EP1087661A1 - Antagonistes des recepteurs d'il-8 - Google Patents

Antagonistes des recepteurs d'il-8

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Publication number
EP1087661A1
EP1087661A1 EP99928764A EP99928764A EP1087661A1 EP 1087661 A1 EP1087661 A1 EP 1087661A1 EP 99928764 A EP99928764 A EP 99928764A EP 99928764 A EP99928764 A EP 99928764A EP 1087661 A1 EP1087661 A1 EP 1087661A1
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EP
European Patent Office
Prior art keywords
alkyl
optionally substituted
heteroaryl
aryl
alkenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99928764A
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German (de)
English (en)
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EP1087661A4 (fr
Inventor
Katherine L. Widdowson
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP1087661A1 publication Critical patent/EP1087661A1/fr
Publication of EP1087661A4 publication Critical patent/EP1087661A4/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to novel benzoisothiazole substituted compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 mediated diseases.
  • Interleukin-8 such as neutrophil attractant/activation protein- 1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
  • Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-l ⁇ , IL-l ⁇ or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M.
  • GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 also belong to the chemokine ⁇ family. Like LL-8, these chemokines have also been referred to by different names. For instance GRO ⁇ , ⁇ , ⁇ have been referred to as MGS A ⁇ , ⁇ and ⁇ respectively
  • LL-8 can induce histamine release from basophils from both normal and atopic individuals
  • GRO- ⁇ and LL-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 (CD 1 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.
  • GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-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., Crit. Rev. Immunol. 12. 17 (1992); Oppenheim et al., Annu. Rev. Immunol. 9, 617 (1991); Seitz et al., J. Clin. Invest. 87. 463 (1991); Miller et al., Am. Rev. Respir. Pis.
  • ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis, see Strieter et al., Science 258, 1798 (1992).
  • LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 induce neutrophil shape change, chemotaxis, granule release, and respiratory burst, by binding to and activating receptors of the seven-transmembrane, G-protein-linked family, in particular by binding to IL-8 receptors, most notably the B-receptor.
  • the development of non-peptide small molecule antagonists for members of this receptor family has precedent.
  • the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
  • LL-8R ⁇ which binds only IL-8 with high affinity
  • LL-8R ⁇ which has high affinity for IL-8 as well as for GRO- ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • LL-8R ⁇ which binds only IL-8 with high affinity
  • LL-8R ⁇ which has high affinity for IL-8 as well as for GRO- ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an LL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (I) or (II) or a pharmaceutically acceptable salt thereof.
  • the chemokine is LL-8.
  • This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) or (II).
  • the present invention also provides for the novel compounds of Formula (I), and (II) and pharmaceutical compositions comprising a compound of Formula (I), and (II) and a pharmaceutical carrier or diluent.
  • Compounds of Formula (I) useful in the present invention are represented by the structure:
  • R is -NH -C(X 2 )-NH- (CR 13 R 14 ) V - Z;
  • (CR 15 R 16 )P Z is W, HET, , optionally substituted C i .i Q alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-I0 alkynyl;
  • HET is an optionally substituted heteroaryl
  • R4 and R5 are independently hydrogen, optionally substituted Ci .4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Cj-4alkyl, heterocyclic, or heterocyclic C i-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
  • Y is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted -io alkoxy, azide, (CR 8 R )q S(O)tR4, hydroxy, hydroxyCi-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, arylC ⁇ .4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl Ci-4 alkyloxy, heterocyclic, heterocyclic C ⁇ _4alkyl, aryl C2-10 alkenyl, heteroaryl
  • RlO is C i-io alkyl C(O) 2 R 8 ;
  • 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 heterocyclicC l -4alkyl
  • Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl
  • Rl 3 and R 14 are independently hydrogen, optionally substituted Cj_4 alkyl, or one of R ⁇ 3 and R14 may be an optionally substituted aryl;
  • Rj5 and Ri g are independently hydrogen, or an optionally substituted Ci-4 alkyl
  • Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC ⁇ _4alkyl, heterocyclic, or heterocyclicC i-4alkyl, wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted
  • Rj 8 is hydrogen, Ci-4 alkyl, aryl, arylC ⁇ .4 alkyl, heteroaryl, heteroarylC ⁇ .4 alkyl, heterocyclic, or heterocyclicC ⁇ .4 alkyl, all of which may be optionally substituted
  • R a is NRgR7, alkyl, arylC ⁇ .4 alkyl, arylC2_4 alkenyl, heteroaryl, heteroaryl-
  • the E containing ring is optionally selected from
  • R is -NH -C(X )-NH- (CR 13 R 14 ) V - Z;
  • Z is W, HET, ( ⁇ ' n , optionally substituted C ⁇ _ 0 alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-10 alkynyl;
  • X is C(X ⁇ );
  • X1 is hydrogen, halogen, Ci-io alkyl, NR4R5, C(O)NR4R5, optionally substituted Ci-io alkyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, hydroxy, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroaryl Ci-4 alkyl, heterocyclic, heterocyclic C ⁇ _4alkyl, or heteroaryl Ci-4 alkyloxy;
  • A is CR 18 ;
  • Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, azide.
  • NR4C(O)Ri 1 (CR 8 R 8 )qC(NR 4 )NR 4 R 5 , (CR 8 R 8 )q NR 4 C(NR 5 )R ⁇ h (CR 8 R 8 )q NHS(O)2Ri7, or (CR 8 R 8 )q S(O)2NR4R5, or two Ri moieties together may form O-(CH2)sO or a 5 to 6 membered saturated or unsaturated ring;
  • m is an integer having a value of 1 to 3;
  • n is an integer having a value of 1 to 3;
  • p is an integer having a value of 1 to 3;
  • q is 0, or an integer having a value of 1 to 10;
  • s is an integer having a value of 1 to 3;
  • t is 0, or an integer having a value of 1 or 2;
  • v is 0, or an integer having a value of 1 to 4;
  • HET is an optionally substituted heteroaryl
  • R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-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;
  • Y is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Cj-io alkyl, C2-10 alkenyl, -io alkoxy, halosubstituted Ci-io alkoxy, azide, (CR R )q S(O)tR4, hydroxy, hydroxyCi-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, arylCi-4 alkyloxy, heteroaryl, heteroaryl C1.4 alkyl, heteroaryl Ci-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR 8 R 8 )q NR4R5, C2-10 alkenyl C(O)NR4R5, (CR 8 R 8 )q C(O)NR4R5, (CR 8 R 8
  • R 8 is independently hydrogen or C 1-4 alkyl; Rio is C ⁇ _ ⁇ o alkyl C(O)2R 8 ;
  • Rl 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl
  • R 2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
  • Rl 3 and R14 are independently hydrogen, optionally substituted Ci-4 alkyl, or one of R ⁇ 3 and R14 may be an optionally substituted aryl;
  • Rl5 and Rig are independently hydrogen, or an optionally substituted Ci-4 alkyl;
  • Rl7 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclic, or heterocyclicC _4alkyl, wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted;
  • Rl 8 is hydrogen, Ci-4 alkyl, aryl, arylC ⁇
  • the E containing ring is optionally selected from
  • the compounds of Formula (I) and (II) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of
  • IL-8 or other chemokines which bind to the 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.
  • the difference between compounds of Formula (I) and (II) lies in the unsaturation of the A containing ring, and hence the substitutions on the X and A moieties.
  • the remaining terms, defined below, are the same for both compounds of Formula (I) and (II) unless otherwise indicated.
  • Rl is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl, such as CF 3 ; C i-io alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-10 alkenyl; Ci-io alkoxy, such as methoxy, or ethoxy; halosubstituted Ci-io alkoxy, such as trifluoromethoxy; azide; (CR 8 R )q S(O) t R4, wherein t is 0, 1 or 2; hydroxy; hydroxy C i-ioalkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aryl Ci-4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl Ci-4 alkyloxy, such as benzyloxy; heteroaryl; heteroaryl; heteroary
  • Ri moiety may be substituted on the benzene ring or the A containing ring, if possible.
  • s is an integer having a value of 1 to 3
  • m is an integer having a value of 1 to 3.
  • s is preferably 1.
  • Ri forms an additional saturated or unsaturated ring, it is preferably 6 membered ring, preferably resulting in a naphthylene ring system. These additional rings may be substituted independently, 1 to 3 times, by the other Ri moieties as defined above.
  • Ri is hydrogen, halogen, cyano, nitro, CF 3 , (CR 8 R )q C(O)NR4R5 , C2- 10 alkenyl C(O)NR4R5 , (CR 8 R 8 )q C(O)R4R 10, C2- 10 alkenyl
  • R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, or heterocyclicC 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 Ci-4 alkyl group, or R and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur.
  • R 8 is independently hydrogen or C ⁇ _4 alkyl.
  • q is 0 or an integer having a value of 1 to 10.
  • Rio is Ci-io alkyl C(O)2R 8 , such as CH2C(O)2H or CH2C(O)2CH 3 .
  • Rl 1 is hydrogen, Ci-4 alkyl, aryl, aryl Ci-4 alkyl, heteroaryl, heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic Ci-4alkyl.
  • R12 is hydrogen, C J.IQ alkyl, optionally substituted aryl or optionally substituted aryl Ci-4 alkyl.
  • Ri 3 and R 14 are independently hydrogen, an optionally substituted
  • Ci-4 alkyl which may be straight or branched as defined herein, or one of Rj 3 and R 14 are an optionally substituted aryl; v is 0, or an integer having a value of 1 to 4.
  • Rj or R14 are an optionally substituted alkyl, the alkyl moiety may be substituted one to three times independently by halogen; halosubstituted Ci .4 alkyl such as trifluoromethyl; hydroxy; hydroxy Ci-4alkyl, Ci-4 alkoxy; such as methoxy, or ethoxy, halosubstituted C ⁇ _ 10 alkoxy, S(O)tR4; aryl; NR4R5; NHC(O)R4; C(O)NR4Rs; or C(O)OR 8 .
  • R17 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclic, or heterocyclicC i-4alkyl, wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted.
  • Y is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, azide, (CR 8 R 8 )q S(O)tR4, hydroxy, hydroxyCi-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, arylCi-4 alkyloxy, heteroaryl, heteroaryl Ci-4 alkyl, heteroaryl Ci-4 alkyl, heteroaryl Ci-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR 8 R 8 )q NR4R5, C 2 -10 alkenyl C(O)NR4R5, (CR 8 R 8 )q C(O
  • n is an integer having a value of 1 to 3.
  • s is preferably 1.
  • the aryl, heteroaryl and heterocyclic containing moieties noted above for Y may all be optionally substituted as defined herein.
  • Y forms an additional saturated or unsaturated ring, it is preferably 6 membered ring, more preferably resulting in a naphthylene ring system.
  • R a is NRgR7, alkyl, aryl C1.4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-Ci-4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC 1.4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted.
  • Y is preferably a halogen, C i-4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or aryl Ci-4 alkoxy, methylenedioxy, NR4R5, thio Ci-4alkyl, thioaryl, halosubstituted Cj-io alkoxy, Ci-io alkyl, or hydroxy Ci-io alkyl.
  • Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl. More preferably these groups are mono or di-substituted in the 2'- position or 2'-, 3 '-position when Z is W and W is a phenyl ring (such as when no E group is present).
  • Y may be substituted in any of the 5 ring positions when W is a phenyl moiety, Y is preferably mono-substituted in the 2'-position or 3'- position, with the 4'- preferably being unsubstituted. If the phenyl ring is disubstituted, the substituents are preferably in the 2 ' or 3' position of a monocyclic ring. While both Ri and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, preferably both rings are substituted.
  • A is suitably CH2, C(S) or C(S). It is noted that in Formula (I) the A containing ring is saturated. In compounds of Formula (II), A is suitably CR ⁇ 8 . It is also noted that in Formula (II) the A containing ring contains unsaturation.
  • Rl 8 is hydrogen, -4 alkyl, aryl, arylC ⁇ .4 alkyl, heteroaryl, heteroarylC i-4 alkyl, heterocyclic, or heterocyclicC 1.4 alkyl, all of which may be optionally substituted.
  • R is suitably -NH -C(X 2 )-NH- (CRj 3 Ri4) v - Z.
  • Z is W, HET, ( ⁇ )n , an optionally substituted C i .
  • IQ alkyl an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl.
  • p is an integer having a value of 1 to 3.
  • W is , or
  • the E containing ring is optionally selected from
  • Z is
  • the E ring denoted by its point of attachment through the asterix (*) may optionally be present. If it is not present, the ring is a phenyl moiety which is substituted by the Y terms as shown above.
  • the E ring may be substituted by the Y moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).
  • X is C(X ⁇ )2, both of Xi can not be hydrogen.
  • X is suitably C(X ⁇ ).
  • Xi is independently hydrogen, halogen, NR4R5, C(O)NR4R5 ; optionally substituted i-io alkyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, aryl, aryl C i-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroaryl Ci-4 alkyl, heterocyclic, heterocyclic Ci-4alkyl; or heteroaryl Ci-4 alkyloxy.
  • the alkyl group may be optionally substituted one or more times by hydroxy, NR4R5, or halogen.
  • X is C(X ⁇ )2
  • at least one of X ⁇ is hydrogen.
  • HET is an optionally substituted heteroaryl moiety, as defined below both for optional substituents and for particular heteroaryl moieties.
  • R 5 and R are independently hydrogen, or an optionally substituted Ci-4 alkyl as defined above for R ⁇ 3 and R14.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy hydroxy substituted Ci-ioalkyl
  • Cj-io alkoxy such as methoxy or ethoxy
  • S(O)m Ci-io alkyl, wherein m" is 0, 1 or 2, such as methyl thio, methyl sulfinyl or methyl sulfonyl
  • amino, mono & di-substituted amino such as in the NR4R5 group; NHC(O)R4; C(O)NR4R5; C(O)OH; S(O)2NR4R5; NHS(O)2Rl9
  • C i-io alkyl such as methyl, ethyl, propyl, isopropyl, or t-butyl
  • halosubstituted C i-io alkyl such CF
  • Rl9 is suitably C1-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclic, or heterocyclicC i-4alkyl.
  • Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
  • pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
  • Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. The following terms, as used herein, refer to:
  • halo all halogens, that is chloro, fluoro, bromo and iodo.
  • cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
  • alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
  • heteroaryl (on its own or in any combination, such as “heteroaryloxy”, or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • heterocyclic (on its own or in any combination, such as
  • heterocyclicalkyl a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
  • arylalkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean C ⁇ _ ⁇ o alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
  • hexene or a C5 cycloalkenyl moiety, cyclopentene, or a fully unsaturated ring 5 or 6 membered ring such as benzene, i.e. resulting in a naphtylene ring.
  • Exemplified compounds of Formula (I) include:
  • N-(2-Bromophenyl) -N' -(1, 3-Dihydro-2, 2-dioxo-2,l-benzisothiazol-7-yl-)urea N-[(l,3-dihydro-2,2-dioxo-4-floro-2,l-benzisothiazo)-7-yl]-N'-(2- bromophenyl)urea N-[(l,3-dihydro-2,2-dioxo-4-chloro-2,l-benzisothiazo)-7-yl]-N'-(2,3- dichlorophenyl)urea N-[(l,3-dihydro-2,2-dioxo-4-chloro-2,l-benzisothiazo)-7-yl]-N'-(2- chlorophenyl)urea
  • Additional exemplified compounds of Formula (I) include: N-(4-Bromophenyl) -N' -(1, 3-Dihydro-2, 2-dioxo-2,l-benzisothiazol-7-yl-)urea
  • Exemplified compounds of Formula (II) include: N-(2-indazole)-N'-(2-bromophenyl)urea
  • the compounds of Formula (I) and (II) may be obtained by applying synthetic procedures, some of which are illustrated in the Schemes below.
  • the synthesis provided for in these Schemes is applicable for the producing of Formula (I) and (II) having a variety of different Z, R ⁇ , and E 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.
  • further compounds of these formulas may be prepared by applying standard techniques for functional group interconversion, well known in the art. While the schemes are shown with various compounds of Formula (I) and (II) this is merely for illustration purposes only and not a limitation on the extent of synthesis available using these methods.
  • the corresponding heterocyclic sulfamide can be prepared from the commercially available compound 1 -scheme 1 with reduction of the nitro group using suitable reducing conditions such as SnCl2, hydrogen and Pd C or zinc metal in a suitable organic solvent such as, ethyl acetate and cyclization using triethylamine in methylene chloride.
  • suitable reducing conditions such as SnCl2, hydrogen and Pd C or zinc metal
  • a suitable organic solvent such as, ethyl acetate and cyclization using triethylamine in methylene chloride.
  • Alternative reaction conditions for the cyclic sulfonamide ⁇ scheme 1 can be achieved by cyclization of 2-chlorobenzylsulfonamide with potassium carbonate and copper-bronze powder in under pressure using a polar solvent or using a high boiling solvent such as 2, 3-dimethylaniline at 100-180°C, preferably about 180°C, or by reacting the 2-aminobenzylsulfonic acid sodium salt with phosphorus oxychloride at 30-170°c, preferably about 170°C, for between 1-24 hours, preferably about 3 hours.
  • Scheme 2
  • the desired heterocyclic compound 2-scheme 2 is not commercially available then it can be prepared from the commercially available compound A scheme 2 with triphenyl phosphine oxide, triethylamine, trifluoroacetic anhydride in an aprotic solvent such as 1, 2 - dichloroethane.
  • the desired heterocyclic compound 2-scheme 3 is not commercially available then it can be prepared from the commercially available compound _ scheme 3 with zinc and ammonium chloride in THF/H2O.
  • the desired heterocyclic compound 2-scheme 4 is not commercially available then it can be prepared from the commercially available compound h scheme 4 with aluminum amalgam in diethyl ether or THF.
  • the desired heterocyclic compound 3-scheme 5 is not commercially available then it can be prepared from the commercially available compound A scheme 5 with nitrous acid to the diazonium salt, followed by treating with sodium sulfite to the hydrazine 2-scheme 5. Cyclization can be achieved with sulfuric acid to give 3-scheme 5.
  • An alternative method to obtain 3-scheme 5 would be reduction of indazolinone with lithium aluminum hydride.
  • the corresponding nitro compound can be prepared from 1 -scheme 6, under standard nitration conditions (using HNO 3 or NaNO 3 ) at 0-100°C, preferably about 23°C, under acid conditions such as acetic acid, acetic anhydride, or under biphasic condition such as aqueous sulphuric acid and a chlorinated solvent such as methylene chloride.
  • acid conditions such as acetic acid, acetic anhydride, or under biphasic condition such as aqueous sulphuric acid and a chlorinated solvent such as methylene chloride.
  • suitable reducing agents such as H2 P in an organic solvent, such as
  • MeOH, DMF or ethylacetate alternatively SnCl2 in EtOH, or LiAlH4 or zinc metal in acetic acid ) at 0-100°C.
  • Other commercially available heterocylic compounds such as Indoline, Indole, Oxindole, Isatin, Indazole and Indazolinone can be converted to the desired anilines through this procedure.
  • Ortho substituted heterocyclic phenyl ureas in 2-scheme 7 may be prepared by standard conditions involving the condensation of the commercially available optionally substituted aryl isocyanate(Aldrich Chemical Co., Milwaukee, Wi) with the corresponding aniline 1 -scheme 7 in an aprotic solvent such as DMSO, DMF, toluene or methylene chloride at room temperature or elevated temperature from 1 h to 24 h.
  • an aprotic solvent such as DMSO, DMF, toluene or methylene chloride
  • the desired isocyanates can be made by condensing the amine with triphosgene in the presence of base (such as potassium carbonate) or by reacting the carboxylic acid with diphenyl phosphoazide in the presence of a base (such as triethyl amine).
  • base such as potassium carbonate
  • diphenyl phosphoazide such as triethyl amine
  • Another aspect of the invention is the novel process for making compounds of Formula (I), in particularly when A is CH2 and X is S(O)m which process comprises a process for producing a compound of Formula (I), as defined above, wherein A is CH2 and X is S(O) m , which process comprises a) reacting a compound of the formula
  • Another aspect of the present invention is the novel process to make a compound of Formula (A) which process comprises reacting the corresponding nitro compound under reducing conditions to yield the corresponding aniline derivative.
  • Another aspect of the present invention is the novel process of producing novel compounds of the formula:
  • Yet another aspect of the present invention is a process for producing a compound of the Formula (C), which process comprises reacting a compound of the formula
  • Example 2 N-(l, 3-Dihydro-4-bromo-l, 2-benzisothiazole-3, 3-dioxide) N - phenylurea
  • Example 3 N-[(l,3-dihydro-2,2-dioxo-4-floro-2,l-benzisothiazo)-7-yl]-N'-(2- bromophenyl)urea; (M " : 398.1, 400.1)
  • Example 4 N-[( l,3-dihydro-2,2-dioxo-4-chloro-2, l-benzisothiazo)-7-yl]-N'-(2,3- dichlorophenyl)urea; (M " : 403.9, 406.2, 408.0)
  • Example 5 N-[(l,3-dihydro-2,2-dioxo-4-chloro-2, l-benzisothiazo)-7-yl]-N'-(2- chlorophenyl)urea; (
  • Example 7 N-[(l,3-dihydro-2,2-dioxo-4-chloro-2,l-benzisothiazo)-7-yl]-N - isopropylurea; (M " : 304.1, 306.2)
  • Example 8 N-[( l,3-Dihydro-2,2-dioxo-4-chloro-2.1-benzisothiazo)-7-yl]-N'- (2-bromophenyl)urea; (M- : 414, 416)
  • Example 9 N-[( l,3-Dihydro-2,2-dioxo-4-cyano-2, l-benzisothiazo)-7-yl]-N'- (2-bromophenyl)urea; (M " : 404.9, 407.1)
  • Example 10 N-[(l,3-Dihydro-2,2-dioxo-4-bromo-2,l-benzisothiazo)-7-yl]-N
  • the compounds of Formula (I), and (II) 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 LL-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 LL-8 ⁇ or ⁇ receptor, also referred to as the type I or type II receptor.
  • Formula (I) will also refer to compounds of Formula (II) unless otherwise indicated.
  • the present invention provides a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the chemokines are IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function, in particular IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78, such that they are biologically regulated down to normal levels of physiological function, or in some case to subnormal levels, so as to ameliorate the disease state.
  • Abnormal levels of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 for instance in the context of the present invention constitute: (i) levels of free IL-8 greater than or equal to 1 picogram per mL; (ii) any cell associated IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 above normal physiological levels; or (iii) the presence IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 above basal levels in cells or tissues in which IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 respectively, is produced.
  • Chemokine mediated diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs.
  • hematopoietic stem cells release, rhinovirus infections, and various bone resorptive indications, such as osteoporosis or osteoarthritis, and diseases caused by respiratory viruses, including but not limited to rhinovirus and influenza virus, herpesvirus, including but not limited to herpes simplex I and II, and hepatitis viruses, including but not limited to Hepatitis B and C virus.
  • respiratory viruses including but not limited to rhinovirus and influenza virus, herpesvirus, including but not limited to herpes simplex I and II, and hepatitis viruses, including but not limited to Hepatitis B and C virus.
  • the association of interleukin-8 and rhinovirus may be found in articles such as: Turner,et al., Clin. Infect. Dis.
  • the ⁇ -chemokines but particularly, GRO ⁇ , GRO ⁇ , GRO ⁇ , or NAP-2, working through the IL-8 type I or II receptor can promote the neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, the inhibition of LL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.
  • the present invention also provides for a means of treating, in an acute setting, as well as preventing, in those individuals deemed susceptible to, CNS injuries by the chemokine receptor antagonist compounds of Formula (I).
  • CNS injuries as defined herein include both open or penetrating head trauma, such as by surgery, or a closed head trauma injury, such as by an injury to the head region. Also included within this definition is ischemic stroke, particularly to the brain area.
  • Ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel.
  • the role of inflammatory cytokines in this are has been emerging and the present invention provides a mean for the potential treatment of these injuries. Relatively little treatment, for an acute injury such as these has been available.
  • TNF- ⁇ is a cytokine with proinflammatory actions, including endothelial leukocyte adhesion molecule expression. Leukocytes infiltrate into ischemic brain lesions and hence compounds which inhibit or decrease levels of TNF would be useful for treatment of ischemic brain injury. See Liu et al., Stoke, Vol. 25., No. 7, pp. 1481-88 (1994) whose disclosure is incorporated herein by reference.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit IL-8, binding to the IL-8 alpha or beta receptors, from binding to these receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation.
  • the discovery that the compounds of Formula (I) are inhibitors of 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 to be inhibitors of type II LL-8 receptors.
  • LL-8 mediated disease or disease state refers to any and all disease states in which IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 plays a role, either by production of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 themselves, or by LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 causing another monokine to be released, such as but not limited to IL- 1 , LL-6 or TNF.
  • chemokine mediated disease or disease state refers to any and all disease states in which a chemokine which binds to an IL-8 ⁇ or ⁇ receptor plays a role, such as but not limited IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78.
  • cytokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response.
  • a cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them.
  • a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and or monocyte.
  • mononuclear cell such as a macrophage and or monocyte.
  • monokines such as natural killer cells, fibroblasts, basophils, neutrophils, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes and B -lymphocytes.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines include, but are not limited to, Interleukin-1 (IL- 1), Interleukin-6 (LL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor beta (TNF- ⁇ ).
  • IL-1 Interleukin-1
  • LL-6 Interleukin-6
  • IL-8 Interleukin-8
  • TNF- ⁇ Tumor Necrosis Factor-alpha
  • TNF- ⁇ Tumor Necrosis Factor beta
  • TNF- ⁇ Tumor Necrosis Factor beta
  • chemokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response, similar to the term “cytokine” above.
  • a chemokine is primarily secreted through cell transmembranes and causes chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells.
  • chemokines include, but are not limited to, IL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , NAP-2, ENA-78, IP- 10, MlP-l ⁇ , MlP- ⁇ , PF4, and MCP 1, 2, and 3.
  • a pharmaceutical composition comprising an effective, non- toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
  • Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
  • the compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures.
  • the compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
  • the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the 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, stearic acid and the like.
  • 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.
  • 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.
  • the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but preferably will be from about 25mg. to about lg.
  • the preparation will be in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampule or nonaqueous liquid suspension.
  • 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.
  • 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 bactericide and may be prepared by methods similar to those for the preparation of drops.
  • Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.
  • Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application. They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or non-aqueous fluid, with the aid of suitable machinery, with a greasy or non-greasy base.
  • the base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or a macrogel.
  • the formulation may incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as a sorbitan ester or a polyoxyethylene derivative thereof.
  • Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicaceous silicas, and other ingredients such as lanolin, may also be included.
  • Drops according to the present invention may comprise sterile aqueous or oily solutions or suspensions and may be prepared by dissolving the active ingredient in a suitable aqueous solution of a bactericidal and or fungicidal agent and/or any other suitable preservative, and preferably including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 C. for half an hour.
  • the solution may be sterilized by filtration and transferred to the container by an aseptic technique.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01%).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • Compounds of formula (I) may be administered parenterally, that is by intravenous, intramuscular, subcutaneous intranasal, intrarectal, intravaginal or intraperitoneal administration. The subcutaneous and intramuscular forms of parenteral administration are generally preferred. Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • Compounds of Formula (I) may also be administered by inhalation, that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight.
  • the daily parenteral dosage regimen about 0.001 to about 80 mg/kg of total body weight.
  • the daily topical dosage regimen will preferably be from 0.1 mg to 150 mg, administered one to four, preferably two or three times daily.
  • the daily inhalation dosage regimen will preferably be from about 0.01 mg/kg to about 1 mg/kg per day.
  • the optimal quantity and spacing of individual dosages of a compound of Formula (I) or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound of Formula (I) or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • IL-8, and GRO- ⁇ chemokine inhibitory effects of compounds of the present invention are determined by the following in vitro assay: Receptor Binding Assays:
  • 125j IL_ 8 (human recombinant) is obtained from Amersham Corp., Arlington Heights, LL, with specific activity 2000 Ci/mmol. Gro- ⁇ is obtained from NEN- New England Nuclear. All other chemicals are 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., 249 pp 2195-2205 (1974)).
  • homogenization buffer is changed to lOmM Tris-HCL, ImM MgS04, 0.5mM EDTA (ethylene-diaminetetra- acetic acid), lm MPMSF ( ⁇ -toluenesulphonyl fluoride), 0.5 mg/L Leupeptin, pH 7.5.
  • Membrane protein concentration is determined using Pierce Co. micro-assay kit using bovine serum albumin as a standard. All assays are performed in a 96-well micro plate format.
  • Each reaction mixture contains ⁇ 5j IL_ 8 (0.25 nM) or 125j_ GRO- ⁇ and 0.5 ⁇ g/mL of LL-8R ⁇ or 1.0 ⁇ g/mL of IL-8R ⁇ membranes in 20 mM Bis-Trispropane and 0.4 mM Tris HC1 buffers, pH 8.0, containing 1.2 mM MgSO4,
  • EDTA 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS.
  • drug or compound of interest is added which has been pre-dissolved in DMSO so as to reach a final concentration of between O.OlnM and 100 uM.
  • the assay is initiated by addition of 125 ⁇ -iL_g After 1 hour at room temperature the plate is harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1 % polyethylenimine/ 0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM TrisHCl, 1 mM MgSO4,
  • the filter is 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 referred to as the permissive receptor.
  • Representative compounds of Formula (I), Example 1, 3 to 10, and a representative compound of Formula (II), Example 11. have been found to have positive inhibitory activity of ⁇ 30 ⁇ mg in this 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.
  • 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 10 6 cells suspended in Ringer's Solution (NaCl 118, 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, Cytochalasin 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 min. before LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ or NAP-2 at a final concentration of 0.01 - 1000 nM was added. The reaction is allowed to proceed for 45 min.
  • This assay provides for examination of the expression of tumor necrosis factor mRNA in specific brain regions which follow experimentally induced lateral fluid- percussion traumatic brain injury (TBI) in rats. Since TNF- ⁇ is able to induce nerve growth factor (NGF) and stimulate the release of other cytokines from activated astrocytes, this post-traumatic alteration in gene expression of TNF- ⁇ plays an important role in both the acute and regenerative response to CNS trauma.
  • a suitable assay may be found in WO 97/35856 or WO 97/49286 whose disclosures are incorporated herein by reference.
  • This assay characterizes the regional expression of interleukin-l ⁇ (IL-l ⁇ ) mRNA in specific brain regions following experimental lateral fluid-percussion traumatic brain injury (TBI) in rats. Results from these assays indicate that following TBI, the temporal expression of IL-l ⁇ mRNA is regionally stimulated in specific brain regions. These regional changes in cytokines, such as IL-l ⁇ play a role in the post- traumatic pathologic or regenerative sequelae of brain injury.
  • TBI lateral fluid-percussion traumatic brain injury
  • Cross-sections of the aortic root are taken as has been described previously (1,2). Briefly, the hearts are bisected just below the level of the atria and the base of the heart plus aortic root are taken for analysis. After equilibrating the tissue in OCT compound overnight the hearts are immersed in OCT compound on a cryostat chuck (Bright Instrument Company Ltd., UK) with the aorta facing the chuck. The tissue is frozen by surrounding the chuck with dry ice. The hearts are then sectioned pe ⁇ endicular to the axis of the aorta, starting within the heart and working in the direction of the aorta.
  • 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 analysed using a PC (Datacell Pentium P5-133, Datacell, Berks, U.K.) fitted with a framegrabbing board (Snapper, Active Imaging Ltd, Berks, U.K.) and running Optimas software (version 5.1, Optimas Co ⁇ ., WA, U.S.A.). The images are captured under identical lighting, microscope, camera and PC conditions. Quantification of the atherosclerotic lesion areas is performed by drawing around the lesions by hand using the Optimas software. Colour thresholds are set that quantify the areas that are stained red within the lesions. Absolute values for the cross-sectional areas of the lesions and the areas stained red are obtained by calibrating the software using an image of the grid on a haemocytometer slide.

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Abstract

L'invention se rapporte à de nouveaux composés représentés par la formule (I), et à des compositions contenant ces composés, qui s'avèrent utiles pour le traitement des états pathologiques liés à une médiation assurée par la chimiokine Interleukine-8 (IL-8).
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997001354A1 (fr) * 1995-06-27 1997-01-16 Genentech, Inc. Antagonistes d'il-8 utilises pour le traitement des troubles inflammatoires et de l'asthme
WO1997049680A1 (fr) * 1996-06-27 1997-12-31 Smithkline Beecham Corporation Antagonistes des recepteurs d'il-8
WO1998032439A1 (fr) * 1997-01-23 1998-07-30 Smithkline Beecham Corporation Antagonistes du recepteur de l'il-8

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WO1996025157A1 (fr) * 1995-02-17 1996-08-22 Smithkline Beecham Corporation Antagonistes des recepteurs d'il-8

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997001354A1 (fr) * 1995-06-27 1997-01-16 Genentech, Inc. Antagonistes d'il-8 utilises pour le traitement des troubles inflammatoires et de l'asthme
WO1997049680A1 (fr) * 1996-06-27 1997-12-31 Smithkline Beecham Corporation Antagonistes des recepteurs d'il-8
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JP2002518300A (ja) 2002-06-25
WO1999065310A1 (fr) 1999-12-23
EP1087661A4 (fr) 2003-04-16
CA2335292A1 (fr) 1999-12-23

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