JP2001512096A - IL-8 receptor antagonist - Google Patents

Abstract

  (57) [Summary] The present invention relates to novel phenylureas useful in the treatment of conditions mediated by the chemokine, interleukin-8 (IL-8).

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a novel group of phenylurea compounds, a method for producing the same, IL-8, GROα,
It relates to its use in the treatment of GROβ, GROγ, NAP-2 and ENA-78 mediated diseases, and to pharmaceutical compositions for use in such treatment.

BACKGROUND OF THE INVENTION Interleukin-8 (IL-8) includes neutrophil attractants / activating proteins
Many different names have been applied, such as 1 (NAP-1), monocyte-derived neutrophil chemoattractant (MDNCF), neutrophil activator (NAF) and T-cell lymphocyte chemoattractant . Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is exposed by the majority of nucleated cells including macrophages, fibroblasts, endothelial cells and epithelial cells exposed to TNF, IL-1α, IL-1β or LPS, and to chemotactic factors such as LPS or FMLP. If produced, it is produced by neutrophils themselves. 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 , 146
7 (1989) and J. Biol. Chem. 264 , 10621 (1989); Cassatella et al, J. Immunol. 148 , 3216 (1992).

[0003] GROα, GROβ, GROγ and NAP-2 also belong to the chemokine α family. Like IL-8, these chemokines have also been referred to by various names. For example, GROα, β, γ are MGSAα, β, and γ, respectively.
(Melanoma growth promoting activity). Richmond et al, J. Cell Physiology 1
29, 375 (1986) and Chang et al, J. Immunol 148, 451 (1992). All of the α-family chemokines that have an ELR motif immediately preceding the CXC motif bind to the IL-8B receptor.

[0004] IL-8, GROα, GROβ, GROγ, NAP-2 and ENA-78 stimulate many functions in vitro. They all showed to have chemoattractant properties on neutrophils, whereas IL-8 and GROα showed T-lymphocyte and basophil chemotactic activity. In addition, IL-8 can induce histamine release from basophils from both normal and atopic individuals. G
RO-α and IL-8 can further induce lysosomal enzyme release from neutrophils and respiratory burst. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b / CD18) on neutrophils without de novo protein synthesis. This contributes to increased attachment of neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. I
Because L-8, GROα, GROβ, GROγ and NAP-2 promote neutrophil accumulation and activation, these chemokines are useful in a wide range of acute and chronic inflammatory diseases, including psoriasis and rheumatoid arthritis. Was involved. Baggiolini et
al, FEBS Lett. 307 , 97 (1992); Miller et al, Crit. Rev. Immunol. 12 , 17,
(1992); Oppenheim et al, Annu. Rev. Immunol. 9 , 617 (1991); Seitz et al.
87 , 463 (1991); Miller et al., Am. Rev. Respir. Dis. 146 , 427 (1992); Donnely et al., Lancet 341 , 643 (1993). In addition, ELR chemokines (containing an amino acid ELR motif immediately before the CXC motif)
He was also involved in hemostasis. Strieter et al, Science 258, 1798 (1992).

[0005] In vitro, IL-8, GROα, GROβ, GROγ and NAP-2
Seven-transmembrane, neutrophil shape change, chemotaxis by binding to and activating G-protein coupled family receptors, particularly by binding to IL-8 receptors, most notably B-receptors. Induces chemotaxis, granule release and respiratory burst. Thomas et al., J. Biol. Chem. 266 , 14839 (1991); and Holmes et al., Science 253 , 1278 (1991). There is precedent for the development of non-peptide small molecule antagonists to this receptor family member. For reference, R Freidinger in: see Progress in Drug Researc h, Vol 40 , pp 33-98, Birkhauser Verlag, Basel 1993.... Therefore,
The IL-8 receptor represents a promising target for the development of new anti-inflammatory drugs.

[0006] Two high affinity human IL-8 receptors (77% homology) were characterized as follows: IL-8Rα, which binds only IL-8 with high affinity, as well as IL-8Rα. And GRO-α, GROβ, GROγ and NAP-
IL-8Rβ with high affinity for 2. Holmes et al., Supra; Murphy et
al., Science 253 , 1280 (1991); Lee et al., J. Biol. Chem . 267, 16283 (1
992); LaRosa et al., J. Biol. Chem. 267 , 25402 (1992); and Gayle et.
al., J. Biol. Chem. 268 , 7283 (1993).

[0007] There remains a need in the art for compounds that have the ability to bind to IL-8α or β receptors for therapy. Thus, a condition associated with increased IL-8 production (which is responsible for chemotaxis of neutrophils and T-cell subsets to sites of inflammation) is obtained with compounds that are inhibitors of IL-8 receptor binding. There will be places.

SUMMARY OF THE INVENTION The present invention is a method of treating a chemokine-mediated disease, wherein the chemokine binds to an IL-8α or β receptor, comprising an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. A method comprising administering to the subject. In particular, the chemokine is IL-8. The present invention also provides a method of inhibiting IL-8 binding to its receptor in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of formula (I). It also relates to the methods involved.

The compounds of formula (I) useful in the present invention have the structural formula:

Embedded imageWherein X is oxygen or sulfur; R is (CR₈R₈)_rC (O)_TwoH, (CR₈R₈)_rNH-C (O) R_a, (CR₈R₈)_rC (
O) NR_{6 '}R_{7 '}, (CR₈R₈)_rNHS (O)_TwoR_b, (CR₈R₈)_rS (O)_TwoNHR_c, (
CR₈R₈)_rNHC (X_Two) NHR_bOr a tetrazolyl ring; X_TwoIs oxygen or sulfur; R₁Is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10A
Lucoxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Al
Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al
Heteroaryl; Heteroarylalkyl; Heterocycle, Heterocycle C_1-4 Alkyl; heteroaryl C_1-4Alkyloxy; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_Four R_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R ₈ )_qC (O) NR_FourR_TenS (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁(CR₈R₈)_qC (O) OR₁₂; (CR₈ R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR_{1 7} ; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveOr two R₁Groups together
O- (CH_Two)_sO- or a 5- or 6-membered saturated or unsaturated ring may be formed.
Wherein the aryl, heteroaryl and heterocyclic containing groups are optionally substituted
Provided that the 2-position of the phenyl ring has an pKa of 3 to 10.
N is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; q is 0, or a value of 1 to 10 R is 0, or an integer having a value of 1 to 4; s is an integer having a value of 1 to 3; t is 0, or an integer having a value of 1 or 2 V is an integer having a value of 1-4; R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, optionally substituted aryl, optionally substituted
Good aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4Alkyl, heterocycle, heterocycle C_1-4Alkyl or R_FourAnd R_FiveRepresents an additional heteroatom, optionally selected from O / N / S, together with the nitrogen to which they are attached.
Forming a 5- to 7-membered ring which may contain₆And R₇Is, independently, hydrogen
Or C_1-4An alkyl group or R₆And R₇Together with the nitrogen to which they are attached, optionally an additional selected from oxygen, nitrogen or sulfur
Forming a 5- to 7-membered ring optionally containing a heteroatom;_{6 '}And R_{7 '}Is independently hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C _1-4 Alkyl, heteroaryl C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl and heterocyclic C_2-4An alkenyl group, provided that R_{6 '}And R_{7 '}Is hydrogen, but not both; Y is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl
C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Al
Coxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Archi
Aryl; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Archi
Heterooxy; heteroarylalkyl; heteroaryl C_1-4Alkyloxy; heterocycle, heterocycle C_1-4Alkyl; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR _Five C_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈) _q C (O) NR_FourR_TenS (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (
O) R₁₁C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR ₁₂ ; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNH
S (O)_TwoR_d; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveOr two Y
The groups together form O- (CH_Two)_sForming an O- or 5- or 6-membered saturated or unsaturated ring
Wherein the aryl, heteroaryl and heterocyclic containing groups are optionally
R may be more substituted;₈Is independently hydrogen or C_1-4R selected from alkyl;_TenIs C_1-10Alkyl C (O)_TwoR₈R₁₁Is hydrogen, C_1-4Alkyl, optionally substituted aryl, optionally substituted
Aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4An alkyl, an optionally substituted heterocycle, or an optionally substituted heterocycle C_{1- Four} R is alkyl;₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl,
Or optionally substituted arylalkyl; R₁₃And R₁₄Is independently hydrogen, optionally substituted C_1-4 Alkyl or R₁₃And R₁₄One of which is optionally substituted
May be aryl; R₁₇Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4Alkyl
Wherein the aryl, heteroaryl and heterocycle are all optionally substituted
May be; R_aIs an alkyl, aryl, aryl C_1-4Alkyl, heteroaryl, hete
Lower aryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4An alkyl group,
Wherein all of these groups may be optionally substituted;_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C _2-4 Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl
Le C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl, heterocyclic C_2-4An alkenyl group or camphor wherein all of these groups are optionally substituted.
May be; R_cIs an alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A
Lucenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4With an alkenyl group
Wherein all of these groups are optionally substituted; R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl-C_1-4Alkyl, heteroaryl C_2-4 Alkenyl, heterocycle, heterocycle C_1-4Alkyl, wherein the aryl, heteroaryl, and heterocycle-containing ring are optionally substituted;

Embedded image An E-containing ring is

Embedded image (Wherein the asterisk * indicates the position of attachment of the ring); R ₂₀ is W ₁ , an optionally substituted heteroaryl, an optionally substituted C _{5 -8} cycloalkyl, optionally substituted C _1-10 alkyl, optionally substituted C _2-10 alkenyl, or optionally substituted C _2-10 alkynyl; W ₁ is

Embedded image An E′-containing ring is

Embedded image (Wherein the asterisk * indicates the bonding position of the ring), if desired.] Or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula (I) may also be used for veterinary treatment of non-human mammals requiring inhibition of IL-8 or another chemokine that binds to IL-8 α and β receptors. Good. Chemokine-mediated diseases for therapeutic or prophylactic treatment of animals include conditions as described in the methods of treatment section herein.

In the compound of formula (I), R is (CR ₈ R ₈ ) _r C (O) ₂ H, (CR ₈ R ₈ ) _r NH—C (O) R _a , (CR ₈ R ₈ ) _r C (O) NR _{6 '} R _{7 '} , (CR ₈ R ₈ ) _r NHS (O) ₂ R _b , (C
R ₈ R ₈ ) _r S (O) ₂ NHR _c , (CR ₈ R ₈ ) _r NHC (X ₂ ) NHR _b , or a tetrazolyl ring. Each of these groups may be directly attached to the ring at position 3 or may be attached to position 3 of the ring via a linker (CR ₈ R ₈ ) _r . Suitably, r is 0 or an integer from 1 to 4, preferably 0. Suitably, X ₂ is oxygen or sulfur, preferably oxygen, and r is 0 or an integer having a value of 1-4.

Suitably, R₆And R₇Is independently hydrogen or C_1-4An alkyl group or R₆And R₇Together with the nitrogen to which they are attached form 5-7
To form a membered ring, wherein said ring optionally has an additional member selected from oxygen, nitrogen or sulfur.
It may contain a hetero atom. Suitably, R_{6 '}And R_{7 '}Is hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C _1-4 Alkyl, heteroaryl C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4An alkenyl group, provided that R_{6 '}And R_{7 '}Is hydrogen, but R_{6 '}And R_{7 '}Are not both hydrogen. these
All groups are halogen; nitro; halo substituted C_1-4Alkyl, CF_ThreeEtc .; C_1-4 Alkyl, methyl, etc .; C_1-4Alkoxy, methoxy, etc .; NR₉C (O) R_a; C (
O) NR₆R₇S (O)_ThreeH; or C (O) OC_1-4It may optionally be independently substituted one to three times by an alkyl group.

Suitably, R _a is an alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic, or heterocyclic C _1-4 alkyl group; All groups may be optionally substituted as defined below.

Suitably, R_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl,
Aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, f
Teloaryl C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C _2-4 An alkenyl group or a camphor wherein the alkyl, aryl, heteroaryl and heterocyclic containing groups are all optionally halogen; nitro;
Halo-substituted C_1-4Alkyl, CF_ThreeEtc .; C_1-4Alkyl, methyl, etc .; C_1-4Arco
Xy, methoxy, etc .; NR₉C (O) R_aC (O) NR₆R₇S (O)_ThreeH; or C (
O) OC_1-4It may be independently substituted one to three times by alkyl. R_bIs preferably phenyl, benzyl, or still optionally substituted
It is. R_bIs a heteroaryl ring, optionally substituted thiazole, optionally substituted thienyl, or
It is preferably an optionally substituted quinolinyl ring. Suitably, R₉Is hydrogen or C_1-4Alkyl, preferably hydrogen
. R₉Is the group NR₉C (O) R_aIf inside, R_aIs preferably an alkyl such as methyl
It is a kill group.

Suitably, R _c is hydrogen, alkyl, aryl, aryl C _1-4 alkyl, aryl C _1-4 alkenyl, heteroaryl, heteroaryl C _1-4 alkyl, heteroaryl C _1-4 alkenyl, A heterocycle, or a heterocycle C _1-4 alkyl, or a heterocycle C _1-4 alkenyl group, all of which are optionally halogen, nitro, halo-substituted C _1-4 alkyl, C _1-4 alkyl, C _1-4 alkyl, Independently of _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
It may be substituted three times. Preferably, R _c is an optionally substituted phenyl.

Suitably, W is

Embedded image It is.

Suitably, the E-containing ring is

Embedded image (In the formula, an asterisk * indicates a bonding position of the ring.)

[0018] In compounds of formula (I), suitably, R ₁ is independently hydrogen, halogen, two Toro; cyano; halosubstituted C _1-10 alkyl, such CF _3; C _1-10 alkyl, methyl, ethyl, isopropyl or n- propyl; C _2-10 alkenyl; C _1-10 alkoxy, such as methoxy or ethoxy; halosubstituted C _1-10 alkoxy, trifluoromethoxy and the like; azide; (CR ₈ R _{8) q} S (O) _t R ₄ ; hydroxy; hydroxy C _1-4 alkyl, methanol or ethanol; aryl, phenyl or naphthyl; aryl C _1-4 alkyl, benzyl; aryloxy, phenoxy; aryl C _{1- 4} alkyloxy, benzyloxy, etc .; heteroaryl; heteroarylalkyl; heteroaryl C _1-4 alkyloxy; aryl C _2-10 alkyl 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 R 8, S (O) 3 H , _{etc.; (C R 8 R 8)} q C (O) R ₁₁ ; C _2-10 alkenyl C (O) R ₁₁ ; C _2-10 alkenyl C (O) O
R 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 ₁₇ ; (CR ₈ R ₈ ) _q S (O) ₂ NR ₄ R ₅ or two R ₁ groups together, O- (CH _{2) s} O- or 5-6 membered saturated or may form an unsaturated ring. The aryl, heteroaryl, and heterocycle-containing groups may all be optionally substituted as defined below.

Suitably, t is an integer having a value of 0, 1 or 2. Suitably, s is an integer having a value from 1 to 3. Suitably, q is 0 or an integer having a value from 1 to 10. When R ₁ forms a dioxy bond, s is preferably 1. If R ₁ forms an additional saturated or unsaturated ring, it is preferably a 6-membered ring resulting in a naphthylene ring system. These saturated and unsaturated ring systems may be optionally substituted independently 1-3 times with another R ₁ group as defined above.

Suitably, R ₄ and R ₅ are independently hydrogen, optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted An optionally substituted aryl C _1-4 alkyl, an optionally substituted heteroaryl, an optionally substituted heteroaryl C _1-4 alkyl, a heterocycle, or a heterocyclic C _1-4 alkyl. Or R ₄ and R ₅ , together with the nitrogen to which they are attached, may optionally contain an additional heteroatom selected from O / N / S Form a ring.

R ₈ is suitably independently selected from hydrogen or C _1-4 alkyl. R ₁₀ is suitably a CH ₂ C (O) ₂ H or CH ₂ C (O) C _1-10 A, such as ₂ CH ₃ alkyl C (O) ₂ R _8. R ₁₁ is suitably independently 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 ₁₇ is suitably C _1-4 alkyl, aryl, arylalkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocycle, or heterocycle C _1-4 alkyl, wherein aryl, hetero All aryls and heterocycles may be optionally substituted.

Preferably, R₁Is halogen, cyano, nitro, CF_Three, C (O) NR_FourR_Five,
Lucenyl C (O) NR_FourR_Five, C (O) R_FourR_Ten, Alkenyl C (O) OR₁₂, Heteroaryl, heteroarylalkyl, heteroarylalkenyl or S (O) NR _Four R_FiveAnd preferably R_FourAnd R_FiveAre both hydrogen or R_Four And R_FiveIs phenyl. R₁Preferred ring substitutions for groups are
At position 4 of the ring.

When R is (CR ₈ R ₈ ) _r OH, (CR ₈ R ₈ ) _r SH or (CR ₈ R ₈ ) _r NHS (O) _{2 Rb} , R ₁ is preferably in position 4 It is substituted or disubstituted at the 2,4-position. Preferably, the R ₁ substituent is an electron withdrawing group such as nitro, halogen, cyano, trifluoromethyl or C (O) NR ₄ R ₅ . When R is a carboxylic acid, R ₁ is preferably hydrogen or R ₁ is preferably substituted at the 4-position, more preferably substituted by trifluoromethyl or chloro. I have.

In the compounds of formula (I), suitably, R ₁₃ and R ₁₄ are independently hydrogen or optionally substituted, which may be straight or branched as defined herein. Is an optionally substituted C _1-4 alkyl, or one of R ₁₃ and R ₁₄ is an optionally substituted aryl.

When R ₁₃ and R ₁₄ are optionally substituted alkyl, the alkyl group is halogen; halo-substituted C _1-4 alkyl, trifluoromethyl and the like; hydroxy; hydroxy C _1-4 alkyl 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 , C _1-4 alkoxy; Or may be independently substituted 1-3 times by C (O) OR ₈ . Suitably, v is 0 or an integer having a value of 1-4.

Suitably, Y is independently hydrogen; halogen; nitro; cyano; halo-substituted C_{1- Ten} Alkyl; C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo substituted
C_1-10Alkoxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl; aryl; aryl C_1-4Alkyl; aryloxy; aryl
C_1-4Alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C_1-4Alkyloxy; heterocycle, heterocycle C_1-4Alkyl; aryl C_2-10Al
Kenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R ₈ )_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five;
(CR₈R₈)_qC (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈, S (O)_ThreeH, etc .; (CR₈ R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) OR_{1 1} ; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (
O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR_d; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from
Or the two Y groups are taken together to form O- (CH_Two)_sO- or 5-6 members
It may form a saturated or unsaturated ring. Aryl, heteroaryl and hetero
All ring-containing groups may be optionally substituted.

When Y forms a dioxy bond, s is preferably 1. If Y forms an additional unsaturated ring, it is preferably a 6-membered ring resulting in a naphthylene ring system. These saturated and unsaturated ring systems may be substituted one to three times by another Y group as defined above,
It may be optionally substituted.

Suitably, R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C _2-4 Alkenyl, heteroaryl, heteroaryl-C_1-4Alkyl, hetero ant
C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4An alkenyl group, wherein the aryl, heteroaryl and heterocyclic-containing groups are
All may be optionally substituted as defined herein.

Preferably, Y is halogen, C _1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylenedioxy, NR ₄ R ₅ , Thio C _1-4 alkyl, thioaryl, halo-substituted alkoxy, optionally substituted C _1-4 alkyl or hydroxyalkyl. More preferably, Y is monosubstituted halogen, disubstituted halogen, monosubstituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl or alkyl. More preferably, these groups are mono- or di-substituted at the 2 'or 2', 3 'positions of the phenyl ring.

Y may be substituted at any of the five ring positions, but preferably, when R is (CR ₈ R ₈ ) _r C (O) ₂ H, Y is preferably 2 It is monosubstituted at the 'or 3' position and the 4 'position is preferably unsubstituted. When the ring is disubstituted, when R is (CR ₈ R ₈ ) _r C (O) ₂ H, the substituent is preferably at the 2 ′ or 3 ′ position of the monocyclic ring . R ₁ and Y may both be hydrogen, but it is preferred that at least one of the rings is substituted, more preferably both rings are substituted.

In the compounds of formula (I), X is suitably oxygen or sulfur, preferably oxygen. The E and E 'rings, indicated by their point of attachment by an asterisk (*), may optionally be present. If this is not present, the ring is a phenyl group substituted by the R ₁ and Y groups as described. Rings E and E ′ may be substituted by R ₁ and Y groups in any of the saturated or unsaturated rings, and in the present specification, those substituted only in the unsaturated ring (s) may be substituted. Show.

In the compounds of formula (I), R₂₀Is W₁An optionally substituted heteroaryl, an optionally substituted C_5-8Cycloalkyl, optionally substituted C_1-10Alkyl, optionally substituted C _2-10 Alkenyl or optionally substituted C_2-10With alkynyl
is there. R₂₀Is optionally substituted C_5-8If cycloalkyl, the ring is (Y) as defined above_nMay be substituted.

When R ₂₀ is optionally substituted C _1-10 alkyl, optionally substituted C _2-10 alkenyl or optionally substituted C _2-10 alkynyl these groups, halogen, nitro, cyano, halosubstituted C _1-10 alkyl, such as trifluoromethyl; C _1-10 alkoxy; halosubstituted C _{1-10 alkoxy; S (O) t R 4} ; hydroxy; hydroxy C _1-4 alkyl ;; Ariruoki sheet; aryl C _1-4 alkyloxy; heteroaryloxy; heteroaryl C _{1 -4} alkyloxy; heterocycle, heterocycle C _1-4 alkyl; heterocyclic-oxy; heterocycle C _{1 -4} alkyloxy; NR ₄ R ₅ ; C (O) NR ₄ R ₅ ; C (O) NR ₄ R ₁₀ ; S (O) ₃ H; S
_{(O) 3 R 8; C} (O) R 11; C (O) OR 12; OC (O) R 11; or by NR ₄ C (O) R ₁₁ substituents, 1 or more, independently optionally It may be.

When R ₂₀ is optionally substituted C _2-10 alkenyl or optionally substituted C _2-10 alkynyl, these groups may also be substituted in addition to those described above. _Optionally substituted with an aryl, aryl C _1-4 alkyl, heteroaryl or heteroaryl C _1-4 alkyl, wherein the aryl and heteroaryl containing rings are optionally substituted. May be.

Suitably, W ₁ is

Embedded image It is.

Suitably, the E′-containing ring is

Embedded image Selected as desired.

In the compounds of formula (I), when R ₂₀ is a heteroaryl (HET) ring, this is suitably a heteroaryl ring or ring system. If the HET group is a multi-ring system, the ring containing the heteroatom need not be directly attached to the urea group or (CR ₁₃ R ₁₄ ) _v . All rings in this ring system may be optionally substituted by (Y _(n) ) as defined above. Preferably, the HET group is pyridyl,
-Or 4-pyridyl. If the ring is a polycyclic system, it is preferably a benzimidazole, dibenzothiophene, or indole ring. Other heterocycles of the present invention include, but are not limited to, thiophene, furan, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline, quinazolinyl, pyridine, oxazole, thiazole, thiadiazole, triazole or imidazole.

Preferably, R₂₀Is an optionally substituted phenyl, allyl, C _1-10 Alkyl, ethoxycarbonylethyl, dimethylacetal, 2-methoxy
An isopropyl or 2-methoxyethyl group.

Representative compounds of formula (I) include: N- (3-carboxyphenyl) -N ′-(2-bromophenyl) urea N- (3-carboxymethylphenyl) -N ′-(2- Bromophenyl) urea N- (3-carboxymethylphenyl) -N '-(2,3-dichlorophenyl) urea N- (3-carboxyphenyl) -N'-(2,3-dichlorophenyl) urea N- [3- (2-carboxyethyl) phenyl] -N '-(2,3-dichlorophenyl) urea N- (2,4-dichloro-3-carboxy) -N'-(2-bromophenyl) urea N- (4-chloro -3-carboxyphenyl) -N '-(2-bromophenyl) urea N- (4-chloro-3-carboxyphenyl) N'-(2,3-dichlorophenyl) urea N- (4-chloro-3-carboxy) Phenyl) -N- (3-chlorophenyl) urea:
Or a pharmaceutically acceptable salt thereof.

As used herein, “optionally substituted”, unless otherwise defined, such as halogen, fluorine, chlorine, bromine or iodine; hydroxy;
Hydroxy-substituted C _1-10 alkyl; C _1-10 alkoxy, methoxy or ethoxy and the like; S (O) _{m ′} C _1-10 alkyl, wherein m ′ is 0, 1 or 2, methylthio, methylsulfinyl or Methyl, sulfonyl, etc .; amino, mono- and di-substituted amino, NR ₄ R ₅ group, etc .; NHC (O) R ₄ ; C (O) NR ₄ R ₅ ; C (O) OH; S (O
) ₂ NR ₄ R ₅ ; NHS (O) ₂ R ₂ , C _1-10 alkyl, methyl, ethyl, propyl, isopropyl or t-butyl, etc .; halo-substituted C _1-10 alkyl, CF ₃ etc .; Optionally substituted aryl, phenyl or the like, or optionally substituted arylalkyl, benzyl or phenethyl, an optionally substituted heterocycle, an optionally substituted heterocyclic alkyl, Refers to groups such as optionally substituted heteroaryl, optionally substituted heteroarylalkyl, etc., wherein these aryl, heteroaryl or heterocyclic groups are halogen; hydroxy; hydroxy-substituted Alkyl; C _1-10 alkoxy; S (O) _{m ′} C _1-10 alkyl; amino, mono & di-C _1-4 alkyl-substituted amino, NR ₄ R ₅ group and the like; C _1-10 alkyl, or halo-substituted C _1-10 alkyl, CF _{3 and the} like may be substituted once or twice.

R ₂ is suitably C _1-4 alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocycle, or heterocycle C _1-4 alkyl. .

Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, acetic, malic, tartaric, citric, Basic salts of inorganic and organic acids such as lactic, oxalic, succinic, fumaric, maleic, benzoic, salicylic, phenylacetic and mandelic acids are included. In addition, pharmaceutically acceptable salts of the compounds of formula (I) may also be formed with pharmaceutically acceptable cations, for example when the substituent contains a carboxy group. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali cations, alkaline earth cations, ammonium cations and quaternary ammonium cations.

The following terms, as used herein, mean the following: "Halo" is all halogens, ie, represents chloro, fluoro, bromo and iodo. “C _1-10 alkyl” or “alkyl” represents both straight-chain and branched-chain groups having 1 to 10 carbon atoms and is not limited, unless the chain length is particularly limited. Is methyl, ethyl, n-propyl, iso-propyl, n-butyl,
sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like. “Cycloalkyl” is used herein to represent a cyclic group, preferably of 3 to 8 carbon atoms, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.

“Alkenyl” as used herein means two to two carbon atoms unless the chain length is limited.
Used to represent ten linear or branched groups and is not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2 -Butenyl and the like. -"Aryl" represents phenyl and naphthyl. “Heteroaryl” (alone or in any combination such as “heteroaryloxy” or “heteroarylalkyl”) includes, but is not limited to, pyrrole, pyrazole, furan, thiophene One or more heterocycles wherein one or more rings are selected from the group consisting of N, O or S, such as quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole. Represents a 5- to 10-membered aromatic ring system containing atoms.

“Heterocycle” (alone or in any combination such as “heterocyclealkyl”) includes, but is not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran Or a saturated or partially unsaturated 4- to 10-membered ring system containing one or more heteroatoms selected from the group consisting of N, O or S, such as imidazolidine. “Arylalkyl” or “heteroarylalkyl” or “heterocyclic alkyl” as used herein, unless otherwise defined, aryl as defined herein;
Used to represent C _1-10 alkyl as defined above attached to a heteroaryl or heterocyclic group.

“Sulfinyl” represents the oxide S (O) of the corresponding sulfide, “thio” represents the sulfide, and “sulfonyl” represents a fully oxidized S (O) ₂ group. The term “two R ₁ groups (or two Y groups) may together form a 5- or 6-membered saturated or unsaturated ring” is used herein to refer to C ₆ cycloalkenyl That is, to form a 6-membered partially unsaturated ring such as hexene, or a naphthalene ring system having a C ₅ cycloalkenyl group such as a cyclopentene ring or a phenyl group.

Preparation Methods The compounds of formula (I) are obtained by using synthetic methods, some of which are described in the following schemes. The syntheses shown in these schemes, using any suitably protected substituents, are compatible with the reactions outlined herein,
It is applicable to the preparation of compounds of formula (I) having various R, R ₁ and aryl groups which react. Then, in these cases, the following deprotection gives compounds having the properties generally described. Once the urea nucleus is established, other compounds of these formulas are prepared by applying standard techniques for functional group interconversion well known in the art. The scheme is shown where W and R ₂₀ are phenyl, for illustration purposes only.

The desired aniline 2-Scheme-1 can be synthesized by reduction of the corresponding nitro, if not commercially available. This reduction can be carried out with a number of reducing agents such as hydrogen and tin chloride in a polar solvent such as palladium on carbon or DMF or ethyl acetate. This aniline (2-Scheme 1) is then added to DMF, D
It can be condensed with commercially available isocyanates in aprotic solvents such as MSO or toluene.

[0050]

Embedded image Scheme 1 R = CH ₂ CH ₂ COOH, COOH, CH ₂ COOH a) H ₂ , Pd / Cb) PhCNO

Alternatively, the desired compound can be synthesized by protecting the carboxylic acid with a condition well known in the art, such as diazomethane, to form the methyl ester. This compound can then be reduced with a number of reducing agents, such as tin chloride in hydrogen and a catalytic solvent such as palladium on carbon or DMF or ethyl acetate. Condensation with a phosgene equivalent such as di or triphosgene in the presence of a base such as triethylamine or bicarbonate to form the isocyanate 4-Scheme- 2. This compound is then reacted with the desired commercially available aniline. The carboxylic acid is then replaced with THF /
In a polar solvent such as water, deprotect under standard conditions in the art such as metal hydroxide,
It can then be acidified with an acid such as HCl to form 3, Scheme 2.

[0052]

Embedded image R = CH ₂ CH ₂ COOH, COOH or CH ₂ COOH; protected R (where R = CH ₂ CH ₂ COOMe, COOMe or CH ₂ COOMe) a) CH ₂ N ₂ , ether b) H ₂ , 5 % Pd / C c) Triphosgene, Et ₃ N d) PhNH ₂ , DMF e) LiOH, THF / H ₂ O f) HCl / H ₂ O

The pharmaceutically acceptable salts of the compounds of formula (I) may be obtained in a known manner, for example by treatment with a suitable amount of an acid or base in the presence of a suitable solvent.

Another embodiment of the present invention is a similar method for preparing a compound of formula (I), comprising:

Embedded image [Wherein R, R ₁ and m are as defined in the formula (I)], a compound of the formula: —N (X) — (CR ₁₃ R ₁₄ ) _v —R _{20 wherein} X, R ₁₃ , R ₁₄ , v and R ₂₀ are as defined in formula (I)] to obtain a compound of formula (I).

Alternatively, formula (A1):

Embedded image Wherein E, R, R ₁ and m are as defined in the formula (I), or a compound of the formula (A2):

Embedded image [Wherein E, R, R ₁ and m are as defined in formula (I)], a compound of the formula: —N (X) — (CR ₁₃ R ₁₄ ) _v —R ₂₀ ; Wherein X, R ₁₃ , R ₁₄ , v and R ₂₀ have the same meanings as defined in formula (I)], to give a compound of formula (I).

Another aspect of the present invention is an alternative method for preparing a compound of the formula:

Embedded image Wherein R ₁ , m and R are as defined in the formula (I), and a compound represented by the formula: NH ₂ — (CR ₁₃ R ₁₄ ) _v —R ₂₀ [wherein R ₁₃ , R ₁₄ , v and R ₂₀ have the same meanings as defined in formula (I)] to give a compound of formula (I); A method that includes protecting.

As described above, the formula (B1):

Embedded image Wherein E, R, R ₁ and m are as defined in the formula (I), or a compound of the formula (B2):

Embedded image [Wherein E, R, R ₁ and m are as defined in the formula (I)], using a compound of the formula: NH _2- (CR ₁₃ R ₁₄ ) _v -R ₂₀ ; , R ₁₃ , R ₁₄ , v and R ₂₀ , as defined in formula (I)], to give a compound of formula (I); Is also good.

In the examples, all temperatures are in degrees Celsius (° C.). Mass spectra were performed on a VG Zab mass spectrometer using fast atom bombardment unless otherwise specified. ¹ H-N
MR (hereinafter referred to as "NMR") spectra were recorded at 250 MHz or 400 MHz using a Bruker AM 250 or Am 400, respectively. The given multiplets are s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br indicates a broad signal. Sat. indicates a saturated solution, and equivalents indicate the ratio of the molar equivalent of the reagent to the main reactant. Flash chromatography is performed on Merck Silica gel 60 (230-400 mesh).

Synthetic Examples The invention is described by the following examples, which are merely illustrative of the invention and are not intended to limit the scope of the invention. All temperatures are given in degrees Celsius, all solvents used herein are of the highest purity available, and all reactions are run under anhydrous conditions in an argon atmosphere unless otherwise noted. Is

Example 1 Preparation of N- (3-carboxyphenyl) -N ′-(2-bromophenyl) urea 3-aminobenzoic acid (1 equivalent (hereinafter referred to as “eq” in the present specification), 1. A solution of 37 grams (hereinafter referred to as "g") in DMF was reacted with 2-bromophenyl isocyanate (1 eq, 1.98 g) at about 80C for about 2 hours. The solution was cooled and the product was purified by recrystallization from methylene chloride and hexane to give 1.28 g of the title compound as a white solid. MS (ES) M-
H = 333

Example 2 Preparation of N- (3-carboxymethylphenyl) -N '-(2-bromophenyl) urea A solution of 3-aminophenylacetic acid (1 eq, .151 g) in DMF was treated with 2-bromophenyl. The reaction was carried out at about 80 ° C. for about 2 hours with isocyanate (1 eq, .198 g). The solution was cooled and the product was purified by recrystallization from methylene chloride and hexane to give 0.32 g of the title compound as a white solid. MS (ES) MH
= 347

[0062] Example 3 N-(3-carboxymethyl-phenyl) -N '- (2,3-dichlorophenyl) urea To a solution of 3- amino-phenylacetic acid (1 eq, 151 mg (herein below,
"Mg")) in DMF was treated with 2,3-dichlorophenyl isocyanate
(1 eq, 188 mg) at 80 ° C. for 2 hours. The solution was cooled and the product was purified by recrystallization from methylene chloride and hexane; 12 g of the title compound were obtained as a white solid. MS (ES) MH = 337

Example 4 Preparation of N- (3-carboxyphenyl) -N '-(2,3-dichlorophenyl) urea A solution of 3-aminobenzoic acid (1 eq, 1.37 g) in DMF was treated with 2,3- It was reacted with dichlorophenyl isocyanate (1 eq, 1.88 g) at 80 ° C. for 2 hours. The solution was cooled and the product was purified by recrystallization from methylene chloride and hexane to give 1.01 g of the title compound as a white solid. MS (ES) MH = 32
Three

[0064] EXAMPLE 5 N-[3- (2-carboxyethyl) phenyl] -N '- (2,3-dichloro phenyl-) producing a urea) 3-amino-dihydro-cinnamic acid 3-nitro-dihydro-cinnamic acid ( 500 mg) in ethyl acetate at 10% Pd /
Treated with C (500 mg). The resulting suspension was flushed with hydrogen and stirred at room temperature overnight. The reaction mixture was purged with argon and then filtered through celite. The filtrate was concentrated and the residue was recrystallized from toluene and ethyl acetate. ¹ H NM
R (DMSO) 6.95t (1H), 6.4m (3H), 2.7t (2H), 2.45t
(2H)

B) A solution of N- [3- (2-carboxyethyl) phenyl] -N ′-(2,3-dichlorophenyl) urea 3-aminodihydrocinnamic acid (1 eq, 83 mg) in DMF was 3-
It was reacted with dichlorophenyl isocyanate (1 eq, 94 mg) at 80 ° C. for 2 hours. The solution was cooled and the product was purified by recrystallization from methylene chloride and hexane to give 0.037 g of the title compound as a white solid. ^{1 H NMR (DM SO) 9.45s} (1H), 8.47s (1H), 8.17d (1H), 7.31m (4
H), 7.24t (1H), 6.88d (1H), 2.73t (2H), 2.54t (2H)
H)

[0066] EXAMPLE 6 N-(2,4-dichloro-3-carboxy) -N '- (2-bromophenyl) producing a urea) 5-amino-2,6-dichlorobenzoic acid 5-nitro-2, A solution of 6-dichlorobenzoic acid (2.0 g) in ethyl acetate was
% Pd / C (1.5 g). The suspension was flushed with hydrogen and stirred at room temperature overnight. The reaction mixture was purged with argon and filtered through celite. The filtrate was concentrated, and the residue was recrystallized from ethyl acetate and hexane to give the title compound (0.7 g) as a white solid. ^{1 H NMR (DMSO) 7.15d (} 1H), 6.8d (
1H), 5.74s (1H, br)

B) N- (2,4-Dichloro-3-carboxy) -N ′-(2-bromophenyl) urea A solution of 5-amino-2,6-dichlorobenzoic acid (1 eq, 250 mg) in DMF , 2-bromophenyl isocyanate (1 eq, 153 uL) at 80 ° C for 2 hours. The solution was cooled and the product was purified by recrystallization from methylene chloride and hexane to give 35 mg of the title compound as a white solid. MS (ES) M
−H = 401

[0068] Example 7 N-(4-chloro-3-carboxyphenyl) -N '- (2-bromophenyl) in DMF urea manufacturing 5-amino-2-chlorobenzoic acid (1 eq, 1.71 g) Solution 2
It was reacted with -bromophenyl isocyanate (1 eq, 1.98 g) at 80 ° C for 2 hours. The solution was cooled and the product was purified by recrystallization from methylene chloride and hexane to give 0.880 g of the title compound as a white solid. MS (ES) M-
H = 367

Example 8 Preparation of N- (4-chloro-3-carboxyphenyl) N '-(2,3-dichlorophenyl) urea 5-Amino-2-chlorobenzoic acid (1 eq, 1.71 g) in DMF Solution 2
, 3-dichlorophenyl isocyanate (1 eq, 1.88 g) at 80 ° C for 2 hours. The solution was cooled and the product was purified by recrystallization from methylene chloride and hexane to give 1.57 g of the title compound as a white solid. MS (ES)
MH = 357

[0070] The DMF solution of Example 9 N-(4-chloro-3-carboxyphenyl)-N-(3- chlorophenyl) urea manufacturing 5-amino-2-chlorobenzoic acid (1 eq, 1.71 g) , 3
Reaction with -chlorophenyl isocyanate (1 eq, 1.53 g) at 80 ° C. for 2 hours. The solution was cooled and the product was purified by recrystallization from methylene chloride and hexane to give 0.66 g of the title compound as a white solid. MS (ES) MH
= 323

Methods of Treatment Excessive or unregulated IL-8 cytokine production by human or other mammalian cells, such as, but not limited to, monocytes and / or macrophages, or also referred to as type I or type II receptors. In the manufacture of a medicament for the prophylactic or therapeutic treatment of conditions aggravated or caused by other chemokines that bind to IL-8α or β receptors, or a compound of formula (I) or a pharmaceutically acceptable salt thereof. Salts can be used.

Accordingly, the present invention is directed to a method of treating a chemokine-mediated disease wherein the chemokine binds to the IL-8α or β receptor, comprising administering an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. The present invention provides a therapeutic method including the step of: In particular, the chemokine is IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78.

Compounds of formula (I) have cytokine function, especially IL-8, GROα, GROβ,
Administered in an amount sufficient to inhibit GROγ, NAP-2 or ENA-78;
As a result, their cytokine function is biologically down-regulated to normal and in some cases subnormal levels of physiological function, ameliorating the condition. For example, in the context of the present invention, abnormal levels of IL-8, GROα, GROβ, GROγ or NAP-2 are: (i) levels of free IL-8 of 1 picogram or more per ml; Cell-bound IL-8, above physiological levels;
GROα, GROβ, GROγ or NAP-2; or (iii) IL-8, GRO
In cells or tissues producing α, GROβ, GROγ or NAP-2, respectively, constitute the presence of IL-8, GROα, GROβ, GROγ or NAP-2 above basal levels.

There are a number of medical conditions where excessive or unregulated IL-8 production is thought to be associated with the worsening and / or onset of the disease. 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, seizures, septic shock, endotoxin shock, Gram-negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft-versus-host reaction, Alzheimer's disease, allograft rejection, malaria, restenosis, angiogenesis or unwanted hematopoiesis Includes stem cell release, rhinovirus infection, and various bone resorbing conditions such as osteoporosis or osteoarthritis.

The relevance of interleukin-8 to rhinovirus has been described by Turner, et al., Clin.
nfect. Dis. (1998), 26 (4), 840-846; Sanders, et al., J. Virol. (1998),
72 (2), 934-942; Sethi, et al., Clin. Exp. Immunol. (1997), 110 (3), 36
2-369; Zhu, et al., Am. J. Physiol. (1997), 273 (4, Pt. 1), L814-L824;
_{... TeR a jima, et} al, Am J. Physiol (1997), 273 (. 4, Pt 1), L749-L759; Gr
unberg, et al., Clin.Exp.Allergy (1997), 27 (1), 36-45; and Johnsto
n, et al., J. Infect. Dis. (1997), 175 (2), 323-329.

The association between interleukin-8 and osteoporosis has been described by Streckfus et al., J. Geronto
l., Ser.A (1997), 52A (6), M343-M351; Hermann, T. WO 95/31722; and C.
haudhary, et al., Endocrinology (Baltimore) (1992), 130 (5), 2528-34.

These diseases are primarily characterized by massive neutrophil infiltration, T-cell infiltration, or angiogenic proliferation and are responsible for neutrophil chemotaxis to inflammatory sites or directional proliferation of endothelial cells. Increased IL-8, GROα, GROβ, GROγ or NA
Related to P-2 production. In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8, GROα, GROβ, GROγ or NAP-2 are not restricted to neutrophil chemotaxis Enzyme release, including elastase release,
And has the unique property of promoting peroxide production and activation.
Α-chemokines, particularly GROα, GROβ, GROγ or NAP-2, acting through IL-8 type I or type II receptors, promote tumor angiogenesis by promoting endothelial cell directional proliferation Can be. Therefore, IL-
Inhibition of 8-induced chemotaxis or activation leads to a direct decrease in neutrophil infiltration.

[0078] Recent evidence also indicates that a role for chemokines is involved in the treatment of HIV infection. Littleman et al., Nature 381, pp. 661 (1996) and
Koupet al., Nature 381, pp. 667 (1996).

The present invention also provides a chemokine receptor antagonist compound represented by the formula (I)
It also provides a means of treating CNS damage in acute sclerosis and a means of preventing CNS damage in individuals likely to be susceptible to CNS damage. CNS injuries as defined herein include both open or penetrating head injuries, such as by surgery, or non-open head injuries, such as injuries to the head. Ischemic stroke, especially to the brain, is also included within this definition. Ischemic stroke is defined as focal neuropathy usually caused by insufficient blood supply to certain brain parts as a result of embolism, thrombus or localized atherosclerotic closure of blood vessels. The role of inflammatory cytokines here is becoming clearer, and the present invention provides an effective method of treating these injuries. For acute injuries such as these, relatively few treatments are available.

There is also evidence indicating the use of IL-8 inhibitors in the treatment of atherosclerosis. First reference, Boisvert et al., J Clin Invest, 1998, 101: 353-3.
63 shows that bone marrow transplantation reduces atherosclerotic plaque development in LDL receptor deficient mice in the absence of IL-8 receptor on stem cells (on monocytes / macrophages). Further supporting references are Aposto
lopoulos et al., Arterioscler Thromb Vasc Biol. 1996, 16: 1007-1012; Liu
et al., Arterioscler Thromb Vasc Biol, 1997, 17: 317-323; Rus et al., A
therosclerosis. 1996, 127: 263-271 .; Wang et al., J Biol Chem. 1996, 271.
: 8837-8842; Yue et al., Eur J Pharmacol. 1993, 240: 81-84; Koch et al.
, Am J Pathol, 1993, 142: 1423-1431 .; Lee et al., Immunol Lett, 1996, 53.
, 109-113 .; and Terkeltaub et al., Arterioscler Thromb, 1994, 14: 47-53.

[0081] TNF-α is a cytokine that has a proinflammatory action, including the expression of endothelial leukocyte adhesion molecules. Leukocytes infiltrate into ischemic brain lesions and, therefore, compounds that inhibit or reduce TNF levels are useful for treating ischemic brain injury.
See Liuet al., Stoke, Vol. 25, No. 7, pp 1481-88 (1994), which is incorporated herein by reference.

A model of non-open head injury and treatment with a mixed 5-LO / CO agent is described in Shoham
i et al., J. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3, No
2, pp. 99-107 (1992), which is incorporated herein by reference. Treatments that reduce edema formation have been found to improve functional outcome in these treated animals.

The compounds of formula (I) bind IL-8 to IL-8 alpha or beta receptors, as evidenced by reduced neutrophil chemotaxis and activation, Is administered in an amount sufficient to inhibit from. The finding that the compound of formula (I) is an inhibitor of IL-8 binding is described in the in vitro described herein.
Based on the effect of the compound of formula (I) in a receptor binding assay. formula
Compounds of (I) have in some cases been shown to be dual inhibitors of both recombinant type I and type II IL-8 receptors. Preferably, the compound is an inhibitor of only one of the receptors, more preferably, only type II.

As used herein, “IL-8 mediated disease or condition” refers to IL-8, GR
By the production of Oα, GROβ, GROγ, NAP-2 or ENA-78 itself,
Alternatively, IL-8, GROα, GROβ, GROγ, NAP-2 or ENA that releases another monokine such as, but not limited to, IL-1, IL-6 or TNF
By -78, IL-8, GROα, GROβ, GROγ, NAP-2 or E
Represents all conditions in which NA-78 plays a role. Thus, for example, IL-1
Is a major factor, and any condition whose production or action is exacerbated or secreted in response to IL-8 may be a condition mediated by IL-8.

As used herein, the term “chemokine-mediated disease or condition” includes, but is not limited to, IL-8, GROα, GROβ, GROγ, NAP-2 or ENA.
Represents all conditions in which chemokines binding to IL-8α or β receptors, such as -78, play a role. This may include the production of IL-8 itself or an I that releases another monokine such as, but not limited to, IL-1, IL-6 or TNF.
L-8 includes conditions in which IL-8 plays a role. Thus, for example, a condition in which IL-1 is a major component and whose production or action is exacerbated or secreted in response to IL-8 may be a condition mediated by IL-8.

As used herein, the term “cytokine” refers to a secreted polypeptide that is a molecule that affects the function of cells and modulates interactions between cells in an immune, inflammatory or hematopoietic response. . Examples of the cytokine include, but are not limited to,
Regardless of which cells produce, they include monokines and lymphokines. For example, monokine is generally said to be produced and secreted by mononuclear cells such as macrophages and / or monocytes. However, many other cells such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes and B-lymphocytes are also
Produces monokine. Lymphokines are generally said to be produced by lymphocyte cells. Examples of cytokines include, but are not limited to, interleukin-1 (IL-1), interleukin-6 (IL-6), interleukin-
8 (IL-8), tumor necrosis factor-alpha (TNF-α) and tumor necrosis factor beta
(TNF-β).

As used herein, the term “chemokine”, similar to the term “cytokine” above, affects the function of cells and describes the interaction between cells in an immune, inflammatory or hematopoietic response. Represents a secreted polypeptide that is a regulating molecule. Chemokines are mainly secreted through cell transmembrane and chemotactic and specific leukocytes and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells. Causes activation. Examples of chemokines include, but are not limited to, IL-8, GRO-α, GRO-β, GRO-γ, NAP-2,
ENA-78, IP-10, MIP-1α, MIP-β, PF4 and MCP
1, 2 and 3.

To use a compound of formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will usually be formulated into a pharmaceutical composition according to standard pharmaceutical practices. Accordingly, the present invention also relates to pharmaceutical compositions comprising an effective non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.

The compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising them are conveniently administered by the routes conventionally used for administration, for example, oral, topical It is administered parenterally or by inhalation. The compound of formula (I) is administered in conventional dosage forms prepared by combining the compound of formula (I) with a standard pharmaceutical carrier according to conventional methods. The compound of formula (I) may also be administered in conventional dosages in combination with a known second therapeutically active compound. These methods include mixing, granulating, and tableting or dissolving the active ingredient as appropriate to the desired preparation. It will be appreciated that the form and properties of the pharmaceutically acceptable carrier or diluent are determined by the amount of active ingredient to be incorporated, the route of administration and other well-known variables. The carrier (s) can be compatible with the other components of the formulation,
Must be "acceptable" in the sense that it is not harmful to its recipients.

The pharmaceutical carrier employed can be, for example, a solid or liquid.
Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid and the like. Examples of liquid carriers include syrup, peanut oil, olive oil, water and the like. Similarly, the carrier or diluent may include time-release agents well known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax.

Various pharmaceutical forms can be used. Therefore, when using a solid carrier,
The preparation may be tableted, placed in a hard gelatin capsule in powder or pellet form, or in the form of a troche or lozenge.
The amount of solid carrier will vary widely but, preferably, will be from about 25 mg to about 1 g.
Will. If a liquid carrier is used, the preparation will be in the form of a syrup, emulsion, soft gelatine capsule, sterile injectable solution such as an ampoule or non-aqueous liquid suspension.

The compounds of formula (I) may be administered locally, ie, by non-systemic administration. This includes external application of the compound of formula (I) to the epidermis or buccal cavity and inhalation of the compound into the ears, eyes and nose, where the compound does not enter the blood stream significantly. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin at sites of inflammation, such as liniments, lotions, creams, ointments or pastes and the like. Drops suitable for administration to the eye, ear or nose. The active ingredient may comprise from 0.001% to 10% w / w, for example 1% to 2% by weight of the formulation for topical administration. However, 10% w /
w may be contained, but preferably less than 5% w / w, more preferably 0.1% to 1% w / w.

The lotions according to the present invention include those applied to the skin or eyes. The eye lotion may contain a sterile aqueous solution optionally containing a bactericide, and may be prepared by a method similar to the method of preparing drops. Lotions or liniments for application to the skin may include agents that dry quickly and cool the skin, such as alcohol or acetone, and / or humectants such as glycerol, or oils such as castor oil or peanut oil.

The creams, ointments or pastes according to the invention are semisolid preparations of the active ingredient for external use. They are prepared by mixing an oily or non-oily base with the active ingredient alone or in finely divided or powdered form, either in solution or in a suspension in an aqueous or non-aqueous liquid, with the aid of suitable machines. It may be prepared. The base is a hydrocarbon such as solid paraffin, soft paraffin or liquid paraffin, glycerol, beeswax, metal soap; a lubricating agent; an oil of a natural material such as tonsil oil, corn oil, peanut oil, castor oil or olive oil; Or a derivative thereof or a fatty acid such as stearic acid or oleic acid together with an alcohol such as propylene glycol or macrogel. The formulation may include a suitable surfactant such as an anionic, cationic or nonionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents may include inorganic substances, such as, for example, natural gums, cellulose derivatives, or silica-containing silica, and other ingredients such as lanolin.

Drops according to the present invention may include sterile aqueous or oily solutions or suspensions, and may include fungicides and / or fungicides and / or other suitable preservatives, preferably It may be prepared by dissolving the active ingredient in a suitable aqueous solution containing a surfactant. The resulting solution is then clarified by filtration, transferred to a suitable container and then sealed and autoclaved or at 98-100 ° C for 1 hour.
Sterilize by maintaining for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by aseptic technique. Examples of fungicides and fungicides suitable for inclusion in the drops include phenylmercuric nitrate or phenylmercuric acetate (0.002).
%), Benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
%). Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

The compounds of formula (I) may be administered parenterally, ie by intravenous, intramuscular, subcutaneous, intranasal, rectal, vaginal or intraperitoneal administration. . Subcutaneous and intramuscular forms of parenteral administration are generally preferred. Suitable dosage forms for such administration may be prepared by conventional techniques. The compounds of formula (I) may also be administered by inhalation, ie by intranasal and oral inhalation. Suitable dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.

For all uses described herein for the compounds of formula (I), the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg / kg of total body weight. The daily parenteral administration policy is about 0.001 to about 80 mg / kg of total body weight.
It is. The daily topical administration policy is preferably between 0.1 mg and 150 mg,
It is administered 1 to 4 times, preferably 2 or 3 times a day. The daily inhalation dosage regimen will preferably be from about 0.01 mg / kg to about 1 mg / kg per day. The optimal amount and interval for individual administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof will depend on the nature and extent of the condition being treated, the mode, route and site of administration, and the particular patient being treated. It will also be recognized by those skilled in the art that such optimal values can be determined by conventional techniques. The optimal treatment method, ie
The number of doses of a compound of formula (I) or a pharmaceutically acceptable salt thereof administered per day for a predetermined number of days may be ascertainable by one skilled in the art using routine treatment determination tests. It will be recognized by those skilled in the art. The present invention will be described with reference to the following biological examples, which are illustrative only and are not intended to limit the scope of the present invention in any way.

Biological Examples The inhibitory effects of the compounds of the present invention on IL-8 and GRO-α chemokines were examined by the following in vitro assays.

Receptor binding assay: [ ¹²⁵ I] IL-8 (human recombinant) with a specific activity of 2000 Ci / mmol was obtained from Amersham Corp. (Arlington Heights, IL). GRO-α is NEN-N
ew Obtained from England Nuclear. All other chemicals were of analytical grade. High levels of recombinant human IL-8α and β-type receptors have been disclosed previously (H
olmes, et al., Science, 1991, 253, 1278) were individually expressed in Chinese hamster ovary cells. The homogenization buffer was added to 10 mM Tris-HCl, 1 mM MgSO ₄ , 0.5 mM EDTA (ethylene-diaminetetraacetic acid), 1 mM PMSF (α-toluenesulfonyl fluoride), 0.5 mg / L leupeptin, pH 7.5. Except for the substitution, Chinese hamster ovary membrane was prepared using a previously disclosed protocol (Haour et al., J Biol Chem., 249 pp. 2195-2205 (1974)).
Homogenized according to The membrane protein concentration was determined using a micro-assay kit from Pierce Co. using bovine serum albumin as a standard. All assays were performed in a 96-well microplate format. Each reaction _{mixture, 1.2mM MgSO 4, 0.1mM EDTA,} 20mM bis containing 25 mM NaCl and 0.0 3% CHAPS - ¹²⁵ in Tris propane and 0.4 mM Tris HCl buffer I IL-8 (0 .25 nM) or ¹²⁵ I GRO-α and 0.1
It contained 5 μg / mL IL-8Rα or 1.0 μg / mL IL-8Rβ membrane. Further, the drug or compound of interest was dissolved in DMSO in advance to a final concentration of 0.01 nM to 100 μM and added. The assay was started by the addition of ¹²⁵ I-IL-8. After 1 hour at room temperature, the plates were collected using a Tomtec 96 well harvester on a glass fiber filter mat blocked with 1% polyethyleneimine / 0.5% BSA, and 25 mM NaCl, 10 mM Tris HCl, 1 mM.
Washed three times with MgSO ₄ , 0.5 mM EDTA, 0.03% CHAPS, pH 7.4. The filters were then dried and counted on a Betaplate liquid scintillation counter. Recombinant IL-8Rα or type I receptors are also referred to as non-permissive receptors, and recombinant IL-8Rβ or type II receptors are also referred to as permissive receptors.

All compounds of formula (I) of Examples 1-9, exemplified herein in the Synthetic Chemistry section, showed inhibition in a permissive model of IL-8 receptor inhibition. The following compounds were found to be inactive in this assay: N- (2,4-dichloro-3-carboxy) -N '-(2,3-dichlorophenyl) urea,
N- (3-carboxyphenyl) -N '-(phenyl) urea and N- (3-methylcarboxyphenyl) -N'-(phenyl) urea.

Chemotaxis assay: The in vitro inhibitory properties of these compounds were measured using the Current Protocols in Immunology,
vol I, Suppl 1, Unit 6.12.3. (determined in a neutrophil chemotaxis assay as described herein). Current Protocols in Immunology
Neutrophils were isolated from human blood as described in Vol I, Suppl 1 Unit 7.23.1 (hereby incorporated by reference). Chemoattractants IL-8, GRO-α, GR
O-β, GRO-γ and NAP-2 are placed in the lower chamber of a 48 multiwell chamber (Neuro Probe, Cabin John, MD) at a concentration between 0.1 and 100 nM. The two chambers are separated by a 5 μm polycarbonate filter. When testing compounds of the present invention, they are mixed with cells (0.001-1000 nM) just before adding the cells to the upper chamber. Incubation is performed at about 37 ° C. for about 45-90 minutes in a humidified incubator with 5% CO ₂ . After the incubation period, the polycarbonate membrane is removed, the top is washed and the membrane is stained using the Diff Quick staining protocol (Baxter Products, McGaw Park, IL, USA). Cells showing chemotaxis to chemokines are counted visually using a microscope. Generally, four regions are counted for each sample and these numbers are averaged to obtain the average number of cells that have migrated. Each sample is tested in triplicate and each compound is repeated at least four times. For some cells (positive control cells) no compound was added and these cells show the maximal chemotactic response of the cells. If a negative control (unstimulated) is desired, no chemokine is added to the lower chamber. Differences between the positive and negative controls are indicative of the chemotactic activity of the cells.

Elastase release assay: The compounds of the invention are tested for their ability to prevent elastase release from human neutrophils. For neutrophils, Current Protocols in Immunology Vol I, Suppl 1 Unit 7.
Isolated from human blood as disclosed in 23.1. Ringer's solution (NaCl 118, KCl 4.56, NaHCO ₃ 25, KH ₂ PO ₄ 1.03, glucose 11
.1 put HEPES 5 mM, the PMN 0.88 × 10 ⁶ cells suspended in pH7.4) to each well of 96-well plates at a capacity 50 [mu] l. To this plate, a test compound (0.001 to 1000 nM) in a volume of 50 μl, and cytochalasin B in a volume of 50 μl.
(20 μg / ml) and Ringer buffer in a volume of 50 μl. After warming the cells for 5 minutes (37 ° C., 5% CO ₂ , 95% RH), IL-8, GROα, GROβ, GROγ or NAP-2 was added to a final concentration of 0.01-1000 nM. After performing the reaction for 45 minutes, the 96-well plate is centrifuged (800 × g, 5 minutes), and 100 μl of the supernatant is removed. This supernatant was added to a second 96-well plate and then an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val) dissolved in phosphate buffered saline until a final concentration of 6 μg / ml. -Add AMC, Nova Biochem, La Jolla, C). Immediately place the plate in a fluorescent 96-well plate reader (Cytofluor 2350, Millipore, Bedford, Mass.) And collect data every 3 minutes according to the method of Nakajima et al J. Biol. Chem. 254 4027 (1979). . The amount of elastase released from PMN is equal to MeO
It is calculated by measuring the rate of Suc-Ala-Ala-Pro-Val-AMC decomposition.

TNF-α in Traumatic Brain Injury Assay Tumor necrosis factor mR in specific brain areas where this assay experimentally induced lateral fluid-percussion traumatic brain injury (TBI) in rats
Experiments on the expression of NA are performed. After this trauma in TNF-α gene expression, TNF-α can induce nerve growth factor (NGF) and stimulate the release of other cytokines from activated astrocytes. Changes play an important role in both the acute and regenerative responses to CNS trauma. Suitable assays can be found in WO 97/35856 or WO 97/49286, the disclosures of which are incorporated herein by reference.

CNS Damage Model for IL-β mRNA This assay demonstrates that interleukin-1β (IL-1β) mRNA in specific brain areas after experimental lateral liquid shock traumatic brain injury (TB I) in rats Is analyzed. The results from these assays indicate that after TBI, the transient expression of IL-1β mRNA is locally stimulated in specific brain areas. IL-1β
These local changes in cytokines, such as, play a role in the post-traumatic pathology or regeneration sequelae of brain injury. A suitable assay is described in WO 97/35856.
Or WO 97/49286 (the disclosures of which are incorporated herein by reference).

In Vivo-Atherosclerosis Assay: An in vivo model for measuring atherosclerosis in mice is based on the assay of Paigen et al, slightly modified as described. Paigen B,
Morrow A, Holmes PA, Mitchell D, Williams _RA . Quantitative assessment
of atherosclerotic lesions in mice.Atherosclerosis 68: 231-240 (1987
); And Groot PHE, van Vlijmen BJM, Benson GM, Hofker MH, Schiffelers
R, Vidgeon-Hart M, Havekes LM.Quantitative assessment of aortic ather
osclerosis in APOE * 3 Leiden tR _a nsgenic mice and its relationship to ser
um cholesterol exposure.Arterioscler Thromb Vasc Biol. 16: 926-933 (1
996).

Aortic sinus sectioning and staining Aortic root cross-sections are taken as previously described (1,2). Briefly, the heart is bisected just below the level of the atria and the base of the heart and the aortic root are taken for analysis. After equilibrating the tissue in OCT compound overnight, the cryostat chuck (Bright
On an Instrument Company Ltd., UK), the heart is immersed in the OCT compound, with the aorta facing the chuck. The tissue is frozen by surrounding the chuck with dry ice. The heart is then cut, starting in the heart and in the direction of the aorta, perpendicular to the axis of the aorta. If the aortic root is identified by the appearance of three valve leaflets, alternately 10
mm sections are taken and fixed on gelatinized slides. Air-dry the sections for 1 hour
Then rinse briefly in 60% isopropyl alcohol. Cut the sections into Oil Re
Stain with dO, counterstain with Mayer's hematoxylin, cover with coverslip using glycerol gelatin, and seal with nail enamel.

Quantification of atherosclerosis in the aortic root Ten alternating sections of the aortic root were taken with a 4 × objective and a video camera (Hitac
The image is processed using an Olympus BH-2 microscope equipped with hi, HV-C10). Obtain a 24-bit color image and use a frame grabbing board (Snapper, Active Imaging L
td, Berks, UK) and Optimas software (version 5.1, Optimas Corp.,
WA, USA), PC (Datacell Pentium P5-133, Datacell, Berks, U
Analyze using .K.). Images are obtained under the same light, microscope, camera and PC conditions. Quantification of atherosclerotic lesion area is performed by delineating the area around the lesion by hand using Optimas software. The colored border is a set that quantifies the red stained area within the lesion. Absolute values of the cross-section and red-stained areas of the lesion are obtained by measuring the software using an image of the grid on a hemocytometer slide.

[0109] All publications, including but not limited to patents and patent applications, cited herein are hereby incorporated by reference as if each and every publication was individually and fully described. And the description in the book. The above description fully describes the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically described 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. Thus, the examples herein are:
It is merely an explanation and does not limit the scope of the present invention in any case. The specifics of the invention in which exclusive ownership and privileges are claimed are defined below.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 9/10 A61P 9/10 11/00 11/00 11/06 11/06 13/12 13/12 17 / 06 17/06 19/08 19/08 25/28 25/28 29/00 29/00 37/00 37/00 43/00 111 43/00 111 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD) , RU, TJ, TM), AL, AU, BA, BB, BG, BR, CA, C , CZ, EE, GE, HU, ID, IL, IS, JP, KP, KR, LC, LK, LR, LT, LV, MG, MK, MN, MX, NO, NZ, PL, RO, SG, SI, SK, SL, TR, TT, UA, US, UZ, VN, YUF term (reference) 4C206 AA01 AA03 HA28 HA30 MA01 MA04 NA14 ZA16 ZA36 ZA45 ZA59 ZA66 ZA81 ZA89 ZA96 ZB08 ZB11 ZB13 ZB35 ZC21 4H006 AA AB20 AB21 AB22 AB23 AB27 AC52 AC57

Claims (18)

[Claims] 1. The method of claim 1, wherein the chemokine is an IL-8α or β receptor in a mammal.
A method of treating a chemokine-mediated condition that binds to a compound, comprising:Wherein X is oxygen or sulfur; R is (CR₈R₈)_rC (O)_TwoH, (CR₈R₈)_rNH-C (O) R_a, (CR₈R₈)_rC (
O) NR_{6 '}R_{7 '}, (CR₈R₈)_rNHS (O)_TwoR_b, (CR₈R₈)_rS (O)_TwoNHR_c, (
CR₈R₈)_rNHC (X_Two) NHR_bOr a tetrazolyl ring; X_TwoIs oxygen or sulfur; R₁Is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10A
Lucoxy; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Alkyl;
Reel; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Alkyloxy
Heteroaryl; heteroarylalkyl; heterocycle, heterocycle C_1-4Alkyl; heteroaryl C_1-4Alkyloxy; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_{Two -Ten} Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O
) NR_FourR_TenS (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R_{1 1} C_2-10Alkenyl C (O) OR₁₁(CR₈R₈)_qC (O) OR₁₂; (CR₈R₈)_qOC (
O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR₁₇; (CR₈ R₈)_qS (O)_TwoNR_FourR_FiveOr two R₁The groups together form O- (CH_Two)_sO- or a 5-6 membered saturated or unsaturated ring may be formed;
, Aryl, heteroaryl, and heterocyclic-containing groups may be substituted; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; R is 0, or an integer having a value of 1 to 10; r is 0, or an integer having a value of 1 to 4; s is an integer having a value of 1 to 3; Or an integer having a value of 1 or 2; v is an integer having a value of 1 to 4;_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 Alkyl, heterocycle, heterocycle C_1-4Alkyl or R_FourAnd R_FiveIs
And additional nitrogen selected from O / N / S together with the nitrogen to which they are attached
Forming a 5- to 7-membered ring optionally containing a heteroatom; R₆And R₇Is independent
And hydrogen or C_1-4An alkyl group or R₆And R₇Is an additional selected from oxygen, nitrogen or sulfur, together with the nitrogen to which they are attached.
Forming a 5- to 7-membered ring optionally containing a heteroatom;_{6 '}And R_{7 '}Is independently hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C _1-4 Alkyl, heteroaryl C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl and heterocyclic C_2-4An alkenyl group, provided that R_{6 '}And R_{7 '}Is hydrogen, but not both; Y is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl
C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Al
Coxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Archi
Aryl; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Archi
Heterooxy; heteroarylalkyl; heteroaryl C_1-4Alkyloxy; heterocycle, heterocycle C_1-4Alkyl; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR _Five C_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈) _q C (O) NR_FourR_TenS (O)_ThreeH; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10A
Lucenyl C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈) _q C (O) OR₁₂; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR_d; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveSelected from; also
Is a group in which two Y groups are combined to form O- (CH_Two)_sO- or 5-6 member saturated or unsaturated
May form a saturated ring; wherein aryl, heteroaryl and heterocyclic containing
The group is optionally substituted; R₈Is independently hydrogen or C_1-4R selected from alkyl;_TenIs C_1-10Alkyl C (O)_TwoR₈R₁₁Is hydrogen, C_1-4Alkyl, optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl
Le C_1-4Alkyl, an optionally substituted heterocyclic ring, or an optionally substituted heterocyclic C_1-4R is alkyl;₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl, or
Optionally substituted arylalkyl; R₁₃And R₁₄Is independently hydrogen, optionally substituted C_1-4Alkyl or R₁₃And R₁₄Is an optionally substituted aryl.
May be; R₁₇Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4Alkyl
Wherein all of the aryl, heteroaryl and heterocycle may be substituted;_aIs an alkyl, aryl, aryl C_1-4Alkyl, heteroaryl, hete
Lower aryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4An alkyl group,
Wherein all of these groups may be substituted;_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C _2-4 Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl
Le C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl, heterocyclic C_2-4An alkenyl group or camphor wherein all of these groups are optionally substituted;_cIs an alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A
Lucenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4With an alkenyl group
Where all of these groups are halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoxy, NR₉C (O) R_a, C (O) NR₆R₇, S (O) _Three H or C (O) OC_1-4May be independently substituted 1-3 times with alkyl.
R;_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl-C_1-4Alkyl, heteroaryl C_2-4 Alkenyl, heterocycle, heterocycle C_1-4Alkyl, wherein the aryl, heteroaryl, and heterocyclic-containing groups are all optionally substituted; W isThe E-containing ring isWherein the asterisk * indicates the bonding position of the ring;₂₀Is W₁An optionally substituted heteroaryl, an optionally substituted C_5-8Cycloalkyl, optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl or optionally substituted C_2-10Alkynyl
; W₁IsAnd the E′-containing ring is(Wherein the asterisk * represents a bonding position of the ring), or a pharmaceutically acceptable salt thereof is administered to the mammal.
A method that includes: 2. The method according to claim 1, wherein R is (CR ₈ R ₈ ) _r C (O) ₂ H. 3. 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 method of claim 1, wherein. 4. The method according to claim ₁ , wherein R ₂₀ is W ₁ . 5. The method according to claim 1, wherein R ₂₀ is heteroaryl. 6. Y is halogen, C_1-4Alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylenedioxy, NR _Four R_Five, Thio C_1-4Alkyl, thioaryl, halo-substituted alkoxy, optionally substituted C_1-4The method according to claim 4, which is an alkyl or hydroxyalkyl. 7. The process according to claim 1, wherein R ¹ is substituted at the 2- or 4-position or di-substituted at the 2,4-position by an electron-withdrawing group. 8. The chemokine-mediated disease is psoriasis or atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, Endotoxin shock, gram-negative sepsis, toxic shock syndrome, seizures, heart and renal reperfusion injury, glomerulonephritis, thrombosis, atherosclerosis, bone resorption disease, Alzheimer's disease, graft-versus-host reaction, or allogeneic The method according to any one of claims 1 to 7, wherein the method is selected from transplant rejection. 9. A compound of the formula:Wherein X is oxygen or sulfur; R is (CR₈R₈)_rC (O)_TwoH, (CR₈R₈)_rNH-C (O) R_a, (CR₈R₈)_rC (
O) NR_{6 '}R_{7 '}, (CR₈R₈)_rNHS (O)_TwoR_b, (CR₈R₈)_rS (O)_TwoNHR_c, (
CR₈R₈)_rNHC (X_Two) NHR_bOr tetrazolyl; X_TwoIs oxygen or sulfur; R₁Is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl; C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10A
Lucoxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Al
Kill; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Al
Heteroaryl; Heteroarylalkyl; Heterocycle, Heterocycle C_1-4 Alkyl; heteroaryl C_1-4Alkyloxy; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_Four R_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R ₈ )_qC (O) NR_FourR_TenS (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_2-10Alkenyl C (O) OR₁₁(CR₈R₈)_qC (O) OR₁₂; (CR₈ R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNHS (O)_TwoR_{1 7} ; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveOr two R₁Groups together
O- (CH_Two)_sO- or a 5- or 6-membered saturated or unsaturated ring may be formed.
Wherein the aryl, heteroaryl and heterocyclic-containing groups may be substituted
N is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; q is 0 or an integer having a value of 1 to 10; S is an integer having a value of 1 to 3; t is an integer having a value of 1 or 2; v is an integer having a value of 1 or 2; An integer having a value of 4; R_FourAnd R_FiveIs independently hydrogen, optionally substituted C_1-4Alkyl, optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C _1-4 Alkyl, heterocycle, heterocycle C_1-4Alkyl or R_FourAnd R_FiveIs
And additional nitrogen selected from O / N / S together with the nitrogen to which they are attached
Forming a 5- to 7-membered ring optionally containing a heteroatom; R_{6 '}And R_{7 '}Is
Independently hydrogen, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, aryl
C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, hetero ant
C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl, heterocyclic C_2-4An alkenyl group, provided that R_{6 '}And R_{7 '}One is hydrogen, but both are hydrogen
Never; R₆And R₇Is independently hydrogen or C_1-4An alkyl group, or R₆And R₇Is, together with the nitrogen to which they are attached, oxygen, nitrogen or
Forming a 5- to 7-membered ring which may contain additional heteroatoms selected from sulfur
Y is independently hydrogen; halogen; nitro; cyano; halo-substituted C;_1-10Alkyl
C_1-10Alkyl; C_2-10Alkenyl; C_1-10Alkoxy; halo-substituted C_1-10Al
Coxy; azide; (CR₈R₈)_qS (O)_tR_Four; Hydroxy; hydroxy C_1-4Archi
Aryl; aryl; aryl C_1-4Alkyl; aryloxy; aryl C_1-4Archi
Heterooxy; heteroarylalkyl; heteroaryl C_1-4Alkyloxy; heterocycle, heterocycle C_1-4Alkyl; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR _Five C_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈) _q C (O) NR_FourR_TenS (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (
O) R₁₁C_2-10Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR ₁₂ ; (CR₈R₈)_qOC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qNH
S (O)_TwoR_d; (CR₈R₈)_qS (O)_TwoNR_FourR_FiveOr two Y
The groups together form O- (CH_Two)_sForming an O- or 5- or 6-membered saturated or unsaturated ring
Wherein the aryl, heteroaryl and heterocycle-containing groups are substituted
R₈Is independently hydrogen or C_1-4R selected from alkyl;_TenIs C_1-10Alkyl C (O)_TwoR₈R₁₁Is hydrogen, C_1-4Alkyl, optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl
Le C_1-4Alkyl, an optionally substituted heterocyclic ring, or an optionally substituted heterocyclic C_1-4R is alkyl;₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl, or
Optionally substituted arylalkyl; R₁₃And R₁₄Is independently hydrogen, optionally substituted C_1-4Alkyl or R₁₃And R₁₄Is an optionally substituted aryl.
May be; R₁₇Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, heteroaryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4Alkyl
Wherein all of the aryl, heteroaryl and heterocycle may be substituted;_aIs an alkyl, aryl, aryl C_1-4Alkyl, heteroaryl, hete
Lower aryl C_1-4Alkyl, heterocycle, or heterocycle C_1-4An alkyl group,
Wherein all of these groups may be substituted;_bIs NR₆R₇, Alkyl, aryl, aryl C_1-4Alkyl, aryl C _2-4 Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl
Le C_2-4Alkenyl, heterocycle, heterocycle C_1-4Alkyl, heterocyclic C_2-4An alkenyl group or camphor wherein all of these groups are optionally substituted;_cIs an alkyl, aryl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A
Lucenyl, heterocycle, heterocycle C_1-4Alkyl or heterocyclic C_2-4With an alkenyl group
Where all of these groups are halogen, nitro, halo substituted C_1-4Alkyl, C_1-4Alkyl, C_1-4Alkoxy, NR₉C (O) R_a, C (O) NR₆R₇, S (O) _Three H or C (O) OC_1-4May be independently substituted 1-3 times with alkyl.
R;_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Alkenyl, heteroaryl, heteroaryl-C_1-4Alkyl, heteroaryl C_2-4 Alkenyl, heterocycle, heterocycle C_1-4W is an alkyl, wherein the aryl, heteroaryl and heterocyclic-containing groups are optionally substituted;The E-containing ring isWherein the asterisk * indicates the bonding position of the ring;₂₀Is W₁An optionally substituted heteroaryl, an optionally substituted C_5-8Cycloalkyl, optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl or optionally substituted C_2-10Alkynyl
; W₁IsAnd the E′-containing ring is(Wherein the asterisk * indicates the bonding position of the ring), if desired.] Or a pharmaceutically acceptable salt thereof. 10. The compound according to claim 9, wherein R is (CR ₈ R ₈ ) _r C (O) ₂ H. 11. 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, heteroaryl alkenyl, or S (O) NR ₄ R ₅ a is the compound of claim 9. 12. The compound according to claim 9, wherein R ₂₀ is W ₁ . 13. The compound according to claim 9, wherein R ₂₀ is heteroaryl. 14. Y is halogen, C _1-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylenedioxy, N
The compound according to claim 12, which is R ₄ R ₅ , thio C _1-4 alkyl, thioaryl, halo-substituted alkoxy, optionally substituted C _1-4 alkyl, or hydroxyalkyl. 15. The compound according to claim 9, wherein R ¹ is monosubstituted at the 2- or 4-position or disubstituted at the 2,4-position by an electron-withdrawing group. 16. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 9 to 15 and a pharmaceutically acceptable carrier or diluent. 17. A process for preparing a compound according to claim 9 wherein the compound has the formula: [Wherein R, R ₁ and m are as defined in formula (I)], a compound of the formula: -N (X)-(CR ₁₃ R ₁₄ ) _v -R _{20 wherein} X, R ₁₃ , R ₁₄ , v and R ₂₀ are as defined in formula (I).
A method comprising reacting with a compound of formula (I). 18. A process for preparing a compound of formula (I), comprising: Wherein R ₁ , m and R are as defined in the formula (I), and a compound represented by the formula: NH ₂ — (CR ₁₃ R ₁₄ ) _v —R ₂₀ [wherein R ₁₃ , R ₁₄ , v and R ₂₀ have the same meanings as defined in formula (I)] to give a compound of formula (I); A method that includes protecting.