KR20020009635A - IL-8 Receptor Antagonists - Google Patents

Abstract

The present invention relates to a pharmaceutical composition and its use for the treatment of disease states mediated by a novel compound of formula I, its chemokines, interleukin-8 (IL-8).

Description

IL-8 receptor antagonists {IL-8 Receptor Antagonists}

Interleukin-8 (IL-8) contains many different names such as neutrophil attractant / activator protein-1 (NAP-1), monoclonal inductive neutrophil chemotactic factor (MDNCF), neutrophil activation factor (NAF) Cell lymphocyte chemotactic factors have been used. Interleukin-8 is a chemoattractant substance in the subpopulations of neutrophils, basophils and T-cells. It has been shown that neutrophils themselves, when exposed to many nucleated cells, including macrophages, fibroblasts, endothelial and epithelial cells, and LPS or chemotactic factors (such as FMLP) exposed to TNF, IL-1 alpha, IL- Lt; / RTI > M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989); J. Schroder et al., J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990); Strieter et al., Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 148, 3216 (1992).

GROα, GROβ, GROγ and NAP-2 also belong to the chemokine α family. Like IL-8, these chemokines have also been called by different names. For example, GRO alpha, beta and gamma have been referred to as MGSA alpha, beta and gamma (melanoma growth promoting activity), respectively (Richmond et al J. Cell Physiology 129, 375 (1986) ), J. Immunol., 148, 451 (1992)). Just before the CXC motif, all of the alpha-family chemokines bearing the ELR motif bind to the IL-8 receptor.

IL-8, GRO [alpha], GRO [beta], GRO [gamma] and NAP-2 promote a number of actions in vitro. All of them showed chemoattractant properties for neutrophils, and IL-8 and GROα showed T-lymphocyte and basophil chemotactic activity. In addition, IL-8 can induce histamine release from basophils in both normal and atopic individuals, and can also induce lysosomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase surface expression of Mac-1 (CD11b / CD18) in neutrophils without new protein synthesis. This may be due to increased neutrophil adhesion to vascular endothelial cells. Many of the diseases are characterized by massive neutrophil infiltration. IL-8, GROα, GROβ, GROγ and NAP-2 promote neutrophil accumulation and activation, but these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis (Bargeolini et al. FEBS Lett 307, 97 (1992) ];.... Miller (Miller), such as reference [Crit Rev. Immunol 12, 17 ( 1992)] of .; literature [Annu Rev. Immunol, such as Oppenheim (Oppenheim) 9, 617 Rev. Respir. Dis. 146, 427 (1992); Miller et al., J. Clin. Invest. 87, 463 (1991); Seitz et al. ]; Donnely et al. Lancet 341, 643 (1993)). In addition, ELR chemokines (which contain amino acid ELR motifs immediately before the CXC motif) have also been associated with hemostasis (Streiter et al., Science 258, 1798 (1992)).

In vitro, IL-8, GRO [alpha], GRO [beta], GRO [gamma] and NAP-2 bind to receptors of seven dural G-protein-binding classes to activate, in particular IL-8 receptors, most notably B- Chemotaxis, granule release and respiratory burst (see, for example, Thomas et al. , J. Biol. Chem. 266, 14839 (1991) and Holmes et al. , Science 253, 1278 (1991)). The development of nonpeptide small molecule antagonists for members of this receptor class has precedent. R. Freidinger et al., Progress in Drug Research , Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993). Thus, IL-8 receptors represent promising targets for the development of novel anti-inflammatory agents.

GRO [alpha], GRO [beta], GRO [gamma] and NAP-8 as well as IL-8R [alpha], which binds only to IL-8 with high affinity, and IL- 2 with high affinity to IL-8R? Holmes et al., Supra; Murphy et al., Science 253, 1280 (1991); Lee et al ., J. Biol. Chem. 267, 16283 (1992); LaRosa et al ., J. Biol. Chem. 267, 25402 (1992); And Gayle et al ., J. Biol. Chem. 268, 7283 (1993).

There is still a need for compounds that are capable of binding to the IL-8 [alpha] or [beta] receptor for therapeutic use in this area. Thus, compounds that are inhibitors of IL-8 receptor binding will be favored for diseases associated with increased IL-8 production, which are the cause of chemotaxis of neutrophils and T-cell currents to inflammatory sites.

SUMMARY OF THE INVENTION [

The present invention provides a method of treating a chemokine mediated disease that binds to an IL-8 alpha or beta receptor, comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. In particular, the chemokine is IL-8.

The invention also relates to a method of inhibiting the binding of IL-8 to its receptor in said mammal comprising administering an effective amount of a compound of formula I to a mammal in need of inhibition of the binding of IL-8 to said receptor .

Compounds useful in the present invention are those compounds represented by formula I:

Wherein Z is cyano, OR ₁₁ , C (O) NR ₁₅ R ₁₆ , R ₁₈ , C (O) R ₁₁ , C (O) OR ₁₁ or S (O) ₂ R ₁₇ ;

R ₁₃ and R ₁₄ are independently hydrogen, optionally substituted C _1-4 alkyl, or one of R ₁₃ and R ₁₄ may be optionally substituted aryl;

v is 0 or an integer from 1 to 4;

W is ;

The E'-containing ring is

(Wherein an asterisk indicates the point of attachment of the ring);

W ₁ is ;

E-include ring

(Wherein an asterisk indicates the point of attachment of the ring);

R is any functional group having an ionizable hydrogen having a pKa of 10 or less;

R < ₁ > is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; (CR ₈ R ₈ ) _q S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heterocyclic, heterocyclic C _1-4 alkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; _{(CR 8 R 8) q NR} 4 R 5; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{(CR 8 R 8) q C} (O) NR 4 R 5; _{(CR 8 R 8) q C} (O) NR 4 R 10; S (O) ₃ H; S (O) ₃ R ₈ ; _{(CR 8 R 8) q C} (O) R 11; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; _{(CR 8 R 8) q C} (O) OR 12; _{(CR 8 R 8) q OC} (O) R 11; (CR ₈ R ₈ ) _q NR ₄ C (O) R ₁₁ ; _{(CR 8 R 8) q NHS} (O) 2 R 19; _{(CR 8 R 8) q S} (O) , or selected from ₂ NR ₄ R _5; Or two R ₁ moieties may together form O- (CH ₂ ) _s O- or a 5- to 6-membered saturated or unsaturated ring;

q is 0 or an integer from 1 to 10;

t is 0 or an integer of 1 or 2;

s is an integer from 1 to 3;

R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Heterocyclic, heterocyclic C _1-4 alkyl, or R ₄ and R ₅ together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing an additional heteroatom selected from oxygen, nitrogen or sulfur ≪ / RTI >

Y is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; (CR ₈ R ₈ ) _q S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; _{(CR 8 R 8) q NR} 4 R 5; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{(CR 8 R 8) q C} (O) NR 4 R 5; _{(CR 8 R 8) q C} (O) NR 4 R 10; S (O) ₃ H; S (O) ₃ R ₈ ; _{(CR 8 R 8) q C} (O) R 11; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; _{(CR 8 R 8) q C} (O) OR 12; _{(CR 8 R 8) q OC} (O) R 11; (CR ₈ R ₈ ) _q NR ₄ C (O) R ₁₁ ; (CR ₈ R ₈ ) _q NHS (O) ₂ R _d , (CR ₈ R ₈ ) _q S (O) ₂ NR ₄ R ₅ , or two Y residues together form O- (CH ₂ ) _s O - or a 5 to 6 membered saturated or unsaturated ring;

n is an integer from 1 to 3;

m is an integer of 1 to 3;

R _d is NR ₆ R ₇ , alkyl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl, heteroaryl, heteroaryl-C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, Heterocyclic C _1-4 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic and heterocyclic alkyl rings may be optionally substituted;

R ₆ and R ₇ are independently hydrogen or a C _1-4 alkyl group or R ₆ and R ₇ together with the nitrogen to which they are attached form a _5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from oxygen, Form a ring;

R ₈ is independently selected from hydrogen or C _1-4 alkyl;

R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ;

R ₁₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic or Optionally substituted heterocyclic C _1-4 alkyl;

R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl;

R ₁₅ and R ₁₆ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Optionally substituted heterocyclic, optionally substituted heterocyclic C _1-4 alkyl, or R ₁₅ and R ₁₆ , together with the nitrogen to which they are attached, may optionally comprise a further heteroatom selected from oxygen, nitrogen or sulfur Lt; RTI ID = 0.0 > 5-7 < / RTI > membered ring;

R ₁₇ is C _1-4 alkyl, NR ₁₅ R ₁₆ , OR ₁₁ , optionally substituted aryl, optionally substituted arylC _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC _1-4 alkyl, optionally Substituted heterocyclic or optionally substituted heterocyclic C _1-4 alkyl;

R ₁₈ is optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic Or optionally substituted heterocyclic C _1-4 alkyl;

R ₁₉ are all optionally C _1-4 alkyl which may be substituted, aryl, arylalkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl.

The present invention relates to a group of novel guanidine compounds, their preparation, their use for treating IL-8, GROa, GROß, GROg, ENA-78 and NAP-2 mediated diseases and pharmaceutical compositions for use in such treatment .

The compounds of formula I can also be used in conjunction with veterinary treatment of non-human mammals in need of inhibition of IL-8 or other chemokines that bind to IL-8 alpha and beta receptors. The chemokine mediated diseases for therapeutic or prophylactic treatment in animals include disease states such as those shown in the Therapeutic Methods section herein.

In the compounds of formula I, W is suitably

to be.

An "E'-containing ring in which the point of attachment is present may be present arbitrarily. If not present, the ring is a phenyl group substituted by R < ₁ > as indicated. The E ring can be substituted with an R < _{1 >} group at any saturated or unsaturated ring, and only those that are substituted herein at the unsaturated ring (s).

R is any functional group that provides an ionizable hydrogen having a pKa of suitably less than 10, preferably from about 3 to 9, and more preferably from about 3 to 7. [ Non-limiting examples of such functional groups include hydroxyl, carboxylic acid, thiol, -SR ₂ , -OR ₂ , -NH-C (O) R _a , -C (O) NR _{6 '} R _7' O) ₂ R _b , -S (O) ₂ NHR _c , NHC (X ₂ ) NHR _b or tetrazolyl, wherein X ₂ is oxygen or sulfur, preferably oxygen. Preferably the functional group is not a sulfonic acid either directly on the aryl, heteroaryl or heterocyclic moiety ring, such as in SR ₂ or OR ₂ , or as a substituent. More preferably, R is OH, SH, or NHS (O) ₂ R _b .

Suitably, R < ₂ > is a substituted aryl, heteroaryl or heterocyclic residue having a functional group that provides an ionizable hydrogen whose ring has a pKa of 10 or less.

Suitably, R _{6 '} and R _7' are independently selected from the group consisting of hydrogen, C _1-4 alkyl, aryl, arylC _1-4 alkyl, arylC _2-4 alkenyl, heteroaryl, heteroarylC _1-4 alkyl, Aryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-4 alkenyl, all of which are independently halogen; Nitro; Halo substituted C _1-4 alkyl, such as CF ₃ ; C _1-4 alkyl, such as methyl; C _1-4 alkoxy, such as methoxy; NR ₉ C (O) R _a ; _{C (O) NR 6 R 7} ; S (O) ₃ H; Or C (O) OC _1-4 alkyl, with the proviso that only one of R _{6 '} and R _7' is hydrogen and not all are hydrogen.

Suitably, R ₆ and R ₇ are independently hydrogen or a C _1-4 alkyl group, or R ₆ and R ₇ together with the nitrogen to which they are attached form a 5-membered aromatic ring optionally containing an additional heteroatom selected from oxygen, To 7-membered ring. The heterocycle may be optionally substituted as defined herein.

Suitably, R _a is as defined for the both random which may be substituted with aryl, C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl group .

Suitably, R < _b > is independently selected from the group consisting of halogen; Nitro; Halo substituted C _1-4 alkyl, such as CF ₃ ; C _1-4 alkyl, such as methyl; C _1-4 alkoxy, such as methoxy; NR ₉ C (O) R _a ; _{C (O) NR 6 R 7} ; S (O) ₃ H, or C (O) OC _1-4 alkyl with from 1 to 3 times any NR ₆ R _7, alkyl, aryl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl which may be substituted, Heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-4 alkenyl or camphor. R _b is preferably optionally substituted phenyl, benzyl or styryl. When R < _{b &} gt _; is heteroaryl, an optionally substituted thiazole, an optionally substituted thienyl or an optionally substituted quinolinyl ring is preferred.

Suitably, R ₉ is hydrogen or C _1-4 alkyl, preferably hydrogen. Preferably, when the substituent is NR ₉ C (O) R _a , R _a is preferably an alkyl group, such as a methyl group.

Suitably, R _c is hydrogen or phenyl which is optionally substituted with up to three substituents independently selected from halogen, nitro, halo substituted C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, NR ₉ C (O) R _a , C _{NR 6 R 7, S (O} ) 3 H , or C (O) OC _1-4 alkyl with from 1 to 3 times any alkyl, aryl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl which may be substituted, Heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl or heterocyclic C _2-4 alkenyl, R ₉ is hydrogen or C _1-4 alkyl. Preferably, R < _c > is optionally substituted phenyl.

When R is OR ₂ or SR ₂ group, the aryl ring is appreciated by those skilled in the art the latter is required including an ionizable hydrogen as required. The aryl ring may also be independently substituted with one to three groups that may include additional ionizable groups, including, but not limited to, halogen, nitro, halo substituted C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, hydroxy, SH, -C (O) NR 6 R 7, -NH-C (O) R a, -NHS (O) 2 R b, S (O) 2 NR 6 R 7, C (O) OR < ₈ > or a tetrazolyl ring.

In the compounds of formula I suitably R < ₁ > is hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl such as CF ₃ ; C _1-10 alkyl such as methyl, ethyl, isopropyl or n-propyl; C _2-10 alkenyl; C _1-10 alkoxy, such as methoxy or ethoxy; Halo substituted C _1-10 alkoxy, such as trifluoromethoxy; Azide; _{(CR 8 R 8) q S} (O) t R 4 ( where, t is 0, 1 or 2); Hydroxy; HydroxyC _1-4 alkyl such as methanol or ethanol; Aryl such as phenyl or naphthyl; Aryl C _1-4 alkyl, such as benzyl; Aryloxy, such as phenoxy; Aryl C _1-4 alkyloxy, such as benzyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; _{(CR 8 R 8) q NR} 4 R 5; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{(CR 8 R 8) q C} (O) NR 4 R 5; _{(CR 8 R 8) q C} (O) NR 4 R 10; S (O) ₃ H; S (O) ₃ R ₈ ; _{(CR 8 R 8) q C} (O) R 11; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; _{(CR 8 R 8) q C} (O) OR 12; _{(CR 8 R 8) q OC} (O) R 11; (CR ₈ R ₈ ) _q NR ₄ C (O) R ₁₁ ; (CR ₈ R ₈ ) _q NHS (O) ₂ R ₁₉ , (CR ₈ R ₈ ) _q S (O) ₂ NR ₄ R ₅ ; Or two R ₁ moieties may together form O- (CH ₂ ) _s O- or a 5- to 6-membered saturated or unsaturated ring, and s is an integer of 1 to 3. The aryl, arylalkyl and heterocyclic moieties may be optionally substituted as defined below.

Suitably, q is 0 or an integer from 1 to 10.

When R &_lt; ₁ > forms a dioxy bridge, s is preferably 1. When R < ₁ > forms an additional saturated or unsaturated 5- to 6-membered ring, a 6-membered unsaturated ring which forms a naphthylene ring system is preferred. The ring may be substituted one to three times by the other R ₁ moieties as defined above independently.

Suitably R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _{1 -4} alkyl, heterocyclic, or heterocyclic C _1-4 alkyl, or R ₄ and R ₅ is from 5 to which they can further include an additional heteroatom selected from O / N / S together with the nitrogen Form a seven-member ring.

R ₈ is suitably independently selected from hydrogen or C _1-4 alkyl.

R ₁₀ is suitably C _1-10 alkyl C (O) ₂ R ₈ , such as CH ₂ C (O) ₂ H or CH ₂ C (O) ₂ CH ₃ .

R ₁₁ is suitably hydrogen, C _1-4 alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl.

R ₁₂ is suitably hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.

R ₁₉ are all optionally C _1-4 alkyl which may be substituted, aryl, arylalkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl.

Preferably R ₁ is selected from the group consisting of halogen, cyano, nitro, CF ₃ , C (O) NR ₄ R ₅ , alkenyl C (O) NR ₄ R ₅ , C (O) R ₄ R ₁₀ , alkenyl C ) OR ₁₂ , heteroaryl, heteroarylalkyl, heteroarylalkenyl or S (O) NR ₄ R ₅ , preferably R ₄ and R ₅ are both hydrogen or one phenyl. The preferred ring substitution for R < ₁ > is at the 4-position of the phenyl ring.

If R is OH, SH or NSO ₂ R _b then R ₁ is preferably substituted in the 3-position, 4-position or in the 3,4-position. The substituent is suitably an electron withdrawing group. Preferably R is OH, SH or NSO ₂ R _b , R ₁ is nitro, halogen, cyano, trifluoromethyl, C (O) NR ₄ R ₅ .

If R is a carboxylic acid, R < _{1 >} is preferably hydrogen or, preferably, R < ₁ > is substituted at the 4-position and is more preferably substituted by trifluoromethyl or chloro.

In compounds of formula I, suitably R ₁₃ and R ₁₄ are independently hydrogen, optionally substituted C _1-4 alkyl optionally linear or branched as defined herein, or one of R ₁₃ and R ₁₄ is optionally substituted Substituted aryl; v is 0 or an integer of 1 to 4;

R ₁₃ and R ₁₄ are optionally substituted alkyl, the alkyl moiety is independently selected from the group consisting of halogen; Halo substituted C _1-4 alkyl, such as trifluoromethyl; Hydroxy; HydroxyC _1-4 alkyl; C _1-4 alkoxy, such as methoxy or ethoxy, halo-substituted C _1-10 alkoxy, S (O) _t R ₄ ; Aryl; NR ₄ R ₅ ; NHC (O) R ₄ ; _{C (O) NR 4 R 5} ; Or C (O) OR < ₈ >.

In the compounds of formula I, W < ₁ >

to be.

An annulus containing E indicating the bond point may be present at random. When not present, said ring is a phenyl group which may be substituted by Y as set forth herein. The E ring may be substituted with a Y group at any saturated or unsaturated ring, and only those that are substituted herein at the unsaturated ring are indicated.

Suitably Y is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; (CR ₈ R ₈ ) _q S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; _{(CR 8 R 8) q NR} 4 R 5; C _2-10 alkenyl C (O) NR ₄ R ₅ ; (CR ₈ R ₈ ) _q C (O) NR ₄ R ₅ ; (CR ₈ R ₈ ) _q C (O) NR ₄ R ₁₀ ; S (O) ₃ H; S (O) ₃ R ₈ ; _{(CR 8 R 8) q C} (O) R 11; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; _{(CR 8 R 8) q C} (O) OR 12; _{(CR 8 R 8) q OC} (O) R 11; (CR ₈ R ₈ ) _q NR ₄ C (O) R ₁₁ ; (CR ₈ R ₈ ) _q NHS (O) ₂ R _d , (CR ₈ R ₈ ) _q SO ₂ NR ₄ R ₅ , or two Y residues together form O- (CH ₂ ) _s O- or 5 To 6-membered saturated or unsaturated ring, and the aryl, heteroaryl, heterocyclic containing moieties may be optionally substituted as defined herein.

When Y forms a dioxy bridge, s is preferably 1. When Y forms an additional saturated or unsaturated ring, a six-membered ring which forms a naphthylene ring system is preferred. The naphthylene ring may be substituted one to three times by other Y moieties as defined above. The abovementioned well known aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocyclic, heterocyclic alkyl and heterocyclic alkenyl moieties are all optionally substituted as defined herein .

Suitably, R _d is NR ₆ R ₇ , alkyl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl, heteroaryl, heteroaryl-C _1-4 alkyl, heteroaryl C _2-4 alkenyl, A heterocyclic C _1-4 alkyl or a heterocyclic C _2-4 alkenyl moiety, wherein the aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocycle The heterocyclic alkyl and heterocyclic alkenyl moieties may all optionally be substituted as defined herein.

Y is preferably selected from the group _consisting of halogen, C _1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylenedioxy, NR ₄ R ₅ , thioC _1-4 alkyl, thioaryl, halo substituted alkoxy , Optionally substituted C _1-4 alkyl or hydroxyalkyl. Y is more preferably monosubstituted halogen, disubstituted halogen, monosubstituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl or alkyl, more preferably these groups are monosubstituted in the 2'- -, 3'-position.

Y is substituted at any five ring positions, but Y is preferably monosubstituted at the 2'- or 3'- position and is preferably unsubstituted at the 4'-position, more preferably R is OH, SH Or NSO ₂ R _b . When the ring is disubstituted, if R is OH, SH or NSO ₂ R _b then the substituent is preferably present at the 2'- or 3'-position of the monocyclic ring. When R ₁ and Y are both hydrogen, it is preferred that at least one ring is substituted, and more preferably both rings are substituted.

Preferably, (Y) _n (wherein n is 1 or 2), when Z is cyano, W is phenyl, R is OH, v is 0 and W ₁ is phenyl, '-methyl, halogen, trifluoromethyl in position, OCF _3, C (O) ₂ H, C (O) _2-alkyl, C (O) ₂ aryl, C (O) amino, CN, alkyl, alkoxy, hydroxy, Nitro, hydroxymethyl, sulfamoyl, amino, aryloxy, alkylcarbonyl, arylcarbonyl, alkylcarbonyloxy or arylcarbonyloxy, or is not monosubstituted at the 3'-position.

Further, Z is cyano, and v is 0, W is phenyl, when R is OH, W ₁ is _{phenyl, (Y) n (n =} 1) is arbitrary as the alkyl or aryl (alkyl substituted 2 Substituted arylalkenyl moiety.

In the compounds of formula I Z is suitably _{cyano, OR 11, C (O)} NR 15 R 16, R 18, C (O) R 11, C (O) OR 11 or S (O) is ₂ R ₁₇ .

Suitably, R ₁₅ and R ₁₆ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _{1 -4} alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C _1-4 alkyl, or R ₁₅ and R ₁₆ are an additional heteroatom selected from oxygen, nitrogen or sulfur together with the nitrogen to which they are attached optionally May form a 5 to 7 membered ring which may be substituted or unsubstituted.

Suitably, R ₁₇ is C _1-4 alkyl, NR ₁₅ R ₁₆ , OR ₁₁ , optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _{1- 4} alkyl, optionally substituted heterocyclic or optionally substituted heterocyclic C _1-4 alkyl.

Suitably R ₁₈ is optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted Heterocyclic or optionally substituted heterocyclic C _1-4 alkyl.

As used herein, " optionally substituted ", unless specifically defined, includes halogens such as fluorine, chlorine, bromine or iodine; Hydroxy; Hydroxy substituted C _1-10 alkyl; C _1-10 alkoxy, such as methoxy or ethoxy; S (O) _{m'C 1-10} alkyl, wherein m 'is 0, 1 or 2, such as methylthio, methylsulfinyl or methylsulfonyl; Amino, single-and disubstituted amino, such as NR ₄ R ₅ group; NHC (O) R ₄ ; _{C (O) NR 4 R 5} ; C (O) OH; _{S (O) 2 NR 4 R} 5; NHS (O) ₂ R ₂₁ , C _1-10 alkyl such as methyl, ethyl, propyl, isopropyl or t-butyl; Halo substituted C _1-10 alkyl such as CF ₃ ; Means optionally substituted aryl such as phenyl or optionally substituted arylalkyl such as benzyl or phenethyl, optionally substituted heterocyclic, optionally substituted heterocyclic alkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl Wherein said aryl, heteroaryl or heterocyclic moiety is selected from the group consisting of halogen; Hydroxy; Hydroxy substituted alkyl; C _1-10 alkoxy; S (O) _{m'C 1-10} alkyl; Amino, single-and disubstituted amino, such as NR ₄ R ₅ group; C _1-10 alkyl or halo substituted C _1-10 alkyl, such as CF ₃ , one or two times.

R ₂₁ is suitably C _1-4 alkyl, aryl, arylC _1-4 alkyl, heteroaryl, heteroarylC _1-4 alkyl, heterocyclic or heterocyclicC _1-4 alkyl.

Suitable pharmaceutically acceptable salts are known in the art and include those derived from inorganic and organic acids such as hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, acetic, malic, Maleic acid, benzoic acid, salicylic acid, phenylacetic acid, and basic salts of mandelic acid. In addition, a pharmaceutically acceptable salt of formula I may be formed, for example, with a pharmaceutically acceptable cation if the substituent comprises a carboxy moiety. Suitable pharmaceutically acceptable cations are well known in the art and include alkali, alkaline earth, ammonium and quaternary ammonium cations.

As used herein, the following terms refer to the following.

&Quot; Halo " - all halogens, i.e. chloro, fluoro, bromo and iodo.

Unless otherwise limited, the term " C _1-10 alkyl " or " alkyl " chain length includes straight and branched chain having from 1 to 10 carbon atoms. Non-limiting examples thereof include methyl, ethyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.

The term " cycloalkyl " is used herein to mean a cyclic radical of preferably 3 to 8 carbon atoms, and non-limiting examples include cyclopropyl, cyclopentyl, cyclohexyl and the like.

The term " alkenyl " is used herein to denote a straight or branched chain moiety having from 2 to 10 carbon atoms, unless otherwise specified in all cases, and non-limiting examples thereof include ethenyl, 1-propenyl Propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

&Quot; Aryl " - phenyl and naphthyl.

&Quot; Heteroaryl " (by itself or in any combination, for example in "heteroaryloxy" or "heteroarylalkyl"), wherein one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S Non-limiting examples of 5- to 10-membered aromatic ring systems include pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, Triazole, imidazole or benzimidazole.

&Quot; Heterocyclic " (either by itself or in any combination, for example, " heterocyclic alkyl ") - a saturated or partially unsaturated ring containing one or more heteroatoms selected from the group consisting of N, Gt; is a 4 to 10 membered ring system, including, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran or imidazolidine.

The term " arylalkyl " or " heteroarylalkyl " or " heterocyclicalkyl ", unless otherwise indicated, means a C _1-10 alkyl as defined above attached to an aryl, heteroaryl or heterocyclic moiety Is used.

"Alkylsulfinyl" means The term is to mean the oxide S (O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term "sulfonyl" is a fully oxidized S (O) ₂ moiety it means.

Herein, the term "two R ₁ residues may (or two Y moieties) may form a 5 to 6 membered saturated or unsaturated ring together" is the naphthylene ring system or a C ₆ cycloalkenyl (i.e., hexene), or C ₅ Refers to the formation of a phenyl group to which a six membered unsaturated ring is bonded, such as a cycloalkenyl moiety (cyclopentene).

Exemplary compounds of the compounds of formula (I) include the following compounds:

N- (2-hydroxy-4-nitrophenyl) -N '- (2-chlorophenyl) -N "-cyanoguanidine;

N- (2-hydroxy-4-nitrophenyl) -N '- (2-chlorophenyl) -N "-cyanoguanidine;

N- (4-cyano-2-hydroxyphenyl) -N '- (phenyl) cyanoguanidine;

N- (2-bromophenyl) -N '- (4-cyano-2-hydroxyphenyl) -N "-cyanoguanidine;

N- (4-cyano-2-hydroxyphenyl) -N '- (2,3-dichlorophenyl) -N "-cyanoguanidine;

N- (2-bromophenyl) -N '- (4-cyano-2-hydroxy-3-propylphenyl) -N "-cyanoguanidine;

N- (2-bromophenyl) -N '- (4-cyano-2-hydroxy-3-isobutylphenyl) -N "-cyanoguanidine;

N- (2-bromophenyl) -N '- (3-bromo-4-cyano-2-hydroxyphenyl) -N "-cyanoguanidine;

N- (4-cyano-2-hydroxy-3-propylphenyl) -N '- (2,3-dichlorophenyl) -N "-cyanoguanidine;

N- (3-bromo-4-cyano-2-hydroxyphenyl) -N'- (2,3-methylenedioxyphenyl) -N "-cyanoguanidine;

N- (2-chlorophenyl) -N'- (4-cyano-2-hydroxy-3-propylphenyl) -N "-cyanoguanidine; and

N- (2-bromophenyl) -N '- (4-cyano-2-hydroxy-3-methoxycarbonylphenyl) -N " -cyanoguanidine.

It should be appreciated that the compounds of the present invention may exist as stereoisomers, regioisomers or diastereomers. These compounds may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are included in the scope of the present invention.

The compound of formula (I) can be obtained by applying a part of the synthesis process described in the following reaction formula. The synthesis provided in these schemes is applicable to produce compounds of formula I having various different R, R < ₁ > and aryl groups which are reacted using any suitably protected substituent to achieve conformity to the reactions described herein . In these cases, subsequent deprotection generally provides a compound of the disclosed nature. Once the urea nuclei are made, additional compounds of these formulas can be prepared by applying standard techniques for functional group interchange well known in the art. The scheme is presented as the only compound of formula I, but for illustration purposes only.

<Manufacturing Method>

The title compound can be synthesized from thiouronium salt (2, Scheme 1). R 'represents a - (R ₁₃ R ₁₄ ) _v -W ₁ linkage as defined in the compounds of formula (I). For purposes of illustration herein, W in the schemes represents substituted phenyl.

The thiouronium salt (2, Scheme 1) is prepared by reacting sodium cyanamide with commercially available isothiocyanate (1), where the isocyanate is not commercially available, by reacting the desired amine with thiophosgene in the presence of a base such as sodium bicarbonate Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt; The thiouronium salt (2) is condensed or acidified with an appropriately substituted aniline in the presence of a coupling agent such as EDC.HCl to form cyanothiourea and then reacted.

Alternatively, compound (4) can be prepared by reacting a commercially available (Aldrich Chemical Company) diphenylcyanocarbomimidate (5, Scheme 2) with an amine to form the intermediate O-phenylisourea (6) (Atwal, KS, Tetrahedron Lett . 35, 8085 (1994)) with an appropriately substituted aniline in the presence of trimethylaluminum. Compounds where R ' is alkyl may be prepared by heating without catalyst, with an appropriately substituted alkylamine.

Alternatively, the title compound can be synthesized using protected ortho-substituted anilines (8, scheme 3) (see U.S. Provisional US Application No. 60/020655, filed June 27, 1996, (Filed on August 22, 1996, Widdowson et al., Agent Litigation P50324-1), and USSN 08 / 701,299 (filed on August 21, 1996, Attorney Litigation P50324-2) )). Ortho-substituted anilines (7, Scheme 3) can be prepared by first protecting an ortho-substituted aniline with an appropriate alkyl or silyl halide in an aprotic solvent in the presence of a suitable base such as cesium carbonate, potassium carbonate or imidazole (E.g., tert-butyldimethylsilyl, allyl, benzyl, mom or other suitable protecting group). Protected ortho-substituted anilines can also be converted to ortho-substituted nitrobenzenes (9) by reaction with protecting groups under conditions known in the art (see Greene, T. Protecting Groups in Organic Synthesis , Wiley & Can be formed. This protected ortho-substituted nitro compound can then be reduced to the corresponding aniline using SnCl ₂ in EtOH or using H ₂ / Pd or LiAlH ₄ in an aprotic solvent.

The protected ortho-aniline (8) is then substituted using the thio phosgene converted to an isothiocyanate and then anion ZNH ^- ₍₂ ZnH by the reaction with a base such as NaH formation) and allowed to react. Z is as defined for a compound of formula (I). The resulting thioanion can then be alkylated with an alkylating agent such as methyl iodide to form a thioimidate such as compound (10) (Scheme 4).

Thioimidate (10, Scheme 5) can be converted to the title compound (4) by reaction with the amine R'NH ₂ . This reaction is facilitated by the addition of a metal salt with a high affinity for sulfur, such as silver oxide or silver acetate, or by oxidation of the sulfur with dimethyloxirane to form a leaving group better. Finally, the phenol protecting group is removed by standard methods to form the title compound (4).

Alternatively, the title compound can be prepared by reacting a protected carbodiimide (11, Scheme 6) with an anion NH-Z (formed by reacting NH ₂ Z with a base such as NaH) or neutral species NH ₂ Z (Z = CN) After the completion of the reaction, the reaction mixture is reacted with an amine base such as a Hunig base (diisopropylethylamine), triethylamine, triisopropylethylamine, N, N-dimethylbenzylamine or N, And the reaction is carried out under the condition that a large amount of neutrophils are present and the reaction time is kept as short as possible. Other bases suitable herein include secondary amines such as pyridine and amino substituted pyridine derivatives. When Z is cyano, suitable solvents for use herein include various aprotic solvents such as acetonitrile; Halogenated solvents such as chloroform and methylene chloride; Ethyl glycol-dimethyl ether (mono GLYME), dioxane, DMF and DMSO; Or mixtures thereof, preferably acetonitrile. It will be appreciated by those skilled in the art that the limiting nature of the solvent used herein is the solubility of the cyano-derived compound. For compounds where Z is not cyano, aprotic solvents are preferred, but it is recognized by those skilled in the art that other suitable solvents may be used, such as protic solvents such as alcohols.

Preferably, the temperature of the reaction (if Z is cyano) is from about -10 ° C to about 100 ° C, preferably from about 10 ° C to about 50 ° C, more preferably about room temperature, such as from 20 ° C to 30 ° C.

The protected R " moiety can be suitably deprotected using techniques known in the art. Preferably deprotection is achieved by deallylation catalysed by palladium (O) if the protecting group is an allyl derivative .

Carbodiimide 11 can be reacted with thiourea 12a or urea 12a by reaction with thiourea 12a (Scheme 7) or with triphenylphosphine, carbon tetrachloride and triethylamine by treatment with phosgene and a tertiary amine base 12b.

The carbodiimide may also be prepared by reacting the thiourea 12b with excess, such as 2 equivalents or more of methanesulfonyl chloride and a tertiary amine base such as the Hünig's base (diisopropylethylamine), triethylamine, triisopropylethylamine, N , N-dimethylbenzylamine or N, N-dimethylisopropylamine, preferably triethylamine. The reaction may be carried out in any halogenated solvent such as methylene chloride, chloroform or tetrachlorethylene, and the like; Suitable reaction temperatures are from about -30 째 C to about 80 째 C, preferably from -10 째 C to about 50 째 C, more preferably from about 0 째 C to about room temperature. See Fell, J.B., Coppola J. B., Syn Communications 25, 43 (1995).

Thiourea or urea may be synthesized as described in U.S. Provisional Application No. USSN 60/020655, filed June 27, 1996, Attorneys' Litigations P50467P and P50324-2, which are incorporated herein by reference. Thiourea (12a, Scheme 8) is also protected ortho-substituted aniline and the appropriate base, such as NaH, KH, calcium hydride and reacted with 2 equivalents, commercially available anion isothiocyanate (-NCS W _1, where, W &lt; ₁ &gt; is as defined for a compound of formula (I). The reaction occurs in any suitable aprotic solvent or halogenated solvent, preferably dimethylformamide. Suitable reaction temperatures for this reaction are from about -10 ° C to about 50 ° C.

If the desired isothiocyanate is not commercially available, it can be prepared by reacting the corresponding aniline with a suitable base such as sodium bicarbonate and thiophosgene.

Another aspect of the present invention is a novel compound of formula II:

W ₁ -N = C = NW

Wherein W and W ₁ are as defined in formula I and W comprises a protected or unprotected R group (R &quot;) as defined for a compound of formula (I).

Another embodiment of the present invention is a novel compound of formula III:

_{W 1 -NH-C (S)} -NH-W

Wherein W and W ₁ are as defined in formula I and W comprises a protected or unprotected R group (R &quot;) as defined for a compound of formula (I).

It is also contemplated that protected (R ") forms of the compounds of formula I are within the scope of the present invention.

The guanidine functionality can be a number of different tautomeric isomers, such as W ₁ -NC (= NZ) -NW; ZN = C (NW ₁ ) -NW; W ₁ -NC (= NW) -NZ, which are all included within the scope of the present invention.

The pharmaceutically acceptable salts of formula I can be obtained by known methods, for example by treatment with an appropriate amount of acid or base in the presence of a suitable solvent.

In an embodiment, all temperatures are degrees Celsius (占 폚). Unless otherwise indicated, mass spectra were performed on a VG Zab mass spectrometer using fast atom bombardment. ¹ H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz or 400 MHz using a Bruker AM 250 or Am 400 spectrometer. The multiplicity is expressed as: s = 1 median, d = 2 median, t = 3 median, q = 4 median, m = Sat represents the saturated solution, and equiv. Represents the ratio of the molar equivalents of the reagents to the main reactants.

Flash chromatography is performed over Merck silica gel 60 (230-400 mesh).

<Synthesis Example>

The present invention will now be described with reference to the following examples, which are for illustrative purposes only and are not to be construed as limiting the scope of the invention. Unless otherwise indicated, all temperatures are given in degrees centigrade, all solvents are the highest available purity, and all reactions are carried out under anhydrous conditions in an argon atmosphere.

&Lt; Example 1 >

Preparation of N- (2-hydroxy-4-nitrophenyl) -N '- (2-chlorophenyl) -N " -cyanoguanidine

a) Sodium salt of N- (2-chlorophenyl) -N " -cyanothiourea

Sodium (1.64 g, 71.3 mmol) was dissolved in ethanol until gas evolution ceased. Cyanamide (1.685 g, 40 mmol) was then added. The reaction mixture was stirred for 15 minutes, 2-chlorophenyl isothiocyanate (7.21 g, 42.66 mmol) was added and the mixture was maintained at reflux temperature for 6 hours. The reaction was cooled and diluted with methylene chloride. The white solid precipitate was filtered off and dried to give the sodium salt of N- (2-chlorophenyl) -N "-cyanothiourea (8.26 g, 87.5%). MS (ES ⁺ ) m / e 210, 212 [ M + H] &lt; ⁺ &gt;.

b) Preparation of N- (2-hydroxy-3-nitrophenyl) -N '- (2- chlorophenyl) -N " -cyanoguanidine

To a stirred solution of sodium salt of N- (2-chlorophenyl) -N'-cyanothiourea (234 mg, 1 mmol) and 2-hydroxy-3-nitroaniline (156 mg, 1 mmol) in 2 ml anhydrous DMF Was added EDC hydrochloride (384 mg, 2 mmol) under Ar and the reaction was stirred at room temperature for 4 days. The reaction mixture was partitioned between EtOAc and 1N HCl and the organic extracts were washed with water and brine. After drying (Na ₂ SO ₄ ) and evaporation of the solvent under reduced pressure, a red oil was isolated. Chromatography (silica gel, 3% acetone / CHCl ₃ ) gave a light yellow solid (30 mg, 9%) which was recrystallized from t-butyl methyl ether to give the title compound. ^{1 H NMR (400 MHz, CDCl} 3) δ10.93 (s, 1H), 8.53 (s, 1H), 7.92 (d, J = 7.8Hz, 1H), 7.61 (d, J = 7.8Hz, 2H), 7.38-7.50 (m, 2H), 7.22 (s, 1 H), 7.08 (t, 1 H); IR (KBr) 2181 cm &lt; ^{-1 &} gt ;; MS (ES &lt; ^- &gt;) m / e 330 [MH] ^- ; mp. 163 to 164 占 폚.

&Lt; Example 2 >

Preparation of N- (2-hydroxy-4-cyanophenyl) -N '- (2-bromophenyl) -N " -cyanoguanidine

a) 1-Allyloxy-5-cyano-2-nitrobenzene

A mixture of 5-cyano-2-nitrophenol (3.0 g, 18.9 mmol), allyl bromide (1.82 mL, 21.0 mmol) and cesium carbonate (7.39 g, 22.7 mmol) in DMF (20 mL) Lt; / RTI &gt; The reaction mixture was partitioned between t-butyl methyl ether and water. The layers were separated and the aqueous fraction further extracted (3 times). The combined organic extract was with water, then washed twice with brine, dried over MgSO ₄ and filtered. Removal of the solvent under reduced pressure gave the title compound (3.89 g, 100%). ^{1 H NMR (400 MHz, CDCl} 3) δ7.87 (d, J = 8.5Hz, 1H), 7.35 (dd, J = 8.4Hz, J = 1.2Hz, 1H), 7.35 (d, J = 1.5Hz, 1H), 6.02 (m, 1H), 5.52 (d, 1H), 5.43 (d, 1H), 4.73 (dd, J = 3.6 Hz, J = 1.2 Hz, 2H).

b) 2-Allyloxy-4-cyanoaniline

A mixture of 1-allyloxy-5-cyano-2-nitrobenzene (3.6 g, 17.46 mmol) and tin (II) chloride (19.7 g, 87.3 mmol) in ethanol (100 mL) was stirred overnight at room temperature. The solvent was removed under reduced pressure. The reaction mixture was partitioned between 5% NaHCO ₃ and ethyl acetate. The mixture was filtered to remove tin salts and the aqueous fraction was further extracted with ethyl acetate (4 times). The combined organic phase was washed with water and brine, dried over MgSO _4. Removal of the solvent under reduced pressure gave a brown solid (2.82 g) which was recrystallized from t-butyl-methyl ether / hexane to give the title compound as a pale brown solid (2.63 g, 93%). MS (ES &lt; ⁺ &gt;) m / e 175 [M + H] &lt; ⁺ &gt;; MS (ES &lt; ^- &gt;) m / e 173 [MH] ^- .

c) N- (2-Allyloxy-4-cyanophenyl) -N '- (2-bromophenyl) -thiourea

To a solution of 2-allyloxy-4-cyanoaniline (522 mg, 3 mmol) in DMF (1.5 mL) at 0 ° C was added sodium hydride (60% oil dispersion, 240 mg, 6.0 mmol) in DMF mmol). After stirring at 0 [deg.] C for 15 minutes, 2-bromophenyl isothiocyanate was added dropwise at 0 [deg.] C, and the reaction was stirred at room temperature for 1 hour. The reaction was quenched by the addition of 0.5 M sodium dihydrogen phosphate. The mixture was extracted with ethyl acetate, washed with water and dried over sodium sulfate. The crude solid was recrystallized from methanol to give the title compound as a white solid (911 mg, 78%). MS (ES &lt; ⁺ &gt;) m / e 388, 390 [M + H] &lt; ⁺ &gt;.

d) Preparation of N- (2-allyloxy-4-cyanophenyl) -N '- (2-bromophenyl) -carbodiimide

To a stirred solution of N- (2-allyloxy-4-cyanophenyl) -N '- (2-bromophenyl) thiourea (900 mg, 2.32 mmol) and triethylamine (1 mL, 6.95 mmol) in methylene chloride Was added methanesulfonyl chloride (360 [mu] L, 4.64 mmol) dropwise at 0 [deg.] C under Ar. The reaction was stirred at 0 &lt; 0 &gt; C for 15 min, indicating that tlc was free of any starting material. The reaction mixture was chromatographed on silica gel eluting with methylene chloride to give the title compound as a yellow solid (1.2 g, &gt; 100%). This was used in the next reaction without further purification.

e) Preparation of N- (2-allyloxy-4-cyanophenyl) -N'- (2-bromophenyl) -N " -cyanoguanidine

To a stirred mixture of cyanamide (560 mg, 13.33 mmol) and Hünige's base (2.6 mL) in acetonitrile was added N- (2-allyloxy-4-cyanophenyl) -N ' - (2-bromophenyl) carbodiimide (600 mg, 1.69 mmol) in tetrahydrofuran was added dropwise. The reaction was stirred at room temperature for 15 minutes, then the solvent was removed under reduced pressure and the residue was hydrolyzed with 0.5 M sodium dihydrogen phosphate. The ethyl acetate extract of the aqueous mixture was washed with 0.5 M sodium dihydrogenphosphate and brine. After drying (MgSO ₄ ), filtration and evaporation under reduced pressure, a crude brown solid (500 mg) was obtained. This was chromatographed on silica gel (50/50 ethyl acetate / hexanes) to give the title compound (455 mg, 95%). MS (ES &lt; ^- &gt;) m / e 394, 396 [MH] ^&lt;&quot;&gt;.

f) Preparation of N- (4-cyano-2-hydroxyphenyl) -N'- (2-bromophenyl) -N " -cyanoguanidine

To a solution of N- (2-allyloxy-4-cyanophenyl) -N '- (2-bromophenyl) -N''- cyano guanidine (100 mg, 0.25 mmol) and sodium borohydride (21 mg, 7 mol%) was added at room temperature to a mixture of triethylamine (20 mg, 0.52 mmol) .The reaction was carried out at room temperature when tlc showed no starting material present The mixture was partitioned between ethyl acetate and 0.5 M sodium dihydrogen phosphate, dried over MgSO ₄ , filtered and evaporated under reduced pressure to give a crude brown solid (100 mg) ¹ H NMR (400 MHz, DMSO): [delta] 10.93 (s, ¹ H) .delta.10.93 (s, , 7.71 (d, J = 7.8 Hz, 2H), 7.50 (s, 1H) -7.42 (m, 2H), 7.30-7.26 (m, 2H), 7.17 (s, 1H), 7.08 (t, 1H); IR (KBr) 2224, 2193 ㎝ -1; MS (ES -) m / e 354, 356 [MH] ^- ; MS (ES ⁺ ) m / e 356, 358 [M + H] ⁺ ; mp 175-176 [deg.] C.

&Lt; Example 3 >

Preparation of N- (4-cyano-2-hydroxyphenyl) -N '- (phenyl) -N' '- cyanoguanidine

a) 5-Cyano-1-methoxymethyloxy-2-nitrobenzene

To a solution of 5-cyano-2-nitrophenol (978 mg, 5.96 mmol) in THF (10 mL) at room temperature was added sodium hydride (60% oil dispersion, 260 mg, 6.5 mmol) in pre- Was added dropwise. The solution turned bright orange and a large amount of precipitate formed. After stirring at room temperature for 15 minutes, bromomethyl methyl ether was added dropwise to the stirred slurry and the reaction was stirred at room temperature for 18 hours. The yellow mixture was then partitioned between t-butyl-O-methyl ether and water, the aqueous fraction was extracted (3 times), washed with 5% sodium bicarbonate solution (4 times) and brine. As a dry (MgSO _4), filtered and after evaporation under reduced pressure, a pale yellow solid (1.05 g, 85%) of the title compound was obtained. ^{1 H NMR (400 MHz, CDCl} 3): δ7.84 (d, J = 8.4Hz, 1H), 7.66 (d, J = 1.4Hz, 1H), 7.35 (dd, J = 8.4Hz, J = 1.5Hz , &Lt; / RTI &gt; 1H), 5.34 (s, 2H), 3.55 (s, 3H).

b) 4-Cyano-2-methoxymethyloxyaniline

A mixture of 5-cyano-1-methoxymethyloxy-2-nitrobenzene (0.5 g, 2.4 mmol) and 10% palladium on carbon (0.05 g) in ethyl acetate (50 mL) Lt; / RTI &gt; The mixture was filtered through celite then the palladium was removed and the residue was chromatographed on silica gel (eluting with 25% ethyl acetate / hexane) to give the title compound (250 mg, 58%). MS (ES &lt; ⁺ &gt;) m / e 179 [M + H] &lt; ⁺ &gt;.

c) Preparation of N- (4-cyano-2-methoxymethyloxyphenyl) -N '- (2-phenyl) -N " -cyanoguanidine

Except that 2-bromophenyl isothiocyanate was replaced by phenyl isothiocyanate and 2-allyloxy-4-cyanoaniline was replaced by 2-methoxymethyloxy-4-cyanoaniline. The title compound was prepared according to examples 1 (c) to 1 (e) (overall 24%). IR (KBr) 2226, 2198 cm &lt; ^{-1 &} gt ;; MS (ES &lt; ^- &gt;) m / e 320 [MH] ^- .

d) Preparation of N- (4-cyano-2-hydroxyphenyl) -N '- (phenyl) -N " -cyanoguanidine

The compound of Example 2b (47 mg, 0.146 mmol) was dissolved in ethyl acetate (20 mL), treated with 6N HCl (10 mL) and stirred at room temperature for 3 hours. Then 6N HCl (5 mL) was added and stirring was continued for 2 more hours. The mixture was diluted with ethyl acetate and brine and the aqueous fraction was further extracted with ethyl acetate (5 times). The combined organic fractions were dried over sodium sulfate and evaporated in vacuo to give the title compound (64 mg) which was recrystallized from t-butyl-O-methyl ether to give the title compound as a white solid (2 mg, 5%). ^{1 H NMR (400 MHz, DMSO} d 6): δ9.70 (s, 1H), 9.12 (s, 1H), 7.62 (d, J = 8.3Hz, 1H), 7.55 (d, 1.2Hz, 1H), 7.49 (dd, J = 1.2 Hz, J = 8.1 Hz, 1H), 7.36 (m, 4H), 7.18 (m, 1H); IR (KBr) 2233, 2192 cm &lt; ^{-1 &} gt ;; MS (ES &lt; ⁺ &gt;) m / e 278 [M + H] &lt; ⁺ &gt;; MS (ES &lt; ^- &gt;) m / e 276 [MH] ^- ; mp. 270 to 271 占 폚.

<Example 4>

Preparation of N- (4-cyano-2-hydroxyphenyl) -N '- (2,3-dichlorophenyl) -N " -cyanoguanidine

The title compound was prepared according to example 1 (a) -1 (e), but replacing 2-bromophenyl isothiocyanate with (2,3-dichlorophenylisothiocyanate) %). IR (KBr) 2231, 2197 cm &lt; ^{-1 &} gt ;; ^{MS (ES +) m / e} 346, 348, 350 [M + H] +; MS (ES &lt; ^- &gt;) m / e 344, 346, 347, 348 [MH] ^- ; mp. 155 to 156 占 폚.

&Lt; Example 5 >

Preparation of N- (2-bromophenyl) -N'- (4-cyano-2-hydroxy-3-propylphenyl) -N " -cyanoguanidine

a) 2-Amino-5-cyano-6-prop-1-en-3-

The compound (1.88 g, 1.29 mmol) prepared in Example 2b was treated with N, N-dimethylaniline (20 ml) under Ar and maintained at 175 ° C (oil bath temperature) for 3.5 hours. The solvent was removed in vacuo and the residue was recrystallized from methyl-t-butyl ether with 10-20% methylene chloride and hexanes to give the title compound as a clear solid (1.67 g, 89%). MS (ES &lt; ⁺ &gt;) m / e 175 [M + H] &lt; ⁺ &gt;; MS (ES &lt; ^- &gt;) m / e 173 [MH] ^- .

b) 2-Amino-5-cyano-6-propylphenol

A mixture of 2-amino-5-cyano-6-prop-1-en-3-yl phenol (0.5 g, 2.4 mmol) and 10% palladium on carbon (0.05 g) in ethyl acetate (50 mL) And the mixture was stirred at room temperature for 2 hours under 1 atm. The mixture was filtered through celite to remove palladium and the filtrate was concentrated under reduced pressure to give the title compound as a pinkish white solid (1.2 g, 78%). MS (ES &lt; ⁺ &gt;) m / e 177 [M + H] &lt; ⁺ &gt;; MS (ES &lt; ^- &gt;) m / e 175 [MH] ^- .

c) Preparation of N- (2-bromophenyl) -N '- (4-cyano-2-hydroxy-3-propylphenyl) -N " -cyanoguanidine

The title compound was obtained according to the procedure of Example 2 (a) -1 (e), except substituting 2-amino-5-cyano-6-propylphenol for 5-cyano- (Total 37%). ^{1 H NMR (400 MHz, DMSO} d 6): δ9.72 (s, 1H), 9.45 (s, 1H), 8.66 (s, 1H), 7.71 (d, J = 7.0Hz, 1H), 7.56 (d J = 8.4 Hz, 1H), 7.45 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H), 7.26 , J = 7.6 Hz, 2H), 0.93 (t, J = 7.3 Hz, 3H); IR (KBr) 2224, 2184 cm &lt; ^{-1 &} gt ;; MS (ES &lt; ⁺ &gt;) m / e 398, 400 [M + H] &lt; ⁺ &gt;; MS (ES &lt; ^- &gt;) m / e 396, 398 [MH] ^- .

&Lt; Example 6 >

Preparation of N- (4-cyano-2-hydroxy-3-propylphenyl) -N '- (2,3-dichlorophenyl) -N'-cyanoguanidine

2-Bromophenyl isothiocyanate was replaced with 2,3-dichlorophenylisothiocyanate, and 2-allyloxy-4-cyanoaniline was reacted with 2-allyloxy-4-cyano- The title compound was obtained (7% overall) following the procedure of Example 1 (b) -1 (e), except substituting. IR (KBr) 2236, 2182 cm &lt; ^{-1 &} gt ;; ^{MS (ES +) m / e} 388, 390, 391 [M + H] +; MS (ES &lt; ^- &gt;) m / e 386, 388, 390 [MH] ^- ; mp 143-147 占 폚.

&Lt; Example 7 >

Preparation of N- (2-chlorophenyl) -N '- (4-cyano-2-hydroxy-3-propylphenyl) -N " -cyanoguanidine

Replacing 2-bromophenyl isothiocyanate with 2-chlorophenyl isothiocyanate and replacing 2-allyloxy-4-cyanoaniline with 2-allyloxy-4-cyano- The title compound was obtained according to the procedure of Example 1 (b) -1 (e) (26% overall). IR (KBr) 2225, 2187 cm &lt; ^{-1 &} gt ;; MS (ES &lt; ⁺ &gt;) m / e 354, 356 [M + H] &lt; ⁺ &gt;; MS (ES &lt; ^- &gt;) m / e 352, 354 [MH] ^- ; mp 159-160 [deg.] C.

&Lt; Example 8 >

Preparation of N- (2-bromophenyl) -N '- (4-cyano-2-hydroxy-3-isobutylphenyl) -N " -cyanoguanidine

The title compound was obtained (16% overall) following the procedure of Example 4 (a) -1 (c), except that allyl bromide was replaced with 3-bromo-2-methyl-l-propene. IR (KBr) 2231, 2189 cm &lt; ^{-1 &} gt ;; MS (ES &lt; ⁺ &gt;) m / e 412, 414 [M + H] &lt; ⁺ &gt;; ^{MS (ES -) m / e} 410, 412 [MH] -

&Lt; Example 9 >

Preparation of N- (2-bromophenyl) -N '- (3-bromo-4-cyano-2-hydroxyphenyl) -N " -cyanoguanidine

a) 2-Bromo-3-hydroxy-4-nitrobenzonitrile

Hexamethylenetetramine compound and hydrogen tribromide (1: 1) (9.91 g, 26.0 mmol) were added to a solution of 3-hydroxy-4-nitrobenzonitrile (3.03 g, 18.4 mmol) in methylene chloride (660 ml) Respectively. The resulting solution was stirred for one week at room temperature. The reaction mixture was acidified with 1N HCl then extracted with a 1/1 mixture of EtOAc / hexanes. The organic layers were combined and dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (50/50: hexane / EtOAc) to give the desired product (1.47 g, 35.0%). MS (ES &lt; ^- &gt;) m / e 241, 243 [MH] ^- .

b) Preparation of N- (2-bromophenyl) -N'- (3-bromo-4-cyano-2- hydroxyphenyl) -N " -cyanoguanidine

Following the procedure of Example 2 (a) -1 (e), except substituting 2-bromo-3-hydroxy-4-nitrobenzonitrile for 5-cyano-2- Obtained as a white solid (44% overall after chromatography, 15% recrystallization). ^{1 H NMR (400 MHz, DMSO} d 6): δ10.66 (s, 1H), 9.56 (s, 1H), 8.92 (s, 1H), 7.71 (d, J = 8.0Hz, 1H), 7.68 (d , J = 8.5 Hz, 1 H), 7.48-7.41 (m, 3 H), 7.26 (t, 1 H); IR (KBr) 2228, 2186 cm &lt; ^{-1 &} gt ;; ^{MS (ES +) m / e} 434, 436, 438 [M + H] +; MS (ES &lt; ^- &gt;) m / e 432, 434, 436 [MH] ^- ; mp 142 [deg.] C.

&Lt; Example 10 >

Preparation of N- (3-bromo-4-cyano-2-hydroxyphenyl) -N '- (2,3-methylenedioxyphenyl) -N " -cyanoguanidine

Following the procedure of Example 8 (a) -1 (b) except that 2-bromophenyl isocyanate was replaced by methylenedioxyphenylisothiocyanate the title compound was obtained (14% overall). IR (KBr) 2230, 2196 cm &lt; ^{-1 &} gt ;; MS (ES &lt; ⁺ &gt;) m / e 400, 402 [M + H] &lt; ⁺ &gt;; MS (ES &lt; ^- &gt;) m / e 398, 400 [MH] ^- ; mp 164-165 [deg.] C.

&Lt; Example 11 >

Preparation of N- (2-bromophenyl) -N '- (4-cyano-2-hydroxy-3- methoxycarbonylphenyl) -N " -cyanoguanidine

a) methyl-2,6-dihydroxybenzoate

A solution of 80% NaH (10.00 g, 333.3 mmol) in DMF (45 mL) was cooled to 0 &lt; 0 &gt; C under Ar. 2,6-Dihydroxybenzoic acid (48.88 g, 317.1 mmol) in DMF (50 mL) was slowly added to the mixture over 45 minutes. The solution was stirred for 45 min, then MeI (21.0 mL, 337 mmol) was added over 20 min. The resulting solution was stirred at room temperature for 70 hours. The mixture was diluted with methylene chloride and filtered through a plug of silica gel using methylene chloride as a washing solution. Evaporation of the solvent gave the desired product (35.22 g, 66.1%). ^{1 H NMR (250 MHz, DMSO} d 6): δ9.91 (s, 2H), 7.09 (t, J = 1.2Hz, J = 2.5Hz, 1H), 6.37 (d, J = 1.1Hz, 2H), 3.78 (s, 3 H).

b) Methyl-2-benzyloxy-6-hydroxybenzoate

To the mixture of methyl-2,6-dihydroxybenzoate (20.00 g, 118.9 mmol) in DMF (100 mL) was added 80% NaH (3.9144 g, 130.5 mmol) under Ar and then benzyl bromide (25.5 mL, 214.5 mmol). The solution was heated to 70 [deg.] C for 20 hours. The mixture was cooled by the addition of saturated sodium bicarbonate, and extracted with EtOAc, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (95/5: hexane / EtOAc) to give the desired product (16.71 g, 54.4%). MS (ES &lt; ^- &gt;) m / e 257 [MH] ^- .

c) Methyl-2-benzyloxy-6-cyanobenzoate

A solution of methyl 2-benzyloxy-6-hydroxybenzoate (2.730 g, 10.6 mmol) in methylene chloride (28.5 mL) under Ar at 0 ° C was treated with N-phenyltrifluoromethanesulfonimide (4.5424 g, 12.7 mmol ) And triethylamine (1.62 mL, 11.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 14 hours. The solution was diluted with diethyl ether and washed with water, 5% sodium hydroxide and brine. The organic layer was dried over MgSO _4, filtered, and evaporated to give the crude triflate (4.476 g, 108%). ^{1 H NMR (250 MHz, CDCl} 3) δ7.35 (m, 6H), 6.95 (m, 2H), 5.16 (s, 2H), 3.94 (s, 3H). The crude triflate was dissolved in DMF (23 mL) and treated with palladium [O] tetrakistriphenylphosphine (0.3036 g, 0.260 mmol) and Zn (CN) ₂ (1.1027 g, 9.39 mmol). The mixture was heated to 80 &lt; 0 &gt; C for 10 hours. The reaction mixture was cooled to room temperature and poured into saturated sodium bicarbonate solution. The mixture was extracted with EtOAc, dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (80/20: hexane / EtOAc) to give the desired product (2.20 g, 78%, step 2). ^{1 H NMR (250 MHz, CDCl} 3) δ7.5-7.2 (m, 8H), 5.19 (s, 2H), 4.00 (s, 3H).

d) Preparation of methyl-6-cyano-2-hydroxybenzoate

To a solution of methyl-2-benzyloxy-6-cyanobenzoate (10.0 g, 37.4 mmol) in EtOAc (330 mL) under Ar was added 10% Pd / C (4.72 g). The reaction vessel was flushed with hydrogen and the reaction mixture was stirred at room temperature under a balloon pressure hydrogen atmosphere. After 3 hours, the reaction was flushed with Ar and the solution was filtered through celite. The solvent was evaporated to give the desired product (6.12 g, 92.2%). Analysis for C ₉ H ₇ NO ₃ : Calculated C, 61.02; H, 3.98; N, 7.91. Found C, 60.74; H, 3.99; N, 7.65.

e) Preparation of methyl-6-cyano-2-hydroxy-3-nitrobenzoate

A suspension of methyl-6-cyano-2-hydroxybenzoate (1.1428 g, 6.45 mmol) in acetic anhydride (21 mL) was treated dropwise at 0 <0> C with concentrated nitric acid (0.41 mL, 6.44 mmol). The mixture was allowed to warm to room temperature and all of the starting material was dissolved. The solution was stirred for 36 h, then poured into water and extracted with EtOAc. The combined organic layers were dried over MgSO ₄ and filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (70/30/1: hexanes / EtOAc / HOAc) to give the desired product (0.50 g, 35.7%). MS (ES &lt; ^- &gt;) m / e 221 [MH] ^- .

f) Methyl-3-amino-6-cyano-2-hydroxybenzoate

To a solution of methyl-6-cyano-2-hydroxy-3-nitrobenzoate (402 mg, 1.81 mmol) in EtOAc (40 mL) was added 10% Pd / C (0.23 g) under Ar. The reaction vessel was flushed with hydrogen and the reaction mixture was stirred at room temperature under a balloon pressure hydrogen atmosphere. After 2 h, the reaction mixture was flushed with Ar and then the solution was filtered through celite. The solvent was evaporated to give the desired product (334 mg, 96.0%). MS (ES &lt; ^- &gt;) m / e 192 [MH] ^- .

g) Synthesis of N- (2-bromophenyl) -N '- (4-cyano-2-hydroxy-3- methoxycarbonylphenyl) -N " -cyanoguanidine

According to the method of Example 2 (a) -1 (e), except substituting methyl-3-amino-6-cyano-2-hydroxybenzoate for 5-cyano- Compound (19% overall). ^{1 H NMR (400 MHz, DMSO} d 6): δ11.08 (s, 1H), 9.69 (s, 1H), 8.89 (s, 1H), 7.99 (d, J = 8.40Hz, 1H), 7.73 (d , J = 7.9 Hz, 1 H), 7.50-7.42 (m, 3 H), 7.28 (t, 1 H); IR (KBr) 2228, 2186 cm ^-1 IR (KBr) 2225, 2177 cm ^-1 ; MS (ES &lt; ^- &gt;) m / e 412, 414 [MH] ^- ; mp 210-211 [deg.] C.

< Treatment method>

The overexpression of IL-8 cytokines by cells of mammals such as, but not limited to, monocytes and / or macrophages, or other chemokines that bind to IL-8a or &bgr; receptors, also referred to as type I or type II receptors Or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human or other mammal that has been worsened or caused by unregulated production.

Accordingly, the present invention provides a method of treating a chemokine mediated disease that binds to an IL-8 alpha or beta receptor, comprising administering an effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof. In particular, the chemokines are IL-8, GROa, GRObeta, GROy, ENA-78 or NAP-2.

The compounds of formula I are administered in an amount sufficient to inhibit cytokine function, in particular IL-8, GROa, GROß, GROγ, ENA-78 or NAP-2, so that they are administered at normal levels of physiological function, Lt; / RTI &gt; to improve the disease state. In the context of the present invention, the abnormal levels of IL-8, GROa, GRObeta, GROy, ENA-78 or NAP-2, for example, comprise: (i) the level of free IL-8 above 1 picogram / ; (Ii) any cell IL-8, GROa, GROß, GROy, ENA-78 or NAP-2 above normal physiological levels; Or (iii) the presence of IL-8, GROα, GROβ, GROγ or NAP-2 is produced above the basal level of the cell or tissue in IL-8, GROα, GROβ, GROγ or NAP-2, respectively.

There are many disease states in which excessive or unregulated production of IL-8 is associated with deterioration and / or the incidence of the disease. The chemokine mediated diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, seizure, septic shock, endotoxic shock, Aplastic anemia, sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft-host response, Alzheimer's disease, allograft rejection, malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, There is an emission.

The compounds of the present invention may also be used in the treatment of respiratory viruses (including, but not limited to, renoviruses and influenza viruses), herpes viruses (including but not limited to herpes simplex I and II) Hepatitis virus). &Lt; / RTI &gt;

These diseases are characterized primarily by massive neutrophil infiltration, T-cell infiltration, or angiogenic growth and are associated with neutrophil chemotaxis to the inflammatory site or IL-8, GROα, GROβ, GROγ or NAP -2. &Lt; / RTI &gt; In contrast to other inflammatory cytokines (IL-1, TNF and IL-6), IL-8, GROα, GROβ, GROγ or NAP-2 inhibits neutrophil chemotaxis, enzyme release (non- Of course, have unique properties that promote excess oxide formation and activation. Alpha-chemokines acting through IL-8 type I or type II receptors, in particular GRO ?, GRO ?, GRO? Or NAP-2, can promote angiogenesis of tumors by promoting endothelial cell-directed growth. Therefore, inhibition of IL-8 induced chemotaxis or activation will result in a direct reduction of neutrophil infiltration.

In the treatment of HIV infection related to Kane evidence on the role of mokin has recently (Little Man (Littleman) et literature [Nature 381, pp.661 (1996) ] , etc., and Coop (Koup) [Nature 381, pp . 667 (1996)).

The present invention also provides a means for preventing CNS damage in an individual that appears to be sensitive to CNS damage, as well as treating CNS damage in an acute situation, by a chemokine receptor antagonist compound of formula (I).

CNS damage as defined herein includes both open or penetrating head trauma (eg, due to surgery) or closed head trauma injury (eg, due to head area damage). Ischemic seizures, particularly in the brain area, are also included within this definition.

Ischemic seizures can be defined as lesion nervous system disorders resulting from insufficient blood supply to a particular brain area, usually as a result of embolization, thrombosis, or local atherosclerotic closure of blood vessels. The role of inflammatory cytokines has been revealed in this area and the present invention provides a means for possible treatment of these injuries. In the case of acute injuries such as these, relatively little treatment was performed.

TNF-α is a cytokine with proinflammatory action, including the expression of endothelial leukocyte adhesion molecules. Since leukocytes invade into ischemic brain lesions, compounds that inhibit or reduce the level of TNF will be useful in the treatment of ischemic brain injury. See Liu et al., Stroke , Vol. 25, No. 7, pp. 1481-88 (1994), which is incorporated herein by reference.

Models of closed head injury and treatment with mixed 5-LO / CO preparations are described in Shohami et al., J. Med. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3, No. 2, pp. 99-107 (1992). Treatment with reduced edema formation has been found to improve functional outcomes in the treated animals.

The compounds of formula I are administered in an amount sufficient to inhibit binding to IL-8 alpha or beta receptors, as evidenced by decreased neutrophil chemotaxis and activation. The finding that the compounds of formula I are inhibitors of IL-8 binding is based on the effect of the compounds of formula I in the in vitro receptor binding assays described herein. In some cases, the compounds of formula I have been shown to be dual inhibitors of both recombinant type I and type II IL-8 receptors. Preferably, the compound is a single receptor, more preferably a type II inhibitor.

The term " IL-8 mediated disease or disease state ", as used herein, refers to an IL-8 mediated disease or condition state in which IL-8, GROa, GRObeta, GROγ, ENA-78 or NAP- GRO-, GRO [gamma], ENA-78 or NAP-2 which results in the release of other monokines (e.g., IL-1, IL-6 or TNF) &Lt; RTI ID = 0.0 &gt; and / or &lt; / RTI &gt; Therefore, for example, a disease state in which IL-1 is a major component and its production or action is exacerbated or secreted in response to IL-8 is regarded as a disease mediated by IL-8.

As used herein, the term " chemokine mediated disease or condition " refers to a chemokine that binds to an IL-8 alpha or beta receptor (including but not limited to IL-8, GRO alpha, GRO beta, GRO gamma, ENA- ) Refers to any and all disease states that play a role. This will include disease states in which IL-8 plays a role by IL-8 itself, or by IL-8, which releases other monokines (non-limiting examples: IL-1, IL-6 or TNF). Thus, for example, a disease state in which IL-1 is a major component and whose production or action is exacerbated or secreted in response to IL-8 will be regarded as a disease mediated by IL-8.

As used herein, the term " cytokine " refers to any secreted polypeptide that affects the function of a cell and is a molecule that modulates intercellular interactions in an immune, inflammatory or hematopoietic response. Cytokines include, but are not limited to, monokines and lymphokines, regardless of which cells produce them. For example, monokines generally are produced and secreted by monocytes such as macrophages and / or monocytes. However, many other cells produce monokines such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes and B-lymphocytes. Lymphokines generally produce lymphocyte cells. Non-limiting examples of cytokines include interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor- (TNF-β).

Similar to the term " cytokine ", as used herein, the term " chemokine " refers to any secreted polypeptide that affects the function of the cell and which is a molecule that modulates intercellular interactions in the immune, inflammatory, Lt; / RTI &gt; Chemokines are mainly secreted through the cell dermis, leading to the chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells. Non-limiting examples of chemokines include IL-8, GRO-α, GRO-β, GRO-γ, ENA-78, NAP-2, IP-10, MIP-1α, MIP-β, PF4, And three.

In order to use a compound of formula I or a pharmaceutically acceptable salt thereof for therapy, it will be formulated into a pharmaceutical composition according to standard pharmaceutical practice. Therefore, the present invention also relates to a pharmaceutical composition comprising an effective non-toxic amount of a compound of formula I and a pharmaceutically acceptable carrier or diluent.

The compounds of formula I, their pharmaceutically acceptable salts and pharmaceutical compositions containing them can be conveniently administered by any route commonly used for drug administration, for example, orally, topically, parenterally or by inhalation &Lt; / RTI &gt; The compounds of formula I can be administered in conventional dosage forms prepared by mixing the compounds of formula I with standard pharmaceutical carriers according to conventional procedures. The compounds of formula I may also be administered in conventional doses with other therapeutically active compounds known in the art. Such processes may include mixing, granulating and compressing or dissolving the components suitable for the desired preparation. It will be appreciated that the form and characteristics of the pharmaceutically acceptable carrier or diluent will be dictated by the amount of active ingredient to be mixed, the route of administration, and other well-known variables. The carrier (s) should be &quot; acceptable &quot; in the sense that they are compatible with the other formulation ingredients and are not harmful to their recipients.

The pharmaceutical carrier used may be, for example, a solid or a liquid. Examples of solid carriers are lactose, white tea, sucrose, talc, gelatin, agar, pectin, gum arabic, masseum stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may comprise a delaying material well known in the art, such as glyceryl monostearate, or glyceryl distearate alone or a mixture of the wax and the glyceryl distearate.

A wide range of pharmaceutical forms can be used. That is, if a solid carrier is used, the preparation may be tableted, or it may be in powder or pellet form, or in hard gelatin capsules in the form of troches or lozenges. The amount of solid carrier will vary widely, but will preferably be from about 25 mg to about 1 g. If a liquid carrier is used, the formulation may be in the form of a syrup, an emulsion, a soft gelatin capsule, a sterile injectable solution (e.g. ampoule) or a non-aqueous liquid suspension.

The compounds of formula I may be administered topically, i. E. By non-pro-inflammatory administration. This involves applying the compound of formula I externally to the epidermis or nidus and injecting the compound into the ear, eye and nose so that the compound hardly enters the blood stream. Conversely, systemic administration refers to oral, intravenous, intraperitoneal, and intramuscular administration.

Suitable formulations for topical administration include liquid or semi-liquid preparations suitable for penetration of the area of inflammation through the skin, such as a dipping agent, lotion, cream, ointment or paste, and a dropping agent suitable for administration to the eye, ear or nose . The active ingredient, for topical administration, may comprise from 0.001% to 10%, such as from 1% to 2% by weight of the combination. However, it may comprise up to about 10% by weight of the formulation, preferably less than 5% by weight, more preferably from 0.1% to 1% by weight.

Lotions according to the present invention include those suitable for application to the skin or eyes. The ophthalmic lotion may optionally comprise a sterile aqueous solution containing a bactericidal agent and may be prepared by a method similar to that for the preparation of a drip agent. Lotions or coatings for application to the skin may also contain a formulation (e.g., alcohol or acetone) and / or a moisturizing agent (e.g., glycerol) or an oil (e. G., Castor oil or peanut oil) that speeds drying and cools the skin .

The cream, ointment or paste according to the invention is a semi-solid formulation of the active ingredient for external application. These may be prepared by mixing the active ingredient, either in fine or powder form, alone or as a solution or suspension in an aqueous or non-aqueous fluid, with an oily or non-inactive base by a suitable machine. The base may include hydrocarbons (e.g., hard, soft or liquid paraffin, glycerol, beeswax, metal soaps); Clot; Oils of natural origin such as almonds, corn, peanuts, castor or olive oil; Bovine bark or its derivatives or fatty acids such as stearic acid or oleic acid and alcohols such as propylene glycol or macrogels. The formulations may incorporate suitable surfactants, for example anionic, cationic or nonionic surfactants, such as sorbitan esters or polyoxyethylene derivatives thereof. Other ingredients such as natural gums, cellulose derivatives or suspending agents such as inorganic substances (e.g. silicic acid silica), and lanolin may also be included.

The dosage form according to the present invention may comprise a sterile aqueous or oily solution or suspension and may be prepared by dissolving the active ingredient in a suitable aqueous solution of the killed bactericide and / or fungicide and / or any suitable preservative, May be prepared by including an active agent. The resulting solution can then be sterilized by filtration, sterilized by transferring it to a suitable container, sealing and autoclaving or holding at 98-100 ° C for 30 minutes. Alternatively, the solution can be sterilized by filtration and transferred to the container by aseptic technique. Examples of suitable bactericides and fungicides for inclusion in the drip agent are phenyl mercury nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for the preparation of oily solutions are glycerol, dilute alcohol and propylene glycol.

The compounds of formula I may be administered parenterally, i. E., By intravenous, intramuscular, subcutaneous, intranasal, rectal, intravaginal or intraperitoneal administration. Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Dosage forms suitable for such administration can be prepared by conventional techniques. The compounds of formula I may also be administered by inhalation, i. E. Intranasal and oral inhalation administration. Dosage forms suitable for such administration, e. G. Aerosol formulations or metered dose inhalers, will be prepared by conventional techniques.

For all methods of use described herein for compounds of formula I, the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg / kg total body weight. The daily parenteral dosage regimen will be from about 0.001 to about 80 mg / kg total body weight. The daily daily dose regimen will be from 0.1 mg to 150 mg, preferably from 1 to 4 times, preferably 2 to 3 times per day. The daily inhalation dosage regimen will preferably be from about 0.01 mg / kg to about 1 mg / kg per day. Those skilled in the art will also appreciate that the optimal amount and interval of individual administration of a compound of Formula I or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition to be treated, the mode of administration, route and site of administration, and the particular patient to be treated, It will be appreciated that the conditions can be determined by conventional techniques. It will also be understood by those skilled in the art that the optimal route of treatment, i.e. the number of doses of a given compound of formula I or its pharmaceutically acceptable salt per day for a given number of days, can be ascertained by those skilled in the art using routine routes of treatment determination testing .

The present invention will now be described with reference to the following Biological Embodiments, which merely illustrate the invention and should not be construed as limiting the scope of the invention.

< Biological Example>

The IL-8 and Gro-alpha chemokine inhibitory effects of the compounds of the present invention were determined by in vitro analysis as follows.

Receptor binding assay:

[ ¹²⁵ I] IL-8 (human recombinant) with an activity of 2000 Ci / mmol was obtained from Amersham Corp., Arlington Heights, Ill. GRO-α was obtained from NEN (New England Nuclear). All other chemicals were of analytical grade. High levels of recombinant human IL-8 alpha and beta type receptors were expressed in chinese hamster ovary cells as previously described (Halles et al., Sicence, 1991, 253, 1278). Chiniz hamster ovary membranes were homogenized according to the protocol previously described (Howard et al., J. Biol. Chem., 249, pp. 2195-2205 (1974)) except that the homogenization buffer was replaced with 10 mM Tris- MgSO _4, 0.5mM EDTA. (ethylene-diaminetetraacetic acid), 1mM PMSF (α- toluenesulfonyl fluoride), 0.5㎎ / ℓ leupeptin, was changed to pH 7.5 membrane protein concentration of bovine serum albumin as a standard substance use was determined using Pierce Co. Needle (Pierce Co.) Microanalysis kits. all analyzes were performed in 96-well micro plate format. each reaction mixture was _{1.2mM MgSO 4, 0.1mM EDTA, 25mM} NaCl and 0.03 % 20mM bistrispropane and 0.4mM tris-HCl buffer containing CHAPS ^{(pH 8.0) 125 I IL-} 8 (0.25nM) or ¹²⁵ I GRO-α and IL-8Rα film 0.5㎍ / ㎖ or IL-8Rβ membranes in 1.0 Mu] g / ml. [0154] Further, preliminarily dissolved in DMSO to a final concentration of 0.01 nM to 100 [mu] M On the enemy a drug or compound was added. ¹²⁵ I-IL-8 was added to initiate the analysis by the addition. After 1 hours at room temperature, 1% of a glass fiber filter cut-off to the polyethylenimine /0.5% BSA mat (filtermat) Plates were harvested using a Tomtec 96-well harvester and washed three times with 25 mM NaCl, 10 mM Tris HCl, 1 mM MgSO ₄ , 0.5 mM EDTA, 0.03% CHAPS (pH 7.4) Recombinant IL-8R [alpha] or I-type receptors are also referred to herein as non-permissive receptors, and recombinant IL-8R [beta] or type II receptors are also referred to as permissive receptors.

All exemplary compounds of formula I shown in the synthetic chemical moieties (Examples 1-11) exhibited an IC ₅₀ of about 5 to about 100 nM in a model of tolerance of IL-8 receptor inhibition (IL-8?). (2-allyloxy-4-cyanophenyl) -N '- (2-bromophenyl) -N " -cyanoguanidine, which is a non-ionizable proton- It turned out.

Chemotoxicity analysis:

In vitro inhibition properties of these compounds are described in Current Protocols in Immunology, vol. I, Suppl. 1, Unit 6.12.3], as determined by neutrophil chemotaxis analysis. Neutrophils are described in Current Protocols in Immunology, Vol. I, Suppl. 1, Unit 7.23.1]. The chemoattractants IL-8, GRO- alpha, GRO- beta, GRO-y and NAP-2 were incubated at a concentration of 0.1-100 nM in a 48 well multiwell chamber (Neuro Probe, Cabinn, Chamber. The two chambers are separated by a 5 탆 polycarbonate filter. When testing the compounds of the present invention, they are mixed with cells (0.001-1000 nM) just prior to adding the cells to the upper chamber. The cultivation is carried out in a humidified incubator (about 37 ° C) containing 5% CO ₂ for about 45 to 90 minutes. At the end of the incubation, the polycarbonate membrane was removed and the top surface washed and stained using the Diff Quick dyeing protocol (Baxter Products, McGow Park, Ill., USA). Use a microscope to visually count the cells chemotically expressed on the chemokine. Generally, four zones are counted for each sample, and the number is averaged to obtain the average number of cells migrated. Each sample is tested in triplicate and each compound is repeated at least four times. No compound is added to any cell (positive control cell), and these cells exhibit the maximum chemotactic response of the cell. If voice control (unstimulated) is desired, no chemokine is added to the bottom chamber. The difference between positive control and negative control indicates the chemotactic activity of the cells.

Elastase Release Analysis:

The compounds of the present invention are tested for their ability to prevent the release of elastase from human neutrophils. Neutrophils are described in Current Protocols in Immunology Vol. I, Suppl. 1, Unit 7.23.1]. 0.88 × 10 ⁶ cells of PMN suspended in Ringer's solution (NaCl 118, KCl 4.56, NaHCO ₃ 25, KH ₂ PO ₄ 1.03, glucose 11.1, HEPES 5 mM, pH 7.4) were added to each well of a 96 well plate in a volume of 50 μl . To this plate is added 50 [mu] l of a test compound (0.001-1000 nM), 50 [mu] l volume (20 [mu] g / ml) cytochalasin B and 50 [ These cells are incubated (37 ° C, 5% CO ₂ , 95% RH) for 5 minutes and then IL-8, GROα, GROβ, GROγ or NAP-2 are added to a final concentration of 0.01 to 1000 nM. The reaction is allowed to proceed for 45 minutes, then the 96-well plate is centrifuged (800 x g, 5 minutes) and 100 μl of the supernatant is collected. This supernatant was added to a second 96-well plate and then diluted in phosphate-buffered saline with an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Zolla) is added. Immediately, the plate was placed in a fluorescent 96 well plate reader (Cytofluor 2350, Millipore, Bedford, Mass.) And analyzed according to Nakajima et al. Biol. Chem. 254 , 4027 (1979)]. The amount of elastase released from the PMN is calculated by measuring the rate of MeOSuc-Ala-Pro-Val-AMC degradation.

TNF-a in traumatic brain injury analysis

This assay provides an investigation of the expression of tumor necrosis factor mRNA in a specific brain region in response to experimentally induced lateral fluid-to-beat traumatic brain injury (TBI) in rats. (2.4 &lt; RTI ID = 0.0 &gt; atm) < / RTI &gt; side-by-side fluids - rinsed brain injury, or "sham" treatment (anesthesia and intact, n = 18). Animals were sacrificed by monkeys 1, 6 and 24 hours after injury, the brain was removed, and the left (injured) parietal cortex (LC), the corresponding area of the contralateral right cortex (RC). Tissue samples of the cortex (LA) adjacent to the injured vertebral cortex, the corresponding adjacent region (RA) of the right cortex, the left hippocampus (LH) and the right hippocampus (RH) are prepared. Total RNA is isolated, Northern blot hybridization is performed, and quantified against TNF- [alpha] positive control RNA (macrophages = 100%). Significant increases in TNF-α mRNA expression were observed in the hemispherical LH (104 ± 17% of positive control, p <0.05 compared to Siam), LC (105 ± 21%, p <0.05) (69 ± 8%, p <0.01). The increase in TNF-α mRNA expression was also observed at 6 h after injury (46 ± 8%, p <0.05), LC (30 ± 3%, p <0.01) and LA (32 ± 3%, p <0.01) And changes by 24 hours. In the contralateral hemisphere, the expression of TNF-α mRNA increased in RH (46 ± 2%, p <0.01), RC (4 ± 3%) and RA (28 ± 11%), RC (7 ± 5%), and RA (26 ± 6%, p <0.05) after 6 h, but not after 6 h. In animals without sham (intact surgery) or experimentation, no change in the expression of TNF-α mRNA is observed in any of the six brain regions of the hemisphere at any time. These results indicate that the transient expression of TNF-α mRNA after fluid-burning brain injury in vivo changes in specific brain regions including the brain regions of hemispheres without trauma. This post-traumatic change in gene expression of TNF-a is associated with both acute and regenerative responses to CNS trauma since TNF-a induces nerve growth factor (NGF) and promotes the release of other cytokines from activated astrocytes It plays an important role.

CNS damage model of IL-β mRNA

This analysis characterizes the area of the expression of interleukin-l [beta] (IL-l [beta]) mRNA in a specific brain area in response to fluid-to-labile traumatic brain injury (TBI). (2.4 &lt; RTI ID = 0.0 &gt; atm) < / RTI &gt; side-by-side fluids - Burning brain injury, or "Sham" treatment (anesthesia and intact surgery). The animals were sacrificed 1, 6 and 24 hours after injury and the brain was removed and the left cortical cortex (LC), the corresponding area of the contralateral right cortex (RC), the cortex (LA) adjacent to the damaged cortex, , The corresponding adjacent region (RA) of the right cortex, the left hippocampus (LH) and the right hippocampus (RH). Total RNA is isolated and Northern blot hybridization is performed and the amount of brain tissue IL-1 beta mRNA is presented as the relative activity (%) of IL-1 beta positive macrophage RNA added to the same gel. One hour after brain injury, a significant and significant increase in IL-1β mRNA expression was observed in the injured hemisphere LC (20.0 ± 0.7%, n = 6, p <0.05 compared to Siamese), LH (24.5 ± 0.9 (4.0 ± 0.4%, n = 6, p <0.05) and LH (5.0 ± 1.3%, p <0.05), respectively, To 6 hours after injury. In animals without Siam or untested, the expression of IL-1 beta mRNA is not observed in any individual brain area. These results indicate that the transient expression of IL-1? MRNA after TBI is regionally promoted in certain brain regions. This alteration of the region in cytokines, such as IL-1, plays a role in post-traumatic events.

All publications, including but not limited to patents and patent applications cited herein, are incorporated herein by reference in their entirety as if each individual article was specifically cited herein as being incorporated by reference.

The above description fully discloses the present invention including preferred embodiments of the present invention. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, the embodiments of the present application are for illustrative purposes only and are not to be construed as limiting the scope of the invention in any way. Embodiments of the present invention in which a monopoly or exclusive rights are claimed are limited as claimed.

Claims (8)

Comprising administering to a mammal in need thereof an effective amount of a compound of formula &lt; RTI ID = 0.0 &gt; (I) &lt; / RTI &gt; or a pharmaceutically acceptable salt thereof, wherein said malarial is selected from the group consisting of malaria, restenosis, angiogenesis, atherosclerosis, osteoporosis, Hematopoietic stem cell release, and diseases caused by respiratory viruses, herpes viruses, and hepatitis viruses (including but not limited to hepatitis B and hepatitis C virus), wherein the chemokine is selected from the group consisting of IL- Or beta receptor) mediated diseases. <Formula I> Wherein Z is cyano, OR ₁₁ , C (O) NR ₁₅ R ₁₆ , R ₁₈ , C (O) R ₁₁ , C (O) OR ₁₁ or S (O) ₂ R ₁₇ ; R ₁₃ and R ₁₄ are independently hydrogen, optionally substituted C _1-4 alkyl, or one of R ₁₃ and R ₁₄ may be optionally substituted aryl; v is 0 or an integer from 1 to 4; W is ; The E'-containing ring is (Wherein an asterisk indicates the point of attachment of the ring); W ₁ is ; E-include ring (Wherein an asterisk indicates the point of attachment of the ring); R is any functional group having an ionizable hydrogen having a pKa of 10 or less; R &lt; ₁ &gt; is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; (CR ₈ R ₈ ) _q S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heterocyclic, heterocyclic C _1-4 alkyl; Heteroaryl C _1-4 alkyloxy; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; _{(CR 8 R 8) q NR} 4 R 5; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{(CR 8 R 8) q C} (O) NR 4 R 5; _{(CR 8 R 8) q C} (O) NR 4 R 10; S (O) ₃ H; S (O) ₃ R ₈ ; _{(CR 8 R 8) q C} (O) R 11; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; _{(CR 8 R 8) q C} (O) OR 12; _{(CR 8 R 8) q OC} (O) R 11; (CR ₈ R ₈ ) _q NR ₄ C (O) R ₁₁ ; _{(CR 8 R 8) q NHS} (O) 2 R 19; _{(CR 8 R 8) q S} (O) , or selected from ₂ NR ₄ R _5; Or two R ₁ moieties may together form O- (CH ₂ ) _s O- or a 5- to 6-membered saturated or unsaturated ring wherein the aryl, heteroaryl and heterocyclic moieties may be optionally substituted; q is 0 or an integer from 1 to 10; t is 0 or an integer of 1 or 2; s is an integer from 1 to 3; R ₄ and R ₅ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Heterocyclic, heterocyclic C _1-4 alkyl, or R ₄ and R ₅ together with the nitrogen to which they are attached form a 5 to 7 membered ring optionally containing an additional heteroatom selected from oxygen, nitrogen or sulfur &Lt; / RTI &gt; Y is independently hydrogen; halogen; Nitro; Cyano; Halo substituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; Halo substituted C _1-10 alkoxy; Azide; (CR ₈ R ₈ ) _q S (O) _t R ₄ ; Hydroxy; HydroxyC _1-4 alkyl; Aryl; ArylC _1-4 alkyl; Aryloxy; Aryl C _1-4 alkyloxy; Heteroaryl; Heteroarylalkyl; Heteroaryl C _1-4 alkyloxy; Heterocyclic, heterocyclic C _1-4 alkyl; Aryl C _2-10 alkenyl; Heteroaryl C _2-10 alkenyl; Heterocyclic C _2-10 alkenyl; _{(CR 8 R 8) q NR} 4 R 5; C _2-10 alkenyl C (O) NR ₄ R ₅ ; _{(CR 8 R 8) q C} (O) NR 4 R 5; _{(CR 8 R 8) q C} (O) NR 4 R 10; S (O) ₃ H; S (O) ₃ R ₈ ; _{(CR 8 R 8) q C} (O) R 11; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) OR ₁₁ ; C (O) R ₁₁ ; _{(CR 8 R 8) q C} (O) OR 12; _{(CR 8 R 8) q OC} (O) R 11; (CR ₈ R ₈ ) _q NR ₄ C (O) R ₁₁ ; (CR ₈ R ₈ ) _q NHS (O) ₂ R _d , (CR ₈ R ₈ ) _q S (O) ₂ NR ₄ R ₅ , or two Y residues together form O- (CH ₂ ) _s O - or a 5 to 6 membered saturated or unsaturated ring wherein the aryl, heteroaryl and heterocyclic moieties may be optionally substituted; n is an integer from 1 to 3; m is an integer of 1 to 3; R _d is NR ₆ R ₇ , alkyl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl, heteroaryl, heteroaryl-C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, Heterocyclic C _1-4 alkyl, wherein the alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclic and heterocyclic alkyl rings may be optionally substituted; R ₆ and R ₇ are independently hydrogen or a C _1-4 alkyl group or R ₆ and R ₇ together with the nitrogen to which they are attached form a _5-7 membered heterocyclic ring optionally containing an additional heteroatom selected from oxygen, Form a ring; R ₈ is independently selected from hydrogen or C _1-4 alkyl; R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ ; R ₁₁ is selected from the group consisting of hydrogen, C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic or Optionally substituted heterocyclic C _1-4 alkyl; R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl; R ₁₅ and R ₁₆ are independently selected from the group consisting of hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl , Optionally substituted heterocyclic, optionally substituted heterocyclic C _1-4 alkyl, or R ₁₅ and R ₁₆ , together with the nitrogen to which they are attached, may optionally comprise a further heteroatom selected from oxygen, nitrogen or sulfur Lt; RTI ID = 0.0 &gt; 5-7 &lt; / RTI &gt; membered ring; R ₁₇ is C _1-4 alkyl, NR ₁₅ R ₁₆ , OR ₁₁ , optionally substituted aryl, optionally substituted arylC _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC _1-4 alkyl, optionally Substituted heterocyclic or optionally substituted heterocyclic C _1-4 alkyl; R ₁₈ is optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 alkyl, optionally substituted heterocyclic Or optionally substituted heterocyclic C _1-4 alkyl; R ₁₉ are all optionally C _1-4 alkyl which may be substituted, aryl, arylalkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl. The method of claim 1, wherein the pKa of the ionizable hydrogen is from 3 to 10. The method of claim 2, wherein, R is hydroxy, carboxylic acid, _{thiol, SR 2, OR 2, NH} -C (O) R a, C (O) NR 6 'R 7', NHS (O) 2 R b , S (O) ₂ NHR _c , NHC (X) NHR _b or tetrazolyl, Wherein R &lt; ₂ &gt; is a substituted aryl, heteroaryl or heterocyclic group having a functional group that provides an ionizable hydrogen whose ring has a pKa of 10 or less; R _{6 '} and R _7' are independently selected from the group consisting of hydrogen, C _1-4 alkyl, aryl, arylC _1-4 alkyl, arylC _2-4 alkenyl, heteroaryl, heteroarylC _1-4 alkyl, heteroarylC _2-4 Alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-4 alkenyl, all of which are independently halogen; Nitro; Halo substituted C _1-4 alkyl, such as CF ₃ ; C _1-4 alkyl, such as methyl; C _1-4 alkoxy, such as methoxy; NR ₉ C (O) R _a ; _{C (O) NR 6 R 7} ; S (O) ₃ H; Or C (O) OC _1-4 alkyl, with the proviso that only one of R _{6 '} and R _7' is hydrogen and not all are hydrogen, R _a is aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic or heterocyclic C _1-4 alkyl group which may all be optionally substituted; R _b are each independently halogen; Nitro; Halo substituted C _1-4 alkyl; C _1-4 alkyl; C _1-4 alkoxy; NR ₉ C (O) R _a ; _{C (O) NR 6 R 7} ; S (O) ₃ H, or C (O) OC _1-4 alkyl with from 1 to 3 times any NR ₆ R _7, alkyl, aryl, aryl C _1-4 alkyl, aryl C _2-4 alkenyl which may be substituted, Heteroaryl C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl, heterocyclic C _2-4 alkenyl, camphor; R ₉ is hydrogen or C _1-4 alkyl; R _c is independently selected from the group consisting of halogen, nitro, halo substituted C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkoxy, NR ₉ C (O) R _a , C (O) NR ₆ R ₇ , S Aryl, arylC _1-4 alkyl, arylC _2-4 alkenyl, heteroaryl, heteroarylC (O) ₃ H or C ₁ -C ₄ alkyl optionally substituted one to three times by C _1-4 alkyl, heteroaryl C _2-4 alkenyl, heterocyclic, heterocyclic C _1-4 alkyl or heterocyclic C _2-4 alkenyl group; And X &lt; _{2 &gt;} is oxygen or sulfur. The compound of claim 3, wherein R ₂ is selected from the group consisting of halogen, nitro, halo substituted C _1-10 alkyl, C _1-10 alkyl, C _1-10 alkoxy, hydroxy, SH, C (O) NR _{6 '} R _7' Wherein said heterocyclic ring is optionally substituted one to three times with NH-C (O) R _a , NHS (O) R _b , S (O) NR ₆ R ₇ , C (O) OR ₈ or tetrazolyl ring. The method of claim 3, wherein R is OH, -NHS (O) ₂ R _b or C (O) OH. The method of claim 1, wherein, R ₁ is halogen, cyano, _{nitro, CF 3, C (O)} NR 4 R 5, alkenyl _{C (O) NR 4 R 5} , C (O) R 4 R 10, alkenyl C (O) OR ₁₂ , heteroaryl, heteroarylalkyl, heteroarylalkenyl or S (O) NR ₄ R ₅ . The compound of claim 1, wherein Y is selected from the group _consisting of halogen, C _1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylenedioxy, NR ₄ R ₅ , thioC _1-4 alkyl, thioaryl, halo substituted alkoxy , Optionally substituted C _1-4 alkyl, hydroxyalkyl. The method according to claim 1, wherein R is OH, SH or NHS (O) _s R _b , wherein R ₁ is substituted in the 3-position, 4-position or in the 3,4-position by an electron withdrawing group .