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WO2000076501A1 - Antagonistes du recepteur d'il-8 - Google Patents

Antagonistes du recepteur d'il-8 Download PDF

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Publication number
WO2000076501A1
WO2000076501A1 PCT/US2000/016506 US0016506W WO0076501A1 WO 2000076501 A1 WO2000076501 A1 WO 2000076501A1 US 0016506 W US0016506 W US 0016506W WO 0076501 A1 WO0076501 A1 WO 0076501A1
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Prior art keywords
alkyl
optionally substituted
heteroaryl
aryl
alkenyl
Prior art date
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PCT/US2000/016506
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English (en)
Inventor
Gregory Martin Benson
Melvin Clarence Rutledge
Katherine L. Widdowson
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Priority to JP2001502834A priority Critical patent/JP2003501463A/ja
Priority to NZ514696A priority patent/NZ514696A/xx
Priority to EP00941455A priority patent/EP1185265A4/fr
Priority to PL00352213A priority patent/PL352213A1/xx
Priority to MXPA01013005A priority patent/MXPA01013005A/es
Priority to HU0201582A priority patent/HUP0201582A3/hu
Priority to BR0011122-8A priority patent/BR0011122A/pt
Priority to IL14576200A priority patent/IL145762A0/xx
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Priority to KR1020017016144A priority patent/KR20020015347A/ko
Priority to CA002377386A priority patent/CA2377386A1/fr
Priority to AU56161/00A priority patent/AU766235B2/en
Publication of WO2000076501A1 publication Critical patent/WO2000076501A1/fr
Priority to NO20016052A priority patent/NO20016052D0/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to novel benzo-2-triazole substituted compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 mediated diseases.
  • Interleukin-8 such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
  • NAP-1 neutrophil attractant/activation protein-1
  • MDNCF monocyte derived neutrophil chemotactic factor
  • NAF neutrophil activating factor
  • T-cell lymphocyte chemotactic factor T-cell lymphocyte chemotactic factor.
  • Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-l ⁇ , IL-l ⁇ or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP.
  • GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 also belong to the chemokine a family. Like IL-8 these chemokines have also been referred to by different names. For instance GRO ⁇ , ⁇ , ⁇ have been referred to as MGSAa, b and g respectively (Melanoma Growth Stimulating Activity), see Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All of the chemokines of the a-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor.
  • IL-8, and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven- transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the B-receptor. Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmes et al., Science 253. 1278 (1991).
  • the development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993.
  • the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
  • IL-8Ra which binds only IL-8 with high affinity
  • IL-8Rb which has high affinity for IL-8 as well as for GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • IL-8Ra which binds only IL-8 with high affinity
  • IL-8Rb which has high affinity for IL-8 as well as for GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.
  • the chemokine is IL-8.
  • This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) or (II).
  • the present invention also provides for the novel compounds of Formula (I), and (II) and pharmaceutical compositions comprising a compound of Formula (I), and (II) and a pharmaceutical carrier or diluent.
  • R is -NH -C(X2)-NH- (CR 13 R 14 ) v - Z;
  • Z is W, HET, , an optionally substituted C ⁇ _ ⁇ Q alkyl, an optionally substituted C2.10 alkenyl, or an optionally substituted C2-I0 alkynyl;
  • R4 and R5 are independently hydrogen, optionally substituted C]-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C]-4alkyl, heterocyclic, or heterocyclic C]_4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S; Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted alkyl; Ci-io alkyl; C2-10 alkenyl; C]_ ⁇ o alkoxy; halosubstituted C(-io alkoxy; azide;
  • R] 1 is hydrogen, C]-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC ⁇ _4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC ⁇ _4alkyl;
  • R]2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
  • R13 and R14 are independently hydrogen, or optionally substituted C] -4 alkyl, or one of R13 and R]4 may be optionally substituted aryl;
  • Rj5 and Ri g are independently hydrogen, or an optionally substituted Cj-4 alkyl;
  • Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC]-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, wherein the aryl, heteroaryl and heterocyclic
  • R ] 8 is hydrogen, optionally substituted Ci-io alkyl, C]_ ⁇ o alkoxy, halosubstituted alkoxy, hydroxy, arylC ] _4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-C ⁇ alkyl, heteroarylC2_4 alkenyl, heterocyclic, or heterocyclicC]_4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
  • R19 is cyano, nitro, S(0)2NR4R5, S(0)2R]7, alkyl, arylCj.4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-C j ⁇ alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC ] _4 alkyl; and wherein the alkyl, aryl, heteroaryl and heterocyclic containing
  • R is -NH -C(X 2 )-NH- (CR 1 R 14 ) V - Z;
  • Z is W, HET, ' ' n , optionally substituted C J . J Q alkyl, optionally substituted .-10 alkenyl, or optionally substituted C2.10 alkynyl;
  • X is N, or C(X 1 );
  • Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; C -io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR 8 R 8 )q S(0) t R4, hydroxy; hydroxy Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; aryl Ci-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C] _4alkyl; heteroaryl Ci-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR 8 R 8 )qNR 4 R5; C 2 -10 alkenyl C(0)NR4R 5 ; (CR 8 R 8 )q C(0)NR4R5; (CR 8 R 8 )q
  • 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
  • t is 0, or an integer having a value of 1 or 2
  • s is an integer having a value of 1 to 3
  • v is 0, or an integer having a value of 1 to 4
  • p is an integer having a value of 1 to 3;
  • HET is an optionally substituted heteroaryl
  • R4 and R5 are independently hydrogen, optionally substituted Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C]-4alkyl, heterocyclic, heterocyclic C]_4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S; Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Cj-io alkyl;
  • Ci-io alkyl C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide;
  • Ci-4alkyl aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl;
  • S(0)2NR4R5; or two Y moieties together may form 0-(CH2)s-0 or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted;
  • R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R6 and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur;
  • R 8 is independently hydrogen or Cj-4 alkyl;
  • RlO is Ci-10 alkyl C(0) 2 R8;
  • Rl i is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicCi-4alkyl;
  • Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
  • Rl3 and R14 are independently hydrogen, or optionally substituted Ci-4 alkyl, or one of R13 and R14 may be optionally substituted aryl;
  • Rl5 and Ri6 are independently hydrogen, or an optionally substituted Ci-4 alkyl
  • Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicC _4alkyl; and wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
  • R a is NR5R7, alkyl, arylC ⁇ _4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl-C j _4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC ⁇ .4 alkyl; and wherein the aryl, heteroaryl and heterocyclic cont l be optionally substituted;
  • the E containing ring is optionally selected from
  • the compounds of Formula (I) and (II) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the IL-8 a and b receptors.
  • Chemokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
  • Ri is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl, such as CF3; C]-io alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-10 alkenyl; Ci-io alkoxy, such as methoxy, or ethoxy; halosubstituted Ci-io alkoxy, such as trifluoromethoxy; azide; (CR R 8 )q S(0) R4, wherein t is 0, 1 or 2; hydroxy; hydroxy Ci-4alkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aryl Ci-4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl Cj-4 alkyloxy, such as benzyloxy; heteroaryl; heteroarylalkyl; hetero
  • aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted as defined herein below.
  • Ri is hydrogen, halogen, cyano, nitro, CF3, (CR R 8 )q C(0)NR4R5, C2-10 alkenyl C(0)NR4R5, (CR 8 R 8 )q C(0)R4R ⁇ o, C 2 -io alkenyl C(0)ORi2, heteroaryl, heteroaryl
  • Ri is halogen, cyano, or nitro.
  • Rj is preferably in the 4-position.
  • the term "the aryl, heteroaryl, and heterocyclic containing moieties” refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings.
  • the term “moieties” and “rings” may be interchangeably used throughout.
  • s is an integer having a value of 1 to 3.
  • Ri moiety may be substituted on either the benzene ring or the X containing ring, if possible.
  • s is preferably 1.
  • Ri forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system.
  • These ring systems may be substituted independently, 1 to 3 times by the other R ⁇ moieties as defined above.
  • R4 and R5 are independently hydrogen, optionally substituted Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C ⁇ _4alkyl, heterocyclic, or heterocyclicCi-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S.
  • R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur.
  • R 8 is independently hydrogen or Ci-4 alkyl.
  • q is 0 or an integer having a value of 1 to 10.
  • Rio is Ci-io alkyl C(0)2R8, such as CH2C(0)2H or CH2C(0)2CH3.
  • Rn is hydrogen, Cj-4 alkyl, aryl, aryl Cj-4 alkyl, heteroaryl, heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic Cl-4alkyl.
  • R12 is hydrogen, C ⁇ IQ alkyl, optionally substituted aryl or optionally substituted arylalkyl.
  • R13 and R14 are independently hydrogen, or an optionally substituted Ci-4 alkyl which may be straight or branched as defined herein, or one of R13 and R14 are an optionally substituted aryl.
  • v is 0, or an integer having a value of 1 to 4.
  • R13 or R14 are an optionally substituted alkyl
  • the alkyl moiety may be substituted one to three times independently by halogen; halosubstituted Cj-4 alkyl such as trifluoromethyl; hydroxy; hydroxy Ci-4alkyl, Ci-4 alkoxy; such as methoxy, or ethoxy, halosubstituted Ci-io alkoxy, S(0) t R4; aryl; NR4R5; NHC(0)R4; C(0)NR4R5; or C(0)OR 8 .
  • Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C ⁇ io alkyl; Ci-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted C]-io alkoxy; azide; (CR 8 R )q S(0)tR4; hydroxy; hydroxyCi-4alkyl; aryl; aryl Cj-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl C]-4 alkyloxy; heterocyclic, heterocyclic C ⁇ _4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR 8 R 8 )q NR4R5; C2-10 alkenyl C(0)NR4R 5 ; (CR 8 R 8 )q C(0)NR4R 5 ; (CR
  • R a is NR ⁇ R7, alkyl, aryl C1.4 alkyl, arylC 2.4 alkenyl, heteroaryl, heteroaryl-C ⁇ _4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclicC ⁇ .4 alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted.
  • Y is preferably a halogen, Ci-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio Ci-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4 alkyl, or hydroxy alkyl.
  • Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2 - position or 2'-, 3 -position on a phenyl ring.
  • n is preferably one. While both Ri and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, preferably both rings are substituted.
  • R is -NH -C(X 2 )-NH- (CR ⁇ 3 R 4 ) v - Z.
  • Z is W, HET, ' n , an optionally substituted C io alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2_ ⁇ o alkynyl.
  • p is an integer having a value of 1 to 3.
  • X is C(X ⁇ ) 2 , C(O), C(S), S(0) 2 , PO(OR ) or
  • R19 is cyano, nitro, S(0)2NR4R5, S(0)2Rj7, alkyl, arylC ⁇ .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-C ⁇ alkyl, heteroarylC2_4 alkenyl, heterocyclic, heterocyclicC ⁇ .4 alkyl, wherein the alkyl, aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted.
  • R] 9 is cyano.
  • X is suitably independently hydrogen, halogen, NR4R5, Ci-io alkylNR R 5 , C(0)NR4R5, CMO alkyl-C(0)NR4R5, optionally substituted Cj-io alkyl, Cj- 10 alkoxy; halosubstituted Ci-io alkoxy, aryl; aryl C]_4 alkyl; aryloxy; aryl Cj-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Ci-4alkyl; or heteroaryl C]-4 alkyloxy.
  • the C ⁇ _ ⁇ o alkyl group may be optionally substituted one or more times by hydroxy, NR4R5, or halogen.
  • at least one of Xi is hydrogen.
  • X is C(S) or a C(O) moiety, more preferably C(O).
  • R ⁇ is hydrogen, optionally substituted alkyl, Cj-jo alkoxy, halosubstituted Ci-io alkoxy, hydroxy, arylC ⁇ .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-C j _4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC ⁇ .4 alkyl, wherein all of the aryl, heteroaryl and heterocyclic rings may all be optionally substituted.
  • Rig is hydrogen or alkyl, more preferably hydrogen.
  • X is N, or C(X ⁇ ), preferably X is N.
  • Xi is hydrogen or halosubstituted alkyl.
  • Z is a heteroaryl (HET) ring
  • HET heteroaryl
  • the ring containing the heteroatom does not need to be directly attached to the urea moiety through the (R13R14N linkage of the ring(s) in these ring systems may be optionally substituted as defined herein.
  • the HET moiety is a pyridyl, which may be 2-, 3- or 4-pyridyl. If the ring is a multi system ring it is preferably benzimidazole, dibenzothiophene, or an indole ring.
  • rings of interest include, but are not limited to thiophene, furan, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline, quinazolinyl, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • the HET ring may be optionally substituted independently one to five, preferably 1 to
  • R15 and R ⁇ are independently hydrogen, or an optionally substituted Ci-4 alkyl as defined above for R13 and R14.
  • W is or
  • the E ring denoted by its point of attachment through the asterix (*) may optionally be present. If it is not present the ring is a phenyl moiety which is substituted by the R terms as shown.
  • the E ring may be substituted by the (Y)n moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).
  • Y in the W term may be substituted in any of the 5 ring positions of the phenyl moiety (when E is absent), Y is preferably mono-substituted in the 2 -position or 3 '- position, with the 4'- preferably being unsubstituted. If the phenyl ring is di substituted, substituents are preferably in the 2' or 3' position of a monocyclic ring. While both Ri and Y can both be hydrogen, it is prefered that at least one of the rings be substituted, preferably both rings are substituted.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy hydroxy substituted Ci-ioalkyl
  • Cj-io alkoxy such as methoxy or ethoxy
  • S(0) m ' C]-io alkyl wherein m' is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl
  • amino, mono & di-substituted amino such as in the NR4R5 group; NHC(0)R4; C(0)NR4R5; C(0)OH; S(0)2NR4R5; NHS(O)2R20
  • Ci-io alkyl such as methyl, ethyl, propyl, isopropyl, or t-butyl
  • halosubstituted Ci-io alkyl such as CF3; an optionally substituted aryl, such
  • R20 is suitably C ⁇ _4 alkyl, aryl, aryl C]-4alkyl, heteroaryl, heteroarylC ] -4alkyl, heterocyclic, or heterocyclicCi-4alkyl.
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
  • pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. The following terms, as used herein, refer to:
  • halo all halogens, that is chloro, fluoro, bromo and iodo.
  • C ⁇ _ ⁇ oalkyl or “alkyl” - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl and the like.
  • cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like. • "aryl” - phenyl and naphthyl;
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”, or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • heterocyclic (on its own or in any combination, such as “heterocyclicalkyl”) - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
  • arylalkyl or heteroarylalkyl or “heterocyclicalkyl” is used herein to mean Ci-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
  • Ri moieties may together form a 5 or 6 membered saturated or unsaturated ring
  • an aromatic ring system such as napthylene, or is a phenyl moiety having attached a 6 membered partially saturated or unsaturated ring such as a C6 cycloalkenyl, i.e. hexene, or a C5 cycloalkenyl moiety, such as cyclopentene.
  • Exemplified compounds of Formula (I) include:
  • Exemplified compounds of Formula (II) include: N-7-(Benzotriazole)-N'-(2-bromophenyl)urea;
  • the compounds of Formula (I) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below.
  • the synthesis provided for in these Schemes is applicable for the producing of Formula (I) having a variety of different Z and Ri groups which are reacted, employing optional substituents which are suitably protected to achieve compatibility with the reactions outlined herein. Subsequent deprotection, in those cases, then affords compounds of the nature generally disclosed.
  • Once the urea nucleus has been established, further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art. While the schemes are shown with various compounds of Formula (I) this is merely for illustration purposes only and not a limitation on the extent of synthesis available using these methods.
  • the 2-nitro substituted heterocyclic compound 2-scheme 1 is not commercially available it can be made by treating the commercially available 3-nitro phenylene diamine scheme 1 with sodium nitrite in a protic solvent such as HOAc.
  • the 2-nitro substituted heterocyclic compound 2-scheme 2 is not commercially available it can be made by treating the commercially available 3-nitro phenylene diamine scheme 2 with triphosgene and triethylamine in DMF or the thiophosgene to form the thio urea. Or alternatively with another carbonyl with no leaving groups such as carbonyl di- imidazole.
  • 2-nitro substituted heterocyclic compound 2-scheme 3 is not commercially available it can be made by treating the commercially available 3-nitro phenylene diamine L scheme 3 with the corresponding anhydride then refluxing in toluene.
  • the 2-nitro substituted heterocyclic compound 3-scheme 4 is not commercially available it can be made by treating compound 2-scheme 4, under standard nitrating conditions (using HNO3 or NaN ⁇ 3) at 23°C. If heterocyclic compound 2-scheme 4 is not commercially available it can be made from the commercially available 1 , 2-dibenzyldiamine 1 -scheme 4 with triethylamine at -70°C, then thionyl chloride followed by oxidation with m-CPBA and reduction of the benzyl groups using H2/ Pd in MeOH.
  • 2-nitro substituted heterocyclic compound 2-scheme 5 is not commercially available it can be made by treating the commercially available 1, 2-diamine 1 -scheme 5 with PhOP(0)Cl2 followed by standard nitrating conditions (using HNO3 or NaN03) at 23°C.
  • heterocyclic compound 2-scheme 6 is not commercially available it can be made by treating the commercially available 1, 2-diamine 1 -scheme 6 with formaldehyde at reflux.
  • the 7-amino substituted heterocyclic compound 4-scheme 8 is not commercially available it can be made by treating the commercially available 2-bromo-5-nitroaniline scheme 8 with a nucleophile such as, copper (I) cyanide or alternatively this can be used for palladium catalysized coupling reactions, and pyridine in an aprotic solvent such as DMF to form the 2-cyano-5-nitroaniline 2-scheme 8.
  • the diamine 3-scheme 8 can be formed by reacting 2-cyano-5-nitroaniline 2-scheme 8 with tetramethyl hydrazine iodide and a strong hindered base such as sodium t-pentoxide, in an aprotic solvent such as DMSO.
  • the 7-amino- 4-cyanobenzotriazole 4-scheme 8 can be made by reacting the diamine 3-scheme 8 with sodium nitrite, in a protic solvent such as HOAc, followed by reduction of the nitro group with a suitably reducing agent, such as Pd/C in MeOH.
  • a suitably reducing agent such as Pd/C in MeOH.
  • the diamine 3-Scheme 8 can be used to synthesize the other named heterocyclics described herein.
  • the aromatic rings of the compounds can be further functionalized by conditions well known in the art such as bromination or other electrophilic substitution reactions. These substituents can be further manipulated using standard nucleophilic substitutions such as reaction with an anion (such as sodium methoxide), or in palladium catalyzed coupling reaction chemistry.
  • the amino substituted heterocyclic compound 4-scheme-8 can then be converted to the corresponding urea by condensation with a commercially available isocyanate.
  • Ri and m are as defined in Formula (II).
  • Ri is bromo or cyano.
  • Ri is substituted in the 4-position of the ring.
  • Ri and m are as defined for Formula (II), provided that Rl is other than hydrogen.
  • Ri is cyano, or bromo.
  • Another aspect of the present invention is the novel process of making a compound of the formula:
  • Another aspect of the present invention is the analagous process for producing a compound of Formula (II) as defined above, which process comprises a) reacting a compound of the formula:
  • N-[benzimidazolin-3-one]-N'-[2-bromophenyl] urea was prepared from 4-amino- benzimidazolin-2-one (80mg, 0.54 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulting solid on silica gel(EtOAc/ hexane(lequiv./lequiv.)). (120mg, 64%). ⁇ NMR (CD3SOCD3): ⁇ 10.68 (s, IH), 10.03 (s,
  • N-[5-cyano-2-benzotriazole]-N'-[2,3-dichlorophenyl] urea was prepared from 7- amino-4-cyanobenzotriazole (95mg, 0.60 mmol) according to the procedure in General
  • N-[5-cyano-2-benzotriazole]-N'-[2-bromophenyl] urea was prepared from 7-amino-4- cyanobenzotriazole (95mg, 0.60 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulting solid on silica gel(EtOAc/ hexane(2equiv./3equiv.)). (410mg, 68%). ⁇ NMR (CD3S0 2 CD3): ⁇ 10.83 (s, IH), 9.18 (s,
  • Example 12 N-(4-Cyano-2-oxo-3-methylbenzimidazol-7-yl)-N'-(2,3-dichlorophenyl) urea IH NMR (DMSO-d 6 ) ⁇ 10.94(s, IH), 9.46(s, IH), 8.65(s, IH), 8.18(m, IH), 7.40-7.31(m, 3H),
  • Example 14 N-(4-Cyano-2-trifluoromethyl-7-benzimidazolyl)-N'-(2-bromophenyl) urea H NMR (DMSO-d 6 ) ⁇ 10.30(s, IH), 9.25(s, IH), 8.24(s, IH), 7.96(m, 2H), 7.85(d, IH,
  • Example 15 N-(4-Cyano-7-benzimidazolyl)-N'-(2,3-dichlorophenyl) urea 1H NMR (DMSO- d 6 ) ⁇ 10.45(s, IH), 10.34(s, IH), 9.48(s, IH), 8.44(s, IH), 8.15(m, 2H), 7.68(d, IH,
  • Example 16 N-(4-Cyano-7-benzimidazolyl)-N'-(2-bromophenyl) urea ⁇ H NMR (Acetone-d ) ⁇ 11.81(s, IH), 9.45(s, IH), 8.84(s, IH), 8.34(s, IH), 8.26(m, 2H), 7.65(d, 2H), 7.41(t, IH), 7.06(t, IH)
  • Example 17 N-(5-cyano-benzimidazolin-3-thione)-N'-(2,3-dichlorophenyl) urea 1H NMR (DMSO-d 6 ) ⁇ 11.54(s, IH), 10.42(s, IH), 9.52(s, IH), 8.62(s, IH), 8.15(m, IH), 7.54(d, IH,
  • the compounds of Formula (I) and/or Formula (II), or pharmaceutically acceptable salts thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated IL-8 cytokine production by such mammal's cell, such as but not limited to monocytes and/or macrophages, or other chemokines which bind to the IL-8 or ⁇ receptor, also referred to as the type I or type II receptor.
  • the term "compounds of Formula (I)", or “Formula (I)” will also refer to “compounds of Formula (II)” or “Formula (II)” unless otherwise indicated.
  • the present invention provides a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the chemokines are IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, or ENA-78.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function, in particular IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, or ENA-78, such that they are biologically regulated down to normal levels of physiological function, or in some case to subnormal levels, so as to ameliorate the disease state.
  • Abnormal levels of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, or ENA-78 for instance in the context of the present invention constitute: (i) levels of free IL-8 greater than or equal to 1 picogram per mL; (ii) any cell associated IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, or ENA-78 above normal physiological levels; or (iii) the presence of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, or ENA-78 above basal levels in cells or tissues in which IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, or ENA-78 respectively, is produced.
  • 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, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs.
  • alzheimers disease alzheimers disease, allograft rejections, malaria, restinosis, angiogenesis, atherosclerosis, osteoporosis, gingivitis, undesired hematopoietic stem cells release and diseases caused by respiratory viruses, including but not limited to rhinovirus and influenza virus, herpesviruses, including but not limited to herpes simplex I and II, and hepatitis viruses, including but not limited to Hepatitis B and Hepatitis C virus.
  • respiratory viruses including but not limited to rhinovirus and influenza virus, herpesviruses, including but not limited to herpes simplex I and II, and hepatitis viruses, including but not limited to Hepatitis B and Hepatitis C virus.
  • interleukin-8 and rhinovirus may be found in articles such as: Turner,et al., Clin. Infect. Dis. (1998), 26(4), 840-846; Sanders, et al., J. Virol. (1998), 72(2), 934-942; Sethi, et al., Clin. Exp. Immunol. (1997), 1 10(3), 362-369; Zhu, et al., Am. J. Physiol. (1997), 273(4, Pt. 1), L814-L824; Terajima, et al., Am. J. Physiol. (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.
  • interleukin-8 and osteoporosis may be found in articles such as: Streckfus et al., J. Gerontol., Ser. A (1997), 52A(6), M343-M351 ; Hermann, T. WO 95/31722; and Chaudhary, et al., Endocrinology (Baltimore) (1992), 130(5), 2528-34.
  • IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ or NAP-2 has the unique property of promoting neutrophil chemotaxis, enzyme release including but not limited to elastase release as well as superoxide production and activation.
  • the a-chemokines but particularly GRO ⁇ , GRO ⁇ , GRO ⁇ or NAP-2, working through the IL-8 type I or II receptor can promote the neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, the inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.
  • the present invention also provides for a means of treating, in an acute setting, as well as preventing, in those individuals deemed susceptible to, CNS injuries 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 a closed head trauma injury, such as by an injury to the head region. Also included within this definition is ischemic stroke, particularly to the brain area.
  • Ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel.
  • the role of inflammatory cytokines in this are has been emerging and the present invention provides a mean for the potential treatment of these injuries. Relatively little treatment, for an acute injury such as these has been available.
  • TNF- ⁇ is a cytokine with proinflammatory actions, including endothelial leukocyte adhesion molecule expression.
  • Leukocytes infiltrate into ischemic brain lesions and hence compounds which inhibit or decrease levels of TNF would be useful for treatment of ischemic brain injury. See Liu et al., Stoke, Vol. 25., No. 7, pp 1481-88 (1994) whose disclosure is incorporated herein by reference.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit IL-8, binding to the IL-8 alpha or beta receptors, from binding to these receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation.
  • the discovery that the compounds of Formula (I) are inhibitors of IL-8 binding is based upon the effects of the compounds of Formulas (I) in the in vitro receptor binding assays which are described herein.
  • the compounds of Formula (I) have been shown to be inhibitors of type II IL-8 receptors.
  • IL-8 mediated disease or disease state refers to any and all disease states in which IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, or ENA-78 plays a role, either by production of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, or ENA-78 themselves, or by IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, or ENA-78 causing another monokine to be released, such as but not limited to IL-1, IL-6 or TNF.
  • a disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease stated mediated by IL-8.
  • chemokine mediated disease or disease state refers to any and all disease states in which a chemokine which binds to an IL-8 ⁇ or ⁇ receptor plays a role, such as but not limited to IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, or ENA-78. This would include a disease state in which, IL-8 plays a role, either by production of IL-8 itself, or by IL- 8 causing another monokine to be released, such as but not limited to IL-1, IL-6 or TNF.
  • cytokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response.
  • a cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them.
  • a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines include, but are not limited to, Interleukin- 1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor beta (TNF- ⁇ ).
  • chemokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response, similar to the term “cytokine” above.
  • a chemokine is primarily secreted through cell transmembranes and causes chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells.
  • chemokines include, but are not limited to, IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, ENA-78, IP-10, MlP-l ⁇ , MlP- ⁇ , PF4, and MCP l, 2, and 3.
  • 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 such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
  • the compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures.
  • the compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • 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 25mg. to about lg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.
  • the active ingredient may comprise, for topical administration, from 0.001 % to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1 % to 1 % w/w of the formulation.
  • Lotions according to the present invention include those suitable for application to the skin or eye.
  • An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non- greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and/or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 C. for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the 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.
  • Compounds of formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily.
  • the daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • BIOLOGICAL EXAMPLES The IL-8, and Gro- ⁇ chemokine inhibitory effects of compounds of the present invention are determined by the following in vitro assay: Receptor Binding Assays:
  • IL_ 8 (human recombinant) is obtained from Amersham Corp., Arlington Heights, IL, with specific activity 2000 Ci/mmol. Gro-a is obtained from NEN- New England Nuclear. All other chemicals are of analytical grade. High levels of recombinant human IL-8 type a and b receptors were individually expressed in Chinese hamster ovary cells as described previously (Holmes, et al., Science, 1991, 253, 1278). The Chinese hamster ovary membranes were homogenized according to a previously described protocol (Haour, et al., J Biol Chem., 249 pp 2195-2205 (1974)).
  • the ho ogenization buffer is changed to lOmM Tris- HCL, ImM MgS04, 0.5mM EDTA (ethylene-diaminetetra-acetic acid), lm MPMSF (a- toluenesulphonyl fluoride), 0.5 mg/L Leupeptin, pH 7.5.
  • Membrane protein concentration is determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard. All assays are performed in a 96- well micro plate format.
  • Each reaction mixture contains ⁇ 5j JL_ 8 (0.25 nM) or 125 I Gro-a and 0.5 ⁇ g/mL of IL-8Ra or 1.0 ⁇ g/mL of IL-8Rb membranes in 20 mM Bis-Trispropane and 0.4 mM Tris HC1 buffers, pH 8.0, containing 1.2 mM MgS ⁇ 4, 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS.
  • drug or compound of interest is added which has been pre-dissolved in DMSO so as to reach a final concentration of between O.OlnM and 100 uM.
  • the assay is initiated by addition of I 25 T _JL_ 8 After 1 hour at room temperature the plate is harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1% polyethylenimine/ 0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM TrisHCl, 1 mM MgS ⁇ 4, 0.5 mM EDTA, 0.03 % CHAPS, pH 7.4. The filter is then dried and counted on the Betaplate liquid scintillation counter.
  • the recombinant IL-8 Ra, or Type I, receptor is also referred to herein as the non-permissive receptor and the recombinant IL-8 Rb, or Type II, receptor is referred to as the permissive receptor.
  • Representative compounds of Formula (I), and (II), Examples 1 to 11, and 13 to 19 herein demonstrated positive inhibitory activity of ⁇ 30 ⁇ mg in this assay.
  • the compound of Example 12 did not demonstrate activity at ⁇ 30 ⁇ mg in this assay, likely due to solubility issues.
  • Chemotaxis Assay The in vitro inhibitory properties of these compounds are determined in the neutrophil chemotaxis assay as described in Current Protocols in Immunology, vol.
  • Incubation is allowed to proceed for between about 45 and 90 min. at about 37°C in a humidified incubator with 5% C02-
  • the polycarbonate membrane is removed and the top side washed, the membrane then stained using the Diff Quick staining protocol (Baxter Products, McGaw Park, IL, USA).
  • Cells which have chemotaxed to the chemokine are visually counted using a microscope. Generally, four fields are counted for each sample, these numbers are averaged to give the average number of cells which had migrated. Each sample is tested in triplicate and each compound repeated at least four times. To certain cells (positive control cells) no compound is added, these cells represent the maximum chemotactic response of the cells. In the case where a negative control (unstimulated) is desired, no chemokine is added to the bottom chamber. The difference between the positive control and the negative control represents the chemotactic activity of the cells.
  • the compounds of this invention are tested for their ability to prevent Elastase release from human neutrophils.
  • Neutrophils are isolated from human blood as described in Current
  • the plate is placed in a fluorescent 96 well plate reader (Cytofluor 2350, Millipore, Bedford, MA) and data collected at 3 min. intervals according to the method of Nakajima et al J. Biol Chem 2544027 (1979).
  • the amount of Elastase released from the PMNs is calculated by measuring the rate of MeOSuc- Ala-Ala-Pro- Val-AMC degradation.
  • This assay provides for examination of the expression of tumor necrosis factor mRNA in specific brain regions which follow experimentally induced lateral fluid-percussion traumatic brain injury (TBI) in rats. Since TNF- ⁇ is able to induce nerve growth factor (NGF) and stimulate the release of other cytokines from activated astrocytes, this post-traumatic alteration in gene expression of TNF- ⁇ plays an important role in both the acute and regenerative response to CNS trauma.
  • a suitable assay may be found in WO 97/35856 or WO 97/49286 whose disclosures are incorporated herein by reference.
  • CNS Injury model for IL- ⁇ mRNA This assay characterizes the regional expression of interleukin-l ⁇ (IL-l ⁇ ) mRNA in specific brain regions following experimental lateral fluid-percussion traumatic brain injury (TBI) in rats. Results from these assays indicate that following TBI, the temporal expression of IL-l ⁇ mRNA is regionally stimulated in specific brain regions. These regional changes in cytokines, such as IL-l ⁇ play a role in the post-traumatic pathologic or regenerative sequelae of brain injury.
  • TBI lateral fluid-percussion traumatic brain injury
  • Cross-sections of the aortic root are taken as has been described previously (1,2). Briefly, the hearts are bisected just below the level of the atria and the base of the heart plus aortic root are taken for analysis. After equilibrating the tissue in OCT compound overnight the hearts are immersed in OCT compound on a cryostat chuck (Bright Instrument Company Ltd., UK) with the aorta facing the chuck. The tissue is frozen by surrounding the chuck with dry ice. The hearts are then sectioned perpendicular to the axis of the aorta, starting within the heart and working in the direction of the aorta.
  • Twenty-four bit colour images are acquired and analysed using a PC (Datacell Pentium P5-133, Datacell, Berks, U.K.) fitted with a framegrabbing board (Snapper, Active Imaging Ltd, Berks, U.K.) and running Optimas software (version 5.1, Optimas Corp., WA, U.S.A.).
  • the images are captured under identical lighting, microscope, camera and PC conditions.
  • Quantification of the atherosclerotic lesion areas is performed by drawing around the lesions by hand using the Optimas software.
  • Colour thresholds are set that quantify the areas that are stained red within the lesions. Absolute values for the cross- sectional areas of the lesions and the areas stained red are obtained by calibrating the software using an image of the grid on a haemocytometer slide.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Oncology (AREA)
  • Rheumatology (AREA)
  • Communicable Diseases (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Biotechnology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne de nouveaux composés représentés par la formule (I), ainsi que leurs compositions pharmaceutiques et des procédés servant à traiter des maladies dans lesquelles la chimiokine, Interleukine-8 (IL-8) joue un rôle.
PCT/US2000/016506 1999-06-16 2000-06-15 Antagonistes du recepteur d'il-8 Ceased WO2000076501A1 (fr)

Priority Applications (12)

Application Number Priority Date Filing Date Title
BR0011122-8A BR0011122A (pt) 1999-06-16 2000-06-15 Antagonistas de receptor il-8
EP00941455A EP1185265A4 (fr) 1999-06-16 2000-06-15 Antagonistes du recepteur d'il-8
PL00352213A PL352213A1 (en) 1999-06-16 2000-06-15 Antagonistic compounds of the il-8 receptor
MXPA01013005A MXPA01013005A (es) 1999-06-16 2000-06-15 Antagonistas de receptor de interleucina-8.
HU0201582A HUP0201582A3 (en) 1999-06-16 2000-06-15 Use of il-8 receptor antagonist benzimidazoles and benzotriazoles
IL14576200A IL145762A0 (en) 1999-06-16 2000-06-15 Il-8 receptor antagonists
KR1020017016144A KR20020015347A (ko) 1999-06-16 2000-06-15 Ｉｌ-8 수용체 길항제
JP2001502834A JP2003501463A (ja) 1999-06-16 2000-06-15 Ｉｌ−８受容体アンタゴニスト
NZ514696A NZ514696A (en) 1999-06-16 2000-06-15 IL-8 receptor antagonists
CA002377386A CA2377386A1 (fr) 1999-06-16 2000-06-15 Antagonistes du recepteur d'il-8
AU56161/00A AU766235B2 (en) 1999-06-16 2000-06-15 IL-8 receptor antagonists
NO20016052A NO20016052D0 (no) 1999-06-16 2001-12-11 IL-8-reseptor-antagonister

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14002499P 1999-06-16 1999-06-16
US60/140,024 1999-06-16

Publications (1)

Publication Number Publication Date
WO2000076501A1 true WO2000076501A1 (fr) 2000-12-21

Family

ID=22489379

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/016506 Ceased WO2000076501A1 (fr) 1999-06-16 2000-06-15 Antagonistes du recepteur d'il-8

Country Status (19)

Country Link
EP (1) EP1185265A4 (fr)
JP (1) JP2003501463A (fr)
KR (1) KR20020015347A (fr)
CN (1) CN1356899A (fr)
AR (1) AR024350A1 (fr)
AU (1) AU766235B2 (fr)
BR (1) BR0011122A (fr)
CA (1) CA2377386A1 (fr)
CO (1) CO5190696A1 (fr)
CZ (1) CZ20014472A3 (fr)
HU (1) HUP0201582A3 (fr)
IL (1) IL145762A0 (fr)
MX (1) MXPA01013005A (fr)
NO (1) NO20016052D0 (fr)
NZ (1) NZ514696A (fr)
PL (1) PL352213A1 (fr)
TR (1) TR200103638T2 (fr)
WO (1) WO2000076501A1 (fr)
ZA (1) ZA200109480B (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005012295A1 (fr) * 2003-07-28 2005-02-10 Sanofi-Aventis Deutschland Gmbh Derives de dioxyde de thiazol-benzoisothiazol substitues, procedes pour leur production et leur utilisation
WO2005021537A1 (fr) 2003-08-21 2005-03-10 Osi Pharmaceuticals, Inc. Inhibiteurs de c-kit pyrazolyle-amidyle-benzimidazolyle n-substitues
WO2006060381A2 (fr) 2004-12-01 2006-06-08 Osi Pharmaceuticals, Inc. Inhibiteurs de c-kit benzimidazolyle n-substitues et banque de benzimidazoles combinatoire
US7094794B2 (en) 2003-07-28 2006-08-22 Sanofi-Aventis Deutschland Gmbh Substituted thiazole-benzoisothiazole dioxide derivatives, process for their preparation and their use
US7338968B2 (en) 2003-12-19 2008-03-04 Schering Corporation Thiadiazoles AS CXC- and CC- chemokine receptor ligands
US7442709B2 (en) 2003-08-21 2008-10-28 Osi Pharmaceuticals, Inc. N3-substituted imidazopyridine c-Kit inhibitors
US7521448B2 (en) 2003-08-21 2009-04-21 Osi Pharmaceuticals, Inc. N-substituted benzimidazolyl c-Kit inhibitors
US7582673B2 (en) 2004-10-21 2009-09-01 High Point Pharmaceuticals, Llc Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use
US7691856B2 (en) 2002-10-09 2010-04-06 Schering Corporation Thiadiazoledioxides and thiadiazoleoxides as CXC- and CC-chemokine receptor ligands
WO2011120604A1 (fr) * 2010-03-30 2011-10-06 Pharmeste S.R.L. Antagonistes du récepteur vanilloïde trpv1 ayant une partie bicyclique
US8648086B2 (en) 2009-08-24 2014-02-11 Ascepion Pharmaceuticals, Inc. 5,6-bicyclic heteroaryl-containing urea compounds as kinase inhibitors

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102060780B (zh) 2010-12-27 2014-11-05 雅本化学股份有限公司 2-(n-取代)-氨基苯并咪唑衍生物的制备方法
CN111116502A (zh) * 2018-10-30 2020-05-08 中国石油化工股份有限公司 一步法合成苯骈三氮唑的方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5900430A (en) * 1991-02-19 1999-05-04 Anormed, Inc. Cytokine inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU726858B2 (en) * 1997-01-23 2000-11-23 Smithkline Beecham Corporation IL-8 receptor antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5900430A (en) * 1991-02-19 1999-05-04 Anormed, Inc. Cytokine inhibitors

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7691856B2 (en) 2002-10-09 2010-04-06 Schering Corporation Thiadiazoledioxides and thiadiazoleoxides as CXC- and CC-chemokine receptor ligands
US7094794B2 (en) 2003-07-28 2006-08-22 Sanofi-Aventis Deutschland Gmbh Substituted thiazole-benzoisothiazole dioxide derivatives, process for their preparation and their use
WO2005012295A1 (fr) * 2003-07-28 2005-02-10 Sanofi-Aventis Deutschland Gmbh Derives de dioxyde de thiazol-benzoisothiazol substitues, procedes pour leur production et leur utilisation
CN100413862C (zh) * 2003-07-28 2008-08-27 塞诺菲-安万特德国有限公司 取代的噻唑-苯并异噻唑二氧化物衍生物、其制备方法和其用途
US7521448B2 (en) 2003-08-21 2009-04-21 Osi Pharmaceuticals, Inc. N-substituted benzimidazolyl c-Kit inhibitors
WO2005021537A1 (fr) 2003-08-21 2005-03-10 Osi Pharmaceuticals, Inc. Inhibiteurs de c-kit pyrazolyle-amidyle-benzimidazolyle n-substitues
US7767673B2 (en) 2003-08-21 2010-08-03 Osi Pharmaceuticals, Inc. N-substituted imidazopyridine c-Kit inhibitors
US7442709B2 (en) 2003-08-21 2008-10-28 Osi Pharmaceuticals, Inc. N3-substituted imidazopyridine c-Kit inhibitors
US7338968B2 (en) 2003-12-19 2008-03-04 Schering Corporation Thiadiazoles AS CXC- and CC- chemokine receptor ligands
US7786149B2 (en) 2003-12-19 2010-08-31 Schering Corp. Thiadiazoles as CXC- and CC- chemokine receptor ligands
US7582673B2 (en) 2004-10-21 2009-09-01 High Point Pharmaceuticals, Llc Bissulfonamide compounds as agonists of GalR1, compositions, and methods of use
US7419995B2 (en) 2004-12-01 2008-09-02 Osi Pharmaceuticals, Inc. N-substituted benzimidazoyl c-Kit inhibitors and combinatorial benzimidazole library
WO2006060381A2 (fr) 2004-12-01 2006-06-08 Osi Pharmaceuticals, Inc. Inhibiteurs de c-kit benzimidazolyle n-substitues et banque de benzimidazoles combinatoire
US8648086B2 (en) 2009-08-24 2014-02-11 Ascepion Pharmaceuticals, Inc. 5,6-bicyclic heteroaryl-containing urea compounds as kinase inhibitors
WO2011120604A1 (fr) * 2010-03-30 2011-10-06 Pharmeste S.R.L. Antagonistes du récepteur vanilloïde trpv1 ayant une partie bicyclique
CN102858742A (zh) * 2010-03-30 2013-01-02 法梅斯特有限公司 具有二环部分的trpv1香草酸受体拮抗剂
CN102858742B (zh) * 2010-03-30 2015-05-27 法梅斯特有限公司 具有二环部分的trpv1香草酸受体拮抗剂
US9216975B2 (en) 2010-03-30 2015-12-22 Serentrix, LLC. TRPV1 vanilloid receptor antagonists with a bicyclic portion

Also Published As

Publication number Publication date
PL352213A1 (en) 2003-08-11
ZA200109480B (en) 2002-11-18
NO20016052L (no) 2001-12-11
IL145762A0 (en) 2002-07-25
HUP0201582A3 (en) 2003-02-28
AR024350A1 (es) 2002-10-02
NZ514696A (en) 2004-03-26
AU5616100A (en) 2001-01-02
CA2377386A1 (fr) 2000-12-21
CN1356899A (zh) 2002-07-03
TR200103638T2 (tr) 2002-04-22
CO5190696A1 (es) 2002-08-29
EP1185265A1 (fr) 2002-03-13
BR0011122A (pt) 2002-02-26
NO20016052D0 (no) 2001-12-11
MXPA01013005A (es) 2002-07-02
JP2003501463A (ja) 2003-01-14
HUP0201582A2 (hu) 2002-12-28
KR20020015347A (ko) 2002-02-27
EP1185265A4 (fr) 2004-02-04
CZ20014472A3 (cs) 2002-06-12
AU766235B2 (en) 2003-10-09

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