CN1356899A - IL-8 receptor antagonists - Google Patents

IL-8 receptor antagonists Download PDF

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CN1356899A
CN1356899A CN00809090A CN00809090A CN1356899A CN 1356899 A CN1356899 A CN 1356899A CN 00809090 A CN00809090 A CN 00809090A CN 00809090 A CN00809090 A CN 00809090A CN 1356899 A CN1356899 A CN 1356899A
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alkyl
heteroaryl
aryl
alkenyl
heterocycle
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G·M·本森
M·C·鲁特莱格
K·L·威多森
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SmithKline Beecham Corp
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Abstract

This invention relates to novel compounds of Formula (I), and pharmaceutical compositions thereof, and methods of 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 the chemical compound that new benzo-2-triazole replaces, its pharmaceutical composition, its preparation method and their purposes in the disease of treatment IL-8, GRO α, GRO β, GRO γ and NAP-2 mediation.
Background of invention
Interleukin-8 (IL-8) has a lot of different names, the neutrophil chemotactic factor (MDNCF) of for example neutrophilic leukocyte attractant/activated protein-1 (NAP-1), mononuclear cell derivation, neutrophilic leukocyte activation factor (NAF) and T-cell lymphocyte chemotactic factor.Interleukin-8 is the chemoattractant of neutrophilic leukocyte, basophilic leukocyte and T-cell subclass.It comprises that by most karyoblasts macrophage, fibroblast, endothelium and epidermis cell contact generation with TNF, IL-1 α, IL-1 β or LPS, and by neutrophil self and LPS or chemotactic factor for example FMLP contact generation.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., Science 243,1467 (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 chemotactic factor a-family.The same with IL-8, these chemotactic factors also have different names, and for example GRO α, β, γ are known as MGSAa, b and g (melanoma growth-stimulating activity) respectively, referring to Richmond etc., J.CellPhysiology 129,375 (1986) and Chang etc., J.Immunol 148,451 (1992).All have directly prior to the a-family chemotactic factor of the ELR primitive of CXC primitive all with the IL-8B receptors bind.
IL-8, GRO α, GRO β, GRO γ, NAP-2 and ENA-78 stimulate many external functions.They all have the character of chemical inhibitor for neutrophil, have T-lymphocyte and a basophilic leukocyte chemotactic activity and IL-8 and GRO α are verified.In addition, IL-8 can induce basophilic leukocyte to discharge histamine from normal and atopic individuals, and GRO-α and IL-8 can also induce the respiratory burst of lysozyme release and neutrophilic leukocyte.IL-8 also show increase Mac-1 (CD11b/CD18) in neutrophilic leukocyte surface expression and do not make that albumen is synthetic to restart.This helps to increase the adhesion of neutrophilic leukocyte and vascular endothelial cell.Many known diseases are feature with a large amount of neutrophilic infiltrations.The same with IL-8, GRO α, GRO β, GRO γ and NAP-2 promote accumulating of neutrophilic leukocyte and activate that these chemotactic factors are with many acute relevant with chronic inflammatory disease, described disease comprises psoriasis and rheumatoid arthritis, Baggiolini etc., FEBS Lett.307,97 (1992); Miller etc., Crit.Rev.Immunol.12,17 (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 (containing just those chemotactic factors prior to the aminoacid ELR primitive of CXC primitive) is also relevant with vasodilation.Strieter etc., Science 258,1798 (1992).
External, IL-8 and NAP-2 by with 7 kinds change film (the banded gang of G-albumen) receptors bind and make its activation, particularly by with IL-8 receptor, especially B-receptors bind, cause that the neutrophilic leukocyte form changes, chemotaxis, particle release and respiratory burst.Thomas etc., J.Biol.Chem.266,14839 (1991); With Holmes etc., Science 253,1278 (1991).For the existing precedent of the exploitation of the non-peptide micromolecule antagonist of this family's receptor.Consult R.Freidinger, Progress in Drug Research, Vol.40, pp.33-98, Birkhauser Verlag, Basel 1993.Therefore the IL-8 receptor has been represented the target likely of new antiinflammatory exploitation.
Depicted the characteristic of two kinds of neutralizing high affinity human IL-8 receptors (77% homology): IL-8Ra only combines with IL-8 highly affinely, and IL-8Rb then all has high-affinity to IL-8 and GRO α, GRO β, GRO γ and NAP-2.Referring to Holmes etc., see above; Murphy etc., Science 253,1280 (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, use for treatment, all the time to having demand with the chemical compound of IL-8a or b receptors bind.Therefore, produce to increase diseases associated with IL-8 and will benefit from chemical compound as IL-8 receptors bind inhibitor, the generation of IL-8 causes neutrophilic leukocyte and T-cell subclass to be tending towards the inflammatory position.
Summary of the invention
The invention provides the method for the chemokine mediated disease of treatment, wherein chemotactic factor is and IL-8 α or the bonded chemotactic factor of beta receptor, and this method comprises the formula (I) of using effective dose or (II) compound or pharmaceutically acceptable salt thereof.Chemotactic factor is IL-8 especially.
The invention still further relates in the mammal of needs the method that suppresses IL-8 and its receptors bind, this method comprises to formula of described administration effective dose (I) or (II) chemical compound.
The present invention also provides new formula (I) and (II) chemical compound, and the pharmaceutical composition that contains formula (I) chemical compound and formula (II) chemical compound and pharmaceutically suitable carrier or diluent.
Be applicable to that formula of the present invention (I) chemical compound represented by following structure:
Figure A0080909000091
Wherein R is-NH-C (X 2)-NH-(CR 13R 14) v-Z; Z be W, HET,
Figure A0080909000092
Optional substituted C 1-10Alkyl, optional substituted C 2-10Alkenyl or optional substituted C 2-10Alkynyl;
X is C (X 1) 2, C (O), C (S), S (O) 2, PO (OR 4) or C=N-R 19
X 1Be hydrogen, halogen, C independently 1-10Alkyl, NR 4R 5, C 1-10Alkyl-NR 4R 5, C (O) NR 4R 5, optional substituted C 1-10Alkyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, hydroxyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycle C 1-4Alkyl or heteroaryl C 1-4Alkoxyl;
X 2Be=O or=S;
R 1Be independently selected from hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, azido, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycle C 1-4Alkyl, heteroaryl C 1-4Alkoxyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocycle C 2-10Alkenyl, (CR 8R 8) qNR 4R 5, C 2-10Alkenyl C (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 10, S (O) 3R 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) qC (NR 4) NR 4R 5, (CR 8R 8) qNR 4C (NR 5) R 11, (CR 8R 8) qNHS (O) 2R 17, or (CR 8R 8) qS (O) 2NR 4R 5Perhaps two R 1Part combines and can form O-(CH 2) sSaturated or the unsaturated ring of O or 5-6 unit; And wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
N is the integer of 1-3;
M is the integer of 1-3;
Q is 0 or the integer of 1-10;
S is the integer of 1-3;
T is 0 or 1 or 2 integer;
V is 0 or the integer of 1-4;
P is the integer of 1-3;
HET is optional substituted heteroaryl;
R 4And R 5Be hydrogen, optional substituted C independently 1-4Alkyl, optional substituted aryl, optional substituted aryl C 1-4Alkyl, optional substituted heteroaryl, optional substituted heteroaryl C 1-4Alkyl, heterocycle or heterocycle C 1-4Alkyl, perhaps R 4And R 5Form 5-7 unit ring with the nitrogen-atoms that links to each other with them, this ring can randomly contain the hetero atom that other are selected from O/N/S;
Y is independently selected from hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, azido, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroarylalkyl, heteroaryl C 1-4Alkoxyl, heterocycle, heterocycle C 1-4Alkyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocycle C 2-10Alkenyl, (CR 8R 8) qNR 4R 5, C 2-10Alkenyl C (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 10, S (O) 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) qC (NR 4) NR 4R 5, (CR 8R 8) qNR 4C (NR 5) R 11, (CR 8R 8) qNHS (O) 2R a, or (CR 8R 8) qS (O) 2NR 4R 5Perhaps two Y partly are combined together to form O-(CH 2) sSaturated or the unsaturated ring of O or 5-6 unit; And wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
R 6And R 7Be hydrogen or C independently 1-4Alkyl, perhaps R 6And R 7Form 5-7 unit ring with the nitrogen-atoms that links to each other with them, this ring can randomly contain the hetero atom that other are selected from oxygen, nitrogen or sulfur;
R 8Be hydrogen or C independently 1-4Alkyl;
R 10Be C 1-10Alkyl C (O) 2R 8
R 11Be hydrogen, C 1-4Alkyl, optional substituted aryl, optional substituted aryl C 1-4Alkyl, optional substituted heteroaryl, optional substituted heteroaryl C 1-4Alkyl, optional substituted heterocycle or optional substituted heterocycle C 1-4Alkyl;
R 12Be hydrogen, C 1-10Alkyl, optional substituted aryl or optional substituted aralkyl;
R 13And R 14Be hydrogen or optional substituted C independently 1-4Alkyl, perhaps R 13And R 14In one can be optional substituted aryl;
R 15And R 16Be hydrogen or optional substituted C independently 1-4Alkyl;
R 17Be C 1-4Alkyl, aryl, aralkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocycle or heterocycle C 1-4Alkyl, wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
R 18Be hydrogen, optional substituted C 1-10Alkyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, hydroxyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocycle or heterocycle C 1-4Alkyl, wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
R 19Be cyano group, nitro, S (O) 2NR 4R 5, S (O) 2R 17, alkyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocycle or heterocycle C 1-4Alkyl; And wherein containing alkyl, aryl, heteroaryl and heterocyclic part can randomly be substituted;
R aBe NR 6R 7, alkyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocycle or heterocycle C 1-4Alkyl; And wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted; W is
Figure A0080909000111
The ring that contains E randomly is selected from Asterisk * is the junction point of finger ring; Or its officinal salt.
Be applicable to that formula of the present invention (II) chemical compound represented by following structure:
Figure A0080909000122
Wherein R is-NH-C (X 2)-NH-(CR 13R 14) v-Z; Z be W, HET, Optional substituted C 1-10Alkyl, optional substituted C 2-10Alkenyl or optional substituted C 2-10Alkynyl;
X is N or C (X 1);
X 1Be hydrogen, halogen, C 1-10Alkyl, NR 4R 5, C 1-10Alkyl-NR 4R 5, C (O) NR 4R 5, C 1-10Alkyl C (O) NR 4R 5, optional substituted C 1-10Alkyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, hydroxyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycle C 1-4Alkyl or heteroaryl C 1-4Alkoxyl;
X 2Be=O or=S;
R 1Be independently selected from hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, azido, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycle C 1-4Alkyl, heteroaryl C 1-4Alkoxyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocycle C 2-10Alkenyl, (CR 8R 8) qNR 4R 5, C 2-10Alkenyl C (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 10, S (O) 3R 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) qC (NR 4) NR 4R 5, (CR 8R 8) qNR 4C (NR 5) R 11, (CR 8R 8) qNHS (O) 2R 17, or (CR 8R 8) qS (O) 2NR 4R 5Perhaps two R 1Part can be combined together to form O-(CH 2) sSaturated or the unsaturated ring of-O or 5-6 unit; And wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
N is the integer of 1-3;
M is the integer of 1-3;
Q is 0 or the integer of 1-10;
T is 0 or 1 or 2 integer;
S is the integer of 1-3;
V is 0 or the integer of 1-4;
P is the integer of 1-3;
HET is optional substituted heteroaryl;
R 4And R 5Be hydrogen, optional substituted C independently 1-4Alkyl, optional substituted aryl, optional substituted aryl C 1-4Alkyl, optional substituted heteroaryl, optional substituted heteroaryl C 1-4Alkyl, heterocycle, heterocycle C 1-4Alkyl, perhaps R 4And R 5Form 5-7 unit ring with the nitrogen-atoms that links to each other with them, this ring can randomly contain the hetero atom that other are selected from O/N/S;
Y is independently selected from hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, azido, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroarylalkyl, heteroaryl C 1-4Alkoxyl, heterocycle, heterocycle C 1-4Alkyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocycle C 2-10Alkenyl, (CR 8R 8) qNR 4R 5, C 2-10Alkenyl C (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 10, S (O) 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) qC (NR 4) NR 4R 5, (CR 8R 8) qNR 4C (NR 5) R 11, (CR 8R 8) qNR 4C (O) R 11, (CR 8R 8) qNHS (O) 2R a, or (CR 8R 8) qS (O) 2NR 4R 5Perhaps two Y parts can be combined together to form O-(CH 2) sSaturated or the unsaturated ring of-O or 5-6 unit; And wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
R 6And R 7Be hydrogen or C independently 1-4Alkyl, perhaps R 6And R 7Form 5-7 unit ring with the nitrogen-atoms that links to each other with them, this ring can randomly contain the hetero atom that other are selected from oxygen, nitrogen or sulfur;
R 8Be hydrogen or C independently 1-4Alkyl;
R 10Be C 1-10Alkyl C (O) 2R 8
R 11Be hydrogen, C 1-4Alkyl, optional substituted aryl, optional substituted aryl C 1-4Alkyl, optional substituted heteroaryl, optional substituted heteroaryl C 1-4Alkyl, optional substituted heterocycle or optional substituted heterocycle C 1-4Alkyl;
R 12Be hydrogen, C 1-10Alkyl, optional substituted aryl or optional substituted aralkyl;
R 13And R 14Be hydrogen or optional substituted C independently 1-4Alkyl, perhaps R 13And R 14In one can be optional substituted aryl;
R 15And R 16Be hydrogen or optional substituted C independently 1-4Alkyl;
R 17Be C 1-4Alkyl, aryl, aralkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocycle or heterocycle C 1-4Alkyl, wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
R aBe NR 6R 7, alkyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocycle or heterocycle C 1-4Alkyl; And wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted; W is
Figure A0080909000141
The ring that contains E randomly is selected from
Figure A0080909000151
Asterisk * is the junction point of finger ring; Or its officinal salt.
Detailed Description Of The Invention
Formula (I) and (II) chemical compound except being used for the people, needing also to can be used for the IL-8 of inhibition and IL-8a and b receptors bind or the mammiferous veterinary treatment of other chemotactic factors.For therapeutic or prophylactic treatment, chemokine mediated Animal diseases comprise for example in the disease described in Therapeutic Method one joint.
Obviously, the difference of formula (I) and formula (II) chemical compound is to contain the unsaturation of the ring of A, and therefore is the substituent group on the X part.Except as otherwise noted, hereinafter remaining term of definition is identical for formula (I) with formula (II) chemical compound.
In formula (I) chemical compound, suitable R 1Be independently selected from hydrogen; Halogen; Nitro; Cyano group; Halo C 1-10Alkyl, for example CF 3C 1-10Alkyl, for example methyl, ethyl, isopropyl or n-pro-pyl; C 2-10Alkenyl; C 1-0Alkoxyl, for example methoxy or ethoxy; Halo C 1-0Alkoxyl, for example trifluoromethoxy; Azido; (CR 8R 8) qS (O) tR 4, wherein t is 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 group, for example phenoxy group; Aryl C 1-4Alkoxyl, for example benzyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C 1-4Alkoxyl; Aryl C 2-10Alkenyl; Heteroaryl C 2-10Alkenyl; Heterocycle C 2-10Alkenyl; (CR 8R 8) qNR 4R 5C 2-10Alkenyl C (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 10S (O) 3H; S (O) 3R 8(CR 8R 8) qC (O) R 11C 2-10Alkenyl C (O) R 11C 2-10Alkenyl C (O) OR 11C (O) R 11(CR 8R 8) qC (O) OR 12(CR 8R 8) qOC (O) R 11(CR 8R 8) qNR 4C (O) R 11(CR 8R 8) qC (NR 4) NR 4R 5(CR 8R 8) qNR 4C (NR 5) R 11(CR 8R 8) qNHS (O) 2R 17Or (CR 8R 8) qS (O) 2NR 4R 5Perhaps two R 1Part can be combined together to form O-(CH 2) sSaturated or the unsaturated ring of-O or 5-6 unit.All contain aryl, heteroaryl and heterocyclic part can such as hereinafter definition randomly be substituted.
Preferably, R 1Be hydrogen, halogen, cyano group, nitro, CF 3, (CR 8R 8) qC (O) NR 4R 5, C 2-10Alkenyl C (O) NR 4R 5, (CR 8R 8) qC (O) R 4R 10, C 2-10Alkenyl C (O) OR 12, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-10Alkenyl or S (O) 2NR 4R 5More preferably, R 1Be halogen, cyano group or nitro.For formula (I) and formula (II) chemical compound, R 1Preferably in the 4-position.
It is finger ring and alkyl that term used herein " contains aryl, heteroaryl and heterocyclic part ", if or comprise that the thiazolinyl ring is aryl, aralkyl and aryl alkenyl ring for example.Term " partly " is with " ring " can exchange use in the text.
Aptly, s is the integer of 1-3.
Should be appreciated that, if possible, R 1Part can be to replace on phenyl ring, also can contain the substitution in ring of X.
Work as R 1When forming two oxo bridges, s is preferably 1.Work as R 1When forming other unsaturated ring, it preferably can form 6 yuan of rings of naphthalene ring system.These ring systems can be by other R as defined above 1Part replaces 1-3 time independently.
Aptly, R 4And R 5Can be hydrogen, optional substituted C independently 1-4Alkyl, optional substituted aryl, optional substituted aryl C 1-4Alkyl, optional substituted heteroaryl, optional substituted heteroaryl C 1-4Alkyl, heterocycle or heterocycle C 1-4Alkyl, perhaps R 4And R 5Form 5-7 unit ring with the nitrogen-atoms that links to each other with them, this ring can comprise randomly that other is selected from the hetero atom of O/N/S.
Aptly, R 6And R 7Be hydrogen or C independently 1-4Alkyl, perhaps R 6And R 7Form 5-7 unit ring with the nitrogen-atoms that links to each other with them, this ring can comprise randomly that other is selected from the hetero atom of oxygen, nitrogen or sulfur.
Aptly, R 8Be hydrogen or C independently 1-4Alkyl.
Aptly, q is 0 or the integer of 1-10.
Aptly, R 10Be C 1-10Alkyl C (O) 2R 8, CH for example 2C (O) 2H or CH 2C (O) 2CH 3
Aptly, R 11Be hydrogen, C 1-4Alkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocycle or heterocycle C 1-4Alkyl.
Aptly, R 12Be hydrogen, C 1-10Alkyl, optional substituted aryl or optional substituted aralkyl.
Aptly, R 13And R 14Be hydrogen or optional substituted C independently 1-4Alkyl, this alkyl can be straight or branched alkyl, perhaps R as herein defined 13And R 14In one be optional substituted aryl.
Aptly, v is 0 or the integer of 1-4.
Work as R 13Or R 14When being optional substituted alkyl, moieties can be replaced 1-3 time by following groups independently: halogen; Halo C 1-4Alkyl is trifluoromethyl for example; Hydroxyl; Hydroxyl C 1-4Alkyl; C 1-4Alkoxyl is methoxy or ethoxy for example; Halo C 1-10Alkoxyl; S (O) tR 4Aryl; NR 4R 5NHC (O) R 4C (O) NR 4R 5Or C (O) OR 8
Aptly, R 17Be C 1-4Alkyl, aryl, aralkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocycle or heterocycle C 1-4Alkyl, wherein all contain aryl, heteroaryl and heterocyclic part and can randomly be substituted.
Aptly, Y is independently selected from hydrogen; Halogen; Nitro; Cyano group; Halo C 1-10Alkyl; C 1-10Alkyl; C 2-10Alkenyl; C 1-10Alkoxyl; Halo C 1-10Alkoxyl; Azido; (CR 8R 8) qS (O) tR 4Hydroxyl; Hydroxyl C 1-4Alkyl; Aryl; Aryl C 1-4Alkyl; Aryloxy group; Aryl C 1-4Alkoxyl; Heteroaryl; Heteroarylalkyl; Heteroaryl C 1-4Alkoxyl; Heterocycle; Heterocycle C 1-4Alkyl; Aryl C 2-10Alkenyl; Heteroaryl C 2-10Alkenyl; Heterocycle C 2-10Alkenyl; (CR 8R 8) qNR 4R 5C 2-10Alkenyl C (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 5(CR 8R 8) qC (O) NR 4R 10S (O) 3H; S (O) 3R 8(CR 8R 8) qC (O) R 11C 2-10Alkenyl C (O) R 11C 2-10Alkenyl C (O) OR 11(CR 8R 8) qC (O) OR 12(CR 8R 8) qOC (O) R 11(CR 8R 8) qC (NR 4) NR 4R 5(CR 8R 8) qNR 4C (NR 5) R 11(CR 8R 8) qNR 4C (O) R 11(CR 8R 8) qNHS (O) 2R aOr (CR 8R 8) qS (O) 2NR 4R 5Perhaps two Y parts can be combined together to form O-(CH 2) sSaturated or the unsaturated ring of-O or 5-6 unit.Above-mentioned all contain aryl, heteroaryl and heterocyclic part can such as hereinafter definition randomly be substituted.
When Y formed two oxo bridges, s was preferably 1.When Y formed other unsaturated ring, it preferably can form 6 yuan of rings of naphthalene ring system.These ring systems can be replaced 1-3 time independently by other Y part as defined above.
Aptly, R aBe NR 6R 7, alkyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocycle, heterocycle C 1-4Alkyl, wherein all contain aryl, heteroaryl and heterocyclic part and all can randomly be substituted.
Y is preferably halogen, C 1-4Alkoxyl, optional substituted aryl, optional substituted aryloxy group or aralkoxy, methylene dioxy base, NR 4R 5, C 1-4Alkylthio group (thio C1-4 alkyl), arylthio (thioaryl), halogenated alkoxy, optional substituted C 1-4Alkyl or hydroxyalkyl.The more preferably monobasic halogen of Y, dibasic halogen, monobasic alkoxyl, dibasic alkoxyl, methylene dioxy base, aryl or alkyl, more preferably these groups be 2 of benzyl ring '-position or 2 '-, 3 '-position one-or two-replace.
Although Y can be substituted on any position of ring, n is preferably 1.Although R 1Can be hydrogen with Y, but preferred at least one ring is substituted, preferred two rings all are substituted.
Aptly, R is-NH-C (X 2)-NH-(CR 13R 14) v-Z.Aptly, Z be W, HET,
Figure A0080909000181
Optional substituted C 1-10Alkyl, optional substituted C 2-10Alkenyl or optional substituted C 2-10Alkynyl.
Aptly, p is the integer of 1-3.
Aptly, X 2Be=0 or=S.
In formula (I) chemical compound, aptly, X is C (X 1) 2, C (O), C (S), S (O) 2, PO (OR 4) or C=N-R 19
Aptly, R 19Be cyano group, nitro, S (O) 2NR 4R 5, S (O) 2R 17, alkyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl-C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocycle, heterocycle C 1-4Alkyl wherein contains alkyl, aryl, heteroaryl and heterocyclic ring and all can randomly be substituted.R 19Be preferably cyano group.
When X is C (X 1) 2The time, X 1Independent aptly is hydrogen, halogen, NR 4R 5, C 1-10Alkyl NR 4R 5, C (O) NR 4R 5, C 1-10Alkyl-C (O) NR 4R 5, optional substituted C 1-10Alkyl, C 1-10Alkoxyl; Halo C 1-10Alkoxyl, aryl; Aryl C 1-4Alkyl; Aryloxy group; Aryl C 1-4Alkoxyl; Heteroaryl; Heteroarylalkyl; Heterocycle, heterocycle C 1-4Alkyl; Or heteroaryl C 1-4Alkoxyl.C 1-10Alkyl can be randomly by hydroxyl, NR 4R 5Or halogen replaces one or many.Preferably, at least one X 1Be hydrogen.
For formula (I) chemical compound, preferably, X is C (S) or C (O) part, more preferably C (O).
Aptly, R 18Be hydrogen, optional substituted C 1-10Alkyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, hydroxyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl-C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocycle or heterocycle C 1-4Alkyl, wherein all aryl, heteroaryl and heterocycle all can randomly be substituted.Preferably, R 18Be hydrogen or alkyl, hydrogen more preferably.
In formula (II) chemical compound, aptly, X is N or C (X 1), preferred X is N.
Preferably, when X be C (X 1) time, X 1Be hydrogen or haloalkyl.
Should be appreciated that in formula (II) chemical compound, ring system can exist with tautomeric form.
Aptly, when Z was heteroaryl (HET) ring, it was suitably heteroaryl ring or ring system.If HET partly is a polycyclic system, then contain heteroatomic ring do not need by the ring (R 13R 14) vConnection directly is connected with the urea part, can randomly replace as defined herein in these ring systems.Preferred HET partly is a pyridine radicals, can be 2-, 3-or 4-pyridine radicals.If this ring is a polycyclic system, then preferred benzimidazole, dibenzothiophenes or indole ring.Other rings that attract people's attention are including, but not limited to thiophene, furan, pyrimidine, pyrroles, pyrazoles, quinoline, isoquinolin, quinazolyl, oxazole, thiazole, thiadiazoles, triazole, imidazoles or benzimidazole.
HET ring can be independently randomly replaced 1-5 time preferably 1-3 time by Y as defined above.These substituent groups can be on arbitrary ring of HET ring system, for example on the benzimidazole ring.
Aptly, R 15And R 16Be hydrogen or independently as above to R 13And R 14The C of defined optional replacement 1-4Alkyl.
Aptly, W is
Figure A0080909000191
Aptly, the ring that contains E randomly is selected from Asterisk * is the junction point of finger ring.
The E ring of representing by junction point shown in the asterisk (*) can randomly exist.If there is no E ring, then this ring by shown in R 1The phenyl moiety that replaces.E ring can partly be replaced by (Y) n on arbitrary ring, is saturated or undersaturated, and only shows on unsaturated ring for purpose of the present invention and to be substituted.
Although replace (when not having the E ring) on any one that the Y in W can be in 5 ring positions of phenyl moiety, Y preferably in 2 '-position or 3 '-position replaced by one, preferred 4 '-position is unsubstituted.If benzyl ring is dibasic, substituent group is preferably placed at 2 ' or 3 ' of monocycle system.Although R 1With Y all can be hydrogen, but preferred at least one ring is substituted, more preferably two rings all are substituted.
Except as otherwise noted, term used herein " optional substituted " is meant following radicals: for example halogen such as fluorine, chlorine, bromine or iodine; Hydroxyl; The C that hydroxyl replaces 1-10Alkyl; C 1-10Alkoxyl such as methoxy or ethoxy; S (O) M 'C 1-10Alkyl, wherein m ' is 0,1 or 2, for example methyl mercapto, methylsulfinyl or methyl sulphonyl; Amino, one-and the two-amino that replaces, for example NR 4R 5Group; NHC (O) R 4C (O) NR 4R 5C (O) OH; S (O) 2NR 4R 5NHS (O) 2R 20, C 1-10Alkyl is methyl, ethyl, propyl group, isopropyl or the tert-butyl group for example; Halo C 1-10Alkyl such as CF 3Optional substituted aryl, phenyl for example, or optional substituted aralkyl such as benzyl or phenethyl, optional substituted heterocycle, optional substituted Heterocyclylalkyl, optional substituted heteroaryl, optional substituted heteroarylalkyl, wherein aryl, heteroaryl or heterocyclic moiety can be replaced 1-2 time by following groups: halogen; Hydroxyl; The alkyl that hydroxyl replaces; C 1-10Alkoxyl; S (O) M 'C 1-10Alkyl; Amino, one-and the two-amino that replaces is NR for example 4R 5Group; C 1-10Alkyl, or halo C 1-10Alkyl such as CF 3
R 20Be C aptly 1-4Alkyl, aryl, aryl C 1-4Alkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocycle or heterocycle C 1-4Alkyl.
Suitable officinal salt is that this area professional is known, comprise that inorganic and organic acid alkali salt, described acid are for example 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 be the salt that forms with pharmaceutically acceptable cation, for example, comprises in substituent group under the situation of carboxy moiety.Suitable pharmaceutically acceptable cation is that this area professional is known, comprises alkali, alkaline earth, ammonium and quaternary ammonium cation.
Defined terms more used herein below:
" halogen "-be meant all halogens, i.e. chlorine, fluorine, bromine and iodine.
" C 1-10Alkyl " or " alkyl " unless-limit chain length in addition, all be meant the straight chain and the branched group of 1-10 carbon atom, they are including, but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, sec-butyl, isobutyl group, the tert-butyl group, n-pentyl etc.
Term described herein " cycloalkyl " is meant cyclic group, and the cyclic group of preferred 3-8 carbon atom is including, but not limited to cyclopropyl, cyclopenta, cyclohexyl etc.
Remove unrestricted chain length, term used herein " alkenyl " all is meant the straight or branched group of 2-10 carbon atom in all cases, and they are including, but not limited to vinyl, 1-acrylic, 2-acrylic, 2-methyl isophthalic acid-acrylic, 1-butylene base, crotyl etc.
" aryl "-be meant phenyl and naphthyl;
" heteroaryl " (itself or any combining form, for example " heteroaryloxy " or " heteroarylalkyl ")-be meant that 5-10 unit aromatic ring is, 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, quinazolyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazoles, triazole, imidazoles or benzimidazole.
" heterocycle " (itself or any combining form, for example " Heterocyclylalkyl ")-be meant saturated or the undersaturated 4-10 of part unit 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 pyrrolidine, piperidines, piperazine, morpholine, Pentamethylene oxide. or imidazolidine.
Except as otherwise noted, term used herein " aralkyl " or " heteroarylalkyl " or " Heterocyclylalkyl " are meant as defined above and are the C that is connected of aryl, heteroaryl or heterocyclic moiety as defined above equally 1-10Alkyl.
" sulfinyl "-be meant the oxide S (O) of corresponding sulfide, term " sulfo-" is meant sulfide, term " sulfonyl " is meant the S (O) of complete oxidation 2Part.
Term used herein " two R wherein 1Partly (perhaps two Y parts) can be combined together to form 5 or 6 yuan of saturated or unsaturated rings " is meant that forming aromatic ring is naphthalene for example, or is connected with 6 yuan of fractional saturations or unsaturated ring such as C 6Cycloalkenyl group is hexene or C 5The cycloalkenyl group part is as the phenyl moiety of cyclopentenes.
Formula (I) examples for compounds comprises:
N-4-(benzimidazoline-2-ketone-N '-(2 '-bromophenyl) urea;
N-4-(1H, 3H-2,1,3-benzothiazole-2,2-dioxide)-N '-(2-bromophenyl) urea;
N-4-(7-cyano group-1-N-methyl-benzo imidazoline-2-thioketone)-N '-(2, the 3-Dichlorobenzene base) urea;
N-4-(7-cyano group-benzo imidazoline-2-thioketone)-N '-(2-bromophenyl) urea;
N-4-(7-cyano group-1-methyl-benzo imidazoline-2-thioketone)-N '-(2-bromophenyl) urea;
N-4-(7-cyano group-1-tolimidazole quinoline-2-ketone)-N '-(2, the 3-Dichlorobenzene base) urea;
N-4-(7-cyano group-benzimidazoline-2-ketone)-N '-(2-bromophenyl) urea;
N-4-(7-cyano group-benzo imidazoline-2-thioketone)-N '-(2, the 3-Dichlorobenzene base) urea;
N-4-(7-cyano group-benzimidazoline-2-imines)-N '-(2-bromophenyl) urea; With
N-(4-cyano group-2-oxo-3-tolimidazole-7-yl)-N '-(2-bromophenyl) urea.
Formula (II) examples for compounds comprises:
N-7-(benzotriazole)-N '-(2-bromophenyl) urea;
N-7-(4-bromobenzene and triazole)-N '-(2, the 3-Dichlorobenzene base) urea;
N-7-(4-bromo-2-trifluoromethyl-benzimidazolyl)-N '-(2-bromophenyl) urea;
N-4-(2-trifluoromethyl-benzimidazolyl)-N '-(2-bromophenyl) urea;
N-7-(4-cyano group-benzotriazole)-N '-(2, the 3-Dichlorobenzene base) urea;
N-7-(4-cyano group-benzotriazole)-N '-(2-bromophenyl) urea;
N-7-(4-cyano group-2-trifluoromethyl-benzimidazolyl)-N '-(2-bromophenyl) urea;
N-7-(4-cyano group-benzimidazolyl)-N '-(2, the 3-Dichlorobenzene base) urea; With
N-7-(4-cyano group-benzimidazolyl)-N '-(2-bromophenyl) urea.
For the present invention, above-mentioned name is based on following ring system numbering:
Figure A0080909000221
(being applicable to formula (I)); (being applicable to formula (II)).
Preparation method
Can obtain formula (I) chemical compound by synthetic method, in following reaction scheme illustrated some of them synthetic method.The synthetic method that provides in these reaction scheme is applicable to that preparation has various differences and can react the formula of Z and R group (I) chemical compound, and this synthetic use is suitable for protecting to reach the optional substituent group compatible with described reaction.Under the sort of situation, deprotection obtains disclosed former form chemical compound usually afterwards.In case made up urea nuclear, the standard technique that other chemical compound of these general formulas can also adopt functional group well known in the art to change mutually is prepared.Although in conjunction with various formulas (I) chemical compound reaction scheme has been described, this only is illustrative, only uses on these methods but not synthetic method is limited in.
Reaction scheme 1
Figure A0080909000231
If the heterocyclic compound 2-reaction scheme 1 that the 2-nitro replaces is not commercially available, then can be prepared by in proton solvent such as HOAc, handling commercially available 3-nitro phenylenediamine 1-reaction scheme 1 with sodium nitrite.
Reaction scheme 2
A) triphosgene, Et 3N, DMF
If the heterocyclic compound 2-reaction scheme 2 that the 2-nitro replaces is not commercially available, then can be prepared by in DMF, handling commercially available 3-nitro phenylenediamine 1-reaction scheme 2 with triphosgene and triethylamine, perhaps handle forming thiourea with thiophosgene.Perhaps react with another carbonyl such as carbonyl dimidazoles that does not contain leaving group.
Reaction scheme 3
Figure A0080909000241
A) toluene trifluoroacetic anhydride b) refluxes
If the heterocyclic compound 2-reaction scheme 3 that the 2-nitro replaces is not commercially available, then can be prepared in reflux in toluene then by handle commercially available 3-nitro phenylenediamine 1-reaction scheme 3 with corresponding acid anhydride.
Reaction scheme 4
If the heterocyclic compound 3-reaction scheme 4 that the 2-nitro replaces is not commercially available, then can be by under the standard nitration condition, (using HNO 3Or NaNO 3), handle chemical compound 2-reaction scheme 4 at 23 ℃ and be prepared.If heterocyclic compound 2-reaction scheme 4 is not commercially available, then can-70 ℃ with triethylamine, handle commercially availablely 1 with thionyl chloride then, 2-dibenzyl diamidogen 1-reaction scheme 4 is then with the m-CPBA oxidation and use H in methanol 2/ Pd is prepared the benzyl reduction.
Reaction scheme 5
Figure A0080909000251
If the heterocyclic compound 2-reaction scheme 5 that the 2-nitro replaces is not commercially available, then can be by using PhOP (O) Cl 2, adopt the standard nitration condition (to use HNO then 3Or NaNO 3) handle commercially availablely 1 at 23 ℃, 2-diamidogen 1-reaction scheme 5 is prepared.
Reaction scheme 6
Figure A0080909000252
A) formaldehyde refluxes
If heterocyclic compound 2-reaction scheme 6 is not commercially available, then can be commercially available 1 by under refluxing, handling with formaldehyde, 2-diamidogen 1-reaction scheme 6 is prepared.
Reaction scheme 7
Figure A0080909000253
If required aniline 2-reaction scheme 7 is not commercially available, then (H under standard conditions 2Pd/C or SnCl 2) corresponding nitro compound 1-reaction scheme 4 is reduced.The phenylurea 3-reaction scheme 7 that the ortho position replaces can adopt standard conditions, make commercially available replacement aryl isocyanate (Aldrich Chemical Co., Milwaukee Wi.) is prepared with corresponding aniline 2-reaction scheme 7 condensation in aprotonic solvent (as DMF or toluene).
Reaction scheme 8
Figure A0080909000261
If the amino heterocyclic compound 4-reaction scheme 8 that replaces of 7-is not commercially available, then can be prepared, perhaps can in aprotonic solvent such as DMF, carry out the palladium catalytic coupling reactions to generate 2-cyano group-5-nitroaniline 2-reaction scheme 8 with pyridine by handling commercially available 2-bromo-5-nitroaniline 1-reaction scheme 8 with nucleopilic reagent such as copper cyanider (I).React in aprotonic solvent such as DMSO by 2-cyano group-5-nitroaniline 2-reaction scheme 8 and iodate tetramethyl hydrazine and strong hindered base such as sodium tert-amyl alcohol, can form diamidogen 3-reaction scheme 8.React in aprotonic solvent such as HOAc by diamidogen 3-reaction scheme 8 and sodium nitrite, then with appropriate reductant for example the Pd/C in MeOH make nitroreduction, can prepare 7-amino-4-cyano group benzotriazole 4-reaction scheme 8.Perhaps diamidogen 3-reaction scheme 8 can be used for synthetic other heterocycles as herein described.The aromatic ring of chemical compound can also adopt condition well known in the art, and for example bromination or other electrophilic substitution reactions are further functionalized.These substituent groups can further be handled with the nucleophilic displacement of fluorine base of standard, for example with anion (as Feldalat NM) reaction, perhaps handle in palladium catalytic coupling reactions chemistry.
Then, can by with commercially available isocyanates condensation, the heterocyclic compound 4-reaction scheme 8 that amino is replaced is converted into corresponding urea.
The present invention relates to new following formula: compound on the other hand: R wherein 1With m such as in formula (II) definition.Preferably, R 1Be bromine or cyano group.R 1Preferably replace in the 4-position of ring.
The present invention relates to new formula (IV) chemical compound on the other hand: R wherein 1With m such as in formula (II) definition, condition is R 1Not hydrogen.R 1Be preferably cyano group or bromine.
The present invention relates to the new method for preparing following formula: compound on the other hand:
Figure A0080909000273
This method is included in the proton solvent following formula: compound
Figure A0080909000274
With the sodium nitrite reaction, make nitroreduction then, obtain formula (III) chemical compound.
At last, the present invention relates on the other hand and prepares the similarity method of formula (II) chemical compound as defined above, and this method comprises a) following formula: compound
Figure A0080909000281
With formula C (X 2)-N-(CR 13R 14) vThe reaction of-Z chemical compound; R wherein 1, m, X 2, R 13, R 14, v and Z such as in formula (II) definition, obtain formula (II) chemical compound.
Synthetic embodiment
Present invention is described with reference to the following example below, and these embodiment only are illustrative, but not limitation of the scope of the invention.Except as otherwise noted, all temperature are degree centigrade, and all solvents all are highest purities, and all reactions all are to carry out under anhydrous condition under argon atmospher.
In an embodiment, all temperature be degree centigrade (℃).Except as otherwise noted, mass spectrum is on VG Zab mass spectrograph, adopts the fast atom bombardment method to carry out. 1H-NMR (hereinafter with " NMR " expression) spectrum uses Bruker AM 250 or Am 400 spectrogrphs at the 250MHz record.The multiplet at peak is: s=is unimodal, d=is bimodal, t=three peaks, q=four peaks, m=multimodal, and br represents broad peak.Sat. represent saturated solution, eq represents the molar equivalent ratio of reagent with respect to the dominant response thing.
Conventional method B: synthetic N, N '-phenylurea.In the solution of Carbimide. phenylester (1.0 equivalent) in dimethyl formamide (1ml), add corresponding aniline (1.O equivalent).At 80 ℃ of stirred reaction mixtures until (3-16 hour), the solvent removed in vacuo then of reacting completely.The purification of each particular compound, productive rate and spectral signature are as described below.
Embodiment 1
Preparation N-[5-bromo-2 benzotriazole]-N '-[2, the 3-Dichlorobenzene base] urea a) prepares the 4-nitrobenzene and triazolam
Under agitation, in the solution of 3-nitro-phenylenediamine (15.3g, 100 mMs (representing with mmol hereinafter)) in acetic acid (50 milliliters (hereinafter with " ml " expression)), add sodium nitrite (6.9g, 100mmol).This mixture is in 60 ℃ of heating 1 hour (hereinafter with " hr " expression).Make reactant be cooled to room temperature then and add entry, required product is precipitated out from solution and mixture is filtered, and obtains required product (10.7 grams (hereinafter with " g " expression), 65%). 1H NMR (CD 3SOCD 3): δ 8.58 (d, 1H), 8.44 (d, 1H), 7.61 (t, 1H).B) the amino benzotriazole of preparation 4-
(4g 24.4mmol) adds 10%Pd/C (1.0g) in the solution in methanol (250ml) to the 4-nitrobenzene and triazolam.Feed argon in this mixture, bubbling fed hydrogen 10 minutes (hereinafter with " min " expression) in this solution then, and pressed the maintenance nitrogen atmosphere 4 hours with ball.In reactant mixture, feed argon, add 10%Pd/C (1.0g) again, and press the maintenance nitrogen atmosphere to spend the night with ball.Mixture is through diatomite filtration, the kieselguhr methanol wash.Evaporating solvent, the gained solid is through silica gel chromatography purification (5%MeOH/CH 2Cl 2), obtain required product (2.0g, 82%). 1H?NMR(CD 3SO 2CD 3)：δ8.71(s，1H)，7.16(t，1H)，6.75(d，1H)，6.36(d，1H)，5.90(s，1H)。C) preparation 4-amino-7-bromobenzene and triazole
To the amino benzotriazole of 4-(550 milligrams (hereinafter with " mg " expression), 4.1mmol) add in the solution in acetic acid (10ml) potassium bromide (520mg, 4.4mmol), ammonium molybdate (67mg, 0.55mmol) and hydrogen peroxide (0.5ml, 30%).This mixture stirred 3 hours 25.Evaporating solvent, the gained solid obtains required product (400mg, 45%) through silica gel chromatography purification (EtOAc/ hexane (1 equivalent/1 equivalent)). 1H?NMR(CD 3SO 2CD 3)：δ7.29(d，1H)，6.49(d，1H)，6.05(bs，3H)。D) preparation N-7-[4-bromo-[2,4]-benzotriazole]-N '-[2, the 3-Dichlorobenzene base] urea
According to the method described in the conventional method B, by 4-amino-7-bromobenzene and triazole (330mg, 1.50mmol) preparation N-[5-bromo-2 benzotriazole]-N '-[2, the 3-Dichlorobenzene base] urea.By the gained solid is composed in the enterprising circumstances in which people get things ready for a trip of silica gel, make product purification (EtOAc/ hexane (2 equivalents/3 equivalents)).(410mg，68％)。 1H?NMR(CD 3SOCD 3)：δ10.42(s，1H)，9.25(s，1H)，8.20(dd，1H)，7.96(d，1H)，7.64(d，1H)，7.33(m，2H)。
Embodiment 2 preparation N-7-[benzimidazoline-3-ketone]-N '-[2-bromophenyl] urea a) prepares 4-nitro-benzimidazoline-2-ketone
To 3-nitro-phenylenediamine (1.0g, 6.53mmol) add in the solution in dimethyl formamide (20ml) triphosgene (0.775g, 2.60mmol) and triethylamine (1ml, 7.80mmol).Then with this mixture heated to 80 ℃ about 1 hour.Evaporating solvent uses dichloromethane/hexane (1 equivalent/20 equivalents) that product is precipitated out from solution.(700mg，64％)。 1H?NMR(CD 3SO 2CD 3)：δ11.61(s，1H)，11.35(s，1H)，7.85(d，1H)，7.34(d，1H)，7.15(t，1H)。B) preparation 4-amino-benzimidazoline-2-ketone
(700mg 3.9mmol) adds 10%Pd/C (200mg) in the solution in methanol (50ml) and acetic acid (10ml) to 4-nitrobenzimidazole quinoline-2-ketone.Feed argon in this mixture, bubbling fed hydrogen 10 minutes in this solution then, and pressed the maintenance nitrogen atmosphere to spend the night with ball.Mixture is through diatomite filtration, the kieselguhr methanol wash.Evaporating solvent, the gained solid is through silica gel chromatography purification (10%MeOH/CH 2Cl 2), obtain required product (500mg, 86%). 1H?NMR(CD 3SO 2CD 3)：δ10.34(s，1H)，10.01(s，1H)，6.66(t，1H)，6.24(d，1H)，6.22(d，1H)，5.15(bs，2H)。C) preparation N-[benzimidazoline-3-ketone]-N '-[2-bromophenyl] urea
According to the method described in the conventional method B, by the amino benzimidazoline of 4--2-ketone (80mg, 0.54mmol) preparation N-[benzimidazoline-3-ketone]-N '-[2-bromophenyl] urea.By the gained solid is composed in the enterprising circumstances in which people get things ready for a trip of silica gel, make product purification (EtOAc/ hexane (1 equivalent/1 equivalent)).(120mg，64％)。 1H?NMR(CD 3SOCD 3)：δ10.68(s，1H)，10.03(s，1H)，9.08(s，1H)，8.15(d，1H)，8.08(s，1H)，7.62(d，1H)，7.34(t，1H)，6.99(t，1H)，6.92(d，2H)，6.73(d，1H)。
Embodiment 3 preparation N-[4-bromo-2-trifluoromethyl-7-benzimidazolyls]-N '-[2-bromophenyl] urea a) prepares 4-nitro-2-trifluoro methyl benzimidazole
To 3-nitro-phenylenediamine (1.0g, 6.53mmol) add in the solution trifluoroacetic anhydride (1.37g, 6.53mmol).Stirred this mixture then 1 hour.Evaporating solvent, product was reflux in toluene 2 hours.Evaporating solvent obtains required product (1.43g, 95%). 1H?NMR(CD 3SO 2CD 3)：δ9.40(s，1H)，8.31(d，1H)，8.39(d，1H)，7.58(t，1H)。B) preparation 4-amino-2-trifluoro methyl benzimidazole
(700mg 3.0mmol) adds 10%Pd/C (200mg) in the solution in methanol (50ml) to 4-nitro-2-trifluoro methyl benzimidazole.Feed argon in this mixture, bubbling fed hydrogen 10 minutes in this solution then.And press to keep nitrogen atmosphere to spend the night with ball.Mixture is through diatomite filtration, the kieselguhr methanol wash.Evaporating solvent, the gained solid is through silica gel chromatography purification (10% MeOH/CH 2Cl 2), obtain required product (560mg, 93%). 1H?NMR(CD 3SO 2CD 3)：δ10.49(s，1H)，7.09(t，1H)，6.72(d，1H)，6.30(d，1H)，5.52(bs，2H)。C) preparation 4-amino-7-bromo-2-trifluoro methyl benzimidazole
To 4-amino-2-trifluoro methyl benzimidazole (180mg, 0.9mmol) add in the solution in acetic acid (10ml) potassium bromide (117mg, 0.99mmol), ammonium molybdate (12mg, 0.099mmol) and hydrogen peroxide (0.2ml, 30%).This mixture stirred 3 hours at 25 ℃, evaporating solvent, and the gained solid obtains required product (103mg, 39%) through silica gel chromatography purification (EtOAc/ hexane (1 equivalent/1 equivalent)). 1H?NMR(CD 3OD)：δ7.11(d，1H)，6.35(d，1H)。D) preparation N-[4-bromo-2-trifluoromethyl-7-benzimidazolyl]-N '-[2-bromophenyl] urea
According to the method described in the conventional method B, by 4-amino-7-bromo-2-trifluoro methyl benzimidazole (33mg, 0.54mmol) preparation N-[4-bromo-2-trifluoromethyl-7-benzimidazolyl]-N '-[2-bromophenyl] urea.The gained solid is through silica gel chromatography purification (EtOAc/ hexane (1 equivalent/1 equivalent)).(35mg，63％)。 1H?NMR(CD 3SOCD 3)：δ9.95(s，1H)，9.54(s，1H)，9.07(s，1H)，8.06(d，1H)，7.99(d，1H)，7.62(d，1H)，7.33(t，1H)，7.01(t，1H)。
Embodiment 4 preparation N-[4-triazol phenyl]-N '-[2-bromophenyl] urea a) prepares 2,6-dinitro (1-benzenesulfonyl) aniline
To 2, the 6-dinitroaniline (2g, 10.92mmol) add in the solution in THF (20ml) sodium hydride (473mg, 10.92mmol).After 10 minutes, and the adding benzene sulfonyl chloride (1.4mL, 10.92mmol).Stirring at room reactant mixture 16 hours.Then reactant mixture is distributed between ethyl acetate and water.The organic layer dried over mgso that merges is filtered and concentrating under reduced pressure, and the gained solid obtains product (2.6g, 74%) through silica gel chromatography purification (hexane/ethyl acetate (5 equivalents/1 equivalent)).EI-MS?m/z?324(M +)。B) preparation 2,6-diaminourea (1-benzenesulfonyl) aniline
To 2,6-dinitro (1-benzenesulfonyl) aniline (450mg, 1.39mmol) add in the solution in ethanol (10mL) stannic chloride (II) (1.57g, 6.95mmol).Made the reactant mixture stirring and refluxing 4 hours.Be cooled to room temperature then.Add NaHCO 3Aqueous solution is to pH=7.Use ethyl acetate extraction (3x) then.The organic layer dried over mgso that merges is filtered and concentrating under reduced pressure, obtains product (338mg, 92%).EI-MS?m/z?264(M +)。C) preparation N-(2-benzenesulfonyl amino-3-aminophenyl)-N '-(2-bromophenyl) urea
To Carbimide. 2-bromophenyl ester (0.16mg 1.28mmol) adds 2 in the solution in DMF (1.5mL), 6-diaminourea (1-benzenesulfonyl) aniline (338mg, 1.28mmol).80 ℃ of stirred reaction mixtures 16 hours, be cooled to room temperature then.Gained liquid obtains product (430mg, 73%) through silica gel chromatography purification (hexane/ethyl acetate (5 equivalents/1 equivalent to 1 equivalent/1 equivalent)).EI-MS?m/z?461(M +)。D) preparation N-(4-triazol phenyl)-N '-(2-bromophenyl) urea
(235mg 0.51mmol) adds HCl/H with N-(2-benzenesulfonyl amino-3-aminophenyl)-N '-(2-bromophenyl) urea 2Among the O (0.51mL/1.02mL), be cooled to 0 ℃.In reactant mixture, add Chile saltpeter (35.4mg, 0.51mmol).Reactant mixture stirred 30 minutes 0.(25mg 0.51mmol), and is warmed to room temperature to add Cyanogran. in reactant mixture.Stirring at room reactant mixture 18 hours, use ethyl acetate extraction then 3 times.Merge organic extracting solution, use dried over mgso, filter and concentrating under reduced pressure, the gained solid obtains product (100mg, 59%) through the silica gel chromatography purification.EI-MS?m/z?333(M +)。
Embodiment 5 preparation N-7-[2-trifluoro methyl benzimidazole bases]-N '-[2-bromophenyl] urea a) prepares 4-nitro-2-trifluoro methyl benzimidazole
To 3-nitro-phenylenediamine (1.0g, 6.53mmol) add in the solution trifluoroacetic anhydride (1.37g, 6.53mmol).Stirred this mixture then 1 hour.Evaporating solvent, product was reflux in toluene 2 hours.Evaporating solvent obtains required product (1.43g, 95%). 1H?NMR(CD 3SO 2CD 3)：δ9.40(s，1H)，8.31(d，1H)，8.39(d，1H)，7.58(t，1H)。B) preparation 4-amino-2-trifluoro methyl benzimidazole
(700mg 3.0mmol) adds 10%Pd/C (200mg) in the solution in methanol (50ml) to 4-nitro-2-trifluoro methyl benzimidazole.Feed argon in this mixture, bubbling fed hydrogen 10 minutes in this solution then, and pressed the maintenance nitrogen atmosphere to spend the night with ball.Mixture is through diatomite filtration, the kieselguhr methanol wash.Evaporating solvent, the gained solid is through silica gel chromatography purification (10% MeOH/CH 2Cl 2), obtain required product (560mg, 93%). 1H?NMR(CD 3SO 2CD 3)：δ10.49(s，1H)，7.09(t，1H)，6.72(d，1H)，6.30(d，1H)，5.52(bs，2H)。C) preparation N-7-[2-trifluoro methyl benzimidazole base]-N '-[2-bromophenyl] urea
According to the method described in the conventional method B, by 4-amino-2-trifluoro methyl benzimidazole (360mg, 1.79mmol) preparation N-7-[2-trifluoro methyl benzimidazole base]-N '-[2-bromophenyl] urea.By the gained solid is composed in the enterprising circumstances in which people get things ready for a trip of silica gel, make product purification (EtOAc/ hexane (1 equivalent/1 equivalent)).(35mg，63％)。 1H?NMR(CD 3SO 2CD 3)：δ9.94(s，1H)，9.89(s，1H)，9.02(s，1H)，8.09(d，1H)，8.00(d，1H)，7.61(d，1H)，7.32(m，2H)，7.20(d，1H)，7.00(t，1H)。
Embodiment 6 preparation N-(4-cyano group-1H-benzotriazole-7-yl)-N '-(2, the 3-Dichlorobenzene base) ureas a) prepare 2-cyano group-5-nitroaniline
Under agitation, to 2-bromo-5-nitroaniline (5.0g, 23mmol) add in the solution in dimethyl formamide (100ml) and pyridine (20ml) copper cyanider (I) (2.05g, 64mmol).Then this mixture was heated 48 hours at 160 ℃.Make reactant be cooled to room temperature then, through diatomite filtration, kieselguhr washs with ethyl acetate.Evaporating solvent, gained solid obtain required product (2.64g, 70%) through silica gel chromatography purification (25%EtOAc/ hexane). 1H?NMR(CD 3COCD 3)：δ7.75(s，1H)，7.70(d，1H)，7.44(dd，1H)，6.25(bs，2H)。B) preparation 2-cyano group-5-nitro-phenylenediamine
To 2-cyano group-5-nitroaniline (435mg, 2.67mmol) add in the solution in dimethyl sulfoxide (25ml) iodate tetramethyl hydrazine (534mg, 2.67mmol) and sodium tert-amyl alcohol (880mg, 8.01mmol).In this mixture of stirring at room 12 hours, with 10% hydrochloric acid cessation reaction.Leach precipitated solid, the rest solution ethyl acetate extraction, evaporating solvent, gained solid obtain required product (254mg, 53%) through silica gel chromatography purification (25%EtOAc/ hexane). 1H?NMR(CD 3COCD 3)：δ7.49(d，1H)，7.03(bs，2H)，6.80(d，1H)，5.78(bs，2H)。C) preparation 4-cyano group-7-nitrobenzene and triazolam
Under agitation, to 2-cyano group-5-nitro phenylenediamine (120mg, 0.67mmol) add in the solution in acetic acid (20ml) sodium nitrite (50mg, 0.72mmol).Heated these mixture 1 hour at 60 ℃ then.Make reactant be cooled to room temperature, evaporating solvent, the gained solid obtains required product (120mg, 95%) through silica gel chromatography purification (50% EtOAc/ hexane). 1H?NMR(CD 3COCD 3)：δ8.70(d，1H)，8.25(d，1H)。D) the amino benzotriazole of preparation 4-cyano group-7-
(120mg 0.63mmol) adds 10%Pd/C (1.0g) in the solution in methanol (250ml) to 4-cyano group-7-nitrobenzene and triazolam.Feed argon in this mixture, bubbling fed hydrogen 10 minutes in this solution then, and pressed the maintenance nitrogen atmosphere 4 hours with ball.In reactant mixture, feed argon, add 10%Pd/C (1.0g) again, and pressed the maintenance nitrogen atmosphere 1 hour with ball.Mixture is through diatomite filtration, the kieselguhr methanol wash.Evaporating solvent, the gained solid is through silica gel chromatography purification (5% MeOH/CH 2Cl 2), obtain required product (95mg, 94%). 1H?NMR(CD 3OD)：δ7.58(d，1H)，6.53(d，1H)。E) preparation N-[5-cyano group-2 benzotriazole]-N '-[2, the 3-Dichlorobenzene base] urea
According to the method described in the conventional method B, by 7-amino-4-cyano group benzotriazole (95mg, 0.60mmol) preparation N-[5-cyano group-2 benzotriazole]-N '-[2, the 3-Dichlorobenzene base] urea.By the gained solid is composed in the enterprising circumstances in which people get things ready for a trip of silica gel, make product purification (EtOAc/ hexane (2 equivalents/3 equivalents)).(410mg，68％)。 1H?NMR(CD 3COCD 3)：δ10.85(s，1H)，9.40(s，1H)，8.34(d，1H)，8.20(d，1H)，7.94(d，1H)，7.36(d，1H)，7.31(t，1H)。
Embodiment 7 preparation N-(2-bromophenyl)-N '-(4-cyano group-1H-benzotriazole-7-yl) ureas
Under agitation, to 2-bromo-5-nitroaniline (5.0g, 23mmol) add in the solution in dimethyl formamide (100ml) and pyridine (20ml) copper cyanider (I) (2.05g, 64mmol).Then this mixture was heated 48 hours at 160 ℃.Make reactant be cooled to room temperature, through diatomite filtration, kieselguhr washs with ethyl acetate.Evaporating solvent, the gained solid obtains required product (2.64g, 70%) through silica gel chromatography purification (25% EtOAc/ hexane). 1H?NMR(CD 3COCD 3)：δ7.75(s，1H)，7.70(d，1H)，7.44(dd，1H)，6.25(bs，2H)。B) preparation 2-cyano group-5-nitro phenylenediamine
To 2-cyano group-5-nitroaniline (435mg, 2.67mmol) add in the solution in dimethyl sulfoxide (25ml) iodate tetramethyl hydrazine (534mg, 2.67mmol) and sodium tert-amyl alcohol (880mg, 8.01mmol).In this mixture of stirring at room 12 hours, with 10% hydrochloric acid cessation reaction.Leach precipitated solid, the rest solution ethyl acetate extraction, evaporating solvent, the gained solid obtains required product (254mg, 53%) through silica gel chromatography purification (25% EtOAc/ hexane). 1H?NMR(CD 3COCD 3)：δ7.49(d，1H)，7.03(bs，2H)，6.80(d，1H)，5.78(bs，2H)。C) preparation 4-cyano group-7-nitrobenzene and triazolam
Under agitation, to 2-cyano group-5-nitro-phenylenediamine (120mg, 0.67mmol) add in the solution in acetic acid (20ml) sodium nitrite (50mg, 0.72mmol).Then this mixture was heated 1 hour at 60 ℃.Make reactant be cooled to room temperature, evaporating solvent, the gained solid obtains required product (120mg, 95%) through silica gel chromatography purification (50% EtOAc/ hexane). 1H?NMR(CD 3COCD 3)：δ8.70(d，1H)，8.25(d，1H)。D) the amino benzotriazole of preparation 4-cyano group-7-
(120mg 0.63mmol) adds 10% Pd/C (1.0g) in the solution in methanol (250ml) to 4-cyano group-7-nitrobenzene and triazolam.Feed argon in this mixture, bubbling fed hydrogen 10 minutes in this solution then, and pressed the maintenance nitrogen atmosphere 4 hours with ball.In reactant mixture, feed argon, add 10%Pd/C (1.0g) again, and pressed the maintenance nitrogen atmosphere 1 hour with ball.Mixture is through diatomite filtration, the kieselguhr methanol wash.Evaporating solvent, the gained solid is through silica gel chromatography purification (5% MeOH/CH 2Cl 2), obtain required product (95mg, 94%). 1H?NMR(CD 3OD)：δ7.58(d，1H)，6。53(d，1H)。E) preparation N-[4-cyano group-[1,4]-benzotriazole-7-yl]-N '-[2-bromophenyl] urea
According to the method described in the conventional method B, by 7-amino-4 cyano group benzotriazole (95mg, 0.60mmol) preparation N-[5-cyano group-2 benzotriazole]-N '-[2-bromophenyl] urea.By the gained solid is composed in the enterprising circumstances in which people get things ready for a trip of silica gel, make product purification (EtOAc/ hexane (2 equivalents/3 equivalents)).(410mg，68％)。 1H?NMR(CD 3SO 2CD 3)：δ10.83(s，1H)，9.18(s，1H)，8.20(d，1H)，8.05(d，1H)，7.99(d，1H)，7.66(d，1H)，7.40(t，1H)，7.06(t，1H)。
Adopt and similar method described in above-mentioned or the reaction scheme, can synthesize following compounds: embodiment 8:N-(2H, 4H-3,2,4-benzothiazole-3,3-dioxide)-N '-(2-bromophenyl) urea. 1H?NMR(DMSO-d 6)δ10.96(s，1H)，10.32(s，1H)，9.05(s，1H)，8.49(s，1H)，8.08(d，1H，J＝11.50Hz)，7.63(d，1H，J＝11.50Hz)，7.35(t，1H)，7.18(d，1H，J＝11.50)，7.01(t，1H)，6.91(t，1H)，6.60(d，1H，J＝11.50)。Embodiment 9:N-(5-cyano group-4-N-tolimidazole quinoline-3-thioketone)-N '-(2, the 3-Dichlorobenzene base) urea. 1H?NMR(DMSO-d 6)δ11.20(s，1H)，9.52(s，1H)，8.62(s，1H)，8.15(m，2H)，7.61(d，IH，J＝13.25Hz)，7.45(d，1H，J＝13.25Hz)，7.37(m，2H)，3.94(d，3H)。Embodiment 10:N-(5-cyano group-benzimidazoline-3-thioketone)-N '-(2-bromophenyl) urea. 1HNMR(DMSO-d 6)δ11.57(s，1H)，10.43(s，1H)，9.51(s，1H)，8.31(s，1H)，8.09(d，1H，J＝13.25Hz)，7.68(d，1H，J＝13.25Hz)，7.54(d，1H，J＝13.25)，7.44-7.36(m，2H)，7.07(t，1H)。Embodiment 11:N-(5-cyano group-4-N-tolimidazole quinoline-3-thioketone))-N '-(2-bromophenyl) urea. 1H?NMR(DMSO-d 6)δ11.25(s，1H)，9.51(s，1H)，8.31(s，1H)，8.09(d，1H，J＝13.25)，7.67(d，1H，J＝13.25Hz)，7.61(d，1H，J＝13.25Hz)，7.50(d，1H，J＝13.25)，7.39(t，1H)，7.06(t，1H)，3.94(s，3H)。Embodiment 12:N-(4-cyano group-2-oxo-3-tolimidazole-7-yl)-N '-(2, the 3-Dichlorobenzene base) urea. 1H?NMR(DMSO-d 6)δ10.94(s，1H)，9.46(s，1H)，8.65(s，1H)，8.18(m，1H)，7.40-7.31(m，3H)，7.26(d，1H，J＝13.25Hz)，3.55(s，3H)。Embodiment 13:N-(4-cyano group-2-oxo-2,3-dihydrobenzo imidazoles-7-yl)-N '-(2-bromophenyl) urea. 1H?NMR(DMSO-d 6)δ11.86(s，1H)，10.82(s，1H)，9.94(s，1H)，8.70(s，1H)，8.65(d，1H，J＝13.25Hz)，8.11(d，1H，J＝13.25Hz)，7.85(t，1H)，7.76(m，2H)，7.50(t，1H)。Embodiment 14:N-(4-cyano group-2-trifluoromethyl-7-benzimidazolyl)-N '-(2-bromophenyl) urea. 1H?NMR(DMSO-d 6)δ10.30(s，1H)，9.25(s，1H)，8.24(s，1H)，7.96(m，2H)，7.85(d，1H，J＝13.25Hz)，7.66(d，1H，J＝13.25Hz)，7.49(t，1H)，7.07(t，1H)。Embodiment 15:N-(4-cyano group-7-benzimidazolyl)-N '-(2, the 3-Dichlorobenzene base) urea. 1H?NMR(DMSO-d 6)δ10.45(s，1H)，10.34(s，1H)，9.48(s，1H)，8.44(s，1H)，8.15(m，2H)，7.68(d，1H，J＝13.25Hz)，7.85(t，1H)，7.37(m，2H)。Embodiment 16:N-(4-cyano group-7-benzimidazolyl)-N '-(2-bromophenyl) urea. 1H NMR (acetone-d 6) δ 11.81 (s, 1H), 9.45 (s, 1H), 8.84 (s, 1H), 8.34 (s, 1H), 8.26 (m, 2H), 7.65 (d, 2H), 7.41 (t, 1H), 7.06 (t, 1H).Embodiment 17:N-(5-cyano group-benzimidazoline-3-thioketone)-N '-(2, the 3-Dichlorobenzene base) urea. 1H?NMR(DMSO-d 6)δ11.54(s，1H)，10.42(s，1H)，9.52(s，1H)，8.62(s，1H)，8.15(m，1H)，7.54(d，1H，J＝13.25Hz)，7.40-7.30(t，m，3H)。Embodiment 18:N-(5-cyano group-N-cyano group-2-guanidine)-N '-(2-bromophenyl) urea. 1H?NMR(DMSO-d 6)δ10.89(s，1H)，11.02(s，1H)，9.66(s，1H)，8.42(s，1H)，8.04(d，1H，J＝13.25Hz)，7.66(d，1H，J＝13.25Hz)，7.50(m，1H)，7.40(t，1H)，7.06(t，1H)。Embodiment 19:N-(4-cyano group-2-oxo-3-tolimidazole-7-yl)-N '-(2-bromophenyl) urea perhaps is called: N-4-(7-cyano group-1-tolimidazole quinoline-2-ketone)-N '-(2-bromophenyl) urea. 1H?NMR(DMSO-d 6)δ10.89(s，1H)，9.39(s，1H)，8.30(s，1H)，8.10(d，1H，J＝13.25)，7.76(d，1H，J＝13.25Hz)，7.45-7.32(m，2H)，7.26(d，1H，J＝13.25)，7.03(t，1H)，3.57(s，3H)。
Therapeutic Method
Formula (I) and/or formula (II) compound or pharmaceutically acceptable salt thereof can be used for preparing preventative or therapeutic treatment people or other are mammiferous, by mammalian cell (for example but be not limited to mononuclear cell and/or macrophage) generation IL-8 cytokine too much or out of control or by the medicine of other and IL-8 α or beta receptor (being also referred to as I type or the II receptor) disease condition that bonded chemotactic factor caused or worsened.
Therefore, except as otherwise noted, for purposes of the present invention, term " formula (I) chemical compound " or " formula (I) " also are meant " formula (II) chemical compound " or " formula (II) ".
Therefore, the invention provides the method for the chemokine mediated disease of treatment, wherein chemotactic factor is bonded with IL-8 α or beta receptor, and this method comprises formula (I) compound or pharmaceutically acceptable salt thereof of using effective dose.Especially, chemotactic factor is IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78.
Formula (I) chemical compound is to be enough to suppress cytokine function, the particularly amount administration of IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78, can make thus and be adjusted downward to the normal level of physiological function its biology, perhaps be adjusted downward to subnormal level under certain conditions, thereby improve disease condition.In the present invention, unusual IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 level are meant: (i) free IL-8 level is more than or equal to 1 microgamma/mL; The bonded IL-8 of (ii) any cell, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 level are greater than normal physiological level; Or (iii) the content of IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 is higher than foundation level in the cell or tissue that produces IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 respectively.
The disease condition of the too much or generation out of control of many wherein IL-8 is with the deterioration of these diseases and/or cause relevant.Chemokine mediated disease comprises psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel, Crohn disease, ulcerative conjunctivitis, apoplexy, septic shock, endotoxin shock, the Gram sepsis, toxic shock syndrome, the heart and renal reperfusion injury, glomerulonephritis, thrombosis, graft is to host's reaction, Alzheimer, homograft rejection, malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, undesirable hematopoietic stem cell release and the disease that causes by respiratory virus, include but not limited to rhinovirus and influenza virus, herpesvirus, include but not limited to I type and II type herpes simplex virus, and hepatitis virus, include but not limited to hepatitis B and hepatitis C virus.
Interleukin-8 and rhinoviral relation are found in following article, for example: Turner etc., Clin.Infect.Dis. (1998), 26 (4), 840-846; Sanders etc., J.Virol. (1998), 72 (2), 934-942; Sethi etc., Clin.Exp.Immunol. (1997), 110 (3), 362-369; Zhu etc., Am.J.Physiol. (1997), 273 (4, Pt.1), L814-L824; Terajima etc., Am.J.Physiol. (1997), 273 (4, Pt.1), L749-L759; Grunberg etc., Clin.Exp.Allergy (1997), 27 (1), 36-45; With Johnston etc., J.Infect.Dis. (1997), 175 (2), 323-329.
Interleukin-8 and osteoporotic relation are found in following article, for example: Streckfus etc., J.Gerontol., Ser.A (1997), 52A (6), M343-M351; Hermann, T.WO95/31722; With Chaudhary etc., Endocrinology (Baltimore) (1992), 130 (5), 2528-34.
The principal character of these diseases is a large amount of neutrophilic infiltrations, T-cellular infiltration or neovascularity growth, and increase relevantly with the generation of IL-8, GRO α, GRO β, GRO γ or NAP-2, cause the chemotaxis of neutrophilic leukocyte to inflammatory position or endotheliocyte directional growth just because of their generation increase.(IL-1, TNF and IL-6) is opposite with other inflammatory cytokines, and IL-8, GRO α, GRO β, GRO γ or NAP-2 have unique promotion neutrophil chemotaxis, enzyme discharges (including but not limited to that elastase discharges) and peroxide produces and activatory character.α-chemotactic factor, especially GRO α, GRO β, GRO γ or NAP-2 by IL-8 I type or the effect of II receptor can promote the neovascularity of tumor to generate by promoting the endotheliocyte directional growth.Therefore, suppress chemotaxis or activation that IL-8 causes and will cause directly reducing neutrophilic infiltration.
Present evidence also relates to the effect of chemotactic factor in treatment HIV infects, Littleman etc., and Nature 381, pp661 (1996) and Koup etc., Nature 381, and pp 667 (1996).
The present invention also provides with chemokine receptor anagonists formula (I) chemical compound emergency action treatment and prevention and has been considered to be subject to the individual method of CNS damage.
The defined CNS damage of the present invention comprises for example surgical operation of opening or penetrance head trauma, the perhaps for example damage of head zone of closure head trauma damage.This definition also comprises ischemic stroke, particularly brain area.
Ischemic stroke can be defined as the kitchen range neurological disorder that particularly causes to blood supply insufficiency of brain, and common result is embolus, thrombosis or the sealing of blood vessel local intra-arterial gruel type.Inflammatory cytokine effect therein takes place, and the invention provides the method for possible these damages of treatment.It has been feasible taking less treatment for acute injury.
TNF-α is the cytokine that has preceding inflammatory effects, comprises the expression of endothelial leucocyte adhesion molecule.Therefore leukocyte infiltration ischemia cerebral lesion position suppresses or the chemical compound of reduction TNF level is applicable to treatment ischemia brain injury.Referring to Liu etc., Stoke, Vol.25., No.7, pp 1481-88 (1994), wherein disclosed content is combined in herein as a reference.
Shohami etc. are at J.of Vaisc ﹠amp; Clinical Physiology andPharmacology, Vol.3, No.2 has discussed the model of closure head injury and has treated with mixing the 5-LO/CO medicine among the pp.99-107 (1992), and wherein disclosed content is combined in herein as a reference.Find that the treatment that reduces edema formation makes the animal of receiving treatment obtain functional improvement.
Present evidence shows that also the IL-8 inhibitor can be used for treating atherosclerosis.First piece of list of references, Boisvert etc., J Clin Invest, 1998,101:353-363 shows through bone marrow transplantation, and the IL-8 receptor deficiency on the stem cell (and so monocyte/macrophage) causes the development of the atherosis speckle of the not enough mice medium-sized artery of ldl receptor to reduce.Other can be for the list of references of supporting: Apostolopoulos etc., ArteriosclerThromb Vasc Biol.1996,16:1007-1012; Liu etc., ArteriosclerThromb Vasc Biol, 1997,17:317-323; Rus etc., Atherosclerosis.1996,127:263-271.; Wang etc., J Biol Chem.1996,271:8837-8842; Yue etc., Eur J Pharmacol.1993,240:81-84; Koch etc., Am J Pathol, 1993,142:1423-1431.; Lee etc., Immunol Lett, 1996,53,109-113.; With Terkeltaub etc., Arterioscler Thromb, 1994,14:47-53.
Formula (I) chemical compound to be being enough to suppress the bonded amount administration of IL-8 and IL-8 α or beta receptor, thereby suppresses and the combining of these receptors, for example with neutrophil chemotaxis and the activatory evidence that is reduced to.Formula (I) chemical compound be the discovery of IL-8 binding inhibitors be with formula (I) chemical compound extracorporeal receptor as herein described in conjunction with the experiment in act as the basis.Shown that formula (I) chemical compound is the inhibitor of II type IL-8 receptor.
All terms of this paper " IL-8 mediation disease or disease condition " are meant any and all disease conditions that wherein IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 work, IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78 or play a role by they self generation perhaps cause that by them another kind of monokine discharges, plays a role such as but not limited to IL-1, IL-6 or TNF.Therefore, wherein for example IL-1 be main component and the disease condition that should be considered to the IL-8 mediation as disease condition to its generation of response of IL-8 or effect aggravation.
Term used herein " chemokine mediated disease or disease condition " is meant wherein any and all disease conditions that work with IL-8 α or the bonded chemotactic factor of beta receptor, for example but be not limited to IL-8, GRO α, GRO β, GRO γ, NAP-2 or ENA-78.This comprise that IL-8 wherein works disease condition, IL-8 or play a role by himself generation perhaps causes that by it another kind of monokine discharges, plays a role such as but not limited to IL-1, IL-6 or TNF.Therefore, wherein for example IL-1 be main component and the disease condition that should be considered to the IL-8 mediation as disease condition to its generation of response of IL-8 or effect aggravation.
Term used herein " cytokine " is meant any excretory polypeptide, and they influence the function of cell, and is the molecule of regulating cell-cell interaction in immunity, inflammatory or the hemopoietic reaction.Cytokine is including, but not limited to monokine and lymphokine, and no matter by which kind of cell produce.For example, monokine typically refers to mononuclear cell for example macrophage and/or the monocyte generation and the excretory factor.Yet many other cells also produce monokine, for example natural killer cell, fibroblast, basophilic leukocyte, neutrophilic leukocyte, endotheliocyte, cerebral astrocytic, marrow stromal cell, keratinization of epidermis cell and B-lymphocyte.Lymphokine typically refers to the factor that is produced by lymphocyte.The example of cytokine is including, but not limited to il-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNF-α) and tumor necrosis factor (TNF-β).
Similar with above-mentioned term " cytokine ", term used herein " chemotactic factor " is meant any excretory polypeptide, and they influence the function of cell, and is the molecule of regulating cell-cell interaction in immunity, inflammatory or the hemopoietic reaction.Chemotactic factor mainly is excretory by cell transmembrane, and makes specific leukocyte and leukocyte, neutrophilic leukocyte, mononuclear cell, macrophage, T-cell, B-cell, endotheliocyte and smooth muscle cell have chemotaxis and activation.The example of chemotactic factor is including, but not limited to IL-8, GRO α, GRO β, GRO γ, NAP-2, ENA-78, IP-10, MIP-1 α, MIP-β, PF4 and MCP1,2 and 3.
For formula (I) compound or pharmaceutically acceptable salt thereof is used for the treatment of, the pharmacy practice according to standard is mixed with pharmaceutical composition with it usually.Therefore, the invention still further relates to the pharmaceutical composition that contains effective, nontoxic amount formula (I) chemical compound and pharmaceutically suitable carrier or diluent.
Formula (I) chemical compound, its officinal salt and the pharmaceutical composition that contains them can be used for example oral, local, non-intestinal or inhalation easily by any conventional route of administration.Formula (I) chemical compound can be with the regular dosage form administration, and this regular dosage form is to make by formula (I) chemical compound is combined according to conventional method with the pharmaceutical carrier of standard.Formula (I) chemical compound can also combine with known second kind of therapeutical active compound, with the regular dosage form administration.According to required dosage form, these methods comprise and will respectively be divided into mixing, pelletize and tabletting or dissolving.Be appreciated that the form of pharmaceutically suitable carrier or diluent and content, route of administration and other known variable factors that characteristic depends on active component bonded with it.From with preparation the compatible meaning of other compositions, carrier must be " acceptable ", and can not damage accepting its therapist.
Employed pharmaceutically suitable carrier can be for example solid or liquid.The example of solid carrier is lactose, hargil, sucrose, Talcum, gelatin, agar, pectin, arabic gum, magnesium stearate, stearic acid etc.The example of liquid-carrier is syrup, Oleum Arachidis hypogaeae semen, olive oil, water etc.Similarly, carrier or diluent can comprise time-delay material well known in the art, for example pure monostearin or glycerol distearate or with the mixture of wax.
Can use multiple medicament forms.Therefore, if use solid carrier, can be with the preparation tabletting, place hard gelatin capsule or make lozenge or lozenge with the form of powder or piller.The content of solid carrier can change in very wide scope, but preferred about 25mg is to about 1g.When using liquid-carrier, said preparation is syrup, emulsion, Perle, aseptic parenteral solution such as ampoule or on-aqueous liquid suspension.
Formula (I) chemical compound can be by the nonsystematic administration the mode local application, comprise imposing on formula (I) chemical compound on the epidermis or in the oral cavity, and chemical compound be instilled in ear, eye and the nose that chemical compound just can not enter in the blood flow in large quantities like this.On the contrary, be administered systemically and be meant oral, intravenous, intraperitoneal and intramuscular administration.
The preparation that is suitable for topical comprises and is suitable for liquid or the semi-solid preparation of transdermal flux to the inflammatory position, for example liniment, lotion, emulsifiable paste, ointment or paste, and be suitable for drop to eye, ear or nasal administration.For topical, active component can account for the 0.001%-10%w/w of weight of formulation, for example 1%-2%.Certainly, its content also can still preferably be less than 5%w/w, more preferably 0.1%-1%w/w up to the 10%w/w that accounts for preparation.
Lotion of the present invention comprises those that are applicable to skin or eye.Eye lotions can contain aseptic aqueous solution, wherein randomly contains antibacterial, and can be according to being prepared with preparation drop similar methods.Be used for the lotion of skin or liniment and can also contain and make the quick-drying and refrigerative reagent of skin, for example alcohol or ketone, and/or humidizer for example glycerol or oil as Oleum Ricini or Oleum Arachidis hypogaeae semen.
Emulsifiable paste of the present invention, ointment or paste are the semi-solid preparations of the outside active component that uses.They can be by being mixed and made into finely divided or pulverous active component itself or its solution or suspension in water or on-aqueous liquid by suitable machine and adipic or non-adipic substrate.Substrate can comprise hydrocarbon such as hard, soft or liquid paraffin, glycerol, Cera Flava, metallic soap; Rubber cement; The oil of natural origin such as Semen Armeniacae Amarum, corn, Semen arachidis hypogaeae, Semen Ricini or olive oil; The mixture of lanoline or derivatives thereof or fatty acid such as stearic acid or oleic acid and pure for example propylene glycol or macrogel.Can mix any suitable surfactant for example anion, cation or non-ionic surface active agent in the preparation, as Isosorbide Dinitrate or its polyethylene oxide derivatives.Can also contain suspending agent for example natural gum, cellulose derivative or inorganic matter such as silicaceoussilicas, and other compositions such as lanoline.
Drop of the present invention can comprise sterilized water or oil solution or suspension, and can be by being prepared in the aqueous solution that active component is dissolved in suitable antibacterial and/or antifungal and/or any other suitable antiseptic, and preferably wherein contain surfactant.Filter then and make the clarification of gained solution, change in the suitable containers, sealed container then, and keep sterilization treatment half an hour with autoclaving or at 98-100 ℃.Perhaps, this solution can pass through filtration sterilization, and adopts aseptic technique that it is changed in the container.Being suitable for as the antibacterial of inclusion in the drop and the example of antifungal is phenylmercuric nitrate or phenylmercuric acetate (0.002%), benzalkonium chloride (0.01%) and Chlorhexidine Diacetate (0.01%).The suitable solvent of preparation oil solution comprises the pure and mild propylene glycol of glycerol, dilution.
Formula (I) chemical compound can be through parenterai administration, promptly by intravenous, intramuscular, subcutaneous, intranasal, internal rectum, intravaginal or intraperitoneal administration.The parenterai administration of usually preferably subcutaneous or intramuscular form.The suitable dosage form of this administering mode can prepare by routine techniques.Formula (I) chemical compound can also pass through inhalation, promptly by intranasal and oral cavity inhalation.The suitable dosage form of this administering mode for example aerosol or metered dose inhaler can prepare by routine techniques.
For the used application process of formula disclosed by the invention (I) chemical compound, a day oral dose scheme optimization is about 0.01 to about 80mg/kg TBW.Day, non-intestinal dosage was preferably about 0.001 to about 80mg/kg TBW.Day, the local dose scheme optimization was 0.1mg-150mg, and every day, administration was 1-4 time, preferred 2-3 time.Day inhalation dose scheme optimization is about 0.01mg/kg extremely about 1mg/kg/ days.This area the professional it should further be appreciated that, the optimum amount of formula (I) compound or pharmaceutically acceptable salt thereof and each time of administration will depend on the nature and extent of the disease for the treatment of at interval, the dosage form of administration, approach and position, and the concrete patient who is treated, and optimum amount can routine techniques be definite excessively all.The professional it is evident that equally for this area, the course of treatment of formula (I) compound or pharmaceutically acceptable salt thereof the best, promptly the number of times of giving construction every day (I) compound or pharmaceutically acceptable salt thereof in certain natural law can adopt the treatment determination test of conventional process to determine by this area professional.
Below with reference to following biology embodiment the present invention will be described, these embodiment only are illustrative, but not are intended to limit the scope of the invention.
Biology embodiment
The IL-8 of The compounds of this invention and Gro-α chemokine inhibiting are measured by following experiment in vitro: the receptors bind experiment:
By Amersham Corp., Arlington Heights, IL obtain [ 125I] IL-8 (people recombinate thing), its specific activity is that 2000Ci/mmol. obtains Gro-α by NEN-New England Nuclear.Every other chemical reagent all is AGs.As mentioned above, the expression in Chinese hamster ovary cell respectively of high-caliber recombined human IL-8 α and beta receptor (Holmes, etc., Science, 1991,253,1278).Make Chinese hamster egg membrane homogenize (Haour, etc., J Biol Chem., 249pp 2195-2205 (1974)) according to such scheme.Just the homogenize cushion is added 10mM Tris HCL, 1mM MgSO 4, in 0.5mM EDTA (ethylenediaminetetraacetic acid), 1m MPMSF (tosyl fluorine), the 0.5mg/L leupeptin (pH7.5).Use the microanalytical reagent box of Pierce Co., as standard substance, measure memebrane protein concentration with bovine serum albumin.All analyses all are to carry out on the microdroplet plate of 96-hole.Each reactant mixture is containing 1.2mM MgSO 4, contain in the 20mM Bis-Trispropane of 0.1mM EDTA, 25mM NaCl and 0.03% CHAPS and the 0.4mM Tris HCl buffer (pH8.0) 125I IL8 (0.25nM) or 125I Gro-α and 0.5 μ g/mL IL-8Ra or 1.0 μ g/mL IL-8Rb films.In addition, add the medicine that attracts people's attention or the chemical compound that are dissolved in advance among the DMSO, to reach the final concentration of 0.01nM to 100uM.By adding 125I-IL-8 begins this experiment., with Tomtec 96-hole catcher this plate is collected on the glass fibre filter after 1 hour in room temperature, this filter is with 1% polyethylene imine based/0.5% BSA blocking-up, and with 25mM NaCl, 10mM Tris HCl, 1mM MgSO 4, 0.5mM EDTA, 0.03%CHAPS (pH7.4) washing 3 times.Count then with the filter drying, and with the Betaplate liquid scintillation counter.In the present invention, the IL-8 Ra of reorganization or I receptor can also be called non-(non-permissive) freely receptor, and reorganization IL-8 Rb or II receptor can also be called free receptor.
Verified in this is analyzed, the embodiment 1-11 of typical formula (I) and formula (II) chemical compound, this paper and the positive of 13-19 suppress activity＜30 μ mg.In this was analyzed, seemingly owing to solubility, the chemical compound of embodiment 12 fails to prove when＜30 μ mg activity.Chemotaxis assay:
As at Immunology, vo1.I, Suppl 1, and (Current Protocols) is described for the current scheme among the Unit 6.12.3., the vitro inhibition character of these chemical compounds of proof in neutrophil chemotaxis is analyzed, the disclosed content of the document all is combined in herein as a reference.As at Immunology Vol.I, the current scheme among the Suppl 1 Unit 7.23.1 is described, separates neutrophilic leukocyte from human blood, and the disclosed content of the document all is combined in herein as a reference.With concentration is that chemoattractant IL-8, GRO α, GRO β, GRO γ and the NAP-2 of 0.1-100nM places porous chambers 48 (Neuro Probe, Cabin John is in floor chamber MD).Separate with the 5um polycarbonate leaching film between two Room.When The compounds of this invention is tested, before adding cell in the upper chambers just, with itself and mixing with cells (0.001-1000nM).At about 37 ℃ and 5%CO 2Exist down, in the incubator of preserving moisture, cultivated about 45-90 minute.Cultivate when finishing, remove polycarbonate membrane, the washing top, (IL USA) dyes film for Baxter Products, McGaw Park to adopt DiffQuick dyeing scheme then.With microscope to chemotactic factor being produced chemotactic cell counting.Usually, four zones of each sample are counted, these data are on average obtained the average of migrating cell.Each sample is repeated three tests, and each chemical compound is repeated at least four tests.Do not add chemical compound in some cell (positive control cell), these cells show maximum cell chemotaxis and reply.Negative control (not stimulating) does not then add chemotactic factor in floor chamber if desired.Difference between positive control and negative control has been represented the chemotactic activity of cell.Elastoser discharges to be analyzed:
The compounds of this invention is tested, to measure it prevents to discharge elastoser from the human neutrophil ability.As at Immunology Vol.I, the current scheme among the Suppl 1 Unit 7.23.1 is described, separates neutrophilic leukocyte from human blood.With PMN 0.88 * 10 6Cell suspension is at Ringer's mixture (NaCl118, KCl4.56, NaHCO 325, KH 2PO 41.03, glucose 11.1, HEPES 5mM, pH7.4) in, and in each hole of 96 orifice plates, add 50ul and mix to this and add 50ul experimental compound (0.001-1000mM), 50ul (20ug/ml) cytochalasin B and 50ul woods Ge Shi buffer in plate.Make these cells warm (37 ℃, 5%CO 2, 95% RH) and 5 minutes, add IL-8, GRO α, GRO β, GRO γ or NAP-2 that ultimate density is 0.01-1000nM then.Reaction was carried out 45 minutes, then with 96 orifice plates centrifugal (800xg 5 minutes), and took out the 100ul supernatant.In 96 orifice plates, add this supernatant, add then ultimate density reach artificial elastin laminin zymolyte in the saline that is dissolved in phosphate-buffered of 6ug/ml (MeOSuc-Ala-Ala-Pro-Va1-AMC, NovaBiochem, La Jolla, CA).With this plate place immediately fluorescence 96 orifice plate readers (Cytofluor 2350, Millipore, Bedford, MA) under, and according to Nakajima etc., the method for J.Biol Chem 254 4027 (1979) was with 3 minutes interval image data.The amount that the speed calculation elastoser of degrading by mensuration MeOSucAla-Ala-Pro-Val-AMC discharges from PMN.The analysis of TNF-α in traumatic brain injury
Thereby this analysis provides tumor necrosis factor mRNA to express the assay method that causes the traumatic brain injury of rat side fluid-percussion (TBI) in specific brain area experimentally.Because TNF-α can induce nerve growth factor (NGF) and stimulate other cytokines to discharge from activatory spider cell, this TNF-α plays an important role in the acute and reproducibility of CNS damage is replied in the changes in gene expression after the damage.Suitable analytical method can see WO 97/35856 or WO 97/49286, and wherein disclosed content combination in the present invention as a reference.The CNS damage model of IL-β mRNA
Il-1 β (IL-1 β) is depicted in this analysis thereby the regionality of mRNA in specific brain area expressed the characteristic that causes the traumatic brain injury of rat side fluid-percussion (TBI) experimentally.After analysis result showed TBI, the temporary table of IL-β mRNA was reached zonal stimulation in specific brain area.These regional cytokines change, and for example IL-1 β plays an important role in pathologic or the reproducibility sequela after the damage of brain injury.Suitable analytical method can see WO 97/35856 or WO 97/49286, and wherein disclosed content combination in the present invention as a reference.Atherosclerosis experiment in the body:
Measure the atherosclerotic model of mice in the body and be experiment, and as described below it is carried out little change based on Paigen etc.Referring to Paigen B, Morrow A, HolmesPA, Mitchell D, the quantitative assay of Williams RA. mice atherosclerotic lesions (Quantitative assessment of atherosclerotic lesions inmice).Atherosclerosis 68:231-240 (1987); With Groot PHE, vanVlijmen BJM, Benson GM, Hofker MH, Schiffelers R, Vidgeon-HartM, the quantitative assay of Havekes LM.APOE*3 Leiden transgenic mice atherosclerosis of aorta and the relation that contacts with serum cholesterol thereof (Quantitative assessment ofaortic atherosclerosis in APOE*3 Leiden transgenic mice andits relationship to serum cholesterol exposure).ArteriosclerThromb?Vasc?Biol.16：926-933(1996)。The dissection of aortic sinus and dyeing
(1,2) as previously described gets the cross section at aortic root.Briefly, exactly in the level that is lower than the atrium just with heart to cutting, and the bottom and the aortic root that take out heart are analyzed.After structural equation being spent the night with the OCT chemical compound, the cryostat chuck (BrightInstrument Company Ltd., UK) on, make aorta towards chuck, heart is immersed in the OCT chemical compound.To organize freezing at chuck placed around dry ice.Then along the dirty section of coring of the vertical direction of aorta axle, beginning and tangential aorta in the heart.In case aortic root occurs finding, then be getting section and be fixed on the slide glass of gelation at interval with 10mm by three valve leaflets.The air drying of will cutting into slices 1 hour is used 60% isopropyl alcohol drip washing then simply.Section, covers with the glycerin gelatine slip, and seals with nial polish with Mai Ershi hematoxylin counterstaining with Oil Red O dyeing.What the aortic root medium-sized artery was atherosis is quantitative
4x object lens and video camera are equipped with in use, and (Hitachi, O1ympusBH-2 microscope HV-C10) make 10 preliminary aortic roots section imaging.Obtain 24 coloured images, frame grabber plate (Snapper, Active Imaging Ltd, Berks are equipped with in use, U.K.) PC (Datacell Pentium P5-133, Datacell, Berks, U.K.), (version 5.1 for operation Optimas software, Optimas Corp., WA U.S.A.) analyzes.Under same light, microscope, photographing unit and PC condition, obtain image.Use Optimas software, go out the infringement zone, the atherosclerotic lesions zone is carried out quantitatively by Freehandhand-drawing.The color threshold is set red zone is arranged to dye in the quantitative damaging part.By using the grid image calibration software on the hemocytometer slide glass, obtain cross section infringement zone and dye the absolute value that red zone is arranged.
Although be in this article with referring to mode specifically and independently introduced each public publication, all public publications of quoting in this manual all are combined in herein as a reference in full including, but not limited to patent and patent application.
Top description fully discloses the present invention, has comprised its preferred specific embodiments.In the scope that the modification and the improvement of the disclosed especially specific embodiments of this paper is included in following claim.Need not further processing, can believe, this area professional can adopt the explanation of front, utilizes the present invention fully.Therefore, the embodiment of this paper only is illustrative, rather than limits the scope of the invention by any way.Required following definition of specific embodiments of the present invention of exclusivity or exclusiveness.

Claims (6)

1. treat mammiferous method by chemokine mediated disease, wherein chemotactic factor combines with IL-8 α or beta receptor, the disease that described disease is selected from malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, the release of undesirable hematopoietic stem cell and is caused by respiratory virus, herpesvirus and hepatitis virus, this method comprises to the formula of described administration effective dose (I) compound or pharmaceutically acceptable salt thereof:
Figure A0080909000021
Wherein R is-NH-C (X 2)-NH-(CR 13R 14) v-Z; Z be W, HET, Optional substituted C 1-10Alkyl, optional substituted C 2-10Alkenyl or optional substituted C 2-10Alkynyl;
X is C (X 1) 2, C (O), C (S), S (O) 2, PO (OR 4) or C=N-R 19
X 1Be hydrogen, halogen, C independently 1-10Alkyl, NR 4R 5, C 1-10Alkyl-NR 4R 5, C (O) NR 4R 5, optional substituted C 1-10Alkyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, hydroxyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycle C 1-4Alkyl or heteroaryl C 1-4Alkoxyl;
X 2Be=O or=S;
R 1Be independently selected from hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, azido, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroarylalkyl, heterocycle, heterocycle C 1-4Alkyl, heteroaryl C 1-4Alkoxyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocycle C 2-10Alkenyl, (CR 8R 8) qNR 4R 5, C 2-10Alkenyl C (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 10, S (O) 3R 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) qC (NR 4) NR 4R 5, (CR 8R 8) qNR 4C (NR 5) R 11, (CR 8R 8) qNR 4C (O) R 11, (CR 8R 8) qNHS (O) 2R 17, (CR 8R 8) qS (O) 2NR 4R 5Perhaps two R 1Part can be combined together to form O-(CH 2) sSaturated or the unsaturated ring of O or 5-6 unit; And wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
N is the integer of 1-3;
M is the integer of 1-3;
Q is 0 or the integer of 1-10;
S is the integer of 1-3;
T is 0 or 1 or 2 integer;
V is 0 or the integer of 1-4;
P is the integer of 1-3;
HET is optional substituted heteroaryl;
R 4And R 5Be hydrogen, optional substituted C independently 1-4Alkyl, optional substituted aryl, optional substituted aryl C 1-4Alkyl, optional substituted heteroaryl, optional substituted heteroaryl C 1-4Alkyl, heterocycle or heterocycle C 1-4Alkyl, perhaps R 4And R 5Form 5-7 unit ring with the nitrogen-atoms that links to each other with them, this ring can randomly contain the hetero atom that other are selected from O/N/S;
Y is independently selected from hydrogen, halogen, nitro, cyano group, halo C 1-10Alkyl, C 1-10Alkyl, C 2-10Alkenyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, azido, (CR 8R 8) qS (O) tR 4, hydroxyl, hydroxyl C 1-4Alkyl, aryl, aryl C 1-4Alkyl, aryloxy group, aryl C 1-4Alkoxyl, heteroaryl, heteroarylalkyl, heteroaryl C 1-4Alkoxyl, heterocycle, heterocycle C 1-4Alkyl, aryl C 2-10Alkenyl, heteroaryl C 2-10Alkenyl, heterocycle C 2-10Alkenyl, (CR 8R 8) qNR 4R 5, C 2-10Alkenyl C (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 5, (CR 8R 8) qC (O) NR 4R 10, S (O) 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) qC (NR 4) NR 4R 5, (CR 8R 8) qNR 4C (NR 5) R 11, (CR 8R 8) qNHS (O) 2R a, or (CR 8R 8) qS (O) 2NR 4R 5Perhaps two Y parts can be combined together to form O-(CH 2) sSaturated or the unsaturated ring of O or 5-6 unit; And wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
R 6And R 7Be hydrogen or C independently 1-4Alkyl, perhaps R 6And R 7Form 5-7 unit ring with the nitrogen-atoms that links to each other with them, this ring can randomly contain the hetero atom that other are selected from oxygen, nitrogen or sulfur;
R 8Be hydrogen or C independently 1-4Alkyl;
R 10Be C 1-10Alkyl C (O) 2R 8
R 11Be hydrogen, C 1-4Alkyl, optional substituted aryl, optional substituted aryl C 1-4Alkyl, optional substituted heteroaryl, optional substituted heteroaryl C 1-4Alkyl, optional substituted heterocycle or optional substituted heterocycle C 1-4Alkyl;
R 12Be hydrogen, C 1-10Alkyl, optional substituted aryl or optional substituted aralkyl;
R 13And R 14Be hydrogen or optional substituted C independently 1-4Alkyl, perhaps R 13And R 14In one can be the optional aryl that replaces;
R 15And R 16Be hydrogen or optional substituted C independently 1-4Alkyl;
R 17Be C 1-4Alkyl, aryl, aralkyl, heteroaryl, heteroaryl C 1-4Alkyl, heterocycle or heterocycle C 1-4Alkyl, wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
R 18Be hydrogen, optional substituted C 1-10Alkyl, C 1-10Alkoxyl, halo C 1-10Alkoxyl, hydroxyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocycle or heterocycle C 1-4Alkyl, wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted;
R 19Be cyano group, nitro, S (O) 2NR 4R 5, S (O) 2R 17Alkyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocycle or heterocycle C 1-4Alkyl; And wherein containing alkyl, aryl, heteroaryl and heterocyclic part can randomly be substituted;
R aBe NR 6R 7, alkyl, aryl C 1-4Alkyl, aryl C 2-4Alkenyl, heteroaryl, heteroaryl C 1-4Alkyl, heteroaryl C 2-4Alkenyl, heterocycle or heterocycle C 1-4Alkyl; And wherein containing aryl, heteroaryl and heterocyclic part can randomly be substituted; W is The ring that contains E randomly is selected from Asterisk * is the junction point of finger ring; Or its officinal salt.
2. according to 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 12Heteroaryl, heteroarylalkyl, heteroaryl alkenyl or S (O) NR 4R 5
3. according to the process of claim 1 wherein that X is C (O) or C (S).
4. according to any one method among the claim 1-3, wherein Z is W.
5. according to the method for claim 4, wherein Y is halogen, C 1-4Alkoxyl, optional substituted aryl, optional substituted aralkoxy, methylene dioxy base, NR 4R 5, C 1-4Alkylthio group, arylthio, halogenated alkoxy, optional substituted C 1-4Alkyl or hydroxyalkyl.
6. according to the process of claim 1 wherein that chemical compound is selected from following one group
N-4-(benzimidazoline-2-ketone)-N '-(2 '-bromophenyl) urea;
N-4-(1H, 3H-2,1,3-benzothiazole-2,2-dioxide)-N '-(2-bromophenyl) urea;
N-4-(7-cyano group-1-N-methyl-benzo imidazoline-2-thioketone)-N '-(2, the 3-Dichlorobenzene base) urea;
N-4-(7-cyano group-benzo imidazoline-2-thioketone)-N '-(2-bromophenyl) urea;
N-4-(7-cyano group-1-methyl-benzo imidazoline-2-thioketone)-N '-(2-bromophenyl) urea;
N-(4-cyano group-2-oxo-3-tolimidazole-7-yl)-N '-(2-bromophenyl) urea;
N-4-(7-cyano group-benzimidazoline-2-ketone)-N '-(2-bromophenyl) urea;
N-4-(7-cyano group-benzo imidazoline-2-thioketone)-N '-(2, the 3-Dichlorobenzene base) urea;
N-4-(7-cyano group-benzimidazoline-2-imines)-N '-(2-bromophenyl) urea; Or its officinal salt.
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CN102060780B (en) * 2010-12-27 2014-11-05 雅本化学股份有限公司 Preparation method of 2-(N-substituted).-aminobenzimidazole derivative
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CN111116502A (en) * 2018-10-30 2020-05-08 中国石油化工股份有限公司 One-step method for synthesizing benzotriazole

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