WO1999006354A1 - Il-8 receptor antagonists - Google Patents

Il-8 receptor antagonists Download PDF

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Publication number
WO1999006354A1
WO1999006354A1 PCT/US1998/015830 US9815830W WO9906354A1 WO 1999006354 A1 WO1999006354 A1 WO 1999006354A1 US 9815830 W US9815830 W US 9815830W WO 9906354 A1 WO9906354 A1 WO 9906354A1
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Prior art keywords
optionally substituted
alkyl
heterocyclic
heteroaryl
aryl
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PCT/US1998/015830
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French (fr)
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Katherine L. Widdowson
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Smithkline Beecham Corporation
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Priority to EP98938138A priority Critical patent/EP1000017A4/en
Priority to CA002294064A priority patent/CA2294064A1/en
Priority to JP2000505116A priority patent/JP2001512096A/en
Priority to AU86731/98A priority patent/AU8673198A/en
Publication of WO1999006354A1 publication Critical patent/WO1999006354A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/42—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by carboxyl groups
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
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    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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

Definitions

  • This invention relates to a novel group of phenyl urea compounds, processes for the preparation thereof, the use thereof in treating IL-8.
  • GRO ⁇ , GRO ⁇ NAP-2, and ENA-78 mediated diseases and pharmaceutical compositions for use in such therapy are novel groups of phenyl urea compounds, processes for the preparation thereof, the use thereof in treating IL-8.
  • Interleuk ⁇ n-8 Interleuk ⁇ n-8
  • NAP 1 neutrophil attractant/activation protein- 1
  • MDNCF monocyte derived neutrophil chemotactic factor
  • NAF neutrophil activating factor
  • Interleuk ⁇ n-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, endothehal 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 M Baggiohni et al, J Clin Invest 84.
  • GRO ⁇ . GRO ⁇ . GRO ⁇ and NAP-2 also belong to the chemokine ⁇ famih Like IL-8 these chemokines have also been referred to by different names For instance GRO ⁇ , ⁇ , ⁇ have been referred to as MGSA ⁇ , ⁇ and ⁇ respectively (Melanoma Growth Stimulating Activity), see Richmond et al. J Cell Physiolog) 129, 375 ( 1986) and Chang et al, J Immunol 148. 451 ( 1992) All of the chemokines of the ⁇ -family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor
  • IL-8 GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 and ENA-78 stimulate a number of functions in vitro They have all been shown to have chemoattractant properties for neutrophils. While IL-8 and GRO ⁇ have demonstrated T-lymphocytes, and basophiles chemotactic activity In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals GRO- ⁇ and IL-8 can in addition induce lysozomal enzyme release and respiratory burst from neutrophils IL-8 has also been shown to increase the surface expression of Mac-1 (CD1 lb/CD 18) on neutrophils without de novo protein synthesis This may contribute to increased adhesion of the neutrophils to vascular endothelial cells Many known diseases are characterized by massive neutrophil infiltration As IL-8, Gro ⁇ , GRO ⁇ GRO ⁇ and ⁇ AP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including p
  • 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 a pharmaceutically acceptable salt thereof.
  • the chemokine is IL-8.
  • This invention also relates to a method of inhibiting the binding of LL-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).
  • Compounds of Formula (I) useful in the present invention are represented by the structure:
  • R is (CR 8 R 8 )r C(O) 2 H, (CR 8 R 8 )r NH-C(O)R a , (CR 8 R 8 )r C(O)NR6'R7',
  • Ri is independently selected from hydrogen: halogen; nitro; cyano: halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl: Cj-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR 8 R )q S(O) t R4; hydroxy; hydroxy Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; aryl Ci-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Ci-4alkyl; heteroaryl C] -4 alkyloxy; aryl C2-10 alkenyl
  • R6 and R7 are independently hydrogen or a C i-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:
  • R6' and R7' are independently hydrogen, C i-4 alkyl, aryl, arylC i-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC i-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C i -4alkyl.
  • heterocyclic C2-4alkenyl moiety provided that one of R6' and R7' is a hydrogen, but not both;
  • Y is independently selected from hydrogen: halogen: nitro: cyano; halosubstituted Ci-io alkyl; Ci-io alkyl: C2- 10 alkenyl; Ci-io alkoxy: halosubstituted Ci- 10 alkoxy; azide; (CR 8 R )q S(O)tR4: hydroxy; hydroxyC i-4aikyl; aryl; aryl Ci-4 alkyl; aryloxy; arylCi -4 alkyloxy: heteroaryl: heteroarylalkyl: heteroaryl Ci .4 alkyloxy: heterocyclic. heterocyclic C i-4alkyl; aryl C2- 10 alkenyl: heteroaryl
  • Ra is an alkyl, aryl, aryl C i-4aTkyl.
  • Rb is a NR6R7, alkyl, aryl,.
  • Re is alkyl, aryl, arylC i-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC i-4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclic C i-4alkyl, or a heterocyclic
  • Rrj is NRgR , alkyl, arylC .4 alkyl. arylC 2-4 alkenyl, heteroaryl, heteroaryl-C[.4alkyl, heteroarylC2-4 alkenyl. heterocyclic, heterocyclicC ⁇ _4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing rings may be optionally substituted:
  • the E containing ring is optionally selected from
  • the compounds of Formula (I) may also be used in association with the vete ⁇ nary treatment of mammals, other than humans, in need of inhibition of LL-8 or other chemokines which bind to the LL-8 ⁇ and ⁇ 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
  • R is (CR 8 R 8 )r C(O)2H, (CR 8 Rg)r NFf-C(O)R a , (CRgR 8 )r C(0)NR 6 'R7', (CR 8 R 8 )rNHS(O)2Rb, (CR 8 R 8 )r S(O) 2 NHR c , (CR 8 R 8 )r
  • NHC(X2)NHRb or a tetrazolyl ring
  • r is 0 or an integer of 1 to 4, preferably 0
  • X2 1S oxygen or sulfur preferably oxygen wherein r is 0 or an integer having a value of 1 to 4
  • R6 and R7 are independently hydrogen or a C 1-4 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
  • R6' and R7' are hydrogen, Ci-4 alkyl, aryl, arylCi-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC i-4alkyl. heteroarylC2-4 alkenyl. heterocyclic. heterocyclic C ⁇ _4dlkyl. or a heterocyclic C2-4alkenyl moiety provided that one of R ⁇ and R7 1 are hydrogen, but not both of R6 1 and R7 1 All of these moieties may be optionally substituted one to three times independently by halogen, nitro. halosubstituted C i-4 alkyl, such as CF3 C j-4 alkyl.
  • R is an alkyl. aryl. arvlC i-4alkyl heteroaryl heteroarylC i-4alkyl, heterocyclic. or a heterocyclic C ] _4alk ⁇ 1 moiety wherein all of these moieties may be optionally substituted as defined herein
  • R is a NRgR7 5 alkyl, aryl. arylC i-4alkyl, arylC2-4alkenyl, heteroaryl. heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Ci-4alkyl. or a heterocyclic C2-4alken ⁇ l moiety, or camphor, wherein the alkyl aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted one to three times independently by halogen, nitro, halosubstituted C1-4 alkyl, such as CF3, Ci-4 alkyl, such as methyl, C j -4 alkoxy, such as methoxy.
  • Rb is preferably an optionally substituted phenyl. benzyl or styryl When R is a heteroarvl ring, it is preferably an optionally substituted thiazole, an optionally substituted thienyl, or an optionally substituted quinolinyl ring
  • R ⁇ . is hydrogen or a C1-4 alkyl group, preferably a hydrogen
  • R9 is in the substituent group NR9C(O)R a
  • R a is preferably an alkyl group, such as methyl
  • R c is hydrogen, alkyl aryl, arylCi-4alkyl, arylCi-4alkenyl, heteroaryl, heteroarylC i-4alkyl, heteroarylCi-4alkenyI, heterocyclic, or heterocyclic C i-4alkyl, or a heterocyclic Ci-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted Cj-4 alkyl.
  • R c is an optionally substituted phenyl
  • W is , or
  • the E containing ring is an optionally substituent which is selected from
  • Ri is independently selected from hydrogen, halogen, nitio cyano. halosubstituted alkyl, such as CF3, alkyl, such as methyl. eth ⁇ 1 isopropyl, or n-propyl, C -lO alkenyl, Ci-io alkoxy. such as methoxy. or etho ⁇ y halosubstituted C ⁇ - ⁇ 0 alkoxy such as t ⁇ fluoromethoxy , azide, (CRgRg)q S(0) t R4 hvdroxy, hydroxy Ci-4alkyl such as methanol or ethanol, aryl.
  • alkyl such as CF3, alkyl, such as methyl. eth ⁇ 1 isopropyl, or n-propyl, C -lO alkenyl, Ci-io alkoxy. such as methoxy. or etho ⁇ y halosubstituted C ⁇ -
  • aryl Ci-4 alkvl such as benzyl, aryloxy, such as phenoxy, aryl Cj-4 alkyloxy, such as benzyloxv heteroaryl, heteroarylalkyl, heteroaryl Cj-4 alkyloxy, aryl Co-lO alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-IO alkenyl, (CR ⁇ R 8 )q R4R5.
  • t is 0, an integer having a value of 1 or 2
  • s is an integer having a value of 1 to 3
  • q is 0. or an integer having a value of 1 to 10
  • s is preferably 1
  • Rj forms an additional saturated or unsaturated ring, it is preferably a 6 membered ring resulting in a naphthylene ring system
  • saturated and unsaturated ring systems may be optionally substituted independently, 1 to 3 times by the other R i moieties as defined above
  • R4 and R5 are independently hydrogen, optionally substituted Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl C i-4alkyl optionally substituted heteroaryl. optionally substituted heteroaryl C ⁇ _4alkyl, heterocyclic or heterocycl ⁇ cC ⁇ _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 R 8 is suitably independently selected from hydrogen or Ci-4 alkyl
  • RlO is suitably C i - io alkyl C(0)2R8, such as CH2C(O)2H or CH2C(0)2CH3
  • Rl 1 is suitably independently hydrogen, C i -4 alkyl.
  • R 12 is suitably hydrogen C 1 - 10 alkyl, optionally substituted aryl or optionally substituted arvlalkyl
  • R l 7 is suitably C i -4alkyl, aryl arylalkyl, heteroaryl, heteroarylC i-4alkyl heterocyclic. or heterocychcC i -4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted
  • R i is halogen, cyano. nitro, CF3, C(0)NR4R5, alkenyl
  • R4 and R5 are both hydrogen or one of R4 and R5 is phenyl
  • R4 and R5 are phenyl
  • R is (CR 8 R 8 ) r OH (CR 8 R 8 ) r SH or (CR 8 R 8 ) r NHS(0) Rb than R 1 is preferably substituted in the 4- position, or disubstituted in the 2.4-pos ⁇ t ⁇ on
  • the Ri substituent group is an electron withdrawing moiety such as nitro, halogen, cyano, t ⁇ fluoromethyl, or C(O)NR4R5
  • R i is preferably hydrogen, or Ri is preferably substituted in the 4-pos ⁇ t ⁇ on. more preferably substituted by t ⁇ fluoromethyl or chloro
  • R 13 and R 14 are independently hydrogen, an optionally substituted C i-4 alkyl which may be straight or branched as defined herein, or one of R13 and R 14 is an optionally substituted aryl
  • R 13 or R 14 are an optionally substituted alkyl
  • the alkyl moiety may be substituted one to three times independently by halogen halosubstituted C i-4 alkyl such as t ⁇ fluoromethyl; hydroxy: hydroxy C i -4alkyl.
  • C j -4 alkoxy such as methoxy.
  • v is 0 or an integer having a value of 1 to 4.
  • Y is independently selected from hydrogen; halogen; nitro cyano; halosubstituted C i-io alkyl; - io alkyl; C2- 10 alkenyl; - io alkoxy. halosubstituted C i- io alkoxy; azide: (CR 8 R )q S(O)tR4; hydroxy; hydroxyC i-4alkyl; aryl; aryl C i-4 alkyl: aryloxy; arylC j-4 alkyloxy: heteroaryl.
  • heteroarylalkyl heteroaryl C i -4 alkyloxy; heterocyclic, heterocyclic C i -4alkyl; aryl C2-10 alkenyl: heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl; (CR R 8 )q NR4R5: C2- IO alkenyl C(O)NR4R5; (CR 8 Rg)q C(0)NR4R5- (CR 8 R 8 )q C(O)NR4R ⁇ o, S(O)3H; S(O)3R 8 . such as S(O)3H. (CR 8 R 8 )q C(O)Rj [ .
  • s is preferably 1
  • Y forms an additional unsaturated ring it is preferably 6 membered resulting in a naphthylene ring system.
  • These saturated and unsaturated rings may be optionally substituted 1 to 3 times by the other Y moieties as defined above
  • Rj is a NRgR7. alkyl. aryl C 1.4 alkyl. arylC 2.4 alkenyl, heteroaryl, heteroaryl-C ] _4alkyl. heteroarylC2_4 alkenyl, heterocyclic. heterocycl ⁇ cC ⁇ _4 alkyl, or heterocyclic C 2-4 alkenyl moiety, wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted as defined herein
  • Y is preferably a halogen, C j -4 alkoxy. optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio C i-4alkyl. thioaryl, halosubstituted alkoxy, optionally substituted C i-4 alkyl, or hydroxy alkyl Y is more preferably a mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy. methylenedioxy, aryl, or alkyl.
  • these groups are mono or di-substituted in the 2'- position or 2'-, 3'-pos ⁇ t ⁇ on of the phenyl ring. While Y may be substituted in any of the 5 ring positions, preferably when R is (CR 8 R 8 ) ⁇ C(O)2H, Y is preferably mono-substituted in the 2'-pos ⁇ t ⁇ on or
  • X is suitably oxygen or sulfur, preferably oxygen
  • X is suitably oxygen or sulfur, preferably oxygen
  • the E and E' rings, denoted by its point of attachment through the aste ⁇ x (*) may optionally be present If it is not present the ring is a phenyl moiety which is substituted by the R ⁇ and Y terms as shown herein
  • the E and E' ring may be substituted by the R i and Y moietv respectively in any ring, saturated or unsaturated and is shown for purposes herein substituted only in the unsaturated ⁇ ng(s)
  • R o i W j an optionally substituted heteroaryl, an optionally substituted C5_ 8 cycloalk l. an optionally substituted C [ " IQ alkyl an optionally substituted C2-10 alkenyl. or an optionally substituted C2-10 alkynyl
  • R20 i an optionally substituted C5_ 8 cycloalkyl ring
  • the ring may be substituted by (Y) n as defined abov e
  • R20 is an optionally substituted C ⁇ . ⁇ Q alkyl an optionally substituted 2-10 alkenyl or an optionally substituted C2-10 alkynyl these moieties may be optionally substituted one or more times independently by halogen, nitro, cyano.
  • halosubstituted Ci- io alkyl such as t ⁇ fluoromethvl C j - io alkoxy, halosubstituted C i- 10 alkoxy S(O)tR4 hydroxv hvdioxy C i -4alk ⁇ l aryloxy aiylC ] .4 alkyloxy, heteroaryloxy, heteroaryl C i-4 alkvlow heterocyclic. heterocyclic C i-4alkyl. heterocychcoxy, heterocyclic Cj_4 alkyloxy. NR4R5. C(O)NR4R5, C(0)NR4R ⁇ o,
  • R20 is an optionally substituted C2-10 alkenyl. or an optionally substituted C2-10 alkynyl these moieties may also, in addition to those moieties noted above, be optionally substituted with aiyl. aryl C 1-4 alkyl, heteroaryl. or a heteroaryl C i-4 alkyl (and wherein these aryl and heteroaryl containing rings may be optionally substituted)
  • Wj is or
  • the E containing ring is optionally selected from
  • R20 1 heteroaryl (HET) ring when R20 1 heteroaryl (HET) ring, it is suitably a heteroaryl ring or ring system
  • the ring containing the heteroatom does not need to be directly attached to the urea moiety or the (CR ⁇ R jqJy term. All the rings in this ring sy stem may be optionally substituted by the (Y ( n) ) term as defined above
  • the HET moiety is a py ⁇ dy l. which may be 2-. 3- or 4-py ⁇ dyl.
  • the ring is a multi system ring it is preferably a benzimidazole. dibenzothiophene.
  • heterocyclic rings of interest include, but are not limited to thiophene. turan. py ⁇ midine. py ⁇ ole, pyrazole. quinoline. lsoquinohne. quinazohnyl, py ⁇ dine. oxazole, thiazole, thiadiazole, t ⁇ azole, or lmidazole
  • R20 is preferably an optionally substituted pheny l. allyl, C I _ Q alkyl, ethoxy carbonyl ethyl, dimethylacetal. 2-methoxy isopropyl, 01 2-methoxy ethyl group.
  • Exemplified compounds of Formula (I) include: N-(3-Carboxyphenyl)-N'-(2-brornophenyl)urea N-(3-Carboxymethylphenyl)-N'-(2-bromophenyl)urea N-(3-Carboxymethylphenyl)-N'-(2,3-d ⁇ chlorophenyl)urea N-(3-Carboxyphenyl)-N'-(2,3-d ⁇ chlorophenyl)urea N-[3-(2-Carboxyethyl)phenyl]-N'-(2,3-dichlorophenyl) urea N-(2.4-Dichloro-3-carboxy)-N'-(2-bromophenyl) ureaN-(4-Chloro-3- carboxyphenyl)-N'-(2-bromophenyl)urea N-(4-Chloro-3-carboxyphenyl) N'-(2,
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy such as fluorine, chlorine, bromine or iodine
  • C j- ioalkyl such as methoxy or ethoxy
  • methyl thio such as methyl sulfinyl or methyl sulfonyl
  • amino. mono & di-substituted amino such as in the NR4R5 group; NHC(O)R4: C(O)NR4Rs; C(O)OH.
  • C i- io alkyl such as methyl, ethyl, propyl. isopropyl, or t-butyl; halosubstituted C i- io alkyl. such CF3: an optionally substituted aryl. such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl. optionally substituted heterocylic. optionally substituted heterocylicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, and wherein these aryl , heteroaryl.
  • heterocyclic moieties may be substituted one to two times by halogen; hydroxy, hydroxy substituted alkyl; C j - io alkoxy; S(O) rn 'Ci -io alkyl: amino. mono & di- _4 alkyl substituted amino. such as in the NR4R5 group; C j - io alkyl, or halosubstituted C 1- 10 alkyl. such as CF3.
  • R2 is suitably C i -4 alkyl. aryl. aryl C i -4alkyl, heteroaryl, heteroaryl- C i-4alkyl, heterocyclic. or heterocycl ⁇ cC ⁇ _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, tarta ⁇ c acid, citric acid, lactic acid, oxalic acid, succinic acid, fuma ⁇ c acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandehc acid.
  • 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, tarta ⁇ c acid, citric acid, lactic acid, oxalic acid, succinic acid, fuma ⁇ c acid, maleic acid, benzoic acid, salicylic acid, phen
  • 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.
  • halo all halogens, that is chloro, fluoro, bromo and lodo
  • cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl. cy ciopentyl, 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.
  • 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, quinolme, lsoquinolme. quinazohnyl. py ⁇ dine, py ⁇ midine. oxazole, thiazole. thiadiazole. t ⁇ azole, lmidazole, or benzimidazole • "heterocyclic (on its own or in any combination, such as
  • heterocychcalkyl 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 ot N, O. or S. such as. but not limited to, pyrrohdine. pipe ⁇ dine. piperazine. morphohne. tetrahydropyran. or lmidazohdine • arylalkyl' or heteroarylalkyl ' or 'heterocychcalkyl” is used herein to mean C j- io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moietv , as also defined herein, unless otherwise indicated
  • 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 compounds of Formula (I) having a variety of different R, R ⁇ . and aryl 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 W and R20 as phenyl this is merely for illustration purposes only
  • the desired aniline 2-scheme- l can be synthesized by the reduction of the corresponding nitro if it is not available commercially This reduction can be accomplished by a number ot reducing agents such as hydrogen and catalytic
  • the desired compound could synthesized by the protection of the carboxylic acid by conditions well known in art. such as diazomethane to form the methyl ester
  • This compound could then be reduced by a number of reducing agents such as hydrogen and catalytic Palladium on carbon or tin chloride in a polar solvent such as DMF or ethyl acetate Condensation with a phosgene equivalent such as di- or t ⁇ phosgene in the presence of a base such as ethyl amme or bicarbonate would form the isocvanate 4-scheme-2
  • This compound could then be reacted with the desired commercially available aniline
  • the carboxylic acid could then be deprotected by conditions standard in the art, such as metal hydroxide in a polar solvent such as THF/water. then acidified with an acid such as HC1 to form 3, scheme 2.
  • compositions of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid or base in the presence of a suitable solvent.
  • Another aspect of the present invention is the analogous process for producing a compound of Formula (I) which process comprises reacting a compound of the formula
  • R, R and m are as defined for Formula ( I), with a compound of the formula: -N(XMCR 13 R 14 ) v -R2o: wherein X, R ⁇ ,, R14, v and R20 are as defined in Formula ( I ) to yield a compound of Formula (I).
  • Another aspect of the present invention is the alternative process for producing a compound of Formula (I) which process comprises reacting a compound of the formula
  • R ⁇ . m and R are as defined for formula (I), with a compound of the formula NH2- ( CR 13 R 14 ) V - R20, wherein R 13, R14, v and R20 are as defined in Formula to yield a compound of
  • E, R. Rj and m are as defined for Formula (I), or a compound of Formula (B2) wherein E. R. R j and m are as defined for Formula (I), or may instead be reacted with a compound of the formula.
  • the compounds of Formula (I), or a pharmaceutically acceptable salt 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 present invention provides a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an LL-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.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function m particular IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78, such that they are biologically legulated 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 (p levels of free IL-8 greater than or equal to 1 picogram per mL. (n) any cell associated LL-8, GRO ⁇ . GRO ⁇ .
  • GRO ⁇ , NAP-2 or ENA-78 above normal physiological levels, or (in) the presence IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 above basal levels in cells or tissues in LL-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, glomeruloneph ⁇ tis, thrombosis graft vs host reaction, Alzheimer s disease, allograft rejections, malaria, restinosis angiogenesis or undesired hematopoietic stem cells release, rhinovirus infections and various bone resorptive indications such as osteoporosis or osteoarth ⁇ tis
  • the association of mterleuk ⁇ n-8 and rhinovirus may be found in articles such as Turner et al .
  • GRO ⁇ GRO ⁇ GRO ⁇ or NAP-2 T cell infiltration, or neovascular growth and are associated with increased LL-8 GRO ⁇ GRO ⁇ GRO ⁇ GRO ⁇ or NAP-2 production w hich is responsible for the chemotaxis of neutrophils into the inflammatory site or the directional growth of endothehal cells In contrast to other inflammatory cy tokines (IL 1 TNF, and IL 6), LL-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 ⁇ -chemokines but particularly, GRO ⁇ GRO ⁇ , GRO ⁇ or NAP-2.
  • 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
  • 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 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 endothehal 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 LL-8. binding to the LL-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 LL-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, in some instances, to be dual inhibitors of both recombinant type I and type II IL-8 receptors.
  • the compounds are inhibitors of only one receptor, more preferably Type II.
  • 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 LL-8.
  • GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 themselves, or by LL-8.
  • GRO ⁇ , NAP-2 or ENA-78 causing another monokine to be released such as but not limited to IL- 1 , IL-6 or TNF
  • IL-8 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 LL-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 LL-8 ⁇ or ⁇ receptor plays a role such as but not limited LL-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 LL-8 itself or bv IL 8 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 LL-8
  • cy tokine refers to any secreted polypeptide that affects the functions ot cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response ⁇ 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 Many other cells however also produce monokines, such as natural killer cells, fibroblasts.
  • cytokines include, but are not limited to. Interleuk ⁇ n- 1 (IL- 1 ) Interleuk ⁇ n-6 (IL-6). Interleuk ⁇ n-8 (LL-8), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor beta (TNF- ⁇ )
  • chemokine refers to anv 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. endothehal cells and smooth muscle cells
  • chemokines include, but are not limited to, LL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , NAP-2. ENA-78 IP- 10, MlP- l ⁇ .
  • 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 camer(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 pharmaceutical carrier employed may be. for example, either a solid or liquid
  • solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate.
  • stea ⁇ c acid and the like Exemplary of liquid carriers are syrup, peanut oil. olive oil water and the like
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax
  • 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 earner 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
  • compounds of Formula (I) may be administered topically, that is by non- systemic administration This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear.
  • systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration
  • Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin 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 bacte ⁇ cide and may be prepared by methods similar to those for the preparation of drops
  • Lotions or liniments tor 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 finelv-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.
  • 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 sihcaceous 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 m 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, transfe ⁇ ed 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 phenylmercu ⁇ c 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. lntrarectal, 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 ill preferably be from about 0.01 mg/kg to about 1 mg/kg per day. It will also be recognized by one of skill in the art that 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.
  • LL-8, and GRO- ⁇ chemokine inhibitory effects of compounds of the present invention were determined by the following in vitro assay Receptor Binding Assays:
  • IL_ human recombinant
  • Amersham Corp Arlington Heights, IL. with specific activity 2000 Ci/mmol
  • GRO- ⁇ was obtained from NEN- New England Nuclear All other chemicals were of analytical grade
  • High levels of recombinant human IL-8 type ⁇ and ⁇ 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 .
  • the filter was then dried and counted on the Betaplate liquid scintillation counter
  • the recombinant IL-8 R ⁇ . or Type I. receptor is also referred to herein as the non- permissive receptor and the recombinant LL-8 R ⁇ , or Type II receptor is refe ⁇ ed to as the permissive receptor
  • 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. I, Suppl 1, Unit 6.12.3.. whose disclosure is incorporated herein by reference in its entirety. Neutrophils where isolated from human blood as described in Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1 , whose disclosure is incorporated herein by reference in its entirety. The chemoattractants LL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ and NAP-2 are placed in the bottom chamber of a 48 multiwell chamber (Neuro Probe. Cabin John, MD) at a concentration between 0.1 and 100 nM.
  • the two chambers are separated by a 5um polycarbonate filter.
  • compounds of this invention are tested, they are mixed with the cells (0 001 - 1000 nM) just prior to the addition of the cells to the upper chamber. Incubation is allowed to proceed for between about 45 and 90 min. at about 37°C in a humidified incubator with 5% CO2. At the end of the incubation period, 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.
  • test compound 0.001 - 1000 nM
  • Cytochalasm B in a volume of 50 ul (20ug/ml)
  • Ringers buffer in a volume of 50 ul
  • 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 lelease 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
  • TNF- ⁇ nerve growth factor
  • a suitable assay may be found in WO 97/35856 or WO 97/49286 whose disclosures are incorporated herein by reference
  • 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 A suitable assay may be found in WO 97/35856 or WO 97/49286 whose disclosures are incorporated herein by reference In vivo - Athereoschlerosis assay:

Abstract

This invention relates to novel phenyl ureas useful in the treatment of disease states mediated by the chemokine, Interleukin-8 (IL-8).

Description

IL-8 RECEPTOR ANTAGONISTS
FIELD OF THE INVENTION
This invention relates to a novel group of phenyl urea compounds, processes for the preparation thereof, the use thereof in treating IL-8. GROα. GROβ, GROγ NAP-2, and ENA-78 mediated diseases and pharmaceutical compositions for use in such therapy
BACKGROUND OF THE INVENTION
Many different names have been applied to Interleukιn-8 (IL-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 Interleukιn-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, endothehal and epithelial cells exposed to TNF, IL-lα, IL-lβ or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP M Baggiohni et al, J Clin Invest 84. 1045 ( 1989), J Schroder et al. J Immunol 139 3474 ( 1987) and J Immunol 144. 2223 (1990) , Stπeter. 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 famih Like IL-8 these chemokines have also been referred to by different names For instance GROα, β, γ have been referred to as MGSAα, β and γ respectively (Melanoma Growth Stimulating Activity), see Richmond et al. J Cell Physiolog) 129, 375 ( 1986) and Chang et al, J Immunol 148. 451 ( 1992) All of the chemokines of the α-family which possess the ELR motif directly preceding the CXC motif bind to the IL-8 B receptor
IL-8. GROα, GROβ, GROγ, NAP-2 and ENA-78 stimulate a number of functions in vitro They have all been shown to have chemoattractant properties for neutrophils. while IL-8 and GROα have demonstrated T-lymphocytes, and basophiles chemotactic activity In addition IL-8 can induce histamine release from basophils from both normal and atopic individuals GRO-α and IL-8 can in addition induce lysozomal enzyme release and respiratory burst from neutrophils IL-8 has also been shown to increase the surface expression of Mac-1 (CD1 lb/CD 18) on neutrophils without de novo protein synthesis This may contribute to increased adhesion of the neutrophils to vascular endothelial cells Many known diseases are characterized by massive neutrophil infiltration As IL-8, Groα, GROβ GROγ and \AP-2 promote the accumulation and activation of neutrophils, these chemokines have been implicated in a wide range of acute and chronic inflammatory disorders including psoriasis and rheumatoid arthritis. Baggiolini et al, FEBS Lett 307. 97 ( 1992). Miller et al. Cπt Rev Immunol 12. 17 (1992) Oppenheim et al Annu Rev Immunol 9. 617 ( 1991 ) Seitz et al . J Chn Invest 87. 463 (1991 ). Miller et al , Am Rev Respir Pis 146. 427 ( 1992) Donnelv et al , Lancet 341 643 (1993) In addition the ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis Stπeter et al . Science 258, 1798 ( 1992)
In vitro IL-8 GROα GROβ GROγ. 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 notablv 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 tarmly has precedent For a review see R Fieidinger in Progress in Drug Research. Vol 40, pp 33-98. Birkhauser Verlag, Basel 1993 Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents
Two high affinity human IL-8 receptors (llZc homology) have been characterized IL-8Rα which binds only IL-8 with high affinity, and IL-8Rβ which has high affinity tor IL-8 as well as foi GRO α GROβ GROγ and NAP-2 See 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 remains a need for treatment, in this field, for compounds which are capable of binding to the IL-8 α or β receptor Therefore conditions associated with an increase in IL-8 production (which is responsible for chemotaxis of neutrophil and T-cells subsets into the inflammatory site) would benefit by compounds which are inhibitors of IL-8 receptor binding
? . SUMMARY OF THE INVENTION
This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 α or β receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In particular the chemokine is IL-8.
This invention also relates to a method of inhibiting the binding of LL-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). Compounds of Formula (I) useful in the present invention are represented by the structure:
Figure imgf000005_0001
W — N N— (CR13R14)v — R 20 (I) wherein X is oxygen or sulfur:
R is (CR8R8)r C(O)2H, (CR8R8)r NH-C(O)Ra, (CR8R8)r C(O)NR6'R7',
(CR8R8)rNHS(O)2Rb, (CR8R8)r S(O)2NHRc, (CR8R8)r NHC(X2)NHRb, or a tetrazolyl ring; X2 is oxygen or sulfur; Ri is independently selected from hydrogen: halogen; nitro; cyano: halosubstituted Ci-io alkyl; Ci-io alkyl; C2-10 alkenyl: Cj-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR8R )q S(O)tR4; hydroxy; hydroxy Ci-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; aryl Ci-4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Ci-4alkyl; heteroaryl C] -4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl: (CR R8)qNR4R5; C2-10 alkenyl
C(O)NR4R5; (CR8R8)q C(O)NR R5; (CR8R8)q C(O)NR4Rlθ; S(O)3Rg; (CR8R8)q C(O)Rπ; C2- 10 alkenyl C(O)Rn; C2- 10 alkenyl C(O)ORn(CR8R8)q C(O)ORi2; (CR8R8)q OC(O) Rπ; (CR8R8)qNR4C(O)Rι ι; (CR8R8)q NHS(O)2Rι7; (CR8R8)q S(O)2NR4R5; or two Ri moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted; provided that there is no ionizable hydrogen having a pKa of 3 to 10 in the 2-position of the phenyl ring; 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; r is 0 or an integer of 1 to 4; s is an integer having a value of 1 to 3; t is 0, or an integer having a value of 1 or 2; v is an integer having a value of 1 to 4; R4 and R5 are independently hydrogen, optionally substituted C \-'4 alkyl, optionally substituted aryl, optionally substituted aryl C i-4alkγl, optionally substituted heteroaryl, optionally substituted heteroaryl C i-4alkyl, heterocyclic, heterocyclic C 1-4 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 C i-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: R6' and R7' are independently hydrogen, C i-4 alkyl, aryl, arylC i-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC i-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic C i -4alkyl. heterocyclic C2-4alkenyl moiety, provided that one of R6' and R7' is a hydrogen, but not both;
Y is independently selected from hydrogen: halogen: nitro: cyano; halosubstituted Ci-io alkyl; Ci-io alkyl: C2- 10 alkenyl; Ci-io alkoxy: halosubstituted Ci- 10 alkoxy; azide; (CR8R )q S(O)tR4: hydroxy; hydroxyC i-4aikyl; aryl; aryl Ci-4 alkyl; aryloxy; arylCi -4 alkyloxy: heteroaryl: heteroarylalkyl: heteroaryl Ci .4 alkyloxy: heterocyclic. heterocyclic C i-4alkyl; aryl C2- 10 alkenyl: heteroaryl
C2-10 alkenyl; heterocyclic C2- 10 alkenyl: (CR R8)q NR4R5; C2- 10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4Rs; (CR8R8)q C(O)NR4R10; S(O)3R8; (CR8R )q C(O)Rn ; C2- 10 alkenyl C(O)Rn ; C2- 10 alkenyl C(O)ORn ; C(O)Rn ; (CR8R8)q C(O)ORi ; (CR8R8)q OC(O) R u ; (CR8R8)qNR C(O)Rn ; (CRgRg)q NHS(O)2Rd; (CR8R8)q S(O)2NR4R5; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring: and wherein the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted; R8 is independently selected from hydrogen or C i-4 alkyl; Rio is C i-10 alkyl C(O)2R8; Rl 1 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; Ri2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl: Rl3 and R 14 are independently hydrogen, optionally substituted Ci .4 alkyl, or one of R13 and R14 may be optionally substituted aryl; Rl7 is Ci-4alkyl, aryl, arylalkyl. heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted; Ra is an alkyl, aryl, aryl C i-4aTkyl. heteroaryl, heteroaryl C i-4alkyl, heterocyclic, or a heterocyclic Ci-4alkyl moiety, wherein all of these moieties may be optionally substituted: Rb is a NR6R7, alkyl, aryl,. arylC 1 -4-ιlkyl, arylC2-4alkenyl, heteroaryl, heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic. heterocyclic Ci-4-Ukyl, heterocyclic C2-4alkenyl moiety, or camphor, wherein all of these moieties may be optionally substituted; Re is alkyl, aryl, arylC i-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC i-4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclic C i-4alkyl, or a heterocyclic
C2-4alkenyl moiety, wherein all of these moieties may be optionally substituted; Rrj is NRgR , alkyl, arylC .4 alkyl. arylC 2-4 alkenyl, heteroaryl, heteroaryl-C[.4alkyl, heteroarylC2-4 alkenyl. heterocyclic, heterocyclicCι_4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing rings may be optionally substituted:
Figure imgf000007_0001
the E containing ring is optionally selected from
Figure imgf000008_0001
asteπx * denoting point ot attachment ot the ring, and R20 is Wi . optιonall substituted heteroaryl, optionally substituted C5- cycloalkyl, optionally substituted C \. [Q alkyl, optionally substituted C2-10 alkenyl, or an opuonally substituted C2-10 alkynyl,
Figure imgf000008_0002
the asteπx * denoting point of attachment of the ring, or a pharmaceutically acceptable salt thereof
DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula (I) may also be used in association with the veteπnary treatment of mammals, other than humans, in need of inhibition of LL-8 or other chemokines which bind to the LL-8 α and β 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
In compounds of Formula (I), R is (CR8R8)r C(O)2H, (CR8Rg)r NFf-C(O)Ra, (CRgR8)r C(0)NR6'R7', (CR8R8)rNHS(O)2Rb, (CR8R8)r S(O)2NHRc, (CR8R8)r
NHC(X2)NHRb, or a tetrazolyl ring Each of these moieties may be directly attached to the ring in the 3-posιtιon or through the linker (CR8R8)r to the 3-posιtιon of the ring. Suitably, r is 0 or an integer of 1 to 4, preferably 0
Suitably. X2 1S oxygen or sulfur, preferably oxygen wherein r is 0 or an integer having a value of 1 to 4
Suitably, R6 and R7 are independently hydrogen or a C 1-4 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
Suitably, R6' and R7' are hydrogen, Ci-4 alkyl, aryl, arylCi-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC i-4alkyl. heteroarylC2-4 alkenyl. heterocyclic. heterocyclic C ι_4dlkyl. or a heterocyclic C2-4alkenyl moiety provided that one of Rβ and R71 are hydrogen, but not both of R61 and R71 All of these moieties may be optionally substituted one to three times independently by halogen, nitro. halosubstituted C i-4 alkyl, such as CF3 C j-4 alkyl. such as methvl, Ci-4 alkoxy such as methoxy, NRQC(O)Rd C(0)NR6R7 S(O)ιH. or C(O)OC ι_4 alkyl Suitably R is an alkyl. aryl. arvlC i-4alkyl heteroaryl heteroarylC i-4alkyl, heterocyclic. or a heterocyclic C ] _4alk\ 1 moiety wherein all of these moieties may be optionally substituted as defined herein
Suitably, R is a NRgR75 alkyl, aryl. arylC i-4alkyl, arylC2-4alkenyl, heteroaryl. heteroarylCi-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Ci-4alkyl. or a heterocyclic C2-4alken\ l moiety, or camphor, wherein the alkyl aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted one to three times independently by halogen, nitro, halosubstituted C1-4 alkyl, such as CF3, Ci-4 alkyl, such as methyl, C j -4 alkoxy, such as methoxy. NRαC(O)Ra C(O)NR6R7- S(O)3H. or C(O)OC i-4 alkyl Rb is preferably an optionally substituted phenyl. benzyl or styryl When R is a heteroarvl ring, it is preferably an optionally substituted thiazole, an optionally substituted thienyl, or an optionally substituted quinolinyl ring
Suitably, Rα. is hydrogen or a C1-4 alkyl group, preferably a hydrogen When R9 is in the substituent group NR9C(O)Ra, then Ra is preferably an alkyl group, such as methyl
Suitably Rc is hydrogen, alkyl aryl, arylCi-4alkyl, arylCi-4alkenyl, heteroaryl, heteroarylC i-4alkyl, heteroarylCi-4alkenyI, heterocyclic, or heterocyclic C i-4alkyl, or a heterocyclic Ci-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted Cj-4 alkyl. C 1.4 alkyl, C 1.4 alkoxy, NR9C(O)Ra, C(O)NR6R7. S(O)3H, or C(O)OC 1.4 alkyl Preferably, Rc is an optionally substituted phenyl Suitably, W is
Figure imgf000010_0001
, or
Suitably, the E containing ring is an optionally substituent which is selected from
Figure imgf000010_0002
wherein the asteπx Λ denotes the point ot attachment ot the ring
In compounds of Formula (I), suitably Ri is independently selected from hydrogen, halogen, nitio cyano. halosubstituted
Figure imgf000010_0003
alkyl, such as CF3,
Figure imgf000010_0004
alkyl, such as methyl. eth\ 1 isopropyl, or n-propyl, C -lO alkenyl, Ci-io alkoxy. such as methoxy. or etho\y halosubstituted C \ - \ 0 alkoxy such as tπfluoromethoxy , azide, (CRgRg)q S(0)tR4 hvdroxy, hydroxy Ci-4alkyl such as methanol or ethanol, aryl. such as phen l or naphthyl, aryl Ci-4 alkvl such as benzyl, aryloxy, such as phenoxy, aryl Cj-4 alkyloxy, such as benzyloxv heteroaryl, heteroarylalkyl, heteroaryl Cj-4 alkyloxy, aryl Co-lO alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-IO alkenyl, (CR§R8)q R4R5. C2-10 alkenyl C(0)NR4R5- (CR8R8)q C(O)NR4R5 (CR8R8)q C(0)NR4RlO- S(O)3R8 such as S(O)3H, (CR8R8)q C(O)Rι 1, C?-10 alkenyl C(0)Rι 1, C2-10 alkenyl C(0)ORι 1 C(O)Rι 1, (CR8R8)q C(O)ORi2, (CR8R8)qOC(O)Rι 1. (CR8R8)q NR C(0)Ri 1 (CR8R8)q NHS(O)2Rj7, (CR Rg)qS(0)2NR4R5, or two R 1 moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring The aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted as defined herein below
Suitable, t is 0, an integer having a value of 1 or 2 Suitably, s is an integer having a value of 1 to 3
Suitably, q is 0. or an integer having a value of 1 to 10
When Ri forms a dioxybπdge, s is preferably 1 When Rj forms an additional saturated or unsaturated ring, it is preferably a 6 membered ring resulting in a naphthylene ring system These saturated and unsaturated ring systems may be optionally substituted independently, 1 to 3 times by the other R i moieties as defined above
Suitably. R4 and R5 are independently hydrogen, optionally substituted Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl C i-4alkyl optionally substituted heteroaryl. optionally substituted heteroaryl C ι _4alkyl, heterocyclic or heterocyclιcC ι _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 R8 is suitably independently selected from hydrogen or Ci-4 alkyl
RlO is suitably C i - io alkyl C(0)2R8, such as CH2C(O)2H or CH2C(0)2CH3
Rl 1 is suitably independently hydrogen, C i -4 alkyl. aryl, aryl Ci-4 alkyl heteroarvl, heteroaryl -qalkyl heterocyclic or heterocvchc C i -4alkyl R 12 is suitably hydrogen C 1 - 10 alkyl, optionally substituted aryl or optionally substituted arvlalkyl
R l 7 is suitably C i -4alkyl, aryl arylalkyl, heteroaryl, heteroarylC i-4alkyl heterocyclic. or heterocychcC i -4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted Preferably R i is halogen, cyano. nitro, CF3, C(0)NR4R5, alkenyl
C(O)NR4R5, C(O) R4R 10, alkenyl C(O)OR i 2, heteroaryl heteroarylalkyl , heteroaryl alkenyl, or S(O)NR4R5, and preferably R4 and R5 are both hydrogen or one of R4 and R5 is phenyl A preferred ring substitution for the R i group is in the
4-posιtιon of the phenvl ring When R is (CR8R8)r OH (CR8R8)r SH or (CR8R8)r NHS(0) Rb than R 1 is preferably substituted in the 4- position, or disubstituted in the 2.4-posιtιon
Preferably, the Ri substituent group is an electron withdrawing moiety such as nitro, halogen, cyano, tπfluoromethyl, or C(O)NR4R5
When R is a carboxylic acid, than R i is preferably hydrogen, or Ri is preferably substituted in the 4-posιtιon. more preferably substituted by tπfluoromethyl or chloro
In compounds of Formula (I), suitably R 13 and R 14 are independently hydrogen, an optionally substituted C i-4 alkyl which may be straight or branched as defined herein, or one of R13 and R 14 is an optionally substituted aryl When R 13 or R 14 are an optionally substituted alkyl, the alkyl moiety may be substituted one to three times independently by halogen halosubstituted C i-4 alkyl such as tπfluoromethyl; hydroxy: hydroxy C i -4alkyl. C j -4 alkoxy. such as methoxy. or ethoxy; halosubstituted - io alkoxy; S(O)tR4: aryl; NR4R5; NHC(0)R4; C(O)NR4Rs or C(O)OR8.
Suitably, v is 0 or an integer having a value of 1 to 4. Suitably. Y is independently selected from hydrogen; halogen; nitro cyano; halosubstituted C i-io alkyl; - io alkyl; C2- 10 alkenyl; - io alkoxy. halosubstituted C i- io alkoxy; azide: (CR8R )q S(O)tR4; hydroxy; hydroxyC i-4alkyl; aryl; aryl C i-4 alkyl: aryloxy; arylC j-4 alkyloxy: heteroaryl. heteroarylalkyl; heteroaryl C i -4 alkyloxy; heterocyclic, heterocyclic C i -4alkyl; aryl C2-10 alkenyl: heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl; (CR R8)q NR4R5: C2- IO alkenyl C(O)NR4R5; (CR8Rg)q C(0)NR4R5- (CR8R8)q C(O)NR4Rιo, S(O)3H; S(O)3R8. such as S(O)3H. (CR8R8)q C(O)Rj [ . C2- 10 alkenyl C(O)R l 1 ; C2- 10 alkenyl C(0)OR ι 1 : (CR8R8)q C(0)OR l2; (CR8R8)q OC(O) R i 1. (CR8R8)q NR4C(O)R i 1. (CR8R8)q NHS(0)2Rd; (CR8R8)q S(O)2NR4R5 or two Y moieties together may form 0-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring The aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted
When Y forms a dioxybπdge, s is preferably 1 When Y forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. These saturated and unsaturated rings may be optionally substituted 1 to 3 times by the other Y moieties as defined above
Suitably. Rj is a NRgR7. alkyl. aryl C 1.4 alkyl. arylC 2.4 alkenyl, heteroaryl, heteroaryl-C ] _4alkyl. heteroarylC2_4 alkenyl, heterocyclic. heterocyclιcC ι_4 alkyl, or heterocyclic C 2-4 alkenyl moiety, wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted as defined herein
Y is preferably a halogen, C j -4 alkoxy. optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio C i-4alkyl. thioaryl, halosubstituted alkoxy, optionally substituted C i-4 alkyl, or hydroxy alkyl Y is more preferably a 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'-posιtιon of the phenyl ring. While Y may be substituted in any of the 5 ring positions, preferably when R is (CR8R8)ιC(O)2H, Y is preferably mono-substituted in the 2'-posιtιon or
3'-posιtιon. with the 4 - preferably being unsubstituted If the ring is disubstituted, when R is (CR R8)ιC(O)2H, substituents are preferably in the 2 or 3' position of a monocvclic ring While both R\ and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, and moie preferably that both rings are substituted
In compounds of Formula (I), X is suitably oxygen or sulfur, preferably oxygen The E and E' rings, denoted by its point of attachment through the asteπx (*) may optionally be present If it is not present the ring is a phenyl moiety which is substituted by the R\ and Y terms as shown herein The E and E' ring may be substituted by the R i and Y moietv respectively in any ring, saturated or unsaturated and is shown for purposes herein substituted only in the unsaturated πng(s)
In compounds of Formula ( I) R o i W j an optionally substituted heteroaryl, an optionally substituted C5_8 cycloalk l. an optionally substituted C [ " IQ alkyl an optionally substituted C2-10 alkenyl. or an optionally substituted C2-10 alkynyl
When R20 i an optionally substituted C5_8 cycloalkyl ring, the ring may be substituted by (Y)n as defined abov e
When R20 is an optionally substituted C \ . \ Q alkyl an optionally substituted 2-10 alkenyl or an optionally substituted C2-10 alkynyl these moieties may be optionally substituted one or more times independently by halogen, nitro, cyano. halosubstituted Ci- io alkyl such as tπfluoromethvl C j - io alkoxy, halosubstituted C i- 10 alkoxy S(O)tR4 hydroxv hvdioxy C i -4alk\l aryloxy aiylC ] .4 alkyloxy, heteroaryloxy, heteroaryl C i-4 alkvlow heterocyclic. heterocyclic C i-4alkyl. heterocychcoxy, heterocyclic Cj_4 alkyloxy. NR4R5. C(O)NR4R5, C(0)NR4Rιo,
S(O)3H, S(O)3Rg, C(O)Rι 1 , C(O)ORi2, OC(O)Rι 1, or NR4C(O)Rι 1
When R20 is an optionally substituted C2-10 alkenyl. or an optionally substituted C2-10 alkynyl these moieties may also, in addition to those moieties noted above, be optionally substituted with aiyl. aryl C 1-4 alkyl, heteroaryl. or a heteroaryl C i-4 alkyl (and wherein these aryl and heteroaryl containing rings may be optionally substituted) Suitably, Wj is
Figure imgf000014_0001
or
Suitably, the E containing ring is optionally selected from
Figure imgf000014_0002
In compounds of Formula ( I), when R20 1 heteroaryl (HET) ring, it is suitably a heteroaryl ring or ring system If the HET moiety is a multi-ring system, the ring containing the heteroatom does not need to be directly attached to the urea moiety or the (CR ^R jqJy term. All the rings in this ring sy stem may be optionally substituted by the (Y( n) ) term as defined above Preferably, the HET moiety is a pyπdy l. which may be 2-. 3- or 4-pyπdyl. If the ring is a multi system ring it is preferably a benzimidazole. dibenzothiophene. or indole ring Other heterocyclic rings of interest include, but are not limited to thiophene. turan. pyπmidine. pyπole, pyrazole. quinoline. lsoquinohne. quinazohnyl, pyπdine. oxazole, thiazole, thiadiazole, tπazole, or lmidazole
R20 is preferably an optionally substituted pheny l. allyl, C I _ Q alkyl, ethoxy carbonyl ethyl, dimethylacetal. 2-methoxy isopropyl, 01 2-methoxy ethyl group.
Exemplified compounds of Formula (I) include: N-(3-Carboxyphenyl)-N'-(2-brornophenyl)urea N-(3-Carboxymethylphenyl)-N'-(2-bromophenyl)urea N-(3-Carboxymethylphenyl)-N'-(2,3-dιchlorophenyl)urea N-(3-Carboxyphenyl)-N'-(2,3-dιchlorophenyl)urea N-[3-(2-Carboxyethyl)phenyl]-N'-(2,3-dichlorophenyl) urea N-(2.4-Dichloro-3-carboxy)-N'-(2-bromophenyl) ureaN-(4-Chloro-3- carboxyphenyl)-N'-(2-bromophenyl)urea N-(4-Chloro-3-carboxyphenyl) N'-(2,3-dιchlorophenyl) urea N-(4-Chloro-3-carboxyphenyl)-N-(3-chlorophenyl)urea; or a pharmaceutically acceptable salt thereof.
As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted C j- ioalkyl; C i- io alkoxy, such as methoxy or ethoxy; S(O)m' C i - io alkyl, wherein nϊ 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(O)R4: C(O)NR4Rs; C(O)OH. S(O)2NR4R5, NHS(O)2R2. C i- io alkyl, such as methyl, ethyl, propyl. isopropyl, or t-butyl; halosubstituted C i- io alkyl. such CF3: an optionally substituted aryl. such as phenyl, or an optionally substituted arylalkyl, such as benzyl or phenethyl. optionally substituted heterocylic. optionally substituted heterocylicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, and wherein these aryl , heteroaryl. or heterocyclic moieties may be substituted one to two times by halogen; hydroxy, hydroxy substituted alkyl; C j - io alkoxy; S(O)rn'Ci -io alkyl: amino. mono & di- _4 alkyl substituted amino. such as in the NR4R5 group; C j - io alkyl, or halosubstituted C 1- 10 alkyl. such as CF3.
R2 is suitably C i -4 alkyl. aryl. aryl C i -4alkyl, heteroaryl, heteroaryl- C i-4alkyl, heterocyclic. or heterocyclιcC ι_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, tartaπc acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaπc acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandehc acid. In addition, 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 lodo
• "C i- ioalkyl" 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, /z-propyl, i vo-propyl. /z-butyl. Λ?e-butyl, iso-butyl, tert- butyl. /2-pentyl and the like
• "cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl. cy ciopentyl, 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-propeny l, 2-propenyl. 2-methyl- l-propenyl, 1-butenyl, 2-butenyl and the like
• "ary l" - pheny l 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, quinolme, lsoquinolme. quinazohnyl. pyπdine, pyπmidine. oxazole, thiazole. thiadiazole. tπazole, lmidazole, or benzimidazole • "heterocyclic (on its own or in any combination, such as
"heterocychcalkyl") - 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 ot N, O. or S. such as. but not limited to, pyrrohdine. pipeπdine. piperazine. morphohne. tetrahydropyran. or lmidazohdine • arylalkyl' or heteroarylalkyl ' or 'heterocychcalkyl" is used herein to mean C j- io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moietv , as also defined herein, unless otherwise indicated
• "sulfinyl" - the oxide S (O) of the corresponding sulfide, the term "thio" refers to the sulfide, and the term 'sulfonyl" refers to the fully oxidized S(O)2 moiety
• the term "wherein two R i moieties (or two Y moieties) may together form a 5 or 6 membered saturated or unsaturated ring" is used herein to mean the formation of a napthylene ring system or a phenyl moiety having attached a 6 membered partially unsaturated ring such as a C cycloalkenyl, I e hexene, or a C5 cycloalkenyl moiety, such as a cyclopentene ring Methods of Preparation
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 compounds of Formula (I) having a variety of different R, R \ . and aryl 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 W and R20 as phenyl this is merely for illustration purposes only
The desired aniline 2-scheme- l can be synthesized by the reduction of the corresponding nitro if it is not available commercially This reduction can be accomplished by a number ot reducing agents such as hydrogen and catalytic
Palladium on carbon or tin chloride in a polar solvent such as DMF or ethyl acetate This aniline (2-scheme 1 ) can then be condensed with a commercially available lsocyanate in an aprotic solvent such as DMF DMSO or toluene
Scheme 1
Figure imgf000017_0001
- 2 2
R=CH2CH2COOH, COOH, CH2COOH a)H2. Pd/C b)PhCNO
Alternately, the desired compound could synthesized by the protection of the carboxylic acid by conditions well known in art. such as diazomethane to form the methyl ester This compound could then be reduced by a number of reducing agents such as hydrogen and catalytic Palladium on carbon or tin chloride in a polar solvent such as DMF or ethyl acetate Condensation with a phosgene equivalent such as di- or tπphosgene in the presence of a base such as ethyl amme or bicarbonate would form the isocvanate 4-scheme-2 This compound could then be reacted with the desired commercially available aniline The carboxylic acid could then be deprotected by conditions standard in the art, such as metal hydroxide in a polar solvent such as THF/water. then acidified with an acid such as HC1 to form 3, scheme 2.
Figure imgf000018_0001
1 4 3 R=CH2CH2COOH, COOH. or CH2COOH; Protected R wherein R=CH2CH2COOMe. COOMe. or CH COOMe a) CH2N2, ether b) H2.5r Pd/C c ) triphosgene. Et3N d) PhNH .DMF e) LiOH, THF/H2O f) HC1/H20
Pharmaceutically acceptable salts of compounds of Formula (I) may be obtained in known manner, for example by treatment thereof with an appropriate amount of acid or base in the presence of a suitable solvent.
Another aspect of the present invention is the analogous process for producing a compound of Formula (I) which process comprises reacting a compound of the formula
Figure imgf000018_0002
wherein R, R and m are as defined for Formula ( I), with a compound of the formula: -N(XMCR13R 14 ) v-R2o: wherein X, R\τ,, R14, v and R20 are as defined in Formula ( I ) to yield a compound of Formula (I).
Alternatively, a compound of Formula (A l )
Figure imgf000018_0003
wherein E. R, Rj and m are as defined for Formula (I), or a compound of Formula (A2)
Figure imgf000019_0001
wherein E, R. R] and m are as defined for Formula (I), or may instead be reacted with a compound of the formula.
-N(X)-(CRι3Ri4)v - R2o; wherein X, R13, R14, v and R20 are as defined in Formula (I) to yield a compound of Formula (I).
Another aspect of the present invention is the alternative process for producing a compound of Formula (I) which process comprises reacting a compound of the formula
Figure imgf000019_0002
wherein R \ . m and R are as defined for formula (I), with a compound of the formula NH2-(CR13R14)V - R20, wherein R 13, R14, v and R20 are as defined in Formula to yield a compound of
Formula (I), and deprotecting the R group if necessary
As above, one may alternatively use a compound of Formula (B 1
Figure imgf000019_0003
wherein E, R. Rj and m are as defined for Formula (I), or a compound of Formula (B2)
Figure imgf000020_0001
wherein E. R. Rj and m are as defined for Formula (I), or may instead be reacted with a compound of the formula.
NH2-(CRi3R 14)v - R2o; wherein R13, R ]4, v and R20 are as defined in Formula (I) to yield a compound of
Formula (I); and deprotecting the R group if necessary.
In the Examples, all temperatures are in degrees Centigrade (°C). Mass spectra were performed upon a VG Zab mass spectrometer using fast atom bombardment, unless otherwise indicated 1 H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz or 400MHz using a Bruker AM 250 or Am 400 spectrometer, respectively Multiplicities indicated are: s=sιnglet, d=doublet, t=tπplet. q=quartet. m=multιplet and br indicates a broad signal. Sat indicates a saturated solution, equiv indicates the proportion of a molar equivalent of reagent relative to the principal reactant.
Flash chromatography is run over Merck Silica gel 60 (230 - 400 mesh)
SYNTHETIC EXAMPLES
The invention will now be described by reference to the following examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. All tempeiatures are given in degrees centigrade, all solvents used herein are of the highest available purity and all reactions are run under anhydrous conditions in an argon atmosphere unless otherwise indicated
Example 1
Preparation of N-(3-Carboxyphenyl)-N'-(2-bromophenyl)urea
A solution of 3-amιno benzoic acid ( 1 equivalent (hereinafter "eq"), 1.37 gram (hereinafter "g")) in DMF was treated with 2-bromo phenyl isocyanate ( 1 eq, 1.98 g) at about 80°C for about 2 hours. The solution was cooled and the product was purified by recrystalization from methylene chloride and hexanes to afford 1.28g of the titled compound as white solid. MS(ES)M-H=333
Example 2 Preparation of N-(3-Carboxymethylphenyl)-N'-(2-bromophenyl)urea A solution of 3-amιno phenyl acetic acid ( leq, .151 g) in DMF was treated with 2-bromo phenyl isocyanate ( 1 eq, .198 g) at about 80 °C for about 2 hours. The solution was cooled and the product was purified by recrystalization from methylene chloride and hexanes to afford 0.32g of the titled compound as white solid. MS(ES)M-H=347
Example 3 Preparation of N-(3-Carboxymethylphenyl)-N'-(2,3-dιchlorophenyl)urea
A solution of 3-amιno phenyl acetic acid (leq, 151 milligrams (hereinafter "mg")) in DMF was treated with 2.3-dιchloro phenyl isocyanate (1 eq, 188 mg) at 80 °C for 2 hours. The solution was cooled and the product was purified by recrystalization from methylene chloride and hexanes to afford 12 g of the titled compound as white solid MS(ES)M-H=337
Example 4 Preparation of N-(3-Carboxyphenyl)-N'-(2.3-dιchlorophenyl)urea
A solution of 3-amιno benzoic acid ( 1 eq, 1 37 g) in DMF was treated with 2.3-dιchloro phenyl isocyanate ( 1 eq, 1 88 g) at 80 °C for 2 hours. The solution was cooled and the product was purified by recrystalization from methylene chloride and hexanes to afford 1 01 g of the titled compound as white solid MS(ES)M-H=323
Example 5 Preparation of N-[3-(2-Carboxyetfιyl)phenyll-N'-(2,3-dιchlorophenyl) urea a) 3-amιno dihydrocinnamic acid
A solution of 3-nιtro dihydrocinnamic acid (500 mg) in ethyl acetate was treated with 10%Pd/C (500 mg) The resulting suspension was flushed with hydrogen and allowed to stir overnight at room temperature The reaction mixture was purged with argon and then filtered through celite The filtrate was concentrated and the residue was recrystalhzed from toluene and ethyl acetate. ^H NMR (DMSO) 6.95 t (1H), 6.4 m (3 H). 2.7 t (2H), 2 45 t (2H)
b) N-[3-(2-carboxyethyI)phenyl]-N'-(2,3-dιchlorophenyl) urea
A solution of 3-amιno dihydro cinnamic acid ( 1 eq, 83 mg) in DMF was treated with 2,3-dιchloro phenyl isocyanate ( 1 eq, 94 mg) at 80 °C for 2 hours. The solution was cooled and the product was purified by recrystalization from methylene chloride and hexanes to afford 0.037g of the titled compound as white solid. *H NMR (DMSO) 9 45 s ( 1H), 8 47 s ( 1H), 8 17 d (1H), 7 31 m (4H), 7 24 t (1H), 6 88 d ( lH). 2 73 t ( 2H), 2 54 t (2H)
Example 6 Preparation of N-(2,4-Dιchloro-3-carboxy)-N'-(2-bromophenyl) urea a) 5-amιno 2,6-dιchloro bcnzoic acid
A solution of 5-nιtro-2 6-dιchloro benzoic acid (2 0 g) in ethyl acetate was treated with 10% Pd/C( 1 5g) The suspension was flushed with hydrogen and allowed to stir at room temperature overnight The reaction mixture was purged with argon and filtered through celite The filtrate was concentrated and the residue was purified by recrystalization from ethyl acetate and hexanes to afford the title compound (0 7g) as a w hue solid ] H NMR (DMSO) 7 15 d ( 1H), 6 8 d ( 1H), 5 74 s ( IH. br)
b) N-(2.4-Dιchloro-3-carboxy ) N (2-bromophenyl) urea
A solution of 5 amino 2 6-dιchloro benzoic acid ( 1 eq, 250 mg) in DMF was treated with 2-bromo phenvl isocyanate ( 1 eq. 153 uL) at 80 °C for 2 hours The solution was cooled and the product was purified by recrvstahzation from methylene chloride and hexanes to af ford 35 mg of the titled compound as white solid MS(ES)M-H=401
Example 7 Preparation of N-(4-Chloro-3 carboxyphenyl)-N -(2 bromophenypurea
A solution of 5 amιno-2-chloro benzoic acid ( l eq 1 71 g) in DMF was treated with 2-bromo phenyl isocyanate ( 1 eq 1 98 g) at 80 °C for 2 houis The solution was cooled and the product was purified by recrystalization from methylene chloride and hexanes to afford 0 880 g ot the titled compound as white solid MS(ES)M-H=367
Example 8 Preparation of N-(4-Chloro-3-carboxyphenyl) N -(2 3-dιchlorophenyl) urea
A solution of 5-amιno-2-chloro benzoic acid ( 1 eq 1 71 g) in DMF was treated with 2,3-dιchloro phenyl isocyanate ( 1 eq, 1 88 g) at 80 °C for 2 hours The solution was cooled and the product was purified by recrystalization from methylene chloride and hexanes to afford 1 57g of the titled compound as white solid MS(ES)M-H=357
Example 9 Preparation of N-(4-Chloro-3-carboxyphenyP-N-(3-chlorophenyl)urea
A solution of 5-amιno-2-chloro benzoic acid ( 1 eq, 1 71 g) in DMF was treated with 3-chloro phenyl isocyanate (1 eq, 1 53 g) at 80 °C for 2 hours The solution was cooled and the product was purified by recrystalization from methylene chloride and hexanes to afford 0 66g of the titled compound as white solid MS(ES)M-H=323
METHOD OF TREATMENT
The compounds of Formula (I), or a pharmaceutically acceptable salt 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 α or β receptor, also referred to as the type I or type II receptor
Accordingly, the present invention provides a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an LL-8 α or β receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof In particular, the chemokines are IL-8. GROα. GROβ. GROγ, NAP-2 or ENA-78
The compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function m particular IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78, such that they are biologically legulated 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. GROα. GROβ, GROγ. NAP-2 or ENA-78 for instance in the context of the present invention, constitute (p levels of free IL-8 greater than or equal to 1 picogram per mL. (n) any cell associated LL-8, GROα. GROβ. GROγ, NAP-2 or ENA-78 above normal physiological levels, or (in) the presence IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 above basal levels in cells or tissues in LL-8. GROα. GROβ, GROγ. NAP-2 or ENA-78 respectively , is produced
There are many disease states in which excessive or unregulated LL-8 production is implicated in exacerbating and/or causing 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, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephπtis, thrombosis graft vs host reaction, Alzheimer s disease, allograft rejections, malaria, restinosis angiogenesis or undesired hematopoietic stem cells release, rhinovirus infections and various bone resorptive indications such as osteoporosis or osteoarthπtis The association of mterleukιn-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 The association of mterleukιn-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 These diseases are pπmaπlv characterized by massive neutrophil infiltration,
T cell infiltration, or neovascular growth and are associated with increased LL-8 GROα GROβ GROγ or NAP-2 production w hich is responsible for the chemotaxis of neutrophils into the inflammatory site or the directional growth of endothehal cells In contrast to other inflammatory cy tokines (IL 1 TNF, and IL 6), LL-8 GROα. GROβ. GROγ 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 α-chemokines but particularly, GROα GROβ, GROγ or NAP-2. working through the LL-8 type I or II receptor can promote the neovasculaπzation of tumors bv promoting the directional growth of endothehal cells Therefore the inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration
Recent evidence also implicates the role of chemokines in the treatment of HIV infections. Littleman et al , Nature 381 , pp 661 ( 1996) and Koup et al , Nature 381. pp 667 ( 1996) 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.
Present evidence also indicates the use of LL-8 inhibitors in the treatment of atherosclerosis. The first reference. Boisvert et al., J Clin Invest, 1998. 101 :353- 363 shows, through bone marrow transplantation, that the absence of IL-8 receptors on stem cells (and, therefore, on monocytes/macrophages) leads to a reduction in the development of atherosclerotic plaques in LDL receptor deficient mice. Additional suppoπing references are: Apostolopoulos et al., Arteπoscler Thromb Vase Biol. 1996. 16: 1007-1012. Liu et al.. Arteπoscler Thromb Vase Biol, 1997. 17.317-323, Rus et al , Atherosclerosis 1996. 127.263-271 . Wang et al.. J Biol Chem. 1996, 271:8837-8842. Yue et al.. Eur J Pharmacol. 1993, 240:81-84. Koch et al., Am J Pathol. 1993, 142: 1423- 1431.; Lee et al., Immunol Lett. 1996, 53, 109-1 13.; and Terkeltaub et al., Arteπoscler Thromb. 1994. 14.47-53.
TNF-α is a cytokine with proinflammatory actions, including endothehal 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.
Models of closed head injuries and treatment with mixed 5-LO/CO agents is discussed in Shohami et al., J. of Vaisc & Clinical Physiology and Pharmacology, Vol. 3. No. 2, pp. 99- 107 ( 1992) w hose disclosure is incorpoiated herein by reference. Treatment which reduced edema formation was found to improve functional outcome in those animals treated
The compounds of Formula (I) are administered in an amount sufficient to inhibit LL-8. binding to the LL-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 LL-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, in some instances, to be dual inhibitors of both recombinant type I and type II IL-8 receptors. Preferably the compounds are inhibitors of only one receptor, more preferably Type II. As used herein, the term "IL-8 mediated disease or disease state refers to any and all disease states in which IL-8. GROα. GROβ, GROγ. NAP-2 or ENA-78 plays a role, either by production of LL-8. GROα, GROβ, GROγ, NAP-2 or ENA-78 themselves, or by LL-8. GROα, GROβ. GROγ, 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 LL-8, would therefore be considered a disease stated mediated by IL-8
As used herein the term chemokine mediated disease or disease state" refers to any and all disease states in which a chemokine which binds to an LL-8 α or β receptor plays a role such as but not limited LL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 This would include a disease state in which. IL-8 plays a role, either by production of LL-8 itself or bv IL 8 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 LL-8 As used herein the term cy tokine refers to any secreted polypeptide that affects the functions ot cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response \ cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them For instance, a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte Many other cells however also produce monokines, such as natural killer cells, fibroblasts. basophils, neutrophils. endothehal cells, brain astrocvtes bone marrow stromal cells. epidermal keratinocytes and B-lymphocytes Lv mphokines are generally referred to as being produced by lymphocyte cells Examples of cytokines include, but are not limited to. Interleukιn- 1 (IL- 1 ) Interleukιn-6 (IL-6). Interleukιn-8 (LL-8), Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta (TNF-β)
As used herein, the term 'chemokine" refers to anv 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. endothehal cells and smooth muscle cells Examples of chemokines include, but are not limited to, LL-8, GRO-α, GRO-β, GRO-γ, NAP-2. ENA-78 IP- 10, MlP- lα. MlP-β, PF4. and MCP 1 , 2, and 3 In order to use a compound of Formula (I) or a pharmaceutically acceptable salt thereof in therapy, it will normally be formulated into a pharmaceutical composition in accordance with standard pharmaceutical practice This invention, therefore, also relates to a pharmaceutical composition comprising an effective, non- toxic amount of a compound of Formula (I) and a pharmaceutically acceptable earner 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 It will be appreciated that 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 camer(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 pharmaceutical carrier employed may be. for example, either a solid or liquid Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate. steaπc acid and the like Exemplary 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 to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax
A wide variety of pharmaceutical forms can be employed Thus, if a solid earner 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 earner will vary widely but preferably will be from about 25mg to about lg When a liquid caπier is used, 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 Compounds of Formula (I) may be administered topically, that is by non- systemic administration This includes the application of a compound of Formula (I) externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear. eye and nose, such that the compound does not significantly enter the blood stream In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin 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 bacteπcide and may be prepared by methods similar to those for the preparation of drops Lotions or liniments tor 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 finelv-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 com, arachis, castor or olive oil wool fat or its derivatives or a fatty acid such as steπc 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 sihcaceous 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 m 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, transfeπed to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 C. for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by an aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuπc 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. lntrarectal, 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.
For all methods of use disclosed herein for the compounds of Formula (I), the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral 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 ill preferably be from about 0.01 mg/kg to about 1 mg/kg per day. It will also be recognized by one of skill in the art that 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.
The invention will now be described by reference to the following biological examples which are merely illustrative and are not to be construed as a limitation of the scope of the present invention. BIOLOGICAL EXAMPLES
The LL-8, and GRO-α chemokine inhibitory effects of compounds of the present invention were determined by the following in vitro assay Receptor Binding Assays:
[125j] IL_ (human recombinant) was obtained from Amersham Corp , Arlington Heights, IL. with specific activity 2000 Ci/mmol GRO-α was obtained from NEN- New England Nuclear All other chemicals were of analytical grade High levels of recombinant human IL-8 type α and β 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)) Except that the homogemzation buffer was changed to lOmM Tπs-HCL I mM MgS04, 0 5mM EDTA (ethylene-diaminetetra- acetic acid), ImMPMSF ( α-toluenesulphonyl fluoride) 0 5 mg/L Leupepun, pH 7 5 Membrane protein concentration was determined using Pierce Co micro-assay kit using bovine serum albumin as a standard All assays were performed in a 96-well micro plate format Each reaction mixture contained l -^I JL_ (O 25 riM) or 125τ Gro-α and 0 5 μg/mL of IL-8Rα oi 1 0 μg/mL of IL-8Rβ membranes in 20 mM Bis- Tπspropane and 0 4 mM Tπs HCl buffers, pH 8 0 containing 1 2 mM MgSO4, 0 1 mM EDTA, 25 mM NaCl and 0 03% CHAPS In addition drug or compound of interest was added which had been pre-dissolved in DMSO so as to reach a final concentration of between 0 O l nM and 100 uM The assay w as initiated by addition of l-5τ-IL-8 After 1 hour at room temperature the plate w as harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1 % polyethylenimine/0 5% BSA and washed 3 times ith 25 mM NaCl, 10 mM TπsHCl. 1 mM MgSθ4, 0 5 mM EDTA. 0 03 % CHAPS pH 7 4 The filter was then dried and counted on the Betaplate liquid scintillation counter The recombinant IL-8 Rα. or Type I. receptor is also referred to herein as the non- permissive receptor and the recombinant LL-8 Rβ, or Type II receptor is refeπed to as the permissive receptor
All of the exemplified compounds of Formulas (I) noted herein in the Synthetic Chemistry Section, Example 1 to 9, demonstrated inhibitory in the permissive models for LL-8 receptor inhibition The following compounds were found to be inactive in this assay N-(2 4-Dιchloro-3-carboxy)-N'-(2,3- dichlorophenyPurea N-(3-Carboxyphenyl)-N'-(phenyl)urea and N-(3- Methylcarboxyphenyl)-N'-(phenypurea.
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. I, Suppl 1, Unit 6.12.3.. whose disclosure is incorporated herein by reference in its entirety. Neutrophils where isolated from human blood as described in Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1 , whose disclosure is incorporated herein by reference in its entirety. The chemoattractants LL-8, GRO-α, GRO-β, GRO-γ and NAP-2 are placed in the bottom chamber of a 48 multiwell chamber (Neuro Probe. Cabin John, MD) at a concentration between 0.1 and 100 nM. The two chambers are separated by a 5um polycarbonate filter. When compounds of this invention are tested, they are mixed with the cells (0 001 - 1000 nM) just prior to the addition of the cells to the upper chamber. Incubation is allowed to proceed for between about 45 and 90 min. at about 37°C in a humidified incubator with 5% CO2. At the end of the incubation period, 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.
Elastase Release Assay: 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 Protocols in Immunology Vol. I. Suppl 1 Unit 7.23.1. PMNs 0.88 x 106 cells suspended in Ringer's Solution (NaCl 1 18, KC1 4.56, NaHCO3 25, KH2PO4 1.03, Glucose 1 1.1, HEPES 5 mM. pH 7.4) are placed in each well of a 96 well plate in a volume of 50 ul. To this plate is added the test compound (0.001 - 1000 nM) in a volume of 50 ul, Cytochalasm B in a volume of 50 ul (20ug/ml) and Ringers buffer in a volume of 50 ul These cells are allowed to warm (37 °C, 5% CO2. 95% RH) for 5 nun. before LL-8, GROα. GROβ. GROγ or NAP-2 at a final concentration of 0 01 - 1000 nM was added The reaction is allowed to proceed for 45 min before the 96 well plate is centrifuged (800 xg 5 min ) and 100 ul of the supernatant removed This supernatant is added to a second 96 well plate followed by an artificial elastase substrate (MeOSuc-Ala-Ala-Pro-Val- AMC. Nova Biochem. La Jolla. CA) to a final concentration of 6 ug/ml dissolved in phosphate buffered saline Immediately, 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 254 4027 (1979) The amount of Elastase released from the PMNs is calculated by measuring the rate of MeOSuc-Ala-Ala-Pro-Val-AMC degradation
TNF-α in Traumatic Brain Injury Assay
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- α is able to induce nerve growth factor (NGF) and stimulate the lelease of other cytokines from activated astrocytes. this post-traumatic alteration in gene expression of TNF- α 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-β mRNA
This assay characterizes the regional expression of interleukin-lβ (IL-lβ) 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- lβ mRNA is regionally stimulated in specific brain regions These regional changes in cytokines, such as IL-lβ play a role in the post- traumatic pathologic or regenerative sequelae of brain injury A suitable assay may be found in WO 97/35856 or WO 97/49286 whose disclosures are incorporated herein by reference In vivo - Athereoschlerosis assay:
In vι\o models for measuring atherosclerosis in mice is based on the assay of Paigen et al with small modifications as described below See Paigen B, Moπow A, Holmes PA, Mitchell D, Williams RA Quantitative assessment of atherosclerotic lesions in mice Atherosclerosis 68 231-240 ( 1987), and Groot PHE. van Vhjmen BJM. Benson GM. Hofker MH. Schiffelers R Vidgeon-Hart M. Havekes LM Quantitative assessment of aortic atherosclerosis in APOE 3 Leiden transgenic mice and its relationship to serum cholesterol exposure Aitenoscler Thromb Vase Biol 16 926-933 (1996) Sectioning and staining of the aortic sinus
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 Once the aortic root has been identified by the appearance of the three valve leaflets, alternate 10 mm sections are taken and mounted on gelatinised slides Sections are air dried for 1 hour and subsequently rinsed briefly in 60% isopropyl alcohol The sections are stained with Oil Red O. counterstained with Mayer s haematoxylm cover slipped using glycerol gelatin and sealed with nail varnish
Quantification of atheios lewsis in the aortic root Ten alternate sections of the aortic root are imaged using an Olympus BH-2 microscope equipped with an 4x objective and a video camera (Hitachi. HV-C10) Twenty-four bit colour images are acquired and analyzed 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 All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth
The above description fully discloses the invention including preferred embodiments thereof Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims Without further elaboration, it is believed that one skilled in the are can, using the preceding description utilize the present invention to its fullest extent Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in anv way The embodiments of the invention in which an exclusive propertv or privilege is claimed are defined as follows

Claims

What is Claimed is:
1. A method of treating a chemokine mediated disease state, wherein the chemokine binds to an IL-8 ╬▒ or ╬▓ receptor in a mammal, which comprises administering to said mammal an effective amount of a compound of the formula:
X
W-N NΓÇö (CR13R14)v ΓÇö R 20 (I) wherein
X is oxygen or sulfur: R is (CR8R8)r C(O)2H. (CR8R8)r NH-C(O)Ra, (CR8R8)r C(O)NR6'R7\
(CR8R8)r NHS(0)2Rb, (CR8Rg)r S(0)2NHRC. (CR8R8)r NHC(X2)NHRb, or a tetrazolyl ring; X2 is oxygen or sulfur:
Rl is independently selected from hydrogen; halogen; nitro: cyano; halosubstituted Cj-io alkyl; C i-io alkyl; C2- 10 alkenyl; Cp io alkoxy; halosubstituted Cpio alkoxy; (CR R8)q S(O)tR4; hydroxy: hydroxy C p4alkyl; aryl; aryl C p4 alkyl; aryloxy: aryl C p4 alkyloxy; heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic C i-4alkyl; heteroaryl C p4 alkyloxy; aryl C2- 10 alkenyl: heteroaryl
C2- 10 alkenyl; heterocyclic C2- 10 alkenyl; (CR R8)qNR4Rs; C2- 10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4R5; (CR8R8)q C(O)NR4Rl0; S(0)3R8;
(CR8R8)q C(O)R ╬╣ 1 ; C2- IO alkenyl C(O)R╬╣ 1 ; C2- 10 alkenyl
C(O)OR ╬╣ ╬╣(CR8R8)q C(O)OR i2; (CR8R8)q OC(O) Rn ;
(CR8R8)qNR4C(0)R ╬╣ 1 ; (CR8R8)q NHS(0)2R i 7: (CR8R8)q S(O)2NR4R5; or two Ri moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl. and heterocyclic containing moieties may be optionally substituted; n is an integer having a value of 1 to 3: m is an integer having a value of 1 to 3; q is 0, or an integer having a value of 1 to 10; r is 0, or an integer having a value of 1 to 4; s is an integer having a value of 1 to 3; t is 0. or an integer having a value of 1 or 2; v is an integer having a value of 1 to 4; R4 and R5 are independently hydrogen, optionally substituted C 1.4 alkyl, optionally substituted aryl, optionally substituted aryl C i-4alkyl, optionally substituted heteroaryl. optionally substituted heteroaryl C i-4alkyl, heterocyclic, or heterocyclic Ci-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 C ╬╣_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,
R6' and R71 are independently hydrogen. C i-4 alkyl, aryl, arylCi-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC i-4alkyl, heteroarylC2-4 alkenyl, heterocyclic. heterocyclic C i -4alkyl. heterocyclic C2-4alkenyl moiety, provided that one of R╬▓' and R7' are hydrogen but not both, Y is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted C i-io alkyl, Ci-io alkyl, C2-10 alkenyl, C pio alkoxy, halosubstituted Cpio alkoxy, azide, (CR R8)q S(O)tR4. hydroxy, hydroxyC i -4alkyl, aryl, aryl C j-4 alkyl, aryloxy, arylC i -4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C p4 alkyloxy. heterocyclic, heterocyclic C i-4alkyl, aryl C2- 10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2- 10 alkenyl, (CR R8)q NR4R5, C2-10 alkenyl
C(O)NR4R5, (CR8R8)q C(O)NR4R5- (CR8R8)q C(O)NR RlO, S(O)3H, S(O)3R8 (CR8R8)q C(O)Rj 1. C2- 10 alkenyl C(O)R ╬╣ l , C2-10 alkenyl C(O)ORi 1 C(O)Rj l , (CR8R8)q C(O)OR ╬╣ 2, (CR8R8)q OC(O) Rl 1 , (CR8R8)qNR4C(O)R ╬╣ l , (CR8R8)q NHS(O)2Rd, (CR8R8)q S(O)2NR4R5. or two Y moieties together may form 0-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring, and wherein the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted. R8 is independently selected from hydrogen or C i-4 alkyl,
RlO is C i- 10 alkyl C(O)2R8, Rl 1 is hydrogen, C i-4 alkyl, optionally substituted aryl, optionally substituted aryl C i-4alkyl optionally substituted heteroaryl, optionally substituted heteroarylC i-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocychcC 1 _4alky 1 , Rl2 is hydrogen, C i- io alkyl, optionally substituted aryl or optionally substituted arylalkyl, Rl3 and R14 are independently hydrogen, optionally substituted Ci-4 alkyl, or one of R13 and R14 may be optionally substituted aryl; Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicCi-4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted; Ra is an alkyl, aryl, aryl C╬╣_4alkyl, heteroaryl, heteroaryl Ci-4alkyl, heterocyclic, or a heterocyclic Ci-4alkyl moiety, wherein all of these moieties may be optionally substituted; Rb is a NR6R7, alkyl. aryl, arylCi-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylCi-4alkyl. heteroarylC2-4 alkenyl, heterocyclic. heterocyclic Ci-4alkyl, heterocyclic C2-4alkenyl moiety, or camphor, wherein all of these moieties may be optionally substituted;
Rc is alkyl. aryl, arylCi-4alkyl, arylC2-4aikenyl, heteroaryl, heteroarylCj-4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclic Cp4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted Cj-4 alkyl, -4 alkyl, C1-4 alkoxy, NR9C(O)Ra, C(O)NR6R7, S(O)3H, or C(0)0C╬╣-4 alkyl;
Rd is NRgR╬│, alkyl, arylC╬╣_4 alkyl, arylC 2.4 alkenyl, heteroaryl, heteroaryl-C╬╣ _4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicCj.4 alkyl. wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
Figure imgf000037_0001
the E containing ring is optionally selected from
Figure imgf000037_0002
the asterix * denoting point of attachment of the ring; R20 is Wi , optionally substituted heteroaryl, optionally substituted C5_g cycloalkyl, optionally substituted C J. JQ alkyl, optionally substituted C2-I0 alkenyl, or an optionally substituted C2-10 alkynyl;
Figure imgf000038_0001
the E' containing ring is optionally selected from
Figure imgf000038_0002
the asterix * denoting point of attachment of the ring; or a pharmaceutically acceptable salt thereof.
2. The method according to Claim 1 wherein the R is (CR8R )rC(O)2H.
3. The method according to Claim 1 wherein Ri is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4R5. C(O) R4R10, alkenyl C(O)ORi2, heteroaryl, heteroarylalkyl , heteroaryl alkenyl, or S(O)NR4R5.
4. The method according to Claim 1 wherein R20 is Wj.
5. The method according to Claim 1 wherein R20 is heteroaryl.
6. The method according to Claim 4 wherein Y is halogen, C i-4 alkoxy, optionally substituted aryl. optionally substituted arylalkoxy, methylene dioxy, NR4R5, thioCi-4alkyl, thioaryl, halosubstituted alkoxy. optionally substituted Ci-4alkyl, hydroxy alkyl.
7. The method according to Claim 1 wherein Ri is mono substituted in the 2- or 4- position, or di-substituted in the 2,4- position by an electron withdrawing moiety.
8. The method according to any of Claims 1 to 7 wherein the chemokine mediated disease selected from psoriasis, or atopic dermatitis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, arthritis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, atheroschlerosis, bone j resorption diseases, Alzheimer's disease, graft vs. host reaction, or allograft rejections.
9. A compound of the formula:
Figure imgf000039_0001
W-N NΓÇö (CR13R14)v ΓÇö R 20 (I) wherein
X is oxygen or sulfur;
R is (CR8R8)r C(O)2H, (CR8R8)r NH-C(O)Ra, (CR8R8)r C(O)NR6'R7\
(CR8R8)rNHS(O) Rb, (CR8R8)r S(O)2NHRc, (CR8R8)r NHC(X2)NHRb, or a tetrazolyl;
X2 is oxygen or sulfur;
Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Cpio alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Cp 10 alkoxy; azide; (CR8Rg)q S(O)tR4; hydroxy; hydroxy Cj-4alkyl; aryl; aryl Cp4 alkyl; aryloxy; aryl Cj-4 alkyloxy: heteroaryl; heteroarylalkyl; heterocyclic, heterocyclic Ci-4alkyl; heteroaryl Cj-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR R8)qNR4R5; C2- 10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4R5; (CR8R8)q C(O)NR4Rl╬╕; S(O)3R8; (CR8R8)q C(O)Rn ; C2-10 alkenyl C(O)R ╬╣ 1 ; C2-10 alkenyl C(O)ORi l(CR8R8)q C(O)OR╬╣2; (CR8R8)q OC(O)R╬╣ 1 ;
(CR8R8)qNR4C(O)Rl 1 ; (CR8R8)q NHS(O)2Rl7; (CR8R8)q S(O)2NR4R5; or two Rj moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted; n is an integer having a value of 1 to 3; m is an integer having a value of 1 to 3; q is 0, or an integer having a value of 1 to 10; r is 0 or an integer of 1 to 4; s is an integer having a value of 1 to 3; t is 0, or an integer having a value of 1 or 2; v is an integer having a value of 1 to 4;
R4 and R5 are independently hydrogen, optionally substituted Cp4 alkyl, optionally substituted aryl, optionally substituted aryl Cp4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C 4alkyl, heterocyclic, or heterocyclic Cp4 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, C 4 alkyl, aryl, arylCi-4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC 4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Cp4alkyl, or heterocyclic C2-4alkenyl moiety, provided that one of Rβ' and R7' are hydrogen, but not both; R6 and R7 are independently hydrogen or a C 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; Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Cpio alkyl; Cpio alkyl; C2-10 alkenyl; C pio alkoxy; halosubstituted C p 10 alkoxy; azide; (CR R )q S(O)tR4; hydroxy; hydroxyCp4alkyl; aryl; aryl C 4 alkyl; aryloxy; arylCp4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Cp4 alkyloxy; heterocyclic, heterocyclic Cp4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR8R )q NR4R5; C2-10 alkenyl C(O)NR4R5; (CR8R8)q C(O)NR4R5; (CR8R8)q C(O)NR4Rl0; S(O)3R8; (CR8R8)q C(O)Rι 1; C2-10 alkenyl C(O)Rι 1 ; C2-10 alkenyl C(O)ORι p C(O)RH; (CR8R8)q C(O)ORl2; (CR8R8)q OC(O) Rπ ; (CR8R8)q
NR4C(O)R╬╣ 1; (CR8R8)q NHS(O)2Rd; (CR8R8)q S(O)2NR4R5; or two Y moieties together may form O-(CH2)sO- or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted; Rg is independently selected from hydrogen or C 4 alkyl;
RlO is C io alkyl C(O)2R8;
Rl 1 is hydrogen, C 4 alkyl, optionally substituted aryl, optionally substituted aryl Cp4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC 4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 -4alkyl ; Rl2 is hydrogen, C o alkyl, optionally substituted aryl or optionally substituted arylalkyl; Rl3 and R14 are independently hydrogen, optionally substituted C 4 alkyl, or one of R13 and R14 may be optionally substituted aryl; Rl7 is C 4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCp4alkyl, heterocyclic, or heterocyclicC 4alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted; Ra is an alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroaryl C 4alkyl, heterocyclic, or a heterocyclic C 4alkyl moiety, wherein all of these moieties may be optionally substituted; Rb is a NR6R7, alkyl, aryl, arylC p4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC 4alkyl, heteroarylC2-4 alkenyl, heterocyclic, heterocyclic Cp4alkyl, heterocyclic C2-4alkenyl moiety, or camphor, wherein all of these moieties may be optionally substituted:
R is alkyl, aryl, arylCp4alkyl, arylC2-4alkenyl, heteroaryl, heteroarylC 4alkyl, heteroarylC2-4alkenyl, heterocyclic, heterocyclic Cp4alkyl, or a heterocyclic C2-4alkenyl moiety, all of which may be optionally substituted one to three times independently by halogen, nitro, halosubstituted C 4 alkyl, C 4 alkyl, C1-4 alkoxy, NR9C(O)Ra, C(O)NR6R7, S(O)3H, or C(O)OCp4 alkyl;
Rrj is NR R7, alkyl, arylC 4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-C 4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC 4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
Figure imgf000041_0001
the E containing ring is optionally selected from
Figure imgf000041_0002
asterix * denoting point of attachment of the ring; 99/06354
R20 is Wp optionally substituted heteroaryl, optionally substituted C5_8 cycloalkyl, optionally substituted Cp 10 aucvl> optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;
Figure imgf000042_0001
the E' containing ring is optionally selected from
Figure imgf000042_0002
the asterix * denoting point of attachment of the ring; or a pharmaceutically acceptable salt thereof.
10. The compound according to Claim 9 wherein the R is (CRgR )rC(O)2H.
11. The compound according to Claim 9 wherein Ri is halogen, cyano, nitro, CF3, C(O)NR4R5, alkenyl C(O)NR4R5, C(O) R4R1O, alkenyl C(O)ORi2, heteroaryl, heteroarylalkyl, heteroaryl alkenyl, or S(O)NR4R5.
12. The compound according to Claim 9 wherein R20 is Wp
13. The compound according to Claim 9 wherein R20 is heteroaryl.
14 The compound according to Claim 12 wherein Y is halogen, Cp4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR4R5, thioCp4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted C 4alkyl, or hydroxy alkyl.
15. The compound according to Claim 9 wherein Ri is mono substituted in the 2- or 4- position, or disubstituted in the 2-4- position by an electron withdrawing moiety.
16. A pharmaceutical composition comprising an effective amount of a compound according to any of Claims 9 to 15, and a pharmaceutically acceptable carrier or diluent.
17. A process for producing a compound according to Claim 9 which process comprises reacting a compound of the formula
Figure imgf000043_0001
wherein R, Ri and m are as defined for Formula (I), with a compound of the formula: -N(XHCRi3R14)v - R2o; wherein X, Rπ, R14, v and R20 are as defined in Formula (I) to yield a compound of Formula (I).
18. A process for producing a compound of Formula (I) which process comprises reacting a compound of the formula:
Figure imgf000043_0002
wherein Rp m and R are as defined for formula (I); with a compound of the formula: NH2-(CR13R14)V - R20; wherein R 3, R14, v and R20 are as defined in Formula (I) to yield a compound of
Formula (I); and deprotecting the R group if necessary.
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