrobenzophenone)-N '-(2-chlorphenyl)-N " cyanoguanidines
N-(2-hydroxyl-4-nitrobenzophenone) N '-(2-chlorphenyl)-N " cyanoguanidines
N-(4-cyano-2-hydroxy-phenyl)-N '-(phenyl) cyanoguanidines
N-(2-bromophenyl) N '-(4-cyano-2-hydroxy-phenyl) N " cyanoguanidines
N-(4-cyano-2-hydroxy-phenyl)-N '-(2, the 3-Dichlorobenzene base)-N " cyanoguanidines
N-(2-bromophenyl)-N '-(4-cyano-2-hydroxy--3-propyl group phenyl)-N " cyanoguanidines
N-(2-bromophenyl)-N '-(4-cyano-2-hydroxy--3-isobutyl phenenyl)-N " cyanoguanidines
N-(2-bromophenyl)-N '-(3-bromo-4-cyano-2-hydroxy-phenyl)-N " cyanoguanidines
N-(4-cyano group--2-hydroxyl-3-propyl group phenyl)-N '-(2, the 3-Dichlorobenzene base)-N " cyanoguanidines; With
N-(3-bromo-4-cyano-2-hydroxy-phenyl)-N '-(2,3-methylenedioxyphenyl base)-N " cyanoguanidines
N-(2-chlorphenyl)-N '-(4-cyano-2-hydroxy--3-propyl group phenyl)-N " cyanoguanidines; With
N-(2-bromophenyl)-N '-(4-cyano-2-hydroxy--3-methoxycarbonyl phenyl)-N " cyanoguanidines.
Should be realized that The compounds of this invention can stereoisomer, regional isomer (regioisomers) or diastereomer exist.These chemical compounds can comprise one or more asymmetric carbon atoms also can raceme and the existence of optical activity form.All these chemical compounds all comprise within the scope of the invention.
Can use the chemical compound of synthetic method, illustrate in the some of them method route hereinafter with acquisition formula (I).The synthetic method that provides in these routes can be used for the chemical compound of production formula (I), and it has various R, the R that reacts 1, and aryl and using by the optional substituent group of due care to reach consistent with listed reaction herein.In these cases, deprotection obtains former chemical compound of the present disclosure subsequently.In case constitute guanidine nuclear, other chemical compounds of these formulas just can prepare by the standard technique that functional group known in the art transforms.And the chemical compound that has only formula (I) that these routes show, this only is in order to illustrate.
Preparation method
Title compound can pass through thiocarbamide salt (thiouronium salt) ( 2, route 1) and synthetic.R ' is as the define and represent-(R in formula (I) chemical compound 13R 14) v-W 1Connect.For illustrative purposes, the phenyl of W for replacing of route representative herein.
Route 1
A) Na, EtOH, cyanamide b) EDCHCl
Thiocarbamide salt ( 2, route 1) and can be by sodium cyanamide and commercially available isothiocyanate 1 synthetic (if buy less than isothiocyanate, it can react synthetic by purpose amine and thio phosgene in the presence of alkali such as sodium bicarbonate).Thiocarbamide salt ( 2) can in the presence of coupling agent such as EDCHCl, react then through condensation or acidify formation cyano group thiourea with the aniline of suitable replacement.
In addition, 4Cyanoimino acid diphenyl (diphenyl cyanocarboimidate) that can be by commercially available (Aldrich Chem.Co.) ( 5, route 2) and generate intermediate O-phenyl isothiourea with the amine reaction 6, in the presence of trimethyl aluminium, pass through the method for Atwal and the aniline reaction of suitable replacement then.(Atwal，K.S.，Tetrahedron?Lett，35，8085(1994))。Wherein R ' is that the chemical compound of alkyl can be by with the alkylamine of suitable replacement, but adds hot preparation in the presence of catalyst-free.
Route 2
Figure A0080892000211
A) acetonitrile, heating b) AlMe 3
In addition, the title compound aniline that can replace with the ortho position of protection ( 8, route 3, synthetic referring to the US provisional application USSN60/020655 that submitted on June 27th, 1996, Attorney Docket No.:P50467P; The WO96/25157 that on August 22nd, 1996 submitted to, Widdowson etc. (Attorney Docket No.:P50324-1); And the USSN 08/701,299 (description among the Attorney Docket No.:P50324-2) of submission on August 21st, 1996, its disclosure all is incorporated herein by reference at this.The aniline that the ortho position replaces ( 7Route 3) aniline that at first replaces by the ortho position and suitable alkyl or silyl halides are reacted be protected (for example t-butyldimethylsilyl, pi-allyl, benzyl, mom or other suitable protecting group) in aprotonic solvent in the presence of suitable alkali (for example cesium carbonate, potassium carbonate or imidazoles).The Nitrobenzol that the also available ortho position of the aniline that the ortho position of protection replaces replaces ( 9) under condition well-known in the art, react to synthesize with blocking group and (see Greene, T Protecting Groups In Organic Synthesis, Wiley﹠amp; Sons, New York, 1981).Use SnCl then 2In EtOH or use H 2/ Pd or LiAlH 4The nitro compound that in aprotic solvent the ortho position of this protection is replaced is reduced into corresponding aniline.
Route 3
Figure A0080892000221
A) alkyl or silyl halides, alkali b) Reducing agent
Then with thio phosgene and subsequently with anion ZNH -(by ZNH 2Form with alkali such as NaH reaction) the reaction aniline that the ortho position of this protection can be replaced ( 8) change into isothiocyanate.Z is suc as formula defining in (I) chemical compound.Then with alkylating reagent such as iodomethane with resulting sulfo-anion alkylation generate sulfo-imino-ester (thioimidate) as 10(route 4).
Route 4
a)ClCSCl，NaHCO 3b)ZNH -c)MeI
By with amine R ' NH 2Reaction can change into title compound with sulfo-imino-ester (10, route 5) 4This reaction can have the slaine of high-affinity such as mercury oxide or silver acetate or by quickening to form leaving group preferably with the dimethyl ethylene oxide sulfur oxide to sulfur by adding.At last, slough the phenol protection with standard method and generate title compound 4
Route 5
Figure A0080892000232
A) RNH 2B) deprotection
In addition, carbodiimides (11, route 6) and the anion N H-Z that title compound can be by protection is (by NH 2Z and alkali for example NaH reaction generate) reaction or with neutral compound NH 2Z (Z=CN) and tertiary amine base; for example H ü nig alkali (diisopropylethylamine), triethylamine, triisopropyl ethamine, N; N-dimethyl benzylamine or N; N-dimethyl isopropylamine; reaction is synthetic under the condition of a large amount of excessive existence of nucleopilic reagent; and the response time should finish short as much as possible by careful monitoring reaction, subsequently deprotection.Be used for herein that other suitable alkali comprises secondary amine, for example pyridine and the amino pyridine derivate that replaces.Be used for suitable solvent herein and comprise various aprotonic solvents, for example acetonitrile during for cyano group as Z; Halogenated solvent, for example chloroform and dichloromethane; Ethohexadiol (gylcol)-dimethyl ether (single GLYME), diox, DMF and DMSO; Or its mixture, preferred acetonitrile.One of ordinary skill in the art would recognize that to the limiting factor of solvent-applied herein be the dissolubility of cyano group derivative compound.For Z wherein is not the chemical compound of cyano group, is simultaneously preferred at aprotonic solvent, one of ordinary skill in the art would recognize that and can use other suitable solvent, for example proton solvent, i.e. alcohol.
Preferred reaction (when Z is cyano group) temperature is-10 ℃ to about 100 ℃ approximately, preferably about 10 ℃ to about 50 ℃, and room temperature more preferably from about, promptly 20～30 ℃.
" part can be utilized suitably deprotection of art-recognized technology to the R of protection.When protecting group was allyl deriv, deprotection preferably took off allylation by palladium (O) catalysis.
Route 6
Figure A0080892000241
A) ZNH -(ZNH 2+ NaH) for Z=OR, COOEt, CHO, RNHSO 2, ArNHSO 2
B) ZNH 2.HCl for Z=OH c) ZNH 2And NR 3For Z=CN d) deprotection
Carbodiimides 11By thiourea ( 12a, route 7) by handle with phosgene and tertiary amine base or with thiourea ( 12a) or urea ( 12b) by with triphenylphosphine, carbon tetrachloride and triethylamine prepared in reaction.
Carbodiimides also can pass through thiourea ( 12b) with excessive, for example 2 or how normal methane sulfonyl chloride and tertiary amine base, for example H ü nig alkali (diisopropylethylamine), triethylamine, triisopropyl ethylamine, N, N-dimethyl benzylamine or N, N-dimethyl 2-aminopropane., preferred triethylamine prepared in reaction.This reacts available any halogenated solvent, for example dichloromethane, chloroform or tetrachloroethylene etc.; Suitable reaction temperature is-30 ℃ to about 80 ℃ approximately, and preferred-10 ℃ to about 50 ℃, more preferably from about 0 ℃ is arrived about room temperature.Referring to Fell and Coppola (Fell, J.B., Coppola, J.B., Syn Communications 25,43, (1995).
Route 7
A) phosgene, Et 3N, b) Ph 3P, CCl 4, Et 3N; C) MsCl, Et 3N
Thiourea or urea synthesize described in Attorney Docket No.:P50467P and the Attorney Docket No.:P50324-2 by the US provisional application USSN60/020655 that submits to as on June 27th, 1996, and its disclosure is hereby incorporated by.Thiourea ( 12a, route 8) and the suitable alkali of the O-substituted aniline of also available protection and two equivalents such as NaH, KH, calcium hydride reaction, and gained anion and the commercially available isothiocyanate (W that gets 1-NCS, wherein W 1As formula (I) chemical compound is defined) prepared in reaction.This reaction can be carried out in the preferred dimethyl formamide at any suitable aprotonic solvent or halogenated solvent.This reaction suitable reaction temperature is-10 ℃ to about 50 ℃ approximately.
If the isothiocyanate of purpose buy less than, can prepare by corresponding aniline and thiophosgene and suitable alkali such as reaction of sodium bicarbonate.
Route 8
A) R ' NCS alkali b)
Another aspect of the present invention is new formula (II) chemical compound
W 1-N＝C＝N-W (II)
Wherein W and W 1Suc as formula (I) definition, and W comprises suc as formula R group (the R ") protection that defines in (I) chemical compound or unprotected.
Another aspect of the present invention is new formula (III) chemical compound
W 1-NH-C(S)-NH-W (III)
Wherein W and W 1Suc as formula (I) definition, and W comprises suc as formula R group (the R ") protection that defines in (I) chemical compound or unprotected.
Therefore, formula (I) chemical compound protection (R ") form also within the scope of the invention.
Should recognize that guanidine functional group can have a lot of different tautomerides, for example, W 1-N-C (=NZ)-NW; ZN=C (NW 1)-NW; W 1-N-C (=NW)-and NZ, all these is within the scope of the invention.
The officinal salt of formula (I) chemical compound can obtain by known method, for example in the presence of suitable solvent with an amount of acid or alkali treatment formula (I) chemical compound.
In these embodiments, all temperature be degree centigrade (℃).Unless otherwise indicated, mass spectrum is to use fast atom bombardment, measures on VG Zab mass spectrograph. 1H-NMR (hereinafter for " NMR ") spectrum be respectively with on Bruker AM 250 or the AM400 spectrometer under 250MHz or 400MHz record.Represented multiplet is: s=is unimodal, d=is bimodal, t=triplet, q=quartet, m=multiplet and br represent wide signal.Sat. refer to saturated solution, equiv. refers to the molar equivalent ratio of reagent with respect to the dominant response thing.
Flash chromatography carries out with Merck silica gel 60 (230-400 order).
Synthetic embodiment
The present invention will be described by the following example, and these embodiment are illustrative, and can not be interpreted as the restriction to field of the present invention.Unless otherwise indicated, all degree centigrade to provide, solvent used herein all is obtainable highest purities to all temperature, and respond and all under argon atmospher, anhydrous condition, carry out.
Embodiment 1
N-(2-hydroxyl-4-nitrobenzophenone)-N '-(2-chlorphenyl)-N " preparation of cyanoguanidines
A) N-(2-chlorphenyl)-N " cyano group thiourea sodium salt
With sodium (1.64g 71.3mmol) is dissolved in the ethanol until stopping to produce gas fully, add then cyanamide (1.685g, 40mmol).Stirred reaction mixture 15 minutes adds 2-chlorphenyl isothiocyanate (7.21g, 42.66) and keeps backflow 6 hours.Reaction mixture and with dichloromethane dilution, the white solid of filtering-depositing and drying obtain N-(2-chlorphenyl)-N " cyano group thiourea sodium salt (8.26g, 87.5%).MS(ES +)m/e?210，212[M+H] +
B) N-(2-hydroxyl-3-nitrobenzophenone)-N '-(2-chlorphenyl)-N " cyanoguanidines stir, under the Ar atmosphere; to N-(2-chlorphenyl)-N '-cyano group thiourea sodium salt (234mg; 1mmol) and 2-hydroxyl-3-nitro-aniline (156mg; (384mg, 2mmol) and at room temperature stirring reaction is 4 days to add the EDC hydrochlorate in 2ml anhydrous DMF solution 1mmol).Reactant mixture is distributed and water and salt water washing organic extract liquid between EtOAc and 1N HCl.Dry (Na 2SO 4) and solvent evaporated under reduced pressure separate and to obtain red oil.Through chromatograph (silica gel, 3% acetone/CHCl 3) obtain glassy yellow solid (30mg, 9%), obtain title compound with the t-butyl methyl ether recrystallization. 1H?NMR(400MHz，CDCl 3)δ10.93(s，1H)，8.53(s，1H)，7.92(d，J＝7.8Hz，1H)，7.61(d，J＝7.8Hz，2H)，7.38-7-50(m，2H)，7.22(s，1H)，7.08(t，1H)；IR(KBr)2181cm -1；MS(ES -)m/e?330[M-H] -；mp.163-164°。
Embodiment 2
N-(2-hydroxyl-4-cyano-phenyl)-N '-(2-bromophenyl)-N " preparation of cyanoguanidines
A) 1-pi-allyl oxygen base-5-cyano group-2-Nitrobenzol
Under room temperature, argon atmospher, stir 5-cyano group-2-nitro-phenol (3.0g, 18.9mmol), pi-allyl bromination thing (1.82ml, 21.0mmol) and cesium carbonate (7.39g, DMF 22.7mmol) (20ml) mixture 18 hours.Reactant mixture is distributed between the tert-butyl group-methyl ether and water, tell organic layer, water layer continues extraction (x3).The organic layer that merges washes twice with water, then with the salt water washing and use MgSO 4Drying is filtered.Removal of solvent under reduced pressure obtains title compound (3.89g, 100%). 1H?NMR(400MHz，CDCl 3)δ7.87(d，J＝8.5Hz，1H)，7.35(dd，J＝8.4Hz?J＝1.2Hz?1H)，7.35(d，J＝1.5Hz，1H)，6.02(m，1H)，5.52(d，1H)，5.43(d，1H)，4.73(dd，J＝3.6Hz?J＝1.2Hz?2H)；
B) 2-pi-allyl oxygen base-4-cyano-aniline
At room temperature stir 1-pi-allyl oxygen base-5-cyano group-2-Nitrobenzol (3.6g, 17.46mmol) stannic chloride (II) (19.7g, ethanol 87.3mmol) (100ml) mixture overnight.Removal of solvent under reduced pressure, with reactant mixture at 5%NaHCO 3And distribute between the ethyl acetate, filtering mixt is removed pink salt and is further used ethyl acetate extraction water layer (x4).Organic facies water and the salt water washing that merges also used MgSO 4Dry.Removal of solvent under reduced pressure obtains brown solid (2.82g), obtains title compound with the tert-butyl group-methyl ether/hexane recrystallization, is the light brown solid.(2.63g，93％)MS(ES +)m/e?175[M+H] +；MS(ES -)m/e?173[M-H] -；
C) N-(2-pi-allyl oxygen base-4-cyano-phenyl)-N '-(2-bromophenyl)-thiourea.
Under 0 °, (60% oil dispersion adds 2-pi-allyl oxygen base-4-cyano-aniline (522mg, DMF 3mmol) (1.5ml) solution among the 240mg, DMF 6.0mmol) (10ml) to the sodium hydride of crossing with hexane wash in advance.Under 0 ℃, Ar atmosphere, stir after 15 minutes, drip isothiocyanic acid (2-bromophenyl) ester and stirring reaction 1 hour at room temperature down, add 0.5M sodium dihydrogen phosphate cessation reaction at 0 °.The mixture ethyl acetate extraction washes and uses dried over sodium sulfate with water.The crude product solid obtains title compound with recrystallizing methanol, is white solid (911mg, 78%) MS (ES +) m/e 388,390[M+H] +
D) N-(2-pi-allyl oxygen base-4-cyano-phenyl)-N '-(2-bromophenyl)-carbodiimides
At 0 ℃, Ar atmosphere, stir under, to N-(2-pi-allyl oxygen base-4-cyano-phenyl)-N '-(2-bromophenyl)-thiourea (900mg, 2.32mmol) and triethylamine (1ml, drip in dichloromethane solution 6.95mmol) methane sulfonyl chloride (360uL, 4.64mmol).0 ℃ of following stirring reaction 15 minutes, tlc showed and does not have raw material.Reactant mixture obtains title compound through the silica gel chromatography purification with the dichloromethane eluting, is yellow solid (1.2g,＞100%).This chemical compound is used for next step reaction without being further purified.
E) N-(2-pi-allyl oxygen base-4-cyano-phenyl)-N '-(2-bromophenyl)-N " cyanoguanidines
Stir down, to cyanamide (560mg, 13.33mmol) and the acetonitrile mixture of Huinig alkali (2.6ml) in drip N-(2-pi-allyl oxygen base-4-cyano-phenyl)-N '-(2-bromophenyl)-carbodiimides (600mg, acetonitrile 1.69mmol) (30ml) solution.At room temperature stirring reaction is 15 minutes, removal of solvent under reduced pressure then, and residue is with the hydrolysis of 0.5M sodium dihydrogen phosphate.The acetic acid ethyl acetate extract of water solution mixture with the 0.5M sodium dihydrogen phosphate and and the salt water washing, dry (MgSO 4) after-filtration and solvent evaporated under reduced pressure obtain crude product brown solid (500mg).This solid obtains title compound (455mg, 95%) through silica gel (50/50 ethyl acetate/hexane) chromatogram purification.MS(ES -)m/e?394，396[M-H] -
F) N-(4-cyano-2-hydroxy-phenyl)-N '-(2-bromophenyl)-N " cyanoguanidines
At room temperature, to N-(2-pi-allyl oxygen base-4-cyano-phenyl)-N '-(2-bromophenyl)-N " cyanoguanidines (100mg; 0.25mmol) and borohydride sodium (20mg, add in THF 0.52mmol) (3ml) mixture tetra-triphenylphosphine palladium [O] (21mg, 7mol%).At room temperature stirring reaction shows that up to tlc no raw material exists.Mixture is distributed between ethyl acetate and 0.5M sodium dihydrogen phosphate.Use MgSO 4Dry after-filtration and vapourisation under reduced pressure obtain brown solid crude product (100mg).Through silica gel chromatography, obtain title compound with 5% methanol/chloroform eluting, be light yellow solid (64mg).Obtain title compound (42mg, 47%) with the chloroform recrystallization. 1H?NMR(400MHz，DMSO)δ10.93(s，1H)，9.57(s，1H)，8.74(s，1H)，7.84(d，J＝8.3Hz，1H)，7.71(d，J＝7.8Hz，2H)，7-50-7.42(m，2H)，7.30-7.26(m，2H7.17(s，1H)，7.08(t，1H)；IR(KBr)2224，2193cm -1；MS(ES-)m/e?354，356[M-H] -；MS(ES +)m/e?356，358[M+H] +；mp.175-176°。
Embodiment 3
N-(4-cyano-2-hydroxy-phenyl)-N '-(phenyl)-N " preparation of cyanoguanidines
A) 5-cyano group-1-methoxy oxygen base-2-Nitrobenzol
At room temperature, to the sodium hydride of crossing with hexane wash in advance (60% oil dispersion, Dropwise 5-cyano group among the 260mg, THF 6.5mmol) (5ml)-2-nitro-phenol (978mg, THF 5.96mmol) (10ml) solution.Solution becomes bright orange and forms the bulk precipitation.After at room temperature stirring 15 minutes, under agitation dripping bromine methyl ether also at room temperature stirred 18 hours in above-mentioned slurry.Yellow mixture is distributed and aqueous phase extracted (X3), with 5% sodium bicarbonate solution (X4) and salt water washing between the tert-butyl group-O-methyl ether and water.Dry (MgSO 4) after-filtration and solvent evaporated under reduced pressure obtain title compound, be light yellow solid (1.05g, 85%). 1H?NMR(400MHz，CDCl 3)δ7.84(d，J＝8.4Hz，1H)，7.66(d，J＝1.4Hz1H)，7.35(dd，J＝8.4Hz?J＝1.5Hz，1H)，5.34(s，2H)，3.55(s，3H)。
B) 4-cyano group-2-methoxy oxygen base aniline
At room temperature, Hydrogen Vapor Pressure is under the 1atm, with 5-cyano group-1-methoxy oxygen base-2-Nitrobenzol (0.5g, 2.4mmol) and 10% palladium charcoal (.05g) mixture in ethyl acetate (50mL) stir 72h.Obtain title compound (250mg, 58%) to remove palladium and residue through silica gel chromatography purification (ethyl acetate/hexane eluting) by the Celite filtering mixt with 25%.MS(ES +)m/e?179[M+H] +
C) N-(4-cyano group-2-methoxy oxygen base phenyl)-N '-(2-phenyl)-N " cyanoguanidines
According to the step of embodiment 1 (c)-1 (e), except replacing isothiocyanic acid 2-bromophenyl ester with the isothiocyanic acid phenylester and replacing 2-pi-allyl oxygen base-4-cyano-aniline, preparation title compound (24% total recovery) with 2-methoxy oxygen base-4-cyano-aniline.IR(KBr)2226，2198cm -1；MS(ES -)m/e?320[M-H] -
D) N-(4-cyano-2-hydroxy-phenyl)-N '-(phenyl)-N " cyanoguanidines
(47mg 0.146mmol) is dissolved in the ethyl acetate (20mL), handles and at room temperature stirs 3 hours with 6NHCl (10mL) with the chemical compound of embodiment 2 (b).Add 6N HCl (5mL) then and continued restir 2 hours.Mixture dilutes water reuse ethyl acetate extraction (X5) with ethyl acetate and saline.The organic facies that merges obtains title compound (64mg) with dried over sodium sulfate and vaporising under vacuum, obtains title compound with the tert-butyl group-O-methyl ether recrystallization, is white solid (2mg, 5%). 1H?NMR(400MHz，DMSO?d 6)δ9.70(s，1H)，9.12(s，1H)，7.62(d，J＝8.3Hz，1H)，7.55(d，J＝1.2Hz，1H)，7.49(dd，J＝1.2Hz，J＝8.1Hz，1H)，7.36(m，4H)，7.18(m，1H)；IR(KBr)2233，2192cm -1；MS(ES +)m/e?278[M+H] +；MS(ES -)m/e?276[M-H] -；mp270-271℃。
Embodiment 4
N-(4-cyano-2-hydroxy-phenyl)-N '-(2, the 3-Dichlorobenzene base)-N " preparation of cyanoguanidines
Remove with isothiocyanic acid (2,3 Dichlorobenzene base) ester and replace outside isothiocyanic acid (2-bromophenyl) ester, make title compound (17% total recovery) according to the method for embodiment 1 (a)-1 (e).IR(KBr)2231，2197cm -1；MS(ES +)m/e?346，348，350[M+H] +；MS(ES -)m/e344，346，347，348[M-H] -；mp?155-156℃。
Embodiment 5
N-(2-bromophenyl)-N '-(4-cyano-2-hydroxy--3-propyl group phenyl)-N " preparation of cyanoguanidines
A) 2-amino-5-cyano-6-third-1-alkene-3-base-phenol
Under argon atmospher, use N, (1.88g 1.29mmol) and at 175 ° (oil bath temperatures) keeps 3.5h down to the chemical compound of accelerine (20mL) Processing Example 2 (b) preparation.Remove under vacuum and desolvate, residue obtains title compound with the methyl-tertbutyl ether recrystallization that contains each 10-20% dichloromethane and hexane, is transparent solid (1.67g, 89%).MS(ES +)m/e175[M+H] +；MS(ES -)m/e?173[M-H] -；
B) 2-amino-5-cyano-6-propyl group-phenol
In the presence of room temperature, 1atm hydrogen, stir 2-amino-5-cyano-6-third-1-alkene-3-base-phenol (0.5g, 2.4mmol) and ethyl acetate (50mL) mixture of 10% palladium charcoal (.05g) 2 hours.Mixture removes by filter palladium and filtrate decompression is concentrated through Celite and obtains title compound, is white powder solid (1.2g, 78%).MS(ES +)m/e?177[M+H] +；MS(ES -)m/e?175[M-H] -。
C) N-(2-bromophenyl)-N '-(4-cyano-2-hydroxy--3-propyl group phenyl)-N " cyanoguanidines
Except that replacing 5-cyano group-2-nitro-phenol, make title compound (37% total recovery) according to the method for embodiment 2 (a)-1 (e) with 2-amino-5-cyano-6-propyl group-phenol. 1H?NMR(400MHz，DMSO?d 6)δ9.72(s，1H)，9.45(s，1H)，8.66(s，1H)，7.71(d，J＝7.0Hz，1H)，7.56(d，J＝8.4Hz，1H)，7.45(m，2H)，7.28(d，J＝8.4Hz，1H)，7.26(t，1H)，2.76(t，J＝7.5，2H)，1.55(hextet，J＝7.6，2H)，0.93(t，J＝7.3，3H)；IR(KBr)2224，2184cm -1；MS(ES +)m/e?398，400[M+H] +；MS(ES -)m/e?396，398[M-H] -；
Embodiment 6
N-(4-cyano-2-hydroxy--3-propyl group phenyl)-N '-(2, the 3-Dichlorobenzene base)-N "-cyanoguanidines Preparation
Remove with isothiocyanic acid (2, the 3-Dichlorobenzene base) ester replaces isothiocyanic acid (2-bromophenyl) ester, replaces outside 2-pi-allyl oxygen base-4-cyano-aniline with 2-pi-allyl oxygen base-4-cyano group-3-propyl group aniline, makes title compound (7% total recovery) according to the method for embodiment 1 (b)-1 (e).IR(KBr)2236，2182cm -1；MS(ES+)m/e?388，390，391[M+H] +；MS(ES -)m/e?386，388，390[M-H] -；mp?143-147℃。
Embodiment 7
N-(2-chlorphenyl)-N '-(4-cyano-2-hydroxy--3-propyl group phenyl)-N " preparation of cyanoguanidines
Except that replacing isothiocyanic acid (2-bromophenyl) ester with isothiocyanic acid (2-chlorphenyl) ester and, make title compound (26% total recovery) according to the method for embodiment 1 (b)-1 (e) with 2-pi-allyl oxygen base-4-cyano group-3-propyl group aniline replacement 2-pi-allyl oxygen base-4-cyano-aniline.IR(KBr)2225，2187cm -1；MS(ES +)m/e?354，356[M+H] +；MS(ES -)m/e352，354[M-H] -；mp?159-160℃。
Embodiment 8
N-(2-bromophenyl)-N '-(4-cyano-2-hydroxy--3-isobutyl phenenyl)-N " system of cyanoguanidines Be equipped with
Remove with 3-bromo-2-methyl isophthalic acid-propylene and replace pi-allyl bromination beyond the region of objective existence, make title compound (16% total recovery) according to the method for embodiment 4 (a)-1 (c).IR(KBr)2231?2189cm -1；MS(ES +)m/e?412，414[M+H] +；MS(ES -)m/e?410，412[M-H] -；
Embodiment 9
N-(2-bromophenyl)-N '-(3-bromo-4-cyano-2-hydroxy-phenyl)-N " preparation of cyanoguanidines
A) 2-bromo-3-hydroxyl-4-nitrobenzonitrile
To 3-hydroxyl-4-nitrobenzonitrile (3.03g, add in dichloromethane 18.4mmol) (660ml) solution hexamethylenetetramine chemical compound (1: 1) contain tribromide hydrogen (9.91g, 26.0mmol).At room temperature stir one week of gained solution.Reactant mixture 1N HCl acidify, the EtOAc/ hexanes mixtures extraction with 1/1.Merge organic layer, use MgSO 4Dry also filtration.Evaporating solvent, (50/50: hexane/EtOAc) purification obtains purpose product (1.47g, 35.0%) to the gained solid with silica gel chromatography.MS(ES -)m/e?241，243[M-H] -。
B) N-(2-bromophenyl)-N '-(3-bromo-4-cyano-2-hydroxy-phenyl)-N " cyanoguanidines
Except that replacing 5-cyano group-2-nitro-phenol with 2-bromo-3-hydroxyl-4-nitrobenzonitrile, make title compound according to the method for embodiment 2 (a)-1 (e), be beige solid.(44% total recovery behind the chromatogram purification, total recovery 15% behind the recrystallization). 1H?NMR(400MHz，DMSO?d 6)δ10.66(s，1H)，9.56(s，1H)，8.92(s，1H)，7.71(d，J＝8.0Hz，1H)，7.68(d，J＝8.5Hz，1H)，7.48-7.41(m，3H)，7.26(t，1H)；IR(KBr)2228，2186cm -1；MS(ES +)m/e?434，436，438[M+H] +；MS(ES -)m/e?432，434，436[M-H] -；mp?142℃
Embodiment 10
N-(3-smelly-4-cyano-2-hydroxy-phenyl)-N '-(2,3-methylenedioxyphenyl base)-N " cyanogen The preparation of base guanidine
Except that replacing Carbimide. (2-bromophenyl) ester, make title compound (14% total recovery) according to the method for embodiment 8 (a)-1 (b) with isothiocyanic acid methylenedioxyphenyl base ester.IR(KBr)2230，2196cm -1；MS(ES +)m/e?400，402[M+H] +；MS(ES-)m/e398，400[M-H] -；mp?164-165℃
Embodiment 11
N-(2-bromophenyl)-N '-(4-cyano-2-hydroxy--3-methoxycarbonyl phenyl)-N " cyanoguanidines Preparation
A) methyl-2,6-resorcylic acid ester
Under Ar atmosphere, (10.00g, DMF 333.3mmol) (45mL) solution is cooled to 0 ℃ with 80%NaH.In this mixture, slowly add 2 in the time more than 45 minutes, 6-resorcylic acid (48.88g, DMF 317.1mmol) (50mL) solution.Stir this solution 45min, then above time of 20min add MeI (21.0mL, 337mmol).At room temperature stir gained solution 70h.Filter with dichloromethane diluted mixture thing and through silicagel column, use the dichloromethane eluting.Evaporating solvent obtains purpose product (35.22g, 66.1%). 1H?NMR(250MHz，DMS0?d 6)δ9.91(s，2H)，7.09(t，J＝1.2Hz，J＝2.5Hz，1H)，6.37(d，J＝1.1Hz，2H)，3.78(s，3H)。
B) methyl-2-benzyl oxygen base-6-hydroxybenzoate
Under Ar atmosphere, to methyl-2,6-resorcylic acid ester (20.00g, add in DMF 118.9mmol) (100mL) solution 80%NaH (3.9144g, 130.5mmol), add subsequently benzyl bromide a-bromotoluene (25.5mL, 214.5mmol).At 70 ℃ of this solution of heating 20h.Cooling mixture adds saturated sodium bicarbonate solution then, with the EtOAc extraction, uses MgSO 4Dry also filtration.Evaporating solvent, (95/5: hexane/EtOAc) obtains purpose product (16.71g, 54.4%) to the gained solid through the silica gel chromatography purification.MS(ES -)m/e?257[M-H] -。
C) methyl-2-benzyl oxygen base-6-cyanobenzoic acid ester.
Under 0 ℃, Ar atmosphere, with N-phenyl trifluoromethanesulfonate amsacrine (4.5424g, 12.7mmol) and triethylamine (1.62mL, 11.6mmol) processing methyl-2-benzyl oxygen base-6-hydroxybenzoate (2.730g, dichloromethane 10.6mmol) (28.5mL) solution.With the reactant mixture temperature to room temperature and stir 14h.Dilute this solution and water, 5% sodium hydroxide solution and salt water washing with ether.Organic layer MgSO 4Drying, filtration and evaporation obtain crude product triflate (4.476g, 108%). 1H?NMR(250MHz，CDCl 3)δ7.35(m，6H)，6.95(m，2H)，5.16(s，2H)，3.94(s，3H)。Crude product triflate is dissolved among the DMF (23mL) and with tetra-triphenylphosphine palladium [O] (0.3036g, 0.260mmol) and Zn (CN) 2(1.1027g 9.39mmol) handles.At 80 ℃ of heating blends 10h, reactant mixture is cooled to room temperature and pours in the saturated sodium bicarbonate solution, this mixture extracts with EtOAc, uses MgSO 4Dry also filtration.Evaporating solvent, (80/20: hexane/EtOAc) obtains purpose product (2.20g, two step yields 78%) to the gained solid through the silica gel chromatography purification. 1HNMR(250MHz，CDCl 3)δ7.5-7.2(m，8H)，5.19(s，2H)，4.00(s，3H)
D) preparation of methyl-6-cyano-2-hydroxy-benzoate
Under Ar atmosphere, (10.0g adds 10%Pd/ charcoal (4.72g) in EtOAc 37.4mmol) (330mL) solution to methyl-2-benzyl oxygen base-6-cyanobenzoic acid ester.With hydrogen be full of reactor and at room temperature, stirred reaction mixture under the nitrogen atmosphere of gasbag pressure (balloon pressure).After 3 hours, be full of reactor, through kieselguhr (celite) filtering solution with Ar.Evaporating solvent obtains purpose product (6.12g, 92.2%).To C 9H 7NO 3Analysis, value of calculation: C, 61.02; H, 3.98; N, 7.91.Experiment value: C, 60.74; H, 3.99; N, 7.65.
E) preparation of methyl-6-cyano-2-hydroxy--3-nitrobenzoyl acid esters
Under 0 ℃, (1.1428g, (0.41mL 6.44mmol) handles to drip concentrated nitric acid in the suspension of acetic anhydride 6.45mmol) (21mL) to methyl-6-cyano-2-hydroxy-benzoate.Mixture is warming to room temperature, in the meantime all material dissolutions.Agitating solution 36 hours is poured into then in the water and with EtOAc and is extracted the organic layer MgSO of merging 4Dry also filtration, evaporating solvent, (70/30/1: hexane/EtOAc/HOAc) purification obtains purpose product (0.50g, 35.7%) to the gained solid through silica gel chromatography.MS(ES -)m/e?221[M-H] -。
F) methyl-3-amino-6-cyano-2-hydroxy-benzoate
Under Ar atmosphere, (402mg adds 10%Pd/ charcoal (0.23g) in EtOAc 1.81mmol) (40mL) solution to methyl-6-cyano-2-hydroxy--3-nitrobenzoyl acid esters.With hydrogen be full of reactor and at room temperature, stirred reaction mixture under the nitrogen atmosphere of gasbag pressure.After 2 hours, be full of reactor, through diatomite filtration solution with Ar.Evaporating solvent obtains purpose product (334mg, 96.0%).MS(ES -)m/e?192[M-H] -。
G) N-(2-bromophenyl)-N '-(4-cyano-2-hydroxy--3-methoxycarbonyl phenyl)-N " cyanoguanidines
Except that replacing 5-cyano group-2-nitro-phenol, make title compound (total recovery 19%) according to the method for embodiment 2 (a)-1 (e) with methyl-3-amino-6-cyano-2-hydroxy-benzoate. 1H?NMR(400MHz，DMSO?d 6)δ11.08(s，1H)，9.69(s，1H)，8.89(s，1H)，7.99(d，J＝8.40Hz，1H)，7.73(d，J＝7.9Hz，1H)，7.50-7.42(m，3H)，7.28(t，1H)；IR(KBr)2228，2186cm -1IR(KBr)2225，2177cm -1；MS(ES -)m/e?412，414[M-H] -；mp?210-211℃
Therapeutic Method
The compound or pharmaceutically acceptable salt thereof of formula (I) can be used for preparing the medicine that is used for preventing or treating the mankind or any morbid state of other mammal, these morbid states are because the too much or irregular institute of the IL-8 cytokine that mammalian cell produces causes or increases the weight of, such as, but not limited to: mononuclear cell and/or macrophage, or other and IL-8 α or beta receptor, be also referred to as the chemotactic factor that I type or II receptor combine.
Therefore, the invention provides-Therapeutic Method of kind of chemokine mediated diseases, wherein, chemotactic factor combines with IL-8 α or beta receptor, and the method comprises formula (I) compound or pharmaceutically acceptable salt thereof of taking effective dose.Especially, chemotactic factor is IL-8, GRO α, GRO β, GRO γ, ENA-78 or NAP-2.
Formula (I) chemical compound of using q.s is to suppress cytokine function, the function of IL-8, GRO α, GRO β, GRO γ, ENA-78 or NAP-2 particularly, make it to turn down biology the normal level of physiological function, or adjust in some sense and be lower than normal level, to improve morbid state.For example in the context of the present invention, the generation of the abnormal level of IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 is made up of following: (i) free IL-8 horizontal exceeding or equal 1 pik/mL; (ii) any cell IL-8, GRO α, GRO β, GRO γ, ENA-78 or NAP-2 surpass the normal physiological level; Or (iii) the existence of IL-8, GRO α, GRO β, GRO γ, ENA-78 or NAP-2 is higher than the basic horizontal of IL-8, the GRO α, GRO β, GRO γ, ENA-78 or the NAP-2 that produce respectively in cell or tissue.
The numerous disease state is arranged, and it is superfluous or irregularly increase the weight of and/or cause disease wherein to produce IL-8.Chemokine mediated disease psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel, Crohn disease, ulcerative colitis, apoplexy, septic shock, endotoxin shock, the negative pyemia of Pueraria lobota Lan Shi, toxic shock syndrome, heart and kidney reperfusion injury, glomerulonephritis, thrombosis, graft versus host disease, Alzheimer, allograft rejection, malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis or bad hematopoietic stem cell discharge.
The compounds of this invention also is used for the treatment of the disease that is caused by the virus of breathing, and includes but not limited to rhinovirus and influenza virus, herpesvirus, includes but not limited to herpes simplexI and II, reaches hepatitis virus, includes but not limited to hepatitis B and hepatitis C virus.
These diseases mainly are grown to feature with a large amount of neutrophil infiltration, T cellular infiltration or neovascularity, and relevant with IL-8, GRO α, GRO β, GRO γ or NAP-2 generation increase, it is responsible for making the directional growth of neutrophilic granulocyte to areas of inflammation chemotactic or endotheliocyte.With other struvite cytokine (IL-1, TNF, with IL-6) compare, IL-8, GRO α, GRO β, GRO γ or NAP-2 have unique release characteristics that impels neutrophilic granulocyte chemotactic, enzyme, and it includes but not limited to discharge elastoser and superoxides produces and activation.α chemotactic factor and particularly GRO α, GRO β, GRO γ or NAP-2 that I or II receptor by IL-8 works, thus the neovascularization of tumor can be impelled by the directional growth of impelling endotheliocyte.Therefore, will cause the direct minimizing of neutrophil infiltration to the inhibition of inductive chemotactic of IL-8 or activation.
Nearest evidence has also shown the effect of chemotactic factor in the HIV treatment of infection, Littleman etc., Nature381, pp 661 (1996) and Koup etc., Nature381, pp 667 (1996).
The present invention also provides a kind of Therapeutic Method, with the chemokine receptor anagonists compounds for treating acute state (setting) of formula (I), and is used for those are considered to susceptible individual prevention CNS damage.
Comprise the open or penetrating trauma of head in the CNS of this definition damage, such as operation, or closure head wound, as the damage in head zone.Also comprise ischemic stroke within this definition, the spy is brain area in addition.
Ischemic stroke can be defined as the focus neurological disorders that the blood supply deficiency by specific brain area causes, and normally result is the atherosis obturation of blood vessel embolism, thrombosis or local intra-arterial.Demonstrate struvite effect of cytokines in this zone, the invention provides a kind of method of possible these damages of treatment.To such as these acute injuries, it is feasible almost not having relevant treatment.
TNF-α is a kind of cytokine with proinflammatory effect, and it comprises the expression of endothelial leukocyte adhesion molecule.Leukocyte infiltration is to the ischemic brain injury zone, and therefore suppress or reduce the chemical compound of TNF level will be useful to the treatment of ischemic brain injury.See Liu etc., Stroke, Vol.25., No.7, pp 1481-88 (1994), its disclosed content is hereby incorporated by.
The model of CHI and with the treatment of blended 5-LO/CO agent at Shohami etc., J.of Vaisc ﹠amp; Clinical Physiology and Pharmacology, Vol.3, No.2, pp.99-107 discusses in (1992), and its disclosed content is hereby incorporated by.Find that in those animals of being treated the treatment that alleviates edema formation can improve the function result.
Formula (I) chemical compound of taking q.s is to suppress and the combining of IL-8 α or the bonded IL-8 of beta receptor and these receptors, as reduction neutrophilic granulocyte chemotactic and activation.Formula (I) chemical compound is the discovery of the bonded inhibitor of IL-8, be based on formula described herein (I) chemical compound extracorporeal receptor in conjunction with the test in effect.In some instances, the chemical compound that demonstrates formula (I) is the double inhibitor of the IL-8 receptor of reorganization I type and II type.Preferably, this chemical compound only is a kind of inhibitor of receptor, more preferably the inhibitor of II type IL-8 receptor.
The term that this paper uses " disease or the morbid state of IL-8 mediation " refers to any He all morbid states, wherein IL-8, GRO α, GRO β, GRO γ, ENA-78 or NAP-2 play effect, perhaps by producing IL-8, GRO α, GRO β, GRO γ, ENA-78 or NAP-2 itself, perhaps cause that by IL-8, GRO α, GRO β, GRO γ, ENA-78 or NAP-2 other monokine discharges, such as, but not limited to IL-1, IL-6 or TNF.A kind of morbid state, wherein for example IL-1 is a main component, and therefore its generation or effect then be considered to the IL-8 disease states mediated corresponding to increase or the minimizing of IL-8.
The term " chemokine mediated disease or morbid state " that this paper uses refers to any He all morbid states, wherein work, such as but not limited to IL-8, GRO α, GRO β, GRO γ, ENA-78 or NAP-2 with IL-8 α or the bonded chemotactic factor of beta receptor.This comprises a kind of morbid state, and wherein IL-8 works, or passes through to produce IL-8 itself, or causes that by IL-8 other monokine discharges, such as, but not limited to IL-1, IL-6 or TNF.A kind of morbid state, wherein, for example IL-1 is a main component, and therefore its generation or effect then be considered to the IL-8 disease states mediated corresponding to increase or the minimizing of IL-8.
The term " cytokine " that this paper uses " refer to influence any excretory polypeptide of cell function, and be the molecule of in immunity, inflammation or hemopoietic reaction, adjusting cell-cell interaction.Cytokine includes but not limited to: monokine and lymphokine, no matter they by which cell are produced.For example: monokine is often referred to by producing such as macrophage and/or monocytic mononuclear cell and excretory.But many other cells also produce monokine, such as natural killer cell, fibroblast, basophilic leukocyte, neutrophilic granulocyte, endotheliocyte, the star-like cell of brain, marrow stromal cell, keratinization of epidermis cell and bone-marrow-derived lymphocyte.Lymphokine is often referred to by lymphocyte and produces.The example of cytokine includes, but are not limited to interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNF-α) and tumor necrosis factor (TNF-β).
The term " chemotactic factor " that this paper uses refers to influence any excretory polypeptide of cell function, and is the molecule of adjusting cell-cell interaction in immunity, inflammation or hemopoietic reaction, with term " cytokine " above " similar.Chemotactic factor is mainly secreted by striding theca cell (celltrausmembranes), and causes the chemotaxis and the activation of particular white blood cells and leukocyte, neutrophilic granulocyte, 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, ENA-78, NAP-2, IP-10, MIP-1 α, MIP-β, PF4 and MCP1,2 and 3.
For the compound or pharmaceutically acceptable salt thereof of application formula (I), the pharmacy practice according to standard is mixed with pharmaceutical composition with it usually in treatment.Therefore the invention still further relates to and comprise effective, formula (I) chemical compound of nontoxic amount and the pharmaceutical composition of pharmaceutically suitable carrier or diluent.
The chemical compound of formula (I), its officinal salt and as above blended pharmaceutical composition can be used by any route of administration easily, for example: oral, local application, parenterai administration or suction.The chemical compound of formula (I) can be used the pharmaceutical carriers of the chemical compound of formula (I) and standard by conventional method in conjunction with making easily dosage form.The chemical compound of formula (I) can also and a kind of known second kind of treatment on activated chemical compound use with dosage combination easily.These methods can relate to mixes suitable composition, granulate and suppresses or be dissolved in the purpose preparation.Should recognize that pharmacy can accept the amount of the form of characteristic or diluent and the active component that characteristic is united use, route of administration and other well-known variablees and arrange.Say that on the meaning compatible carrier must be " acceptable " and can be not toxic to its receptor with other composition of preparation.
For example, pharmaceutical carrier can be solid or liquid, and the typical solid carrier is lactose, Gypsum Fibrosum powder, sucrose, Pulvis Talci, gel, agar, colloid, Radix Acaciae senegalis, magnesium stearate, stearic acid etc.Exemplary of liquid carriers is syrup, Oleum Arachidis hypogaeae semen, olive oil, water etc.Equally, carrier or diluent can comprise well-known time delay material in this area, such as: separately or contain the glyceryl monostearate or the distearin of paraffin.
Operable medicament forms is very extensive, and therefore, if what use is a kind of solid carrier, preparation can be prepared into tablet, with powder or become the bead form or put into hard capsule with lozenge or lozenge form.The amount of solid carrier can great changes have taken place, but preferably from about 25mg to about 1g.When the using liquid carrier, preparation can be syrup, Emulsion, soft capsule, sterile injectable liquid, as ampoule or non-aqueous suspension.
The chemical compound of formula (I) can local application, promptly by non-systemic administration.This comprises that the chemical compound of formula (I) uses epidermis or cheek chamber outward and this mixture is splashed into ear, eye and nose, and this chemical compound will can significantly not enter blood like this.In contrast, systemic administration refers to oral cavity, intravenous, intraperitoneal and intramuscular administration.
The preparation that is applicable to local application comprises and is suitable for liquid or the semi-liquid preparations that transdermal reaches inflammation part, such as liniment, lotion, cream, ointment or paste be applicable to the drop of eye, ear or nose medication.For local application, active component can comprise 0.001% to 10%w/w in weight of formulation, and for example from 1% to 2%.But it can contain the 10%w/w up to preparation, but preferably is less than 5%w/w, more preferably 0.1% arrives 1%w/w.
Lotion of the present invention comprises those that are suitable for skin or ophthalmic applications.Eye lotions can comprise the optional aseptic aqueous solution that contains antibacterial and can be with the preparation method preparation that is similar to drop.The lotion or the liniment that are used for skin can also comprise that a kind of acceleration is dry and make the refrigerative reagent of skin, such as ethanol or acetone, and/or a kind of wetting agent, as glycerol or a kind of oil, as Oleum Ricini or Oleum Arachidis hypogaeae semen.
Cream of the present invention, ointment or paste are the semi-solid preparations of external active component.These preparations can be by the active component of finely divided or powder type, separately or in the solution or suspension of water or on-aqueous liquid, mixes with oils and fats or non-oils and fats substrate and makes with suitable machinery help.Substrate can comprise hydrocarbon such as hard, soft or liquid paraffin, glycerol, Cera Flava, metallic soap; Cement; The oil of natural origin such as almond oil, Semen Maydis oil, Oleum Arachidis hypogaeae semen, Oleum Ricini or olive oil; Lanoline or derivatives thereof or fatty acid such as stearic acid or oleic acid and alcohol are such as propylene glycol or macrogel.Preparation can comprise any suitable surfactant such as anion, cation or non-ionic surface active agent such as Isosorbide Dinitrate or its polyoxyethylene deriv.Preparation can comprise that suspending agent such as natural gum, cellulose derivative or inorganic matter such as silicaceous silicon and other compositions are such as lanoline.
Drop of the present invention comprises sterilized water or oil solution or suspension, and can be by preparing in the aqueous solution that active component is dissolved into suitable antibacterial and/or antifungal and/or other any suitable preservatives, and preferably includes surfactant.Then resulting solution is made it clarification by filtration, transfer to proper container and seal then, by autoclaving or maintain sterilization 98-100 ℃ of half an hour.In addition, this solution can also be transferred in the container by filtration sterilization and with aseptic technique.Being suitable for being included in the antibacterial in the drop and the example of antifungal is phenylmercuric nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).The suitable solvent that is used to prepare oily solution comprises glycerol, rare ethanol and propylene glycol.
The chemical compound of formula (I) can the parenteral medication, promptly by intravenous, intramuscular, subcutaneous, intranasal, internal rectum, intravaginal or intraperitoneal administration.Usually preferred parenteral medication is subcutaneous and the intramuscular form.The suitable dosage forms that is applicable to this application method can prepare by routine techniques.The chemical compound of formula (I) can also pass through inhaled medication, promptly sucks by intranasal and oral cavity.Suitable dosage forms such as the aerosol or the metered dose inhaler that are applicable to this application method can prepare by routine techniques.
For all application processes of formula disclosed herein (I) chemical compound, every day the oral dose scheme optimization from about 0.01 to about 80mg/kg body weight.Every day the parenteral dosage preferably from about 0.001 to about 80mg/kg body weight.Every day, local application's dosage was preferably from 0.1mg to 150mg, medication every day 1 to 4 time, preferred 2 or 3 times.Every day inhaled medication dosage preferably from about 0.01mg/kg to about 1mg/kg.Those skilled in the art recognizes that also the optimised quantity of the individual dose of formula (I) chemical compound or officinal salt will depend on nature and extent, dosage form, route of administration and the position of disease to be treated and particular patient to be treated with the interval, and this therapeutic regimen can be by technology decision easily.Those skilled in the art also recognizes best therapeutic process, promptly for the treatment of a definite natural law, takes the dosage of formula (I) compound or pharmaceutically acceptable salt thereof every day, can use conventional treatment determination test process by those skilled in the art and determine.
The present invention now will be described by following biology of embodiment.These embodiment just are used to illustrate rather than as the restriction of the scope of the invention.
Biology embodiment
The IL-8 of The compounds of this invention and GRO-α chemotactic factor depression effect are measured with following analyzed in vitro method:
Receptor binding assay:
From Amersham Corp., Arlington Heights, the IL acquisition [ 125I] IL-8 (human recombinant body), specific activity is 2000 Ci/mmol.Obtain GRO-α from NEN-New EnglandNuclear.All other chemical reagent are AG.High-caliber recombinant human IL-8 α type and β receptor are to express (Holmes etc., Science, 1991,253,1278) as previously mentioned on Chinese hamster ovary cell respectively.(Haour etc., J Biol Chem., 249 pp 2195-2205 (1974)) homogenize the Chinese hamster ovary film according to preceding method.In addition, the buffer that homogenizes changes 10mM Tris-HCL, 1mM MgSO4,0.5mM EDTA (ethylenediaminetetraacetic acid), 1mM PMSF (α-tosyl fluorine), 0.5mg/L leupeptin into, and pH 7.5.Use bovine serum albumin as standard with Pierce Co. microanalysis test kit (Pierce Co.micro-assay kit), measure the concentration of memebrane protein.All analyses are all carried out in 96 hole micropore flat boards.Each reactant mixture contains in 20mM Bis-Trispropane and 0.4mM Tris HCl buffer (pH 8.0) 125I IL-8 (0.25nM) or 125The IL-8R β film of the IL-8R α of IGro-α and 0.5 μ g/mL or 1.0 μ g/mL contains 1.2mM MgSO in the buffer 4, 0.1mM EDTA, 25mM NaCl and 0.03%CHAPS.In addition, add the medicine to be measured be dissolved in advance among the DMSO or chemical compound with the ultimate density that reaches between 0.01nM and 100uM.By adding 125I-IL-8 begins test, after at room temperature 1 hour, with Tomtec96 hole catcher this flat board collected with containing on the glass fibre filtermat that 1% polymine/0.5%BSA stops, and with 25mM NaCl, 10mMTrisHCl, 1mM MgSO 4, 0.5mM EDTA, 0.03%CHAPS, pH 7.4 washing three times.Then that filter is dry and count on the Betaplate liquid scintillation counter.Recombinant IL-8R α, or the I receptor also refers to non-permission receptor at this paper, and recombinant IL-8R β, or the II receptor refers to permit receptor.
The proof of chemical compound for example in all formulas (I) that this paper synthetic chemistry part embodiment 1 to 11 shows suppresses IC in the licensing model (IL-8) at the IL-8 receptor 50Be about 5 to about 100nM/mL.Discovery does not have the chemical compound of disassociation proton, N-(2-pi-allyl oxygen base-4-cyano group-phenyl)-N '-(2-bromophenyl)-N in the 2-position "-cyanoguanidines non-activity in this analysis.
Chemotactic is analyzed:
The vitro inhibition characteristic of these chemical compounds is measured with neutrophilic granulocyte chemotaxis analytical method, as at Current Protocols in Immunology, and Vol I, Suppl 1, and Unit6.12.3 is described, and its disclosure all is incorporated herein by reference at this.As at CurrentProtocols in Immunology, Vol I, Suppl 1, and Unit 7.23.1 is described, separates neutrophilic granulocyte from human blood, and its disclosure all is incorporated herein by reference at this.With chemical inhibitor IL-8, GRO-α, GRO-β, GRO-γ and NAP-2 insert porous chambers 48 (NeuroProbe, Cabin John, bottom compartment MD), concentration is 0.1～100nM.Polycarbonate filter with 5um between two Room is separated.When test during chemical compound of the present invention, just before last chamber adding cell and mixing with cells (0.001-1000nM).The 5%CO that contains in humidity 2Couveuse in continue hatching about 45-90 minute at about 37 ℃.Last in the incubation period, the top side is removed and washed to polycarbonate membrane, (IL USA) dyes film for Baxter Products, McGaw Park to use Diff Quick colouring method then.Chemotactic is counted with microscopic visual measurement to the cell of chemotactic factor.Usually, each 4 zone of sample counting, these digital averages are as the par of migrating cell.Each sample survey three times and each chemical compound retest at least 4 times.Do not add chemical compound for specific cells (positive control cell), these cells have the maximum chemotactic response of cell.Under the situation of need negative control (not irriate), the bottom compartment does not add chemotactic factor.Difference between positive control and the negative control has been represented the chemotactic activity of cell.
Elastoser discharges to be analyzed:
The ability of test The compounds of this invention to stoping elastoser to discharge from human neutrophil.According to Current Protocols in Immunology Vol I, from human blood, isolate neutrophilic granulocyte described in Suppl 1 Unit7.23.1.(NaCl 118, and KCl 4.56, NaHCO will to be suspended in Ringer ' sSolution 325, KH 2PO 41.03 glucose 11.1, HEPES 5mM, pH 7.4) in PMNs 0.88 * 10 6Individual cell is put into 96 hole flat boards, every pore volume 50ul.To this dull and stereotyped 50ul testing compound (0.001-1000nM), cytochalasin B 50ul (20ug/ml) and Ringers buffer 50ul of adding.Adding before final concentration is 0.01-1000nM IL-8, GRO α, GRO β, GRO γ or NAP-2, with these cell incubations (37 ℃, 5%CO 2, 95%RH) 5 minutes.Reaction continues 45 minutes, removes with 96 hole flat boards centrifugal (800 * g 5 minutes) and with the 100ul supernatant then.This supernatant is joined in another 96 hole flat board, and adding final concentration subsequently is artificial elastin laminin zymolyte (MeOSuc-Ala-Ala-Pro-Val-AMC, NovaBiochem, La Jolla, phosphate buffer CA) of 6ug/ml.Immediately flat board is inserted 96 hole panel fluorescent readers (Cytofluor 2350, Millipore, Bedford, MA) in, press J.Biol Chem such as Nakajima 2544027 (1979) method was with 3 minutes interval record data.The amount of the elastoser that discharges from PMNs can be calculated by the degradation speed of measuring MeOSuc-Ala-Ala-Pro-Val-AMC.
TNF-α in traumatic brain injury analyzes:
The check that this analytical method provides tumor necrosis factor mRNA to express in rat specific brain regions zone, this brain zone causes traumatic brain injury (TBI) because of being hit by the experimental side fluidity that causes.Grow up Sprague-Dawley rat (n=42) with pentobarbital sodium anesthesia (60mg/kg, lumbar injection) and be subjected to moderate side liquid and hit brain injury (2.4atm.), it is centered close to left side temporo top cortex (n=18), or " simulation " handled, and (not damaged anesthesia is also performed the operation, n=18).The damage 1,6 and 24 hour after with the animal sacrificed by decapitation, take out brain, preparation left side (hindering side) top cortex (LC), to the tissue samples of corresponding close region (RA), left hippocampus (LH) and the right side Hippocampus (RH) of near the cortex (LA) the top cortex of the corresponding zone of right side of face cortex (RC), damage, right side cortex.Separate total RNA and implement Northern marking hybridization and carry out quantitatively with respect to TNF-α positive control RNA (macrophage=100%).Injured side hemisphere in the time of injured back 1 hour is observed (104 ± 17% of positive control in LH, compare p＜0.05 with the simulation group), in LC (105 ± 21%, p＜0.05) the remarkable increase that (69 ± 8%, p＜0.01) TNF α mRNA expresses and in LA.Also observed in LH (46 ± 8%, p＜0.05) in back 6 hours in wound, (30 ± 3%, p＜0.01) and (32 ± 3%, p＜0.01) TNF-α mRNA expresses in LA increase in LC, just disappeared in back 24 hours in wound.At offside hemisphere, in wound back 1 hour, in RH (46 ± 2%, p＜0.01), among the RC among (4 ± 3%) and the RA (22 ± 8%), in back 6 hours RH of wound among (28 ± 11%), the RC among (7 ± 5%) and the RA (26 ± 6%, p＜0.05) expression of TNF-α mRNA increases, but does not then have in back 24 hours in wound.Simulation group (not damaged operation) or blank animal, at any time, no matter which side hemisphere, the consistent change that TNF-α mRNA expresses all do not observed in 6 brain zones.After these results are presented at other sagittal plane liquid strike brain injury, there are temporary transient TNF-α mRNA to express in the specific brain regions district and change, comprise the variation of non-wound hemisphere.Because TNF-α can induce nerve growth factor (NGF) and stimulate the release of other cytokines from the star-like cell of activatory brain, the change of TNF-α gene expression all plays an important role in the acute and reproducibility of CNS wound is responded after the wound.
The CNS damage model of IL-β mRNA
This analytical method is expressed as feature with the regionality of interleukin-1 ' beta ' (IL-1 β) mRNA in specific brain regions district after hitting brain injury (TBI) at rat experiment side liquid.The Sprague-Dawley rat (n=42) that grows up is anaesthetized (60mg/kg with pentobarbital sodium, lumbar injection) and suffer moderate side liquid to hit brain injury (2.4atm.), it is centered close to left side temporo top cortex (n=18), or " simulation " handles (not damaged anesthesia and operation).The damage 1,6 and 24 hour after with the animal sacrificed by decapitation, take out brain, preparation left side (hindering side) top cortex (LC), to the tissue samples of corresponding close region (RA), left hippocampus (LH) and the right side Hippocampus (RH) of near the cortex (LA) the top cortex of the corresponding zone of right side of face cortex (RC), damage, right side cortex.Separate total RNA and implement the hybridization of the Northern marking, the amount that obtains cerebral tissue IL-1 β mRNA is represented with the percentage ratio of the relative radioactivity of the positive macrophage RNA of the IL-1 β of load on same gel.At brain injury after 1 hour, at injured side hemisphere, observe (20.0 ± 0.7% of positive control, n=6 among the LC, compare p＜0.05 with simulated animal), among the LH (24.5 ± 0.9%, p＜0.05) expression of (21.5 ± 3.1%, p＜0.05) IL-1 β mRNA has significantly and significant increasing and among the LA, hinders the back by 6 hours, in LC (4.0 ± 0.4%, n=6, p＜0.05) (5.0 ± 1.3%, p＜0.05) above-mentioned observe phenomena still exists and among the LH.In simulation or blank animal, not in of the expression of any relevant brain regional observation to IL-1 β mRNA.After these results are presented at TBI, be upset in the temporary transient expression part of specific brain regions district IL-1 β mRNA.The cytokine that these are regional works after wound such as the variation of IL-1 β.
All publications of quoting in this manual include but not limited to that patent and patent application are hereby incorporated by, and at length and are individually pointed out to be incorporated herein by reference in full as each independent publication.
The foregoing description full disclosure the present invention, comprise its preferred embodiment.In the scope that the improvement and the improvement of this special disclosed embodiment belongs to following claims.If further do not elaborate, it is believed that those skilled in the art can use the front and describe, farthest utilize the present invention.Therefore, embodiment will be only explains as an illustration herein, does not limit the scope of the invention going up all in all senses.The patent rights that the present invention is claimed or the particular content of royalty right such as hereinafter qualification.

Claims (8)

1. the method for the chemokine mediated disease of treatment, wherein chemotactic factor is attached on mammal IL-8 α or the beta receptor, disease is selected from malaria, restenosis, blood vessel generation, atherosclerosis, osteoporosis, gingivitis, bad hematopoietic stem cell release and the disease that is caused by respiratory virus, herpesvirus and hepatitis virus, hepatitis virus includes but not limited to hepatitis B and hepatitis C virus
It comprises to the formula of described administration effective dose (I) compound or pharmaceutically acceptable salt thereof:
Figure A0080892000021
Wherein
Z is cyano group, OR 11, C (O) NR 15R 16, R 18, C (O) R 11, C (O) OR 11, or S (O) 2R 17
R is that any functional group and pKa with dissociable hydrogen are 10 or lower;
R 1Independently be selected from hydrogen, halogen, nitro, cyano group, halogenated C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halogenated C 1-10Alkoxyl, azide, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy, aryl C 1-4Alkyl oxy, heteroaryl, heteroaryl alkyl, heterocyclic radical, heterocyclic radical C 1-4Alkyl, heteroaryl C 1-4Alkyl oxy, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocyclic radical 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, (CR 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 19, (CR 8R 8) qS (O) 2NR 4R 5, or two R 1Part can form O-(CH jointly 2) sO-or 5 to 6 yuan of saturated or unsaturated rings, and wherein aryl, heteroaryl and heterocyclic radical can be chosen wantonly and be substituted;
Q is 0 or 1～10 integer;
T is 0 or 1 or 2 integer;
S is 1～3 integer;
V is 0 or 1～4 integer;
R 4And R 5Independent is hydrogen, 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 or R 4And R 5With 5 to 7 yuan of rings of the common formation of coupled nitrogen, it can be chosen wantonly and comprise the hetero atom that another is selected from oxygen, nitrogen or sulfur;
Y independently is selected from hydrogen, halogen, nitro, cyano group, halogenated C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halogenated C 1-10Alkoxyl, azide, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy, aryl C 1-4Alkyl oxy, heteroaryl, heteroaryl alkyl, heteroaryl C 1-4Alkyl oxy, 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 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, (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 d, (CR 8R 8) qS (O) 2NR 4R 5, or two Y form O-(CH jointly 2) sO-or 5 to 6 yuan of saturated or unsaturated rings, and wherein aryl, heteroaryl and heterocyclic radical can be chosen wantonly and be substituted;
N is 1～3 integer;
M is 1～3 integer;
R 6And R 7Independent is hydrogen or C 1-4Alkyl; Or R 6And R 7With 5 to 7 yuan of rings of the common formation of coupled nitrogen, this ring can be chosen wantonly and comprise the hetero atom that another is selected from oxygen, nitrogen or sulfur;
R 8Independently be 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, the optional aryl that replaces or the optional aryl alkyl that replaces;
R 13And R 14Independent is hydrogen, the optional C that replaces 1-4Alkyl or R 13And R 14One of be the optional aryl that replaces;
R 15And R 16Independent is hydrogen, 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, the optional heterocyclic radical that replaces, the optional heterocyclic radical C that replaces 1-4Alkyl or R 15And R 16Form 5 to 7 Yuans rings together with the nitrogen that is attached thereto, this ring is chosen wantonly and is comprised the hetero atom that another one is selected from oxygen, nitrogen or sulfur;
R 17Be C 1-4Alkyl, NR 15R 16, OR 11, 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 18Be 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, the optional heterocyclic radical that replaces or the optional heterocyclic radical C that replaces 1-4Alkyl;
R 19Be C 1-4Alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl, wherein all these groups can be chosen wantonly and 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, wherein alkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, heterocyclic radical and heterocyclic radical alkyl ring can be optionally substituted;
W is
Figure A0080892000041
Or
The ring that comprises E ' is selected from following:
Or
Asterisk * represents and encircles the point that is connected;
W 1Be
Figure A0080892000051
Or
Figure A0080892000052
The ring that comprises E is selected from following:
Figure A0080892000053
Figure A0080892000054
Or
Figure A0080892000055
Asterisk * represents and encircles the point that is connected.
2. the process of claim 1 wherein that the pKa of dissociable hydrogen is 3～10.
3. the method for claim 2, wherein R is hydroxyl, carboxyl, thiol, SR 2, OR 2, NH-C (O) R a, C (O) NR 6 'R 7 ', NHS (O) 2R b, S (O) 2NHR c, NHC (X 2) NHR bOr tetrazole radical;
R wherein 2It is 10 or the functional group of littler dissociable hydrogen that the aryl, heteroaryl or the heterocyclic moiety that be to replace, this ring contain pKa;
R 6 'And R 7 'Be 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, all these groups can be chosen wantonly independently and be replaced for 1-3 time by following groups: halogen, nitro, halogenated C 1-4Alkyl, for example CF 3C 1-4Alkyl, for example methyl; C 1-4Alkoxyl, for example methoxyl group; NR 9C (O) R aC (O) NR 6R 7, S (O) 3H or C (O) OC 1-4Alkyl, condition are R 6 'And R 7 'One of be hydrogen, but can not the both be hydrogen;
R aBe aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocyclic radical or heterocyclic radical C 1-4Alkyl, all these groups can be chosen wantonly and 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 part, Camphora, all these groups can be chosen wantonly independently and be replaced for 1-3 time by following groups: halogen, nitro, halogenated 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 9Be hydrogen or C 1-4Alkyl;
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 part, all these groups can be chosen wantonly independently and be replaced for 1-3 time by following groups: halogen, nitro, halogenated 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; And
X 2Be oxygen or sulfur.
4. the method for claim 3, wherein R 2Optional by 1-3 replacement of following groups: halogen, nitro, halo C 1-10Alkyl, C 1-10Alkyl, C 1-10Alkoxyl, hydroxyl, SH, C (O) NR 6 'R 7 ', NH-C (O) R a, NHS (O) R b, S (O) NR 6R 7, C (O) OR 8Or tetrazolium basic ring.
5. the method for claim 3, wherein R be OH ,-NHS (O) 2R bOr C (O) OH.
6. 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
7. the process of claim 1 wherein that Y is halogen, C 1-4Alkoxyl, the optional aryl that replaces, optional alkoxy aryl, methylene dioxy base, the NR that replaces 4R 5, sulfo-C 1-4Alkyl, thioaryl, halogenated alkoxyl, the optional C that replaces 1-4Alkyl, hydroxy alkyl.
8. the process of claim 1 wherein that R is OH, SH or NHS (O) sR bAnd R 1In the 3-position, the 4-position is replaced by drawing electron group or 3, the 4-position is replaced by drawing electron group two.
CNA008089205A 1999-06-16 2000-06-16 IL-8 receptor antagonists Pending CN1494424A (en)

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