JP2002509105A - IL-8 receptor antagonist - Google Patents

Abstract

  (57) [Summary] The present invention relates to novel compounds of formula (I) and compositions thereof useful in the treatment of conditions mediated by chemokines, interleukin-8 (IL-8).

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to novel benzoisothiazole-substituted compounds, pharmaceutical compositions, methods for their preparation, and IL-8, GROα, GROβ, GROγ, ENA-78 and N
It relates to their use in the treatment of AP-2 mediated diseases.

BACKGROUND OF THE INVENTION [0002] Neutrophil attracting / activating protein-1 (interleukin-8 (IL-8))
NAP-1), monocyte-derived neutrophil chemotactic factor (MDNCF), neutrophil activator (
Many different names are used, such as NAF) and T-cell lymphocyte chemotactic factor. Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is exposed to macrophages, most nucleated cells including fibroblasts, endothelial cells and epithelial cells, and chemotactic factors such as LPS or FMLP exposed to TNF, IL-1α, IL-1β or LPS. 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 , 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 referred to by different names. For example, GROα, β, γ are referred to as MGSAα, β, and γ, respectively (melanoma growth stimulating activity). Richmond et al., J. Cell Physiology 129, 375
(1986) and Chang et al., J. Immunol 148, 451 (1992). C
All α-family chemokines with an ELR motif immediately preceding the XC motif bind to the IL-8β receptor.

[0003] IL-8, GROα, GROβ, GROγ, NAP-2 and ENA-78 stimulate many functions in vitro. These were all shown to be chemoattractant for neutrophils, whereas IL-8 and GROα showed T-lymphocyte and basophil chemotaxis. In addition, IL-8 can induce histamine release from basophils from both normal and atopic individuals. GROα and IL-8 can also trigger lysosomal enzyme release from neutrophils and respiratory bursts. IL-8 has also been shown to increase the surface expression of Mac-1 (CD11b / CD18) on neutrophils without newly synthesizing proteins. This may contribute to increased attachment of neutrophils to vascular endothelial cells. Many known diseases are characterized by massive neutrophil infiltration. IL-8,
Since GROα, GROβ, GROγ and NAP-2 promote neutrophil accumulation and activation, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis [ Baggiolini et al., FEB S 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., J. Clin. Invest. 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) have also been associated with hemophilia. Strieter et al., Science 258, 1798 (19
92).

In vitro, IL-8, GROα, GROβ, GROγ and NAP-2 bind to and activate the seven transmembrane G-protein binding family of receptors, in particular the IL-8 receptor. , Most notably by binding to β-receptors, induce neutrophil shape change, chemotaxis, granule release and respiratory burst. Thomas e
.. t al, J. Biol Chem 266, 14839 (1991);.. and Holmes et al, Science 2 53, 1278 (1991). The development of non-peptidic small molecule antagonists for members of this receptor family has been pursued. For a review, see R. Freidinger in:
Progress in Drug Research , Vol. 40, pp. 33-98, Birkhauser Verlag, Basel
See 1993. Thus, the IL-8 receptor represents a promising target for developing new anti-inflammatory agents.

[0005] Two high-affinity human IL-8 receptors (77% homology): for IL-8Rα and IL-8, which bind only IL-8 with high affinity, and for GROα, GR
IL-8Rβ with high affinity for Oβ, GROγ and NAP-2 has been characterized. 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 in the art for treatment of compounds capable of binding to IL-8α or β receptors. Thus, the symptoms associated with increased IL-8 production, which involves chemotaxis of neutrophils and T-cell subsets to sites of inflammation, will benefit from compounds that are inhibitors of IL-8 receptor binding. Will.

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 medicament thereof. A method comprising administering a pharmaceutically acceptable salt. In particular, the chemokine is IL-8. The present invention further relates to a method of inhibiting the binding of IL-8 to its receptor in a mammal in need thereof, wherein the mammal is administered with an effective amount of a compound of formula (I). A method comprising: The present invention also provides novel compounds of formula (I), and pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutical carrier or diluent.

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

Embedded image[Where A is CR₂₀R_{twenty one}R is NH-C (= NX) -NH- (CR₁₃R₁₄)_vX is cyano, OR₁₁, C (O) R₁₁, C (O) OR₁₁, S (O)_TwoR_{twenty two}, R_{twenty three}Or C (O) NR_{twenty four}R_{twenty five}Z is W, optionally substituted heteroaryl, optionally substituted C_{Five- 8} Cycloalkyl, optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl or optionally substituted C_2-10N is an integer of 1 to 3; m is an integer of 1 or 3; q is 0 or an integer of 1 to 10; s is an integer of 1 to 3 T is 0, or an integer of 1 or 2; v is 0, or an integer of 1 to 4;₁Is 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, a
Reel, aryl C_1-4Alkyl, aryloxy, aryl C_1-4Alkyloxy
Si, heteroaryl, heteroaryl C_1-4Alkyl, heterocyclic, heterocyclic C_1-4Alkyl, heteroaryl C_1-4Alkyloxy, ally
Le C_2-10Alkenyl, heteroaryl C_2-10Alkenyl, heterocyclic C _2-10 Alkenyl, (CR₈R₈)_qNR_FourR_Five, C_2-10Alkenyl C (O) NR_FourR_Five, (C
R₈R₈)_qC (O) NR_FourR_Five, (CR₈R₈)_qC (O) NR_FourR_Ten, S (O)_ThreeR₈, (CR₈R ₈ )_qC (O) R₁₁, C_2-10Alkenyl C (O) R₁₁, C_2-10Alkenyl C (O) OR₁₁ , (CR₈R₈)_qC (O) R₁₁, (CR₈R₈)_qC (O) OR₁₂, (CR₈R₈)_qOC (O) R_{1 1} , (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qC (NR_Four) NR_FourR_Five, (CR₈R₈)_q NR_FourC (NR_Five) R₁₁, (CR₈R₈)_qNHS (O)_TwoR₁₇, Or (CR₈R₈)_qS (O)_Two NR_FourR_FiveOr two R₁The groups together form O- (CH_Two)_s O or a 5- or 6-membered saturated or unsaturated ring may be formed, wherein
, Heteroaryl, and heterocyclic containing rings are substituted
May be; 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, heterocyclic, heterocyclic C_1-4Is alkyl
Or R_FourAnd R_FiveTogether with the nitrogen to which they are attached form O / N /
Forming a 5- to 7-membered ring optionally having an additional heteroatom selected from S
And R₆And R₇Is independently hydrogen or C_1-4An alkyl group or R₆ And R₇Together with the nitrogen to which they are attached form a 5- to 7-membered ring which may have additional heteroatoms selected from oxygen, nitrogen or sulfur
And R₈Is independently hydrogen or C_1-4R is 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_1-4Alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C_1-4Alkyl; R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or substituted
An optionally substituted arylalkyl; R₁₃And R₁₄Is independently hydrogen, optionally substituted C_1-4Alkyl or R₁₃And R₁₄One is an optionally substituted aryl
May be; R_FifteenAnd R₁₆Is independently hydrogen or optionally substituted C_1-4Alkyl; R₁₇Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, heteroaryl C_1-4Alkyl, heterocyclic, or heterocyclic C_1-4Where all the rings containing aryl, heteroaryl and heterocyclyl are optionally substituted;₁₈Is NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Arche
Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A
Lucenyl, heterocyclic, heterocyclic C_1-4Alkyl, where all rings containing aryl, heteroaryl, and heterocyclic are
May be substituted; R₂₀And R_{twenty one}Is independently hydrogen, halogen, cyano, halo-substituted C_1-10Al
Kill, C_1-10Alkyl, aryl, aryl C_1-4Alkyl, heteroaryl, heteroaryl C_1-4Alkyl, heterocyclic, heterocyclic C_1-4 Alkyl, (CR₈R₈)_qOR_Four, (CR₈R₈)_qC (O) R₁₁, (CR₈R₈)_qC (O) OR ₁₂ , (CR₈R₈)_qOC (O) R₁₁, (CR₈R₈)_qNR_FourR_Five, (CR₈R₈)_qNR_FourC (O)
R₁₁, Or (CR₈R₈)_qC (O) NR_FourR_TenWhere aryl, heteroa
Reels and rings containing heterocyclic may be substituted;
But R₂₀And R_{twenty one}Are never both hydrogen; R_{twenty two}Is C_1-4Alkyl, NR_FifteenR₁₆, OR₁₁An optionally substituted aryl, an optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4Alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic
C_1-4R is alkyl;_{twenty three}Is an optionally substituted C_1-4Alkyl, optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4Alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic
C_1-4R is alkyl;_{twenty four}And R_{twenty five}Is independently hydrogen, optionally substituted C_1-4Alkyl, optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl
C_1-4Alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic C_1-4Alkyl or R_{twenty four}And R_{twenty five}Is selected from oxygen, nitrogen or sulfur, together with the nitrogen to which they are attached.
Y independently forms a hydrogen, halogen, nitro, cyano, halo-substituted C_1-10Alkyl
, C_1-10Alkyl, C_2-10Alkenyl, C_1-10Alkoxy, halo-substituted C_1-10Al
Koxy, (CR₈R₈)_qS (O)_tR_Four, Hydroxy, hydroxy C_1-4Alkyl, ant
, Aryl C_1-4Alkyl, aryloxy, aryl C_1-4Alkyloxy
, Heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_1-4Archi
Leoxy, heterocyclic, heterocyclic C_1-4Alkyl, aryl C_2-10Alkenyl, heteroaryl C_2-10Alkenyl, heterocyclic C_{2- Ten} Alkenyl, (CR₈R₈)_qNR_FourR_Five, C_2-10Alkenyl C (O) NR_FourR_Five, (CR ₈ R₈)_qC (O) NR_FourR_Five, (CR₈R₈)_qC (O) NR_FourR_Ten, S (O)_ThreeR₈, (CR₈R₈) _q C (O) R₁₁, C_2-10Alkenyl C (O) R₁₁, C_2-10Alkenyl C (O) OR₁₁, (
CR₈R₈)_qC (O) OR₁₂, (CR₈R₈)_qOC (O) R₁₁, (CR₈R₈)_qNR_FourC (O)
R₁₁, (CR₈R₈)_qC (NR_Four) NR_FourR_Five, (CR₈R₈)_qNR_FourC (NR_Five) R₁₁, (CR ₈ R₈)_qNHS (O)_TwoR₁₈, Or (CR₈R₈)_qS (O)_TwoNR_FourR_FiveOr two Y groups are taken together to form O- (CH_Two)_sO or 5 or 6 member saturation
Or form an unsaturated ring, wherein aryl, heteroaryl, and hetero
The ring containing a cyclic is optionally substituted; W is

Embedded image An E-containing ring is

Embedded image Asterisk * means the point of attachment of the ring] or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION The compounds of formula (I) may further be used in non-human mammals in need of inhibition of IL-8 or other chemokines that bind to IL-8 α and β receptors. Used in connection with veterinary treatment. Chemokine-mediated diseases for therapeutic or prophylactic treatment in animals include the conditions as listed herein in the Therapies section.

In the compounds of formula (I), suitably₁Is independently hydrogen; halogen; nitro; cyano; halo-substituted C_1-10Alkyl, for example CF_ThreeC_1-10Alkyl, for example methyl, ethyl, isopropyl or n-propyl; C_2-10A
Lucenyl; C_1-10Alkoxy, eg, methoxy or ethoxy; halo-substituted C_{1- Ten} Alkoxy, such as trifluoromethoxy; azide; (CR₈R₈)_qS (O)_tR _Four (Where t is 0, 1 or 2); hydroxy; hydroxy C_1-4Al
Kill, for example, methanol or ethanol; aryl, for example, phenyl or
Is naphthyl; aryl C_1-4Alkyl, such as benzyl; aryloxy, such as phenoxy; aryl C_1-4Alkyloxy, such as benzyloxy; heteroaryl; heteroarylalkyl; heteroarylC_1-4Alkyloxy; aryl C_2-10Alkenyl; heteroaryl C_2-10Alkenyl; heterocyclic C_2-10Alkenyl; (CR₈R₈)_qNR_FourR_FiveC_2-10Alkenyl C (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_Five; (CR₈R₈)_qC (O) NR_FourR_TenS (O)_Three H; S (O)_ThreeR₈; (CR₈R₈)_qC (O) R₁₁C_2-10Alkenyl C (O) R₁₁C_{2-1 0} Alkenyl C (O) OR₁₁C (O) R₁₁; (CR₈R₈)_qC (O) OR₁₂; (CR₈R₈) _q OC (O) R₁₁; (CR₈R₈)_qNR_FourC (O) R₁₁; (CR₈R₈)_qC (NR_Four) NR_FourR_Five , (CR₈R₈)_qNR_FourC (NR_Five) R₁₁, (CR₈R₈)_qNHS (O)_TwoR₁₇; Or (CR ₈ R₈)_qS (O)_TwoNR_FourR_FiveOr two R₁Groups together
O- (CH_Two)_sO- or may form a 5- or 6-membered saturated or unsaturated ring
. The aryl-, heteroaryl-, and heterocyclic-containing rings are
It may be substituted as defined below.

[0010] Suitably, m is an integer from 1 to 3. Suitably, s is an integer from 1 to 3. Suitably, q is 0 or an integer from 1 to 10. When R ₁ forms a dioxy bridge, s is preferably 1. If R ₁ forms one additional saturated or unsaturated ring, it is preferably an unsaturated 6-membered ring forming a naphthalene ring system. These rings may be independently substituted one to three times by 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 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 which may have additional heteroatoms selected from O / N / S. Suitably, R ₆ and R ₇ are independently hydrogen or a C _1-4 alkyl group, or R ₆ and R ₇ are taken together with the nitrogen to which they are attached to oxygen, 5 to 7 optionally having an additional heteroatom selected from nitrogen or sulfur
Form a member ring.

Suitably, R ₈ is independently hydrogen or C _1-4 alkyl. Suitably, R ₁₀ is C _1-10 alkyl C (O) ₂ R ₈ , for example, CH ₂ C (O) ₂ H or CH ₂ C (O) ₂ CH ₃ . Suitably, R ₁₁ is hydrogen, C _1-4 alkyl, aryl, aryl C _1-4 alkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic, or heterocyclic C _1-4 alkyl. It is. Suitably, R ₁₂ is hydrogen, C _1-10 alkyl, optionally substituted aryl or optionally substituted arylalkyl.

Suitably, R ₁₃ and R ₁₄ are independently hydrogen, C _1-4 alkyl, which may be straight or branched chain as defined herein; Or one of R ₁₃ and R ₁₄ is an optionally substituted aryl; v is 0 or 1
Or an integer from 4 to 4. When R ₁₃ or R ₁₄ is an alkyl which may be substituted, the alkyl group, halogen, halo-substituted C _1-4 alkyl, e.g., trifluoromethyl; hydroxy sheet; hydroxyalkyl C _1-4 alkyl; C _{1 -4} alkoxy, for example, 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 ; It may be independently substituted one to three times by C (O) OR ₈ .

Suitably, R ₁₇ is C _1-4 alkyl, aryl, arylalkyl, heteroaryl, heteroaryl C _1-4 alkyl, heterocyclic, or heterocyclic C _1-4 alkyl, wherein Wherein the rings containing aryl, heteroaryl and heterocyclic are all optionally substituted.

[0015] Suitably, Y is independently hydrogen, halogen, nitro, cyano, halosubstituted C _1-10 alkyl; C _1-10 alkyl; C _2-10 alkenyl; C _1-10 alkoxy; halosubstituted C _1-10 alkoxy; (CR ₈ R ₈ ) _q S (O) _t R ₄ ; hydroxy; hydroxy C _1-4 alkyl; aryl; aryl C _1-4 alkyl; aryloxy; aryl C _1-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C _1-4 alkyloxy; heterocyclic, heterocyclic C _1-4 alkyl; the 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 R ₈ ;
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; (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 C (NR 4} ) NR 4 R 5, (CR 8 R 8) q NR 4 C (NR 5) R 11, (CR 8 R 8) q NHS (O) 2 R 18; (CR 8 R _{8) q S (O) 2} NR 4 is selected from R _5, or two Y groups together, O- (CH _{2) s} O or a 5 to 6 membered saturated or unsaturated ring May be formed. The above aryl, heteroaryl and heterocyclic containing rings may all be substituted as defined herein.

Suitably, n is an integer from 1 to 3. When Y forms a dioxy bridge, s is preferably 1. Y is 1
If it forms two additional saturated or unsaturated rings, it is preferably an unsaturated 6-membered ring forming a naphthalene ring system. These rings may be independently substituted one to three times by another Y group as defined above. Suitably, R ₁₈ 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, heterocyclyl. Click, heterocyclic C _1-4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing rings are all optionally substituted.

Y is preferably halogen, C _1-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or aryl C _1-4 alkoxy, methylenedioxy, NR ₄ R _5, thio C _1-4 alkyl, thioaryl, halo-substituted C _1-10 alkoxy, optionally C _1-4 alkyl optionally substituted or hydroxy C _{1 -4} alkyl. Y is more preferably a monosubstituted halogen, disubstituted halogen, monosubstituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl. More preferably, these groups are mono- or disubstituted at the 2 ′ or 2 ′, 3 ′ position when Z is W and W is a phenyl ring (eg, when no E group is present). ing.

Y may be substituted at any of the five ring positions when W is a phenyl group, but Y is preferably monosubstituted at the 2 ′ or 3 ′ position, and is preferably Is not substituted at the 4 ′ position. When the phenyl ring is disubstituted, these substituents are preferably at the 2 'or 3' position of the monocyclic ring. R ₁ and Y can both be hydrogen, but preferably at least one of the rings is substituted, and preferably both rings are substituted.

A is suitably CR₂₀R_{twenty one}It is. Suitably, R₂₀And R_{twenty one}Is independently hydrogen, halogen, cyano, halo substituted
C_1-10Alkyl, C_1-10Alkyl, aryl, aryl C_1-4Alkyl, heteroaryl, heteroarylC_1-4Alkyl, heterocyclic, heterocyclic C_1-4Alkyl, (CR₈R₈)_qOR_Four, (CR₈R₈)_qC (O) R₁₁, (CR₈R₈) _q C (O) OR₁₂, (CR₈R₈)_qOC (O) R₁₁, (CR₈R₈)_qNR_FourR_Five, (CR₈R₈)_q NR_FourC (O) R₁₁, Or (CR₈R₈)_qC (O) NR_FourR_TenWherein the ring containing aryl, heteroaryl, and heterocyclic is substituted
Or R₂₀And R_{twenty one}Are not both hydrogen. Suitably, R_FifteenAnd R₁₆Is independently hydrogen or R₁₃And R₁₄And optionally substituted C as defined above for_1-4Alkyl.

In the compounds of formula (I), suitably Z is W, optionally substituted heteroaryl, _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.

Suitably, W is

Embedded image It is.

Suitably, the E-containing ring is

Embedded image May be selected.

An E-containing ring indicated by its point of attachment via an asterisk (*) may be present. If not present, the ring is a phenyl group substituted with a Y group as shown. The E ring may be substituted with a (Y) _n group in either a saturated or unsaturated ring, and is shown herein as being substituted only on an unsaturated ring.

When Z is an optionally substituted C _5-8 cycloalkyl ring, the ring may be optionally substituted by (Y) _{n as} defined above. When Z is an optionally substituted C _1-10 alkyl, an optionally substituted C _2-10 alkenyl, or an optionally substituted C _2-10 alkynyl, these groups are halogen; Cyano; halo-substituted C _1-10 alkyl, such as trifluoromethyl; C _1-10 alkoxy; halo-substituted C _1-10 alkoxy; S (O) _t R ₄ ; hydroxy; hydroxy C _1-4 alkyl; aryloxy; ; aryl C _1-4 alkyloxy; heteroaryloxy; heteroaryl C _1-4 alkyloxy; Heterosai click, heterocyclic C _1-4 alkyl; heterocyclic-oxy; hetero cyclic C _1-4 alkyloxy; _{NR 4 R 5; C (O} ) NR 4 R 5; C (O) N R 4 R 10; S (O) 3 R 8; C (O) R 11; C (O) OR 12; OC (O) R ₁₁ ; or independent of NR ₄ C (O) R ₁₁ And may be substituted one or more times.

C wherein Z is optionally substituted_2-10Alkenyl or optionally substituted C _2-10 When alkynyl, these groups may also be aryl, in addition to the groups mentioned above.
Le, aryl C_1-4Alkyl, heteroaryl, and heteroaryl C_1-4Al
It may be replaced by a kill.

In the compounds of formula (I), when Z is a heteroaryl (HET) ring, it is suitably a heteroaryl ring or ring system. If the HET group is polycyclic, the ring containing the heteroatom need not be directly attached to the urea moiety.
All rings in these ring systems may be optionally substituted as defined herein. Preferably, the HET moiety is pyridyl, which may be 2-, 3- or 4-pyridyl. If the ring is a polycyclic system, it is preferably a benzimidazole, dibenzothiophene or indole ring. Other heterocyclic rings include, but are not limited to, thiophene, furan, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline, quinazolinyl, pyridine, oxazole, thiazole, thiadiazole, triazole, imidazole or benzimidazole is not. In the compound represented by formula (I), the HET ring may be independently substituted with (Y) _n one to three times as described above.

Suitably, R_dIs NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C _2-4 Alkenyl, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl
Le C_2-4Alkenyl, heterocyclic, heterocyclic C_1-4With alkyl
Where alkyl, aryl, heteroaryl, and heterocyclic
The moieties containing the alkenyl may be substituted as defined herein. In the compounds of formula (I), X is suitably cyano, OR₁₁, C (O) NR_{twenty four}R_{twenty five}, R_{twenty three}, C (O) R₁₁, C (O) OR₁₁Or S (O)_TwoR_{twenty two}It is.

Suitably, R ₂₂ is C _1-4 alkyl, NR ₁₅ R ₁₆ , OR ₁₁ , optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, substituted Or an optionally substituted heteroaryl C _1-4 alkyl, an optionally substituted heterocyclic, or an optionally substituted heterocyclic C _1-4 alkyl. Suitably, R ₂₃ is _optionally substituted C _1-4 alkyl, optionally substituted aryl, optionally substituted aryl C _1-4 alkyl, optionally substituted heteroaryl, An optionally substituted heteroaryl C _1-4 alkyl, an optionally substituted heterocyclic, or an optionally substituted heterocyclic C _1-4 alkyl.

Suitably, R ₂₄ and R ₂₅ are independently 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 ₂₄ and R ₂₅ , together with the nitrogen to which they are attached, may have an additional heteroatom selected from oxygen, nitrogen or sulfur. A member ring may be formed.

As used herein, “optionally substituted” means “unsubstituted” unless otherwise specified.
, Halogen, for example, fluorine, chlorine, bromine or iodine; hydroxy;
Xy substitution C_1-10Alkyl; C_1-10Alkoxy, such as methoxy or ethoxy
S (O)_{m '}C_1-10Alkyl (where m 'is 0, 1 or 2), for example, methylthio, methylsulfinyl or methylsulfonyl; amino, one and
Disubstituted amino, for example, NR_FourR_FiveGroup; NHC (O) R_FourC (O) NR_FourR_FiveC (O)
OH; S (O)_TwoNR_FourR_Five; NHS (O)_TwoR₁₉, C_1-10Alkyl, for example, methyl,
Ethyl, propyl, isopropyl, or t-butyl; halo-substituted C_1-10Alkyl
, For example, CF_ThreeAn optionally substituted aryl, for example, phenyl, or an optionally substituted arylalkyl, for example, benzyl or phenethyl;
Optionally substituted heterocyclic, optionally substituted heterocyclic
Alkyl, optionally substituted heteroaryl, optionally substituted
Heteroarylalkyl (wherein these aryl, heteroaryl or
The telocyclic moiety is halogen; hydroxy; hydroxy-substituted alkyl; _1-10 Alkoxy; S (O)_{m '}C_1-10Alkyl; amino, mono- and disubstituted amino, eg
For example, NR_FourR_FiveGroup; C_1-10Alkyl or halo substituted C_1-10Alkyl, for example C
F_ThreeMay be substituted once or twice). R₁₉Is, appropriately, C_1-4Alkyl, aryl, aryl C_1-4Alkyl, Hete
Low aryl, heteroaryl C_1-4Alkyl, heterocyclic or heterocyclic C_1-4Alkyl.

The guanidine function has been found to have many types of tautomers, for example, RN-C (= NX) -NZ; RN = C (NX) -NZ; NC (-NX) = NZ, all of which are within the scope of the invention; wherein the Z group is a W and E containing ring as defined for compounds of formula (I). Including system.

[0032] 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, and the like. Acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid,
Includes basic salts of inorganic and organic acids such as salicylic acid, phenylacetic acid and mandelic acid. In addition, pharmaceutically acceptable salts of the compounds of formula (I) may be further formed together with a pharmaceutically acceptable cation, for example when the substituent comprises a carboxy group. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkali metal, alkaline earth metal, ammonium and quaternary ammonium cations.

The following terms, as used herein, mean: “halo” —refers to all halogens, ie, chloro, fluoro, bromo and iodo. “C _1-10 alkyl” or “alkyl” _{—unless the} chain length is particularly limited, straight-chain and branched groups having 1 to 10 carbon atoms, methyl, ethyl, n-propyl, iso- Propyl, n-butyl, sec-butyl, iso-
Butyl, tert-butyl, n-pentyl, and the like, but are not limited thereto. -The term "cycloalkyl" as used herein refers to a cyclic radical preferably having 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl and the like. The term "alkenyl", as used herein, in all cases, unless the chain length is limited, means a straight-chain or branched group having 2 to 10 carbon atoms, ethenyl, 1-pro- Phenyl, 2-propenyl, 2-methyl-
Examples include, but are not limited to, 1-propenyl, 1-butenyl, 2-butenyl, and the like.

"Aryl"-refers to phenyl and naphthyl. "Heteroaryl" (in itself or in combination as "heteroaryloxy" or "heteroarylalkyl")-pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole One or more rings containing one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited to, triazole, imidazole, or benzimidazole; Refers to a 10-membered aromatic ring system. "Heterocyclic" (in itself or in combination, such as "heterocyclylalkyl")-such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine
Refers to a saturated or partially unsaturated 4- to 10-membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S.

“Arylalkyl” or “heteroarylalkyl” or “heterocyclicalkyl”, as used herein, unless otherwise indicated, is attached to an aryl, heteroaryl or heterocyclic group as defined herein. Means the above C _1-10 alkyl. "Sulfinyl"-refers to the oxide S (O) of the corresponding sulfide, the term "thio" refers to sulfide and the term "sulfonyl" refers to a fully oxidized S (O) ₂ group. The term “two R ₁ groups (or two Y groups) may form a 5- or 6-membered saturated or unsaturated ring” as used herein is defined as , Naphthalene ring system, or the formation of a C ₆ cycloalkenyl, ie, a partially unsaturated 6-membered ring such as hexene, or a C ₅ cycloalkenyl moiety, ie, a ring system such as a phenyl group to which cyclopentene is attached.

Examples of the compound represented by the formula (I) include N- [4-chloro- (1,3) -dihydro-2,2-dioxo-2,1-benzoisothiazo-7-yl] -N ′ — [2-bromophenyl] -N ″ -cyanoguanidine.

Production Method The compound represented by the formula (I) can be obtained by using a synthesis method partially shown in the following scheme. The synthetic methods used in these schemes are applicable to the preparation of compounds of formula (I) having a variety of different Z, R ₁ and E ′ groups, and may be substituted with any of the appropriately protected optional substitutions. The group is reacted to make it compatible with the reactions outlined herein. In these cases, deprotection is then obtained to give compounds whose properties are generally disclosed. Once a substituted guanidine nucleus has been established, other compounds of these formulas can be prepared using standard techniques for functional group interconversion well known in the art. Although the scheme is illustrated for various compounds of formula (I), this is merely illustrative and does not limit the scope of synthesis available using these methods.

[0038]

Embedded image

If the desired heterocyclic compound (5-Scheme 1) is not commercially available, a commercially available 2
, 6-dichlorobenzyl bromide is treated with potassium thioacetate to form the thioacetate, then forming a Suruhoniruku Rorido (3-scheme 1) is oxidized using chlorine gas in AcOH / H ₂ O in Can be. The sulfonyl chloride, using NH ₄ OH, then can be converted to the corresponding sulfonamide (4-Scheme 1) by acidification. The cyclic sulfonamide (5-Scheme 1) is treated with copper metal as a catalyst under basic conditions such as potassium carbonate,
Then, it can be cyclized by acidification.

[0040]

Embedded image

Cyclic sulfonamides (6-Scheme 2) can be prepared by protecting the nitrogen with allyl bromide, followed by alkyl halide in the presence of a strong base such as sodium hexamethyldisilazane. Is used to alkylate the methylene. Nitro compound (8-Scheme 2), (using NaNO ₃ or NH ₄ NO ₃₎ standard nitration conditions can be prepared from 7-Scheme 2 with, then methanol, ethanol, DMF or The corresponding aniline (9-Scheme 2) can be reduced using tin chloride in a polar solvent such as ethyl acetate using standard conditions.

[0042]

Embedded image

Another method for forming the aniline compound (9-Scheme 2) is shown in Scheme 3.
Nitro compounds unprotected (10 Scheme 3), at 25 ° C., standard nitration conditions (using HNO ₃ or NaNO ₃₎ can it to manufacture from 5-Scheme 1 below. The aniline compound (9-Scheme 2) protects the nitrogen of compound 10 with allyl bromide and then alkylates methylene with an alkyl halide to give E
It can be produced by reduction with SnCl ₂ in tOH.

[0044]

Embedded image

An ortho-substituted heterocyclic phenylthiourea (12-Scheme 4) is used to condense a commercially available optionally substituted arylisothiocyanate with the corresponding aniline 9 in an aprotic solvent (eg, DMF). It is manufactured under standard conditions including: Alternatively, aniline 10 is treated with thiophosgene to form an isothiocyanate (13-Scheme 4), which is then reacted with a commercially available, optionally substituted aniline to form aniline 10 in a two-step process. To form thiourea 12.

[0046]

Embedded image

The carbodiimides (14-Scheme 5) were obtained from Fell and Coppola (Fell, J. B.
, Coppola, JB, Syn Communications 25, 43, 1995)
Prepared from thiourea (12-Scheme 4) by reaction with methanesulfonyl chloride and a tertiary amine base such as triethylamine. Carbodiimides can also be treated with phosgene and tertiary amines or thiourea 1
2 may be prepared by reacting 2 with triphenylphosphine, carbon tetrachloride and triethylamine.

The title compound converts the protected carbodiimide (14-Scheme 5) under conditions where the nucleophile is present in large excess and the reaction time is kept as short as possible by careful monitoring of the completion of the reaction. anion NH-X (obtained by the reaction of a base such as NH ₂ X and NaH) or the neutral species NH ₂ X (X = CN) and a tertiary amine base (e.g., Hunig's base or triethylamine) is reacted with, then It is synthesized by deprotecting allyl using palladium catalyst in the presence of a nucleophilic reagent such as NaBH _4.

Alternatively, suitable substituted guanidines are described in PCT application PCT / US97 / 13863, PCT application PCT / US97 / 13864; and PCT application PCT / US97 / 13858, which are hereby incorporated by reference in their entirety. )).

Another embodiment of the present invention relates to a compound of formula (II):

Embedded image [Wherein A, R ₁ and m are the same as defined above in formula (I), and R _a is hydrogen or a nitrogen protecting group].

Another embodiment of the present invention relates to a compound of formula (IV):

Embedded image [Wherein A, R ₁ and m are the same as defined above in formula (I), and R _a is hydrogen or a nitrogen protecting group].

[0052]

Embedded image Wherein A, R ₁ , m, v, Z, R ₁₃ and R ₁₄ are the same as defined above in formula (I), and R _a is hydrogen or a nitrogen protecting group.

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

Embedded image [Wherein A, R ₁ , m, v, Z, R ₁₃ and R ₁₄ are the same as defined above in formula (I), and R _a is hydrogen or a nitrogen protecting group]. it is reacted with NH-X or NH ₂ X and a tertiary amine, to give a compound of formula (I), then, if necessary, by the formula (I) X is deprotected is cyano A method for producing a compound represented by the formula (I), which comprises obtaining the compound represented by the formula (I).

Synthetic Examples The present invention will be described with reference to the following examples, which are merely illustrative and do not limit the scope of the present invention in any way. Unless otherwise indicated, all temperatures are in degrees Celsius, all solvents are of the highest purity available, and all reactions are performed under anhydrous conditions under an argon atmosphere. 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-NMR
Spectra (hereinafter referred to as "NMR") were recorded at 400 MHz using a Bruker or Am400 spectrometer. The multiplicity is: s = single line, d = double line, t =
Triplet, q = quadruple, m = multiplet, br represents broad signal. Sat
. Represents a saturated solution, and eq represents a molar equivalent ratio of the reagent to the main reactant.

Example 1 N- [4-chloro-1,3-dihydro-2,2-dioxo-1,2-benzisothiazo) -7-yl] -N ′-[2-bromophenyl] -N ″ Preparation of -cyanoguanidine a) Preparation of 2,6-dichlorobenzyl thioacetate Potassium thioacetate (31.3 g, 276 mmol) was added to a solution of 2,6-dichlorobenzyl bromide (60 g, 248 mmol) in DMF (200 ml). ) Was added. The reaction mixture was stirred at room temperature for 2 hours. It was then partitioned between ethyl acetate and water. The combined organic phases were dried and concentrated to give a yellow oil (58.71 g, 99%). EI-MS m / z 235, 237 (M + H) ⁺ , 257, 259
(M + Na) ⁺ .

B) Preparation of 2,6-dichlorobenzylsulfonyl chloride 2,6-dichlorobenzylthioacetate (29.19 g, 124 mmol) and sodium acetate (68 g) were added to glacial acetic acid (646 ml) and water (141 ml).
Was dissolved in the mixture. Chlorine gas was bubbled through the solution for 15 minutes. The mixture was evaporated and the residue was extracted with t-butyl-O-methyl ether. The combined organic layers were dried and concentrated to give the desired product as a white solid (24.1 g, 75%). NMR (400 MHz, CDCl ₃ ) 7.45 (d, J = 7.7 Hz, 2H), 7.36 (t, J = 8 Hz, 1H), 5.44 (s, 1H).

C) Preparation of 2,6-dichlorobenzylsulfonamide 2,6-dichlorobenzylsulfonyl chloride (23.9 g, 92.3 mmol) in concentrated ammonium hydroxide (200 ml) was stirred overnight at room temperature. The precipitate was separated by acidification at −10 ° C. with chilled concentrated hydrochloric acid and filtered to give the desired product as a white crystalline plate (14.38 g, 65%). EI-MS m / z
240, 242 (M + H) ⁺ .

D) Preparation of 4-chloro-1,3-dihydro-2,2-dioxo-1,2-benzisothiazole Potassium carbonate (2.89 g, 20.92 mmol) in a round bottom flask, copper powder (
To 376 mg) and N, N-dimethylaniline (30 ml) was added 2,6-dichlorobenzylsulfonamide (5 g, 20.92 mmol). The reaction mixture was stirred at 170 ° C. for 4 hours, then cooled to room temperature, partitioned between t-butyl-O-methyl ether and 1N aqueous HCl and extracted three times with t-butyl-O-methyl ether. . The combined organic phases were washed with 1N HCl (3 times), water (3 times), and brine, then dried (MgSO ₄ ) and concentrated to give the desired product (
4.2 g, 98%). NMR (400 MHz, CDCl ₃ ) 7.24 (t, J = 8H
z, 1H), 7.06 (d, J = 8 Hz, 1H), 6.96 (s, 1H), 6.79 (d, J = 8 Hz, 1H), 4.42 (s, 2H); MS (ES ^-) m / e 202
, 204 [M−H] ⁻ .

E) 1-allyl-4-chloro-2,2-dioxo-1,2-benzoisothiazoline using 4-chloro-1,3-dihydro-2,2-dioxo-1,2-benzoisothiazole Before, water was removed by azeotropy with toluene. Dry 4-chloro-1,3-dihydro-2,2-dioxo-2,1-benzoisothiazole (5.2 g, 25.5
(3 mmol) in DMF (15 ml) was added dropwise to a slurry of sodium hydride (60%, 1.072 g, 26.8 mmol) and after 15 minutes, allyl bromide (2.4).
(3 ml, 28.08 mmol). The reaction mixture was stirred at room temperature for 16 hours. It was then partitioned between ethyl acetate and water. Dry the combined organic phases,
Concentration gave the desired product (6.04 g, 97%). NMR (400 MHz, C
DCl ₃ ) 7.21 (t, J = 8.17 Hz, 1 H), 6.97 (d, J = 8.2 Hz,
1H), 6.62 (d, J = 8.17 Hz, 1H), 5.93-5.86 (m, 1H), 5.38 (d, J = 17.1 Hz, 1H), 5.30 ( d, J = 10.3 Hz, 1
H), 4.36 (s, 2H), 4.19 (d, J = 5.4H).

F) 1-allyl-4-chloro-2,2-dioxo-7-nitro-1,2-benzo
Preparation of isothiazoline 1-allyl-4-chloro-2,2-dioxo-1,2-benzisothiazoline (
4.24 g, 17.4 mmol) in chloroform (25 ml)
Ammonium nitrate (1.5 g, 18.7 mmol) and trifluoroacetic anhydride (
15 ml) was added. The mixture was stirred at room temperature under Ar. After 72 hours, the reaction mixture was concentrated under reduced pressure and the residue was washed with t-butyl-O-methyl ether and 5% NaHCO 3._ThreeAnd then extracted with ether. MgSO 4 combined organic layer _Four And filtered. The solvent was evaporated and the resulting solid was chromatographed on silica gel (15% ethyl acetate / hexane) to give the desired product in a trace amount.
Obtained with the pure. The column was recrystallized from ethanol to give pure product (
998 mg, 19.9%). NMR (400 MHz, CDCl_Three) 7.91 (d, J = 9 Hz, 1H), 7.19 (d, J = 9.1 Hz, 1H), 5.65-5.55 (m
, 1H), 5.24 (dd, J = 17.2 Hz, J = 10 Hz, 2H), 4.43 (m, 4H).

G) Preparation of 1-allyl-7-amino-2,2-dioxo-4-chloro-1,2-benzisothiazoline 1-allyl-4-chloro-2,2-dioxo-7-nitro-1 To a solution of 1,2-benzoisothiazoline (1.184 g, 4.1 mmol) in ethanol (120 ml) was added tin (II) chloride (4 g, 17.7 mmol). The reaction mixture was stirred at room temperature for 18 hours. EtOH was removed under reduced pressure and NaHCO ₃ (aq) was added to the reaction mixture. The tin salt was removed by filtration. The filtrate was extracted with ethyl acetate (3 times). The combined organic layers were washed with 5% NaHCO ₃ , water, then brine, dried over MgSO ₄ , filtered and concentrated under reduced pressure to give 1.2 g. This was chromatographed (silica gel) to give the desired product as a yellow crystalline solid (720 mg, 6 mg).
9%). ES ^<+> -MS m / z 259, 261 (M + H) ^<+> .

H) 1-allyl-4-chloro-2,2-dioxo-7-isothiocyanato-1,
Preparation of 2-benzoisothiazoline 1-allyl-7-amino-4-chloro-2,2-dioxo-1,2-benzoisothiazoline (258 mg, 1 mmol), chloroform (50 ml), sodium bicarbonate (1.25 g, To a stirred mixture of 14.8 mmol) and water (25 ml) was added thiophosgene (266 uL, 3.3 mmol). After stirring at room temperature for 72 hours, tlc showed the starting material was still present and thiophosgene (133 uL, 1.65 mmol) was added. After stirring overnight, the mixture was extracted three times with chloroform, dried (MgSO ₄ ) and evaporated under reduced pressure to give the desired product in quantitative yield. NMR (400 MHz, CDCl ₃ ) 7.25 (d, 1
H), 7.04 (d, 1H), 5.92 (m, 1H), 5.42 (d, 1H), 5.
31 (d, 1H), 4.52 (d, 2H), 4.34 (s, 2H).

I) Preparation of N-[(1-allyl-4-chloro-2,2-dioxo-1,2-benzoisothiazolin) -7-yl] -N ′-(2-bromophenyl) thiourea 1-allyl-2,2-dioxo-4-chloro-7-isothiocyanato-2,1 in a solution of -bromoaniline (172 mg, 1 mmol) in DMF (5.0 ml).
-Benzoisothiazoline (300 mg, 1 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was partitioned between ethyl acetate and 0.5M sodium dihydrogen phosphate and extracted with further ethyl acetate. Dried (MgSO ₄ ) and evaporated under reduced pressure to give a yellow oil, which was recrystallized from chloroform to give the desired product as a white solid (338 mg, 72%). ^{MS (ES +) m / e} 472,474,476 [M + H] +; MS (ES -) m / e 470,472, 474 [M-H] -.

J) N-[(1-allyl-4-chloro-2,2-dioxo-1,2-benzoisothiazolin) -7-yl] -N ′-(2-bromophenyl) -carbodiimide N- [ (1-allyl-2,2-dioxo-4-chloro-1,2-benzoisothiazoline) -7-yl] -N '-[2-bromophenyl] thiourea (335 mg, 0.71
To a stirred solution of triethylamine (0.3 mmol, 2.1 mmol) in methylene chloride at 0 ° C. under Ar was added methanesulfonyl chloride (115 uL, 1.
48 mmol) was added dropwise. The reaction was stirred at 0 ° C. for 15 minutes and tlc showed no starting material. The reaction mixture was chromatographed on silica gel eluting with methylene chloride to give the title compound as a tan solid (3
38 mg,> 100%). This was used for the next reaction without further purification. IR (K
Br) 2146, 2108 cm ^-1 .

K) N-[(1-allyl-4-chloro-2,2-dioxo-1,2-benzoisothiazolin) -7-yl] -N ′-(2-bromophenyl) -N ″- Cyanoguanidine cyanamide (330 mg, 8.85 mmol) and Huinig base (0.66 ml)
) In acetonitrile was added to N-[(1-allyl-4-chloro-2,2-dioxo-2,1-benzoisothiazolin) -7-yl] -N '-(2-bromophenyl) -carbodiimide (330 mg, 0.7 mmol) of acetonitrile (25 m
The solution in l) was added dropwise. The reaction was stirred at room temperature for 15 minutes, then the solvent was removed in vacuo and the residue was hydrolyzed with 0.5M sodium dihydrogen phosphate. The ethyl acetate extract of the aqueous mixture was washed with 0.5M sodium dihydrogen phosphate and brine. After drying (MgSO ₄ ), it was filtered and evaporated under reduced pressure to give a tan colored crude solid (500 mg). This was subjected to silica gel chromatography (2% methanol / chloroform) to give the title compound as a cream solid (280 mg,
82%). ^{MS (ES -) m / e} 478,480,482 [M-H] -.

1) N-[(4-Chloro-1,3-dihydro-2,2-dioxo-1,2-benzoisothiazo) -7-yl] -N ′-(2-bromophenyl) -N ′ '-Cyanoguanidine N-[(1-allyl-4-chloro-2,2-dioxo-1,2-benzoisothiazoline) -7-yl] -N'-(2-bromophenyl) -N ''-cyano Guanidine (80 mg, 0.166 mmol) and sodium borohydride (20 mg, 0.2
(1 mmol) in THF (8 ml) at room temperature was added tetrakistriphenylphosphinepalladium [0] (8 mg). The reaction was stirred at room temperature for 2 hours.
The mixture was partitioned between ethyl acetate and 0.5M sodium dihydrogen phosphate. After drying over MgSO ₄ , filtered and evaporated under reduced pressure to give a tan skin crude solid (100 mg). Silica gel chromatography, eluting with 5% methanol / chloroform, provided a pale yellow solid (10 mg), which was recrystallized from ethyl acetate / hexane to give the desired product (5 mg, 7%). ). ¹ H NMR (
400 MHz, CD ₃ CN) 7.70 (d, J = 8 Hz, 1 H), 7.52 (d, J = 8 Hz, 1 H), 7.43 (t, 1 H), 7.26-7.21 (m , 2H), 7.05 (d, 1H), 4.47 (d, 2H); IR (KBr) 2183, 1603,
^{1580,1548cm -1; MS (ES -)} m / e 438,440,442 [M -H] -; MS (ES +) m / e 440,442,444 [M + H] +; mp 135 -140 ° C..

Therapeutic Methods Compounds of formula (I), or pharmaceutically acceptable salts thereof, may be used in humans or other mammals to treat cells of such mammals, eg, monocytes and / or macrophages, Or prevention of conditions exacerbated or caused by excessive or unregulated IL-8 cytokine production by, but not limited to, other chemokines that bind to IL-8α or β receptors (also referred to as type I or type II receptors) Can be used in the manufacture of a medicament for therapeutic or therapeutic treatment. Accordingly, the present invention is directed to 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. There is provided a method comprising administering a salt.
In particular, the chemokine is IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78.

Compounds of formula (I) have cytokine function, in particular IL-8, GROα,
Inhibits GROβ, GROγ, NAP-2 or ENA-78 and is effective in biologically down-regulating physiological functions to normal levels or, in some cases, lowering normal levels to improve pathology. Is administered in an appropriate amount. For example, abnormal levels of IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 according to the present invention are defined as (i) 1 picogram / mL or more of free IL-
(Ii) any cellular IL-8 above normal physiological levels
, GROα, GROβ, GROγ, ENA-78 and NAP-2; or (i
ii) IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-7
, GRO above basal levels in cells or tissues producing each of
presence of α, GROβ, GROγ, NAP-2 or ENA-78.

There are many diseases in which excessive or unregulated IL-8 production is involved in the progression and / or development 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, stroke, 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 hematopoietic stem cell release, rhinovirus infection, periodontal disease, and various bones Resorption indications include, for example, osteoporosis or osteoarthritis.

The relationship between interleukin-8 and rhinovirus is described in the following literature; Turner et al., Clin. Infect. Dis. (1998), 26 (4), 840-846;
s et al., J. Virol. (1998), 72 (2), 934-942; Sethi et al., Clin. Exp. Imm
unol. (1997), 110 (3), 362-369; Zhu et al., Am. J. Physiol. (1997), 273 (4
, Pt. 1), L814-L824; Terajima et al., Am. J. Physil. (1997), 273 (4, Pt.
1), L749-L759; Grunberg et al., Clin. Exp. Allergy (1997), 27 (1), 36-45; and Johnston et al., J. Infect. Dis. (1997), 175 (2) , 323-329. The relationship between interleukin-8 and osteoporosis is described in the following literature: St.
reckfus et al., J. Gerontol., Ser. A (1997), 52A (6), M343-M351; Hermann,
T. PCT Application Publication WO95 / 31722; and Chaudhary et al., Endocrinology (Bal
timore) (1992), 130 (5), 2528-34.

These conditions are characterized by massive neutrophil infiltration, T cell infiltration, or neovascular growth, and IL-ILs cause neutrophil chemotaxis to inflammatory sites or directional growth of endothelial cells. 8, GROα, GROβ, GROγ, NAP-2 or ENA-7
8 associated with production. Other inflammatory cytokines (IL-8, GROα, GROβ,
Unlike GROγ or NAP-2), it has unique properties that promote neutrophil chemotaxis, enzyme release including but not limited to elastase release, and superoxide production and activation. Α-Chemokines, other than GROα, GROβ, GROγ or NAP-2, acting through IL-8 type I or II receptors, can promote neovascularization of tumors by promoting directional growth of endothelial cells.
Thus, inhibition of IL-8-induced chemotaxis or activation results in a direct decrease in neutrophil infiltration.

Recently, the role of chemokines in the treatment of HIV infection has also been demonstrated in Little.
man et al., Nature 381, pp. 661 (1996) and Koup et al., Nature 381, p.
p. 667 (1996). There is also evidence suggesting that IL-8 inhibitors are useful in treating atherosclerosis. First reference, Boisvert et al., J. Clin. Invest., 1998, 101: 353-363.
Shows IL-8 on stem cells (ie monocytes / macrophages) by bone marrow transplantation.
The absence of the receptor has been shown to reduce the development of atherosclerotic plaque in LDL receptor deficient mice. Another supporting document is Apostolo
poulos et al., Arterioscler Thromb Vasc Biol. 1996, 16: 1007-1012; Liu et
al., Arterioscler Thromb Vasc Biol., 1997, 17: 317-323; Rus et al., Athe
rosclerosis. 1996, 127: 263-271; Wang et al., J. Biol. Chem. 1996, 271: 88.
37-8842; 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.
It is.

The present invention further provides therapeutic and prophylactic measures in acute conditions in individuals deemed susceptible to CNS injury by the chemokine receptor antagonist compounds of formula (I). CNS injuries as defined herein include both open or penetrating head trauma, such as by surgery, or closed head trauma, such as by damage to the head area. In particular, ischemic strokes to brain parts are also included in this definition. Ischemic stroke is defined as a localized neuropathy usually caused by insufficient blood supply to certain brain regions as a result of an embolus, thrombus or localized atheromatous occlusion of a blood vessel. The role of inflammatory cytokines in this area has been elucidated, and the present invention provides potential therapeutics for these injuries. There are relatively few treatments available for acute injuries such as these.

TNF-α is a cytokine with pro-inflammatory effects, including endothelial leukocyte adhesion molecule expression. Because leukocytes invade into ischemic brain lesions, compounds that inhibit or reduce the level of TNF are useful for treating ischemic brain injury.
See Liu et al., Stoke, Vol. 25, No. 7, pp. 1481-88 (1994), the disclosure of which is incorporated by reference. A model of closed head injury and treatment with a 5-LO / CO mixture has been described by Shohami et al.
al., J. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3, No. 2,
pp. 99-107 (1992), the disclosure of which is hereby incorporated by reference. Treatments that reduce edema formation have been found to improve functional outcome in these treated animals.

The compounds of formula (I) can be used to bind IL-8 to IL-8 alpha or beta receptors, as evidenced by reduced neutrophil chemotaxis and activation. Administered in an amount sufficient to inhibit binding. The finding that the compound of formula (I) is an inhibitor of IL-8 binding is based on the effect of the compound of formula (I) in the in vitro receptor binding assay described herein. Compounds of formula (I) have been shown to be inhibitors of the type II IL-8 receptor.

As used herein, the term “IL-8 mediated disease or condition” is defined as
IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78,
Producing IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 itself, or IL-8, GROα, GROβ, GROγ, NAP-
2 or ENA-78 refers to any condition in which it plays a role by releasing another monokine such as, but not limited to, IL-1, IL-6 or TNF. Thus, for example, a condition in which IL-1 is the major component and whose production or action is exacerbated or secreted in response to IL-8 is considered to be a condition mediated by IL-8.

As used herein, the term “chemokine-mediated disease or condition” refers to chemokines that bind to IL-8α or β receptors, such as IL-8, GROα
, GROβ, GROγ, NAP-2 or ENA-78 (but not limited to)
Means any condition that plays a role. This is because IL-8 plays a role by producing IL-8 itself or by causing IL-8 to release another monokine such as, but not limited to, IL-1, IL-6 or TNF. Includes pathology. Thus, for example, IL-1 is the main component and its production or action is I
Conditions that are exacerbated or secreted in response to L-8 are considered to be conditions 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. Cytokines include, but are not limited to, monokines and lymphokines, regardless of which cells produce them. For example, monokine generally refers to those produced and secreted by mononuclear cells, such as macrophages and / or monocytes. However, many other cells also produce monokines, such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epidermal keratinocytes and B-lymphocytes I do. Lymphokines generally refer to those produced by lymphocytes. Examples of cytokines include interleukin-1 (IL-1),
Examples include, but are not limited to, 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”, like the aforementioned “cytokine”, refers to a molecule that affects cell function and modulates cell-cell interactions in the immune, inflammatory or hematopoietic response. Means a secreted polypeptide that is Chemokines are secreted mainly through cell transmembrane, and specific leukocytes, neutrophils,
Causes chemotaxis and activation of monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells. Examples of chemokines are IL-8, GROα, GRO
β, GROγ, NAP-2, ENA-78, IP-10, MIP-1α, MIP-β, PF4, and MCPs 1, 2, and 3, but are not limited thereto.

For use in therapy, the compounds of formula (I) or pharmaceutically acceptable salts thereof are usually formulated into pharmaceutical compositions according to standard pharmaceutical practice. Accordingly, the present invention further relates to a pharmaceutical composition comprising an effective non-toxic amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent. Compounds of formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating them may be prepared by any of the routes conventionally employed for drug administration, for example, orally, topically, parenterally or by inhalation. It is often administered. The compounds of formula (I) are administered in the usual dosage forms prepared by combining the compounds of formula (I) with standard pharmaceutical carriers according to the usual methods. The compounds of the formula (I) can furthermore be administered in customary administration forms in combination with known second therapeutically active compounds. These methods consist of mixing, granulating, and then compressing or dissolving the ingredients as appropriate to obtain the desired preparation. The form and characteristics of the pharmaceutically acceptable carrier or diluent will depend on the amount of active ingredient to be combined, the route of administration and other well-known factors. The carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and is not harmful to the consumer.

The pharmaceutical carrier employed may be, for example, either a solid or liquid. Examples of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin,
Gum arabic, magnesium 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 include time delay material well known in the art, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. A wide variety of pharmaceutical forms can be used. Thus, if a solid carrier is used, the preparation can 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. When a liquid carrier is used, the preparation will be in the form of a sterile injectable liquid or non-aqueous liquid suspension such as a syrup, emulsion, soft gelatin capsule or ampoule.

The compounds of formula (I) are administered locally, ie by non-systemic administration.
This includes topical application of the compound of formula (I) to the epidermis or into the oral cavity, and instillation of such compound into the ear, eye and nose, so that the compound does not significantly enter the bloodstream. In contrast, systemic administration means oral, intravenous, intraperitoneal and intramuscular administration. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration into the site of inflammation through the skin, such as liniments, lotions, creams, ointments or pastes, and administration to the eyes, ears or nose And suitable drops. The active ingredient, when administered topically, comprises from 0.001% to 10% w / w of the formulation, for example from 1% to 2% by weight. However, it may comprise 10% w / w of the formulation, but preferably comprises less than 5% w / w, more preferably from 0.1% to 1% w / w.

The lotions of the present invention include those suitable for application to the skin or eyes. Ophthalmic lotions include a sterile aqueous solution which may optionally contain a bactericide, and are prepared in a manner similar to the preparation of drops. Lotions or liniments for application to the skin may further comprise agents that promote drying of the skin, such as alcohol or acetone, and / or moisturizing agents such as glycerol, or any oil such as castor oil or peanut oil.

The creams, ointments or pastes according to the invention are semisolid formulations of the active ingredient for external use. These are prepared by mixing the active ingredient in finely divided powder or powder form, alone or in solution or suspension in aqueous or non-aqueous fluids, with a suitable grease or non-greasy base, using a suitable machine. Be prepared. Bases are hydrocarbons, for example, solid, soft or liquid paraffin, glycerol, beeswax, metal soaps; slurries; oils of natural sources such as tonsil oil, corn oil, peanut oil, castor oil or olive oil; wool fat or Derivatives or fatty acids such as stearic or oleic acid and the like may be included with alcohols, for example, propylene glycol or macrogels. The formulation may incorporate any suitable surfactant, such as an anionic, cationic or nonionic surfactant, such as a sorbitan ester or a polyoxyethylene derivative thereof. Suspending agents, such as natural gums, cellulose derivatives or inorganic substances, such as siliceous silicas, and other ingredients, such as lanolin, may be incorporated.

The drops of the present invention may include sterile aqueous or oily solutions or suspensions, wherein the active ingredient is dissolved in a suitable aqueous solution of a bactericide and / or fungicide and / or other suitable preservative. , Preferably by incorporating a surfactant. The resulting solution is then clarified by filtration, transferred to a suitable container, which is sealed and sterilized by autoclaving or maintaining at 98-100 ° C for half an hour. Alternatively, the solution is filter sterilized and transferred to the container by aseptic technique. Examples of fungicides and fungicides suitable for incorporation into drops are phenylmercuric nitrate or 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) are administered parenterally, ie by intravenous, intramuscular, subcutaneous, intranasal, rectal, vaginal or intraperitoneal administration. Parenteral administration in subcutaneous and intramuscular forms is generally preferred. Suitable forms for such administration are prepared by conventional techniques. The compounds of the formula (I) can furthermore be administered by inhalation, ie by intranasal or oral inhalation. Dosage forms suitable for such administration, such as an aerosol formulation or a metered dose inhaler, are prepared by conventional techniques.

For any of the uses described herein for the compounds of formula (I), the daily oral dose will preferably be from about 0.01 to about 80 mg / kg of total body weight. The daily parenteral dosage is from about 0.001 to about 80 mg / kg of total body weight. The daily topical dose is preferably between 0.1 mg and 150 mg and is administered 1 to 4 times, preferably 2 or 3 times a day. The daily inhalation dose is preferably between about 0.01 mg / kg and about 1 mg / kg per day. The optimal amount of the compound of formula (I) or pharmaceutically acceptable salt thereof and the interval between each administration will be determined by the nature and extent of the condition to be treated, the mode of administration, the route and site, and the individual patient to be treated. Those skilled in the art will also understand that such optimum values can be determined by conventional techniques. Also, the optimal treatment unit, ie,
The number of administrations of a compound of formula (I) or a pharmaceutically acceptable salt thereof administered per day for a particular number of days can be ascertained by those skilled in the art using conventional therapeutic unit determination tests, Those skilled in the art will understand. The invention will be described with reference to the following biological examples, which are merely illustrative and do not limit the scope of the invention.

Biological Examples The inhibitory effect of the compounds of the invention on IL-8 and GRO-α chemokines was determined by the following in vitro assay: Receptor binding assay [ ¹²⁵ I] IL with specific activity of 2000 Ci / mmol -8 (human recombinant) was transferred to Amersham Corporation, Arlington Heights, Illinois.
p.). GRO-α is obtained from NEN-New England Nuclear. All other chemicals are for analysis. As already disclosed [Holmes et al., Science, 1991, 253,
1278], high levels of recombinant human IL-8α and β-type receptors were expressed in Chinese hamster ovary cells, respectively. Chinese hamster ovary membranes were homogenized according to the protocol described previously [Haour et al., J. Biol. Chem., 249, 2195-2205 (1974)]. However, the homogenizing buffer is changed to 10 mM Tris-HCL, 1 mM MgSO ₄ , 0.5 mM EDTA (ethylenediaminetetraacetic acid), 1 mM PMSF (α-toluenesulfonyl fluoride), 0.5 mg / L leupeptin, pH 7.5. . Membrane protein concentration is determined using the Pierce Co. microanalytical kit, using bovine serum albumin as a standard. All tests are performed in a 96-well microplate format. Each reaction mixture contained 1.2 mM MgSO ₄ , 0.1 mM EDTA,
¹²⁵ I IL-8 (0.25 nM) or ¹²⁵ I GRO-α and 0.5 μg in 20 mM Bis-Tris propane and 0.4 mM Tris HCl buffer (pH 8.0) containing 25 mM NaCl and 0.03% CHAPS. / ML IL-8R
Contains α- or 1.0 μg / mL IL-8Rβ membrane. In addition, the drug or compound of interest, previously dissolved in DMSO, is added so that the final concentration is between 0.01 nM and 100 uM. The assay is started by the addition of ¹²⁵ I-IL-8. After 1 hour at room temperature, the plates were harvested using a Tomtec 96-well harvester onto glass fiber filter mats blocked with 1% polyethyleneimine / 0.5% BSA, 25 mM NaCl, 10 mM Tris HCl, 1 mM.
Wash 3 times with mM MgSO ₄ , 0.5 mM EDTA, 0.03% CHAPS (H7.4). The filters are then dried and counted on a Betaplate liquid scintillation counter. Recombinant IL-8Rα (or type I) receptor is further referred to herein as non-permissive receptor, and recombinant IL-8Rβ (or type II) receptor is referred to as permissive receptor.

The compound of Example 1, a representative compound of formula (I), was found to have a positive inhibitory activity of less than 30 μmg in this assay.

Chemotaxis Assay The in vitro inhibitory properties of these compounds are described in Current Protocols in Immunology,
vol I, Suppl 1, Unit 6.12.3., the disclosure of which is incorporated herein by reference, is measured by the neutrophil chemotaxis assay. Neutrophils
Isolated from human blood as disclosed in Current Protocols in Immunology Vol I, Suppl 1 Unit 7.23.1, the disclosure of which is hereby incorporated by reference in its entirety. Chemoattractant IL-8, GRO-α, GRO-β, GRO-
Gamma and NAP-2 at concentrations between 0.1 and 100 nM are placed in the bottom chamber of a 48 multiwell chamber (Neuro Probe, Cabin John, MD). The two chambers are separated by a 5um polycarbonate filter. When testing compounds of the invention, they are mixed with cells (0.001-1000 nM) immediately before adding the cells to the upper chamber. Incubations are performed for about 45-90 minutes at about 37 ° C. in a humidified incubator with 5% CO ₂ . At the end of the incubation period, the polycarbonate membrane is removed, the apex is washed, and the membrane is then stained using the Diff Quick stain method (Baxter Products, McGow, Ill., USA). Cells showing chemotaxis to chemokines are counted visually using a microscope. Generally, four fields are counted for each sample and these numbers are averaged to determine the average number of cells that have migrated. Each sample is tested in triplicate and each compound is tested at least four times. No compounds were added to certain cells (positive control cells) and these cells show the maximal chemotactic response of the cells. If a negative control (no stimulation) is desired, no chemokine is added to the bottom chamber. The difference between the positive and negative controls is indicative of the chemotactic activity of the cells.

Elastase Release Assay: Compounds of the invention are tested for their ability to prevent elastase release from human neutrophils. Neutrophils are collected from Current Protocols in Immunology Vol I, Suppl 1 Uni
t Isolate from human blood as described in 7.23.1. PMN 0.88 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)
× 10 ⁶ cells are placed in each well of a 96-well plate in a volume of 50 ul. To this plate is added 50 ul volume of test compound (0.001-1000 nM), 50 ul (20 ug / ml) volume of cytochalasin B and 50 ul volume of Ringer's buffer. The cells are harvested before adding a final concentration of 0.01-1000 nM IL-8, GROα, GROβ, GROγ or NAP-2.
Warm for minutes (37 ° C., 5% CO ₂ , 95% RH). The reaction is allowed to proceed for 45 minutes before centrifugation of a 96-well plate (800 × g for 5 minutes) and removal of 100 ul of supernatant. This supernatant was added to another 96-well plate, followed by phosphate buffered physiology of an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val-AMC, Nova Biochem, La Jolla, CA). Dissolve in saline and add to a final concentration of 6 ug / ml. Immediately, the plates were placed in a fluorescent 96-well plate reader (Cytofluor 2350, Millipore, Bedford, Mass.) And the data were collected according to the method of Nakajima et al.
Collect at 3 minute intervals according to Biol Chem 254 4027 (1979)). The amount of elastase released from PMN was determined by MeOSuc-Ala-Ala-Pro-Val-AM.
Calculated by measuring C decomposition rate.

TNF-α Traumatic Brain Injury Assay This assay is based on experimentally induced lateral fluid shock traumatic brain injury (T
It is performed to examine the expression of tumor necrosis factor mRNA in specific brain regions occurring after BI). Post-traumatic changes in TNF-α gene expression are acute and regenerative to CNS trauma, as TNF-α can induce nerve growth factor (NGF) and stimulate the release of other cytokines from activated astrocytes. Plays an important role in both responses. Suitable assays are described in PCT applications WO 97/35856 or WO 97/49286, the contents of which are incorporated herein by reference.

CNS Injury Model for IL-β mRNA This assay demonstrates the localization of interleukin-1β (IL-1β) mRNA in specific brain regions in rats following experimental lateral fluid shock traumatic encephalopathy (TBI). Characterize expression. The results of these assays show that after TBI, IL-1βm
Figure 4 shows that transient expression of RNA is locally stimulated in specific brain regions. I
These local changes in cytokines such as L-1β play an important role in the pathology or sequelae following brain injury. A suitable assay is described in PCT application WO 97/35856.
Or described in PCT application WO 97/49286, the contents of which are hereby incorporated by reference.

In Vivo-Atherosclerosis Assay In vivo experiments to measure atherosclerosis in mice were performed using Pa
Based on the assay of igen et al. with minor modifications as described above. For example, Paigen
B., Norrow A., Holmes PA, Mitchell D., Williams RA, Quantitative as
sessment of atheroscleotic lesion in mice, Atherosclerosis 68: 231-240
(1987); and Groot PHE, Van Vlijmen BJM, Benson GM, Hofker MH, Schiffe
lers R., Vidgeon-Hart M, Havekes LM, Quantitative assessment of aortic a
therosclerosis in serum cholesterol exposure.Arterioscler Thromb Vasc B
iol. 16: 926-933 (1996).

Aortic sinus fragmentation and staining Aortic root sections are removed according to previous disclosures (1,2). Briefly, the heart is bisected just below the atrial level and the base of the heart with the aortic root is removed for analysis. After allowing the tissue to equilibrate overnight in the OCT compound, the heart was immersed in the OCT compound on a cryostat chuck (Bright Instrument Company Ltd., UK) and the aorta was allowed to contact the chuck. Face to face. The tissue is frozen by surrounding the chuck with dry ice. The heart is then subdivided starting from inside the heart and toward the aorta, perpendicular to the axis of the aorta. As soon as the aortic root is identified by the appearance of three foliate flaps, alternately 10 mm sections are removed and fixed on gelatin-coated slides. The sections are air-dried for 1 hour and then briefly rinsed with 60% isopropyl alcohol. The sections are stained with oil red O, counterstained with Mayer's hematoxylin, coverslipped with glycerol gelatin, and sealed with nail enamel.

Quantification of atherosclerosis in aortic roots Image processing of 10 alternating aortic root sections using an Olympus BH-2 microscope equipped with a 4x objective and a video camera (Hitachi, HV-C10) I do. Performs 24-bit hue image processing, mounts a frame grabbing board (Snapper, Active Imaging Ltd., Berks, UK), and uses Optimas Software (version 5.1, United States of America) PC (Datacell, ActiveP5-133) running at Optimas Corp., Washington; Datacell, Berks, UK
). Images are captured under the same light intensity, microscope, camera and PC conditions. Quantification of atherosclerotic lesion area optimizes so around the lesion
This is done by handwriting using ftware. The hue threshold for quantifying the area that stains red within the lesion is set. The absolute value of the cross-sectional area of the lesion and the absolute value of the cross-sectional area of the area stained red are obtained by correcting the software using the image of the grid on the hemocytometer slide.

All disclosures, including, but not limited to, patents and patent applications cited herein, are hereby expressly incorporated by reference as if each disclosure were fully and individually described herein. Part of the invention. The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments 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, it is believed that the examples herein are merely illustrative and do not limit the scope of the invention in any way. Embodiments of the present invention that claim exclusive properties or priorities are defined as follows.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) / 12 13/12 17/00 17/00 17/06 17/06 19/02 19/02 19/08 19/08 19/10 19/10 25/28 25/28 31/04 31/04 31/12 31/12 33/06 33/06 37/06 37/06 43/00 111 43/00 111 C07D 513/04 343 C07D 513/04 343 (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, B) Y, KG, KZ, MD, RU, TJ, TM), AL, AU, BA, BB, BG, BR, CA, CN, CZ, EE, GE, GH, GM, HR, HU, ID, IL, IN, 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, YU (72) Inventor Catherine El Widson, United States 19406 Old Valley Forge Road, King of Prussia, Pennsylvania 1047 F term (reference) 4C033 AA12 AA17 AA20 4C072 AA10 4C086 AA01 AA03 BC80 MA01 MA04 NA14 ZA16 ZA36 ZA54 ZA59 ZA66 ZA67 ZA81 ZA89 ZA96 ZB02 ZB08 ZB11 ZB33 ZB35 ZC02

Claims (16)

[Claims] 1. The formula: embedded image[Where A is CR₂₀R_{twenty one}R is NH-C (= NX) -NH- (CR₁₃R₁₄)_vX is cyano, OR₁₁, C (O) R₁₁, C (O) OR₁₁, S (O)_TwoR_{twenty two}, R_{twenty three}Or C (O) NR_{twenty four}R_{twenty five}Z is W, optionally substituted heteroaryl, optionally substituted C_{Five- 8} Cycloalkyl, optionally substituted C_1-10Alkyl, optionally substituted C_2-10Alkenyl or optionally substituted C_2-10N is an integer of 1 to 3; m is an integer of 1 or 3; q is 0 or an integer of 1 to 10; s is an integer of 1 to 3 T is 0, or an integer of 1 or 2; v is 0, or an integer of 1 to 4;₁Is 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, a
Reel, aryl C_1-4Alkyl, aryloxy, aryl C_1-4Alkyloxy
Si, heteroaryl, heteroaryl C_1-4Alkyl, heterocyclic, heterocyclic C_1-4Alkyl, heteroaryl C_1-4Alkyloxy, ally
Le C_2-10Alkenyl, heteroaryl C_2-10Alkenyl, heterocyclic C _2-10 Alkenyl, (CR₈R₈)_qNR_FourR_Five, C_2-10Alkenyl C (O) NR_FourR_Five, (C
R₈R₈)_qC (O) NR_FourR_Five, (CR₈R₈)_qC (O) NR_FourR_Ten, S (O)_ThreeR₈, (CR₈R ₈ )_qC (O) R₁₁, C_2-10Alkenyl C (O) R₁₁, C_2-10Alkenyl C (O) OR₁₁ , (CR₈R₈)_qC (O) R₁₁, (CR₈R₈)_qC (O) OR₁₂, (CR₈R₈)_qOC (O) R_{1 1} , (CR₈R₈)_qNR_FourC (O) R₁₁, (CR₈R₈)_qC (NR_Four) NR_FourR_Five, (CR₈R₈)_q NR_FourC (NR_Five) R₁₁, (CR₈R₈)_qNHS (O)_TwoR₁₇, Or (CR₈R₈)_qS (O)_Two NR_FourR_FiveOr two R₁The groups together form O- (CH_Two)_s O or a 5- or 6-membered saturated or unsaturated ring may be formed, wherein
, Heteroaryl, and heterocyclic containing rings are substituted
May be; 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, heterocyclic, heterocyclic C_1-4Is alkyl
Or R_FourAnd R_FiveTogether with the nitrogen to which they are attached form O / N /
Forming a 5- to 7-membered ring optionally having an additional heteroatom selected from S
And R₆And R₇Is independently hydrogen or C_1-4An alkyl group or R₆ And R₇Together with the nitrogen to which they are attached form a 5- to 7-membered ring which may have additional heteroatoms selected from oxygen, nitrogen or sulfur
And R₈Is independently hydrogen or C_1-4R is 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_1-4Alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic C_1-4Alkyl; R₁₂Is hydrogen, C_1-10Alkyl, optionally substituted aryl or substituted
An optionally substituted arylalkyl; R₁₃And R₁₄Is independently hydrogen, optionally substituted C_1-4Alkyl or R₁₃And R₁₄One is an optionally substituted aryl
May be; R_FifteenAnd R₁₆Is independently hydrogen or optionally substituted C_1-4Alkyl; R₁₇Is C_1-4Alkyl, aryl, arylalkyl, heteroaryl, heteroaryl C_1-4Alkyl, heterocyclic, or heterocyclic C_1-4Where all the rings containing aryl, heteroaryl and heterocyclyl are optionally substituted;₁₈Is NR₆R₇, Alkyl, aryl C_1-4Alkyl, aryl C_2-4Arche
Nil, heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_2-4A
Lucenyl, heterocyclic, heterocyclic C_1-4Alkyl, where all rings containing aryl, heteroaryl, and heterocyclic are
May be substituted; R₂₀And R_{twenty one}Is independently hydrogen, halogen, cyano, halo-substituted C_1-10Al
Kill, C_1-10Alkyl, aryl, aryl C_1-4Alkyl, heteroaryl, heteroaryl C_1-4Alkyl, heterocyclic, heterocyclic C_1-4 Alkyl, (CR₈R₈)_qOR_Four, (CR₈R₈)_qC (O) R₁₁, (CR₈R₈)_qC (O) OR ₁₂ , (CR₈R₈)_qOC (O) R₁₁, (CR₈R₈)_qNR_FourR_Five, (CR₈R₈)_qNR_FourC (O)
R₁₁, Or (CR₈R₈)_qC (O) NR_FourR_TenWhere aryl, heteroa
Reels and rings containing heterocyclic may be substituted;
But R₂₀And R_{twenty one}Are never both hydrogen; R_{twenty two}Is C_1-4Alkyl, NR_FifteenR₁₆, OR₁₁An optionally substituted aryl, an optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4Alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic
C_1-4R is alkyl;_{twenty three}Is an optionally substituted C_1-4Alkyl, optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C_1-4Alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclic
C_1-4R is alkyl;_{twenty four}And R_{twenty five}Is independently hydrogen, optionally substituted C_1-4Alkyl, optionally substituted aryl, optionally substituted aryl C_1-4Alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl
C_1-4Alkyl, optionally substituted heterocyclic, optionally substituted heterocyclic C_1-4Alkyl or R_{twenty four}And R_{twenty five}Is selected from oxygen, nitrogen or sulfur, together with the nitrogen to which they are attached.
Y independently forms a hydrogen, halogen, nitro, cyano, halo-substituted C_1-10Alkyl
, C_1-10Alkyl, C_2-10Alkenyl, C_1-10Alkoxy, halo-substituted C_1-10Al
Koxy, (CR₈R₈)_qS (O)_tR_Four, Hydroxy, hydroxy C_1-4Alkyl, ant
, Aryl C_1-4Alkyl, aryloxy, aryl C_1-4Alkyloxy
, Heteroaryl, heteroaryl C_1-4Alkyl, heteroaryl C_1-4Archi
Leoxy, heterocyclic, heterocyclic C_1-4Alkyl, aryl C_2-10Alkenyl, heteroaryl C_2-10Alkenyl, heterocyclic C_{2- Ten} Alkenyl, (CR₈R₈)_qNR_FourR_Five, C_2-10Alkenyl C (O) NR_FourR_Five, (CR ₈ R₈)_qC (O) NR_FourR_Five, (CR₈R₈)_qC (O) NR_FourR_Ten, S (O)_ThreeR₈, (CR₈R₈) _q C (O) R₁₁, C_2-10Alkenyl C (O) R₁₁, C_2-10Alkenyl C (O) OR₁₁, (
CR₈R₈)_qC (O) OR₁₂, (CR₈R₈)_qOC (O) R₁₁, (CR₈R₈)_qNR_FourC (O)
R₁₁, (CR₈R₈)_qC (NR_Four) NR_FourR_Five, (CR₈R₈)_qNR_FourC (NR_Five) R₁₁, (CR ₈ R₈)_qNHS (O)_TwoR₁₈, Or (CR₈R₈)_qS (O)_TwoNR_FourR_FiveOr two Y groups are taken together to form O- (CH_Two)_sO or 5 or 6 member saturation
Or form an unsaturated ring, wherein aryl, heteroaryl, and hetero
The cyclic-containing ring may be substituted; W isThe E-containing ring isAsterisk * means the point of attachment of the ring] or a pharmaceutically acceptable salt thereof. Wherein R ₁ is halogen, cyano, _{nitro, CF 3, (CR 8 R} 8) q C (O
) NR ₄ R ₅ , C _2-10 alkenyl C (O) NR ₄ R ₅ , (CR ₈ R ₈ ) _q C (O) NR ₄ R ₁₀ , C _2-10 alkenyl C (O) OR ₁₁ , heteroaryl The compound according to claim 1, which is a heteroaryl C _1-4 alkyl, a heteroaryl C _2-10 alkenyl, or (CR ₈ R ₈ ) _q S (O) ₂ NR ₄ R ₅ . 3. The compound according to claim 2, wherein R ₁ is halogen. 4. The compound according to claim 1, wherein at least one of R ₂₀ and R ₂₁ is alkyl or halogen. 5. The compound according to claim 1, wherein Z is W. 6. Y is halogen, C _1-4 alkoxy, optionally substituted aryl, optionally substituted aryl C _1-4 alkoxy, methylenedioxy, NR ₄ R ₅ , thioC _1-. The compound according to claim 5, which is ₄ alkyl, thioaryl, halo-substituted C _1-10 alkoxy, optionally substituted C _1-4 alkyl, or hydroxy-substituted C _1-4 alkyl. 7. The compound according to claim 6, wherein Y is halogen. 8. The compound according to claim 1, wherein Z is an optionally substituted heteroaryl. 9. The compound according to claim 1, wherein X is cyano. 10. N-[(1,3) -dihydro-2,2-dioxo-4-chloro-2,1-benzoisothiazo-7-yl] -N ′-[2-bromophenyl] -N ″ -The compound according to claim 1, which is cyanoguanidine. 11. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 10 and a pharmaceutically acceptable carrier or diluent. 12. A method for treating a chemokine-mediated disease in which a chemokine binds to IL-8α or β receptor in a mammal, comprising administering to the mammal an effective amount of the compound according to claim 1. How to treat. 13. The mammal may be psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, 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, Unwanted hematopoietic stem cell release, rhinovirus infection, periodontal disease,
Or a chemokine-mediated disease selected from bone resorption diseases.
The described method. 14. The formula: embedded image [Wherein A, R ₁ and m are the same as defined above in formula (I), and R _a is hydrogen or a nitrogen protecting group]. 15. The process for producing a compound according to claim 1, wherein the compound has the formula: Wherein A, R ₁ , m, v, Z, R ₁₃ and R ₁₄ are the same as defined above in formula (I), and _Ra is hydrogen or a nitrogen protecting group. the NH-X or NH ₂ X, and reacted with tertiary amine, to give a compound of formula (I), then, if necessary, by deprotection X
A compound of formula (I) wherein is cyano. 16. The formula: embedded image Wherein A, R ₁ , m, v, Z, R ₁₃ and R ₁₄ are the same as defined above in formula (I), and R _a is hydrogen or a nitrogen protecting group. .