EP1121360A1 - Il-8 receptor antagonists - Google Patents

Il-8 receptor antagonists

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Publication number
EP1121360A1
EP1121360A1 EP99956537A EP99956537A EP1121360A1 EP 1121360 A1 EP1121360 A1 EP 1121360A1 EP 99956537 A EP99956537 A EP 99956537A EP 99956537 A EP99956537 A EP 99956537A EP 1121360 A1 EP1121360 A1 EP 1121360A1
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EP
European Patent Office
Prior art keywords
optionally substituted
alkyl
alkenyl
heteroaryl
aryl
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Withdrawn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
EP99956537A
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German (de)
French (fr)
Other versions
EP1121360A4 (en
Inventor
Katherine L. Widdowson
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SmithKline Beecham Corp
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SmithKline Beecham Corp
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Publication of EP1121360A1 publication Critical patent/EP1121360A1/en
Publication of EP1121360A4 publication Critical patent/EP1121360A4/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61P37/08—Antiallergic agents
    • 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
    • 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 novel cyclic pyridyl substituted compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2, and ENA-78 mediated diseases.
  • Interleukin-8 Interleukin-8
  • NAP-1 neutrophil attractant/activation protein- 1
  • MDNCF monocyte derived neutrophil chemotactic factor
  • NAF neutrophil activating factor
  • T-cell lymphocyte chemotactic factor T-cell lymphocyte chemotactic factor.
  • Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells. It is produced by a majority of nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL-la, IL-lb or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP.
  • GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 also belong to the chemokine a family. Like IL-8 these chemokines have also been referred to by different names. For instance GRO ⁇ , ⁇ , ⁇ have been referred to as MGSAa, b and g respectively
  • 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 basophilic chemotactic activity.
  • 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.
  • 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. Strieter et al., Science 258, 1798 (1992).
  • IL-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.
  • IL-8Ra which binds only IL-8 with high affinity
  • IL-8Rb which has high affinity for IL-8 as well as for GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • IL-8Ra which binds only IL-8 with high affinity
  • IL-8Rb which has high affinity for IL-8 as well as for GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
  • This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (I), (II), or (III) or a pharmaceutically acceptable salt thereof.
  • the chemokine is IL-8.
  • This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I), (II) or (III).
  • the present invention also provides for the novel compounds of Formula (I), (II), or (III) and pharmaceutical compositions comprising a compound of Formula (I), (II, or (III) and a pharmaceutical carrier or diluent.
  • R is -NH -C(X)-NH- (CR 13 R 14 ) V - Z;
  • X is oxygen or sulfur
  • Z is W, HET, ( ⁇ Y ⁇ )n ⁇ , an optionally substituted C i . ⁇ Q alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-I0 alkynyl;
  • Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Cj-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, (CRgRg)q S(O) t R_ ⁇ , hydroxy, hydroxy Ci-4alkyl, aryl, aryl C ⁇ -4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, heteroaryl Ci-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)qNR4R5, C2-10 alkenyl C(O)NR 4 R5, (CRgR 8 )q C(O)NR 4 R5, (CRgRg)q C(O)NR
  • aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted;
  • 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 Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, 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, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted -io alkoxy, (CRgRg)q S(O) t R4, hydroxy, hydroxyCi-4alkyl, aryl, aryl -4 alkyl, aryloxy, arylCj-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl Cj-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)q NR4R5, C2-10 alkenyl C(O)NR 4 R5, (CRgRg)q C(O)NR 4 R 5 , (CRgRg)q C(O)
  • Rg is hydrogen or C 1-4 alkyl
  • RlO is C 1-10 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 heterocyclicC 1 -4alkyl;
  • Rl2 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 optionally substituted aryl;
  • Rl7 is 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 1 -4alkyl;
  • R g is hydrogen, optionally substituted C ⁇ _ ⁇ o alky
  • the E containing ring is optionally selected from
  • the compounds of Formula (I), (II) and (III) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the IL-8 ⁇ and ⁇ receptors.
  • Chemokine mediated diseases for treatment, therapeutic ally or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
  • Ri is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl, such as CF 3 ; Ci-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; (CRgRg)q S(O) t R4, wherein t is 0, 1 or 2; hydroxy; hydroxy C ⁇ _4alkyl, 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; heteroarylalkyl; heteroaryl Ci-4
  • the term "the aryl, heteroaryl, and heterocyclic containing moieties” refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings.
  • the term “moieties” and “rings” may be interchangeably used throughout.
  • 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, 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.
  • Rg is independently hydrogen or C 1-4 alkyl.
  • q is 0 or an integer having a value of 1 to 10.
  • Rio is C ⁇ _ ⁇ o alkyl C(O)2R 8 , such as CH2C(O)2H or
  • Ri i is hydrogen, Ci-4 alkyl, aryl, aryl Ci-4 alkyl, heteroaryl, heteroaryl Cj-4alkyl, heterocyclic, or heterocyclic C -4alkyl.
  • R12 is hydrogen, C _IQ alkyl, optionally substituted aryl or optionally substituted arylalkyl.
  • R ⁇ 3 and R14 are independently hydrogen, or an optionally substituted C _4 alkyl which may be straight or branched as defined herein, or one of R ⁇ 3 and R 14 are an optionally substituted aryl.
  • v is 0, or an integer having a value of 1 to 4.
  • R ⁇ 3 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 Cj-4alkyl; Cj-4 alkoxy; such as methoxy, or ethoxy; halosubstituted Ci-io alkoxy; S(O)tR4; aryl; NR4R5; NHC(O)R4; C(O)NR4Rs; or C(O)OR 8 .
  • R17 is C ⁇ _4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC ⁇ _4alkyl, heterocyclic, or heterocyclicC i-4alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted.
  • Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Cj-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR R 8 )q S(O) t R4; hydroxy; hydroxyCi-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR Rg)q
  • NR4R5; C2-10 alkenyl C(O)NR4R5; (CRgRg)q C(O)NR 4 R 5 ; (CR 8 Rg)qC(O)NR 4 Rl0; S(O) 3 H; S(O) 3 R 8 ; (CR 8 R 8 )q C(O)Rn; C 2 -10 alkenyl C(O)Rn; C2-10 alkenyl C(O)ORn ; (CR 8 R 8 )q C(O)OR ⁇ 2 ; (CR 8 R 8 )q OC(O) Rn; (CR 8 R )qC(NR4)NR4R 5 ; (CRgRg)q NR 4 C(NR 5 )R ⁇ ⁇ ; (CRgR 8 )q NR4C(O)Ri i; (CRgRg)q NHS(O) 2 R a ; or (CR 8 R 8 )q S(O)2NR 4 R5; or two Y moieties together may
  • s is an integer having a value of 1 to 3.
  • s is preferably 1.
  • Y forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system.
  • These ring systems may be substituted 1 to 3 times by other Y moieties as defined above.
  • R a is NR4R5, alkyl, aryl C ⁇ _4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-C ⁇ _4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC 1.4 alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted.
  • Y is preferably a halogen, C ⁇ _4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio Ci-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4 alkyl, or hydroxy alkyl.
  • Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2'- position or 2'-, 3 '-position.
  • n is preferably one. While both R and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, preferably both rings are substituted.
  • R is -NH -C(X)-NH- (CR 3 R 4) v - Z.
  • Z is W, HET, ( ⁇ ) n , an optionally substituted C io alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl.
  • p is an integer having a value of 1 to 3.
  • X is oxygen or sulfur, preferably oxygen.
  • Z is a heteroaryl (HET) ring
  • HET heteroaryl
  • the ring containing the heteroatom does not need to be directly attached to the urea moiety through the (Rl 3 Rj4) v linkage. Any of the ring(s) in these systems may be optionally substituted as defined herein.
  • the HET moiety is a pyridyl, which may be 2-, 3- or 4-pyridyl. If the ring is a multi system ring it is preferably benzimidazole, dibenzothiophene, or an indole ring.
  • rings of interest include, but are not limited to thiophene, furan, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline, quinazolinyl, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • the HET ring may be optionally substituted independently one to five, preferably 1 to 3 times by Y as defined above.
  • the substitutions may be in any of the ring(s) of the HET system, such as in a benzimidazole ring.
  • R15 and R are independently hydrogen, or an optionally substituted Ci-4 alkyl as defined above for R ⁇ 3 and R14.
  • W is , or
  • the E containing ring is optionally selected from ent of the ring.
  • 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.
  • the E ring may be substituted by the (Y)n moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).
  • Y in the W term may be substituted in any of the 5 ring positions of the phenyl moiety (when E is absent), Y is preferably mono-substituted in the 2 - position or 3'- position, with the 4'- preferably being unsubstituted. If the phenyl ring is disubstituted, 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.
  • R ⁇ 8 is hydrogen, optionally substituted Ci-io alkyl, Ci-io alkoxy, halosubstituted C ⁇ _ ⁇ o alkoxy, hydroxy, arylC ⁇ .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-C ⁇ _4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC j .4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted.
  • R ⁇ 8 is hydrogen or alkyl, more preferably hydrogen.
  • halogen such as fluorine, chlorine, bromine or iodine
  • hydroxy hydroxy substituted Ci-ioalkyl
  • Ci-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 alkyl amino such as in the NR4R5 group; NHC(O)R4; C(O)NR R 5 ; C(O)OH; S(O) 2 NR4R5; NHS(O) 2 R20, Cl-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl
  • halosubstituted Ci-io alkyl such CF 3 ;
  • 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.
  • 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.
  • aryl - phenyl and naphthyl; • “heteroaryl” (on its own or in any combination, such as “heteroaryloxy", or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
  • heterocyclic (on its own or in any combination, such as “heterocyclicalkyl”) - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
  • arylalkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean Ci-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
  • sulfinyl - the oxide S (O) of the corresponding sulfide
  • thio refers to the sulfide
  • sulfonyl refers to the fully oxidized S(O)2 moiety.
  • Ri moieties may together form a 5 or 6 membered saturated or unsaturated ring
  • an aromatic ring system such as naphthalene, or is a phenyl moiety having attached a 6 membered partially saturated or unsaturated ring such as a C6 cycloalkenyl, i.e, hexene, or a C5 cycloalkenyl moiety, such as cyclopentene.
  • Compounds of Formula (II) are useful in a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (II) or a pharmaceutically acceptable salt thereof.
  • the chemokine is IL-8.
  • This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (II).
  • the present invention also provides a novel pharmaceutical composition
  • a novel pharmaceutical composition comprising a compound of Formula (II) and a pharmaceutical carrier or diluent.
  • R is -NH -C(X)-NH- (CR ⁇ 3 R ⁇ 4 ) v - Z;
  • X is oxygen or sulfur
  • Z is W, HET, ' ) n , an optionally substituted C -io alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;
  • Rj is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-10 alkoxy, halosubstituted Ci-io alkoxy, (CR 8 R 8 )q S(O)tF 4, hydroxy, hydroxy Ci-4alkyl, aryl, aryl C ⁇ _4 alkyl, aryloxy, aryl Cj-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci_4alkyl, heteroaryl Ci-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR 8 R 8 )qNR4R5, C2-10 alkenyl C(O)NR R5, (CR 8 R 8 )q C(O)NR4R5, (CR 8 R 8 )q C(O)NR 4
  • R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, 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, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, (CR R 8 )q S(O) t R4, hydroxy, hydroxyCi-4alkyl, aryl, aryl Cj-4 alkyl, aryloxy, arylCi-4 alkyloxy, heteroaryl, heteroaryl
  • R 8 is hydrogen or Ci-4 alkyl;
  • RlO is C i-io alkyl C(O) 2 R 8 ;
  • Rl l is hydrogen, Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCj-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC i _4alkyl ;
  • Rl2 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 ⁇ and R14 may be optionally substituted aryl;
  • R 17 is C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl;
  • Rl is hydrogen, optionally substituted Ci-io alkyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, hydroxy, arylC ⁇ .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-
  • R a is NR4R5, alkyl, arylC ⁇ .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl- C ⁇ _4 alkyl, heteroarylC2_4 alkenyl, heterocyclic, or heterocyclicC 1.4 alkyl; and wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
  • the E containing ring is optionally selected from
  • Illustrative compounds of Formula (II) include: N-(l,3-dihydro-2,2-dioxidoisothiazolo[4,3-b]pyridin-7-yl)-N-(2- bromophenyl)urea;
  • Compounds of Formula (III) are useful in a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (III) or a pharmaceutically acceptable salt thereof.
  • the chemokine is IL-8.
  • This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (III).
  • the present invention also provides a novel pharmaceutical composition
  • a novel pharmaceutical composition comprising a compound of Formula (III) and a pharmaceutical carrier or diluent.
  • R is - ⁇ H -C(X)- ⁇ H- (CR ⁇ 3 R 14 ) v - Z;
  • X is oxygen or sulfur
  • Z is W, HET, ( ⁇ ) n , an optionally substituted C 10 alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;
  • 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, (CR R 8 )q S(O)tR4, hydroxy, hydroxy C ⁇ _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 R 8 )qNR4R5, C2-10 alkenyl C(O)NR 4 R5, (CR 8 R 8 )q C(O)NR4R5, (CR 8 R 8 )q C(O)NR
  • HET is an optionally substituted heteroaryl
  • R4 and R5 are independently hydrogen, optionally substituted C ⁇ -A alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C ⁇ _4alkyl, heterocyclic, 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, C ⁇ io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, (CR 8 Rg)q S(O)tR4, hydroxy, hydroxyC i-4alkyl, aryl, aryl Ci-4 alkyl, aryloxy, arylCj-4 alkyloxy,
  • RlO is C 1-10 alkyl C(O)2R 8 ;
  • Rl 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 -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 optionally substituted aryl;
  • R17 is Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cj-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC ⁇ _4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl ;
  • Rjg is hydrogen, optionally substituted Ci-io alkyl, Cj-io alkoxy, halosubstituted Ci- io alkoxy, hydroxy, arylC ⁇ .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-
  • R a is NR4R5, alkyl, arylC ⁇ .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl- C ⁇ alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC j .4 alkyl; and wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
  • the E containing ring is optionally selected from
  • Ilustrative compounds of Formula (III) include:
  • the compounds of Formulas (I), (II) and (III) 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 Formulas (I), (II) and (III) having a variety of different R, Ri, and Z 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.
  • compound 1 -scheme 1 is then brominated under standard conditions (H2SO4 and Br2).
  • compound 2-scheme 1 is then oxidized under standard conditions ( Fuming H2SO4/ 30% H2O2).
  • Compound 3-scheme 1 can be treated with standard bromination conditions (NBS), followed by standard sulfamide formation via the thioacetate(sodium thioacetate, DMF), sulfonyl chloride(AcOH/sodium acetate/C ⁇ ), and then sulfamide formation (ammonium hydroxide or ammonia gas) to give compound 4-scheme 1.
  • NBS standard bromination conditions
  • the aniline 5-scheme 1 may be prepared by cyclization of compound 4-scheme 1, followed by standard reduction condition (Pd/C and H2 or SnCl2, thiol, or zinc in acetic acid).
  • the ortho substituted phenyl urea in 6-scheme 1 may be prepared by standard conditions involving the condensation of the commercially available substituted aryl isocyanate (Aldrich Chemical Co., Milwaukee,Wi.) with the corresponding aniline 5-scheme 7 in an aprotic solvent such as (DMF or toluene).
  • the bromo substituent on 4-6- scheme-1 can be further eleaborated using palladium catalyzed arylation, Heck reactions or carbonylation. Alternately the bromide can be displaced using nucleophilic conditions such as sodium alkoxides, azide, thiols or cyanide. These functional groups can then be further interconverted using conditions well known in the art.
  • the sulfonyl chloride hydrolyses to the sulfonic acid it can be converted back to the sulfonyl chloride using POCl .
  • the sulfonyl chloride can then be reacted with ammonium hydroxide or ammonia gas to form the sulfonamide 3-scheme-2.
  • the sulfonamide can then be cyclized using potassium carbonate in an aprotic polar solvent such as DMF, DMSO or propionitrile to form the corresponding cyclic sulfonamide.
  • the nitro can then be reduced using standard conditions such as Pd/C and H2 or SnCl2, thiol, or zinc in acetic acid to form the amine 4-scheme-2.
  • the amine can be coupled with the commericially available isocyanate, 5-scheme-2.
  • 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 phosphorazide in the presence of a base (such as triethyl amine).
  • base such as potassium carbonate
  • the aromatic rings can be further functionalized by halogenation using a halogen in the presence of an acid or lewis acid or a perhalogenated salt such as pyridinium bromide perbromide to form the brominated aromatic. It is recognized that a mixture of isomers may be produced in this reaction.
  • the isomers can be separated by chromatography.
  • the bromine can then be displaced by a nucleophile such as cupric cyanide or sodium methoxide in a polar aprotic solvent such as DMF or DMSO.
  • a nucleophile such as cupric cyanide or sodium methoxide
  • a polar aprotic solvent such as DMF or DMSO.
  • the bromide can be used for palladium-catalyzed coupling or carbonylation reactions.
  • the amine can be converted the chlorine by diazotization with sodium nitrite in aqueous hydrochloric acid followed the addition of copper chloride to form the corresponding aromatic chloride.
  • This compound can then be oxidized to form the nitro pyridine n-oxide to form 2-scheme-3.
  • the methyl can then be brominated under radical bromination conditions such as NBS.
  • the bromide can be converted to the corresponding sulfonamide using the following three step procedure.
  • the bromide can be reacted with sodium thioacetate.
  • This thioacetate can be converted to the sulfonyl chloride using chlorine gas in aqueous acetic acid. If the sulfonyl chloride hydrolyses to the sulfonic acid it can be converted back to the sulfonyl chloride using POCl 3 .
  • the sulfonyl chloride can then be reacted with ammonium hydroxide or ammonia gas to form the sulfonamide 3-scheme-3.
  • the sulfonamide can then be cyclized using potassium carbonate in an aprotic polar solvent such as DMF, DMSO or propionitrile to form the corresponding cyclic sulfonamide 3-scheme-3.
  • the nitro can then be reduced using standard conditions such as Pd/C and H2 or SnCl2, thiol, or zinc in acetic acid to form the amine 4-scheme-3.
  • the amine can be coupled with the commericially available isocyanate.
  • 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 phosphorazide in the presence of a base (such as triethyl amine) to form 5-scheme-3.
  • base such as potassium carbonate
  • diphenyl phosphorazide such as triethyl amine
  • All of the aromatic rings can be further functionalized by halogenation using a halogen in the presence of an acid or lewis acid or a perhalogenated salt such as pyridinium bromide perbromide to form the brominated aromatic. It is recognized that a mixture of isomers may be produced in this reaction. The isomers can be separated by chromatography. The bromine can then be displaced by a nucleophile such as cupric cyanide or sodium methoxide in a polar aprotic solvent such as DMF or DMSO. Alternatively the bromide can be used for palladium-catalyzed coupling or carbonylation reactions.
  • the nitro pyridine n-oxide l-scheme-4 which was described previously can be alkylated with an allyl group to form 2-scheme-4 in the presence of a base such as potassium carbonate, or sodium hydride to form 2-scheme-4.
  • the methylene of the cyclic sulfonamide can then be alkylated by an alkyl halide in the presence of sodium hydride or lithium heaxamethyldisilazine to form 3-scheme -4.
  • the methylene can also be functionalized by reaction with an isocyanate or thio isocyanate in the presence of a base to form the corresponding amide or thio amide.
  • the methylene can be halogenated using an electrophilic halogen source such as N-fluoro benzene-sulfonimide or N-bromosuccinimide in the presence of a base such as sodium hydride, triethyl amine or sodium heaxamethyl disilazine.
  • an electrophilic halogen source such as N-fluoro benzene-sulfonimide or N-bromosuccinimide
  • a base such as sodium hydride, triethyl amine or sodium heaxamethyl disilazine.
  • This benzylic halide can be displaced by a variety of nucleophiles such as alcohols, thiols, or amines in the presence of a base such as sodium hydride, triethyl amine or sodium heaxamethyl disilazine.
  • the allyl can be deprotected using a palladium catalyst in the presence of a reducing agent such as sodium borohydride and the nitro can be reduced by standard conditions such as conditions such as Pd/C ' and H2 or SnCl2, thiol, or zinc in acetic acid to form the amine 4-scheme-4.
  • the amine can be coupled with the commericially available isocyanate.
  • 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 phosphorazide in the presence of a base (such as triethyl amine).
  • Another aspect of the present invention is the novel process of making a compound of Formula (I) which process comprises condensing an isocyanate derivative of the formula
  • Another aspect of the present invention is the process of making a compound of Formula (II) which process comprises condensing an isocyanate derivative of the formula wherein R ⁇ , R 4, v and Z are as defined for Formula (II); with a compound of the Formula (Ha) :
  • Another aspect of the present invention is the process of making a compound of Formula (III) which process comprises condensing an isocyanate derivative of the formula
  • 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, (CRgRg)q S(O) t R4, hydroxy, hydroxy Cj-4alkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, heteroaryl Ci-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CRgRg)q C(O)NR 4 R5, (CR 8 R 8 )q C(O)NR 4 Rl
  • NR4C(O)Rn (CR 8 R 8 )qC(NR 4 )NR 4 R5, (CR 8 Rg)q NR 4 C(NR 5 )Rn, (CR 8 R 8 )q NHS(O) Ri7, or (CR 8 Rg)q S(O)2NR4R 5 ; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted;
  • m is an integer having a value of 1 to 3; q is 0, or an integer having a value of 1 to 10;
  • s is an integer having a value of 1 to 3;
  • t is 0, or an integer having a value of 1 or 2;
  • R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclic C ⁇ _4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S;
  • R 8 is hydrogen or Cj-4 alkyl;
  • RlO is C 1-10 alkyl C(O)2R 8 ;
  • Rl l i hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl C ⁇ _4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl;
  • Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
  • Rl7 is Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cj-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC ⁇ _4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 -4alkyl.
  • Yet another aspect of the present invention is the novel intermediate compounds of Formula (II) and (III) which are the pyridine isomers of Formula (I) as described above.
  • Yet another aspect of the present invention is the novel process of making a compound of Formula (la) which process comprises cyclizing a compound of the formula: under standard conditions and then reducing under standard conditions to yield a compound of Formula (la).
  • Yet another aspect of the present invention is the novel process of making a compound of Formula (Ila) which process comprises cyclizing a compound of the formula:
  • Yet another aspect of the present invention is the novel process of making a compound of Formula (Ilia) which process comprises cyclizing a compound of the formula:
  • 2-amino-3,5-dibromo-4-methylpyridine (8g, 30.0mmol) was cooled to 10° C, followed by the addition of concentrated sulfuric acid(l ⁇ ml). The mixture was stirred, maintaining the temperature at 10° C for 2hrs, with the addition of a mixture of 30% hydrogen peroxide in 30% fuming sulfuric acid(25ml/50ml). The mixture was allowed to warm to room temperature and stirred for an additional 48 hrs. The reaction was then added to 300ml of water with cooling and made very slightly basic with dropwise addition of 505 NaOH solution while the temperature was maintained at 20-25o C. The product was extracted using ether(4x 150ml) and dried with
  • N-[pyrsulfonamide]-N'-[2-bromophenyl] urea is prepared from 2-amino-5- bromo-4-cyclicsulfonamide pyridine (wt, mol) according to the procedure in General
  • Method B The product is purified by chromatography of the resulting solid on silica gel (EtOAc/ hexane(2equiv./3equiv.)). (yield) ⁇ NMR (CD 3 SO 2 CD 3 ): ⁇ ( proton nmr).
  • 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 IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • the chemokines are IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function, in particular IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78, such that they are biologically regulated down to normal levels of physiological function, or in some case to subnormal levels, so as to ameliorate the disease state.
  • Abnormal levels of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 for instance in the context of the present invention constitute: (i) levels of free IL-8 greater than or equal to 1 picogram per mL; (ii) any cell associated IL-8, GRO ⁇ , GRO ⁇ GRO ⁇ , NAP-2 or ENA-78 above normal physiological levels; or (iii) the presence of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 above basal levels in cells or tissues in which IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 respectively, is produced.
  • Chemokine mediated diseases include psoriasis, atopic dermatitis, arthritis, asthma, chronic obstructive pulmonary disease, adult respiratory distress syndrome, inflammatory bowel disease, Crohn's disease, ulcerative colitis, stroke, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, cardiac and renal reperfusion injury, glomerulonephritis, thrombosis, graft vs. host reaction, Alzheimer's disease, allograft rejections, malaria, restinosis, angiogenesis or undesired hematopoietic stem cells release, rhinovirus infections, and various bone resorption indications.
  • the ⁇ -chemokines but particularly, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78, working through the IL- 8 type I or II receptor can promote the neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, the inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.
  • the present invention also provides for a means of treating, in an acute setting, as well as preventing, in those individuals deemed susceptible to, CNS injuries by the chemokine receptor antagonist compounds of Formula (I).
  • CNS injuries as defined herein include both open or penetrating head trauma, such as by surgery, or a closed head trauma injury, such as by an injury to the head region. Also included within this definition is ischemic stroke, particularly to the brain area.
  • Ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel.
  • the role of inflammatory cytokines in this are has been emerging and the present invention provides a mean for the potential treatment of these injuries. Relatively little treatment, for an acute injury such as these has been available.
  • TNF- ⁇ is a cytokine with proinflammatory actions, including endothelial leukocyte adhesion molecule expression.
  • Leukocytes infiltrate into ischemic brain lesions and hence compounds which inhibit or decrease levels of TNF would be useful for treatment of ischemic brain injury. See Liu et al., Stoke, Vol. 25., No. 7, pp. 1481-88 (1994) whose disclosure is incorporated herein by reference.
  • the compounds of Formula (I) are administered in an amount sufficient to inhibit IL-8, binding to the IL-8 alpha or beta receptors, from binding to these receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation.
  • the discovery that the compounds of Formula (I) are inhibitors of IL-8 binding is based upon the effects of the compounds of Formulas (I) in the in vitro receptor binding assays which are described herein.
  • the compounds of Formula (I) have been shown to be inhibitors of type II IL-8 receptors.
  • IL-8 mediated disease or disease state refers to any and all disease states in which IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 plays a role, either by production of IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 themselves, or by IL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 causing another monokine to be released, such as but not limited to IL- 1 , IL-6 or TNF.
  • a disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease stated mediated by IL-8.
  • chemokine mediated disease or disease state refers to any and all disease states in which a chemokine which binds to an IL-8 ⁇ or ⁇ receptor plays a role, such as but not limited to IL-8, GRO- ⁇ , GRO- ⁇ , GRO ⁇ , NAP- 2 or ENA-78.
  • a disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease stated mediated by IL-8.
  • cytokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response.
  • a cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them.
  • a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte.
  • Lymphokines are generally referred to as being produced by lymphocyte cells.
  • cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF- ⁇ ) and Tumor Necrosis Factor beta (TNF- ⁇ ).
  • chemokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response, similar to the term “cytokine” above.
  • a chemokine is primarily secreted through cell transmembranes and causes chemotaxis and activation of specific white blood cells and leukocytes, neutrophils, monocytes, macrophages, T-cells, B-cells, endothelial cells and smooth muscle cells.
  • chemokines include, but are not limited to, IL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , NAP-2, ENA-78, IP- 10, MlP-l ⁇ , MlP- ⁇ , PF4, and MCP 1, 2, and 3.
  • 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 also relates to a pharmaceutical composition comprising an effective, non- toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
  • Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating 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.
  • 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:
  • [125 ⁇ ] iL_g (human recombi ⁇ ant) is obtained from Amersham Corp., Arlington Heights, IL, 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), lmMPMSF ( ⁇ -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 25 jL_g (0.25 nM) or 125 ⁇ Gro- ⁇ and 0.5 ⁇ g/mL of IL-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, 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 0.0 InM and 100 uM.
  • the assay is initiated by addition of 25 ⁇ _iL- _ 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 IL-8 R ⁇ , or Type II, receptor is referred to as the permissive receptor.
  • 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 IL-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 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.
  • test compound 0.001 - 1000 nM
  • Cytochalasin B in a volume of 50 ul (20ug/ml)
  • Ringers buffer in a volume of 50 ul.
  • These cells are allowed to warm (37 °C, 5% CO2, 95% RH) for 5 min. before IL-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. 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.
  • 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.
  • the present 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.
  • TBI experimentally induced lateral fluid- percussion traumatic brain injury
  • LC left (injured) parietal cortex
  • RC contralateral right cortex
  • LA cortex adjacent to injured parietal cortex
  • RA right cortex
  • RH right hippocampus
  • TNF- ⁇ mRNA expression is observed in LH (104 ⁇ 17% of positive control, p ⁇ 0.05 compared with sham), LC (105 ⁇ 21%, p ⁇ 0.05) and LA (69 ⁇ 8%, p ⁇ 0.01) in the traumatized hemisphere 1 hr. following injury.
  • An increased TNF- ⁇ mRNA expression is also observed in LH (46 ⁇ 8%, p ⁇ 0.05), LC (30 ⁇ 3%, p ⁇ 0.01) and LA (32 ⁇ 3%, p ⁇ 0.01) at 6 hr. which resolves by 24 hr. following injury.
  • TNF- ⁇ mRNA In the contralateral hemisphere, expression of TNF- ⁇ mRNA is increased in RH (46 ⁇ 2%, p ⁇ 0.01), RC (4 ⁇ 3%) and RA (22 ⁇ 8%) at 1 hr. and in RH (28 ⁇ 11%), RC (7 ⁇ 5%) and RA (26 ⁇ 6%, p ⁇ 0.05) at 6 hr. but not at 24 hr. following injury. In sham (surgery without injury) or naive animals, no consistent changes in expression of TNF- ⁇ mRNA are observed in any of the 6 brain areas in either hemisphere at any times.
  • 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.
  • NGF nerve growth factor
  • This assay characterizes the regional expression of interleukin-l ⁇ (IL-1B) mRNA in specific brain regions following experimental lateral fluid-percussion traumatic brain injury (TBI) in rats.
  • TBI lateral fluid-percussion traumatic brain injury
  • LC left (injured) parietal cortex
  • RC contralateral right cortex
  • LA cortex adjacent to injured parietal cortex
  • RA right cortex
  • LH left hippocampus
  • RH right hippocampus

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Abstract

This invention relates to novel compounds of Formula (I), and compositions thereof, 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 novel cyclic pyridyl substituted compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating IL-8, GROα, GROβ, GROγ, NAP-2, and ENA-78 mediated diseases.
BACKGROUND OF THE INVENTION
Many different names have been applied to Interleukin-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. 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-la, IL-lb or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987) and J. Immunol. 144, 2223 (1990) ; Strieter, et al., Science 243, 1467 (1989) and J. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 148, 3216 (1992).
GROα, GROβ, GROγ and NAP-2 also belong to the chemokine a family. Like IL-8 these chemokines have also been referred to by different names. For instance GROα, β, γhave been referred to as MGSAa, b and g respectively
(Melanoma Growth Stimulating Activity), see Richmond et al., J. Cell Physiology 129, 375 (1986) and Chang et al., J. Immunol 148, 451 (1992). All of the chemokines of the 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 basophilic 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 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. 146, 427 (1992); Donnely 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. Strieter 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 notably the B -receptor. Thomas et al., J. Biol. Chem. 266, 14839 (1991); and Holmes et al., Science 253, 1278 (1991). The development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research, Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993. Hence, the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
Two high affinity human IL-8 receptors (77% homology) have been characterized: IL-8Ra, which binds only IL-8 with high affinity, and IL-8Rb, which has high affinity for IL-8 as well as for GROα, 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 a or b 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 a or b receptor and which method comprises administering an effective amount of a compound of Formula (I), (II), or (III) 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 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), (II) or (III).
The present invention also provides for the novel compounds of Formula (I), (II), or (III) and pharmaceutical compositions comprising a compound of Formula (I), (II, or (III) and a pharmaceutical carrier or diluent.
Compounds of Formula (I) useful in the present invention are represented by the structure:
wherein
R is -NH -C(X)-NH- (CR13R14)V - Z;
X is oxygen or sulfur;
(CR15R16)P
Z is W, HET, ( ^Y τ)nπ , an optionally substituted C i . \ Q alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-I0 alkynyl;
Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Cj-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, (CRgRg)q S(O)tR_ι, hydroxy, hydroxy Ci-4alkyl, aryl, aryl C}-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, heteroaryl Ci-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CRgR8)q C(O)NR4R5, (CRgRg)q C(O)NR4RlO, S(O)3R8, (CRgRg)q C(O)R 1 1 , C2- 10 alkenyl C(O)R 11 , C2- 10 alkenyl C(O)OR 11 , C(O)Rι 1, (CRgRg)q C(O)ORι2, (CRgRg)q OC(O) Rl 1, (CRgRg)q NR4C(O)Rι 1, (CR8R8)qC(NR4)NR4R5, (CRgRg)q NR4C(NR5)R! h (CRgRg)q NHS(O)2Ri7, or (CRgRg)q S(O) NR R5; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted; 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 Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, 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, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted -io alkoxy, (CRgRg)q S(O)tR4, hydroxy, hydroxyCi-4alkyl, aryl, aryl -4 alkyl, aryloxy, arylCj-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl Cj-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)q NR4R5, C2-10 alkenyl C(O)NR4R5, (CRgRg)q C(O)NR4R5, (CRgRg)q C(O)NR4RlO, S(O)3R8; (CRgRg)q C(O)Ri 1 , C2-10 alkenyl C(O)Rj 1 , C2-10 alkenyl C(O)ORι 1 , (CRgRg)q C(O)ORi2, (CRgRg)q OC(O) Rl 1, (CRgRg)q NR4C(O)Rι 1,
(CRgR8)qC(NR4)NR4R5, (CRgRg)q NR4C(NR5)Rι (CRgRg)q NHS(O)2Ra, or (CRgRg)q S(O)2NR4R5; or two Y moieties together may form O-(CH2)s-O or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted;
Rg is hydrogen or C 1-4 alkyl;
RlO is C 1-10 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 heterocyclicC 1 -4alkyl; Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; Rl3 and R14 are independently hydrogen, optionally substituted Ci-4 alkyl, or one of Rι3 and R14 may be optionally substituted aryl; Rl7 is 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 1 -4alkyl; R g is hydrogen, optionally substituted Cι_ιo alkyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, hydroxy, arylC .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl- Cι_4alkyl, heteroarylC2_4 alkenyl, heterocyclic, or heterocyclicC 1.4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted; Ra is NR4R5, alkyl, arylC .4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-
Cι_4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC 1.4 alkyl; and wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
the E containing ring is optionally selected from
the asterix * denoting point of attachment of the ring; or a pharmaceutically acceptable salt thereof.
Compounds of Formula (II) and (III) described herein are the pyridine isomers of the Formula (I) and are represented by the structures as shown below. DETAILED DESCRIPTION OF THE INVENTION
The compounds of Formula (I), (II) and (III) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of IL-8 or other chemokines which bind to the IL-8 α and β receptors. Chemokine mediated diseases for treatment, therapeutic ally or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
Suitably Ri is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl, such as CF3; Ci-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; (CRgRg)q S(O)tR4, wherein t is 0, 1 or 2; hydroxy; hydroxy Cι_4alkyl, 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; heteroarylalkyl; heteroaryl Ci-4 alkyloxy; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CRgR8)qNR4R5; C2-10 alkenyl C(O)NR4R5; (CR8Rg)qC(O)NR4R5; (CR Rg)qC(O)NR4Rlθ; S(O)3H; S(O)3Rg; (CR8Rg)qC(O)Rn; C2-10 alkenyl C(O)Rn ; C2-10 alkenyl C(O)ORπ ; C(O)Rn ; (CRgR8)qC(O)ORi2; (CR8R8)q OC(O)Ri 1 ; (CR8Rg)qNR4C(O)Ri 1 ; (CR R8)qC(NR4)NR4R5; (CR8R8)q
NR4C(NR5)R! i ; (CR8R8)qNHS(O)2Ri7; or (CR8R8)qS(O)2NR4R5. All of the aryl, heteroaryl, and heterocyclic containing moieties may be optionally substituted as defined herein below.
For use herein the term "the aryl, heteroaryl, and heterocyclic containing moieties" refers to both the ring and the alkyl, or if included, the alkenyl rings, such as aryl, arylalkyl, and aryl alkenyl rings. The term "moieties" and "rings" may be interchangeably used throughout.
Suitably, R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl C ι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, 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. Suitably, Rg is independently hydrogen or C 1-4 alkyl.
Suitably, q is 0 or an integer having a value of 1 to 10.
Suitably, Rio is Cι_ιo alkyl C(O)2R8, such as CH2C(O)2H or
CH C(O) CH3.
Suitably, Ri i is hydrogen, Ci-4 alkyl, aryl, aryl Ci-4 alkyl, heteroaryl, heteroaryl Cj-4alkyl, heterocyclic, or heterocyclic C -4alkyl.
Suitably, R12 is hydrogen, C _IQ alkyl, optionally substituted aryl or optionally substituted arylalkyl.
Suitably, Rι3 and R14 are independently hydrogen, or an optionally substituted C _4 alkyl which may be straight or branched as defined herein, or one of Rι3 and R 14 are an optionally substituted aryl.
Suitably, v is 0, or an integer having a value of 1 to 4.
When Rι3 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 Cj-4alkyl; Cj-4 alkoxy; such as methoxy, or ethoxy; halosubstituted Ci-io alkoxy; S(O)tR4; aryl; NR4R5; NHC(O)R4; C(O)NR4Rs; or C(O)OR8.
Suitably, R17 is Cι_4alkyl, aryl, arylalkyl, heteroaryl, heteroarylCι_4alkyl, heterocyclic, or heterocyclicC i-4alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted.
Suitably, Y is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted Ci-io alkyl; Cj-io alkyl; C2-10 alkenyl; Ci-io alkoxy; halosubstituted Ci-io alkoxy; azide; (CR R8)q S(O)tR4; hydroxy; hydroxyCi-4alkyl; aryl; aryl Ci-4 alkyl; aryloxy; arylCi-4 alkyloxy; heteroaryl; heteroarylalkyl; heteroaryl Ci-4 alkyloxy; heterocyclic, heterocyclic Ci-4alkyl; aryl C2-10 alkenyl; heteroaryl C2-10 alkenyl; heterocyclic C2-10 alkenyl; (CR Rg)q
NR4R5; C2-10 alkenyl C(O)NR4R5; (CRgRg)q C(O)NR4R5; (CR8Rg)qC(O)NR4Rl0; S(O)3H; S(O)3R8; (CR8R8)q C(O)Rn; C2-10 alkenyl C(O)Rn; C2-10 alkenyl C(O)ORn ; (CR8R8)q C(O)ORι2; (CR8R8)q OC(O) Rn; (CR8R )qC(NR4)NR4R5; (CRgRg)q NR4C(NR5)Rι ι ; (CRgR8)q NR4C(O)Ri i; (CRgRg)q NHS(O)2Ra; or (CR8R8)q S(O)2NR4R5; or two Y moieties together may form O-(CH2)s-O or a 5 to 6 membered saturated or unsaturated ring. The aryl, heteroaryl and heterocyclic containing moieties noted above may all be optionally substituted as defined herein.
Suitably s is an integer having a value of 1 to 3.
When Y forms a dioxybridge, s is preferably 1. When Y forms an additional unsaturated ring, it is preferably 6 membered resulting in a naphthylene ring system. These ring systems may be substituted 1 to 3 times by other Y moieties as defined above.
Suitably, Ra is NR4R5, alkyl, aryl Cι_4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-Cι_4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC 1.4 alkyl, wherein all of the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted.
Y is preferably a halogen, Cι_4 alkoxy, optionally substituted aryl, optionally substituted aryloxy or arylalkoxy, methylene dioxy, NR4R5, thio Ci-4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4 alkyl, or hydroxy alkyl. Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl, more preferably these groups are mono or di-substituted in the 2'- position or 2'-, 3 '-position.
While Y may be substituted in any of the ring positions, n is preferably one. While both R and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, preferably both rings are substituted.
In compounds of Formula (I), R is -NH -C(X)-NH- (CR 3R 4)v - Z.
Suitably, Z is W, HET, (γ)n , an optionally substituted C io alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl. -•
Suitably, p is an integer having a value of 1 to 3.
X is oxygen or sulfur, preferably oxygen.
Suitably when Z is a 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 through the (Rl3Rj4)v linkage. Any of the ring(s) in these systems may be optionally substituted as defined herein. Preferably the HET moiety is a pyridyl, which may be 2-, 3- or 4-pyridyl. If the ring is a multi system ring it is preferably benzimidazole, dibenzothiophene, or an indole ring. Other rings of interest include, but are not limited to thiophene, furan, pyrimidine, pyrrole, pyrazole, quinoline, isoquinoline, quinazolinyl, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
The HET ring may be optionally substituted independently one to five, preferably 1 to 3 times by Y as defined above. The substitutions may be in any of the ring(s) of the HET system, such as in a benzimidazole ring.
Suitably R15 and R are independently hydrogen, or an optionally substituted Ci-4 alkyl as defined above for Rι3 and R14.
Suitably, W is , or
Suitably, the E containing ring is optionally selected from ent of the ring.
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. The E ring may be substituted by the (Y)n moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).
While Y in the W term may be substituted in any of the 5 ring positions of the phenyl moiety (when E is absent), Y is preferably mono-substituted in the 2 - position or 3'- position, with the 4'- preferably being unsubstituted. If the phenyl ring is disubstituted, 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.
Suitably, Rι8 is hydrogen, optionally substituted Ci-io alkyl, Ci-io alkoxy, halosubstituted Cι_ιo alkoxy, hydroxy, arylCι.4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-Cι_4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC j .4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted. Preferably, for compounds of formula (I), Rι8 is hydrogen or alkyl, more preferably hydrogen.
As used herein, "optionally substituted" unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted Ci-ioalkyl; Ci-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 alkyl amino, such as in the NR4R5 group; NHC(O)R4; C(O)NR R5; C(O)OH; S(O)2NR4R5; NHS(O)2R20, Cl-10 alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted Ci-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 heterocyclicalkyl, optionally substituted heteroaryl, optionally substituted heteroaryl alkyl, wherein these aryl , heteroaryl, or heterocyclic moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Ci-io alkoxy; S(O)m'Ci- o alkyl; amino, mono & di-substituted alkyl amino, such as in the NR4R5 group; Ci-io alkyl, or halosubstituted Ci-io alkyl, such as CF3. R20 is suitably Ci-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylCi-4alkyl, heterocyclic, or heterocyclicC 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, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic 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 iodo. • "C -io lkyl" 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, «-propyl, wσ-propyl, n-butyl, sec-butyl, wo-butyl, tert- butyl, π-pentyl and the like.
• "cycloalkyl" is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
• "alkenyl" is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like.
• "aryl" - phenyl and naphthyl; • "heteroaryl" (on its own or in any combination, such as "heteroaryloxy", or "heteroaryl alkyl") - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
• "heterocyclic" (on its own or in any combination, such as "heterocyclicalkyl") - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
• "arylalkyl" or "heteroarylalkyl" or "heterocyclicalkyl" is used herein to mean Ci-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated. • "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.
• "wherein two Ri 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 an aromatic ring system, such as naphthalene, or is a phenyl moiety having attached a 6 membered partially saturated or unsaturated ring such as a C6 cycloalkenyl, i.e, hexene, or a C5 cycloalkenyl moiety, such as cyclopentene.
Illustrative compounds of Formula (I) wherein v=0 and Z is phenyl, include: N-[5-bromo 1,3-dihydro 2,2 dioxidoisothiazolo[3,4-c]pyridin-7-yl]-N'-[2- bromophenyl] urea N-[5-chloro 1,3-dihydro 2,2 dioxidoisothiazolo[3,4-c]pyridin-7-yl]-N'-[2- bromophenyl] urea N-[5-cyano 1,3-dihydro 2,2 dioxidoisothiazolo[3,4-c]pyridin-7-yl]-N'-[2- bromophenyl] urea
N-[5-chloro 1,3-dihydro 2,2 dioxidoisofhiazolo[3,4-c]pyridin-7-yl]-N'-[2,3- dichlorophenyl] urea N-[5-bromo 1,3-dihydro 2,2 dioxidoisothiazolo[3,4-c]pyridin-7-yl]-N'-[2,3- dichlorophenyl] urea N-[5-cyano 1,3-dihydro 2,2 dioxidoisothiazolo[3,4-c]pyridin-7-yl]-N'-[2,3- dichlorophenyl] urea; or pharmaceutically acceptable salts thereof. Another aspect of the present invention are the novel compounds of Formulas (II) as described below. It is noted that these compounds are position isomers on the pyridine ring of the isothiazolopyridine ring system. For purposes herein, all of the substituent groups for Formula (II) are the same as those defined hereinabove for Formula (I).
Compounds of Formula (II) are useful in a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (II) 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 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 (II).
The present invention also provides a novel pharmaceutical composition comprising a compound of Formula (II) and a pharmaceutical carrier or diluent.
Compounds of Formula (II) are represented by the structure:
wherein
R is -NH -C(X)-NH- (CRι3Rι4)v - Z;
X is oxygen or sulfur;
Z is W, HET, ' )n , an optionally substituted C -io alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;
Rj is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-10 alkoxy, halosubstituted Ci-io alkoxy, (CR8R8)q S(O)tF 4, hydroxy, hydroxy Ci-4alkyl, aryl, aryl Cι_4 alkyl, aryloxy, aryl Cj-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci_4alkyl, heteroaryl Ci-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR R5, (CR8R8)q C(O)NR4R5, (CR8R8)q C(O)NR4Rι0, S(O)3R8, (CR8Rg)q C(O)Ri 1, C2-10 alkenyl C(O)Ri 1, C2-10 alkenyl C(O)ORι 1, C(O)Rn, (CR8R8)q C(O)ORi2, (CR8R8)q OC(O) Rn, (CR8R8)q NR4C(O)Rn, (CR8R8)qC(NR4)NR4R5, (CR8R8)q NR4C(NR5)Rn, (CRgRg)q NHS(O)2Ri7, or (CR8R8)q S(O) NR4R5; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted; 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 Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, 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, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, (CR R8)q S(O)tR4, hydroxy, hydroxyCi-4alkyl, aryl, aryl Cj-4 alkyl, aryloxy, arylCi-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl Cj-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)q NR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R5, (CR8R8)q C(O)NR4RlO, S(O)3R8; (CR8Rg)q C(O)Ri 1, C2-10 alkenyl C(O)Ri 1, C2-10 alkenyl C(O)ORi 1, (CRgRg)q C(O)ORi2, (CRgRg)q OC(O) Rn, (CRgRg)q NR4C(O)Rn,
(CRgRg)qC(NR4)NR4R5, (CRgR )q NR4C(NR5)Rι 1, (CRgRg)q NHS(O)2Ra, or (CR8R8)q S(O)2NR4R5; or two Y moieties together may form O-(CH2)s-O or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted;
R8 is hydrogen or Ci-4 alkyl; RlO is C i-io alkyl C(O)2R8;
Rl l is hydrogen, Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCj-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC i _4alkyl ;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; Rl3 and R14 are independently hydrogen, optionally substituted Ci-4 alkyl, or one of Rι and R14 may be optionally substituted aryl; R 17 is C 1-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl; Rl is hydrogen, optionally substituted Ci-io alkyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, hydroxy, arylCι.4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-
Cj_4alkyl, heteroarylC2_4 alkenyl, heterocyclic, or heterocyclicC 1.4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted; Ra is NR4R5, alkyl, arylCι.4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl- Cι_4 alkyl, heteroarylC2_4 alkenyl, heterocyclic, or heterocyclicC 1.4 alkyl; and wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
the E containing ring is optionally selected from
the asterix * denoting point of attachment of the ring; or a pharmaceutically acceptable salt thereof.
Illustrative compounds of Formula (II) include: N-(l,3-dihydro-2,2-dioxidoisothiazolo[4,3-b]pyridin-7-yl)-N-(2- bromophenyl)urea;
N-(l,3-dihydro-2,2-dioxidoisothiazolo[4,3-b]pyridin-7^1)-N-(phenyl)urea, or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention are the novel compounds of Formulas (III) as described below. It is noted that these compounds are position isomers on the pyridine ring of the isothiazolopyridine ring system. For purposes herein, all of the substituent groups for Formula (III) are the same as those defined hereinabove for Formula (I).
Compounds of Formula (III) are useful in a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 a or b receptor and which method comprises administering an effective amount of a compound of Formula (III) 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 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 (III).
The present invention also provides a novel pharmaceutical composition comprising a compound of Formula (III) and a pharmaceutical carrier or diluent.
Compounds structure:
wherein
R is -ΝH -C(X)-ΝH- (CRι3R14)v - Z;
X is oxygen or sulfur; (CR15R16)P
Z is W, HET, (γ)n , an optionally substituted C 10 alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl;
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, (CR R8)q S(O)tR4, hydroxy, hydroxy Cι_4alkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, heteroaryl Cι_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)NR4RlO, S(O)3R8, (CR8R8)q C(O)R 11 , C2- 10 alkenyl C(O)R 11 , C2- 10 alkenyl C(O)OR 11 ,
C(O)Rn, (CR8R8)q C(O)ORι2, (CR8R8)q OC(O) Rn, (CRgRg)q NR4C(O)Rι 1, (CR Rg)qC(NR4)NR4R5, (CRgR )q NR4C(NR5)Rι h (CRgRg)q NHS(O)2Rπ, or (CR8R8)q S(O)2NR4Rs; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted; 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 C\-A alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Cι_4alkyl, heterocyclic, 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, Cμio alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, (CR8Rg)q S(O)tR4, hydroxy, hydroxyC i-4alkyl, aryl, aryl Ci-4 alkyl, aryloxy, arylCj-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl Ci-4 alkyloxy, heterocyclic, heterocyclic Cι_4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgR8)q NR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R5, (CRgRg)q C(O)NR4RlO, S(O)3R8; (CR8R8)q C(O)Rι 1, C2-10 alkenyl C(O)Ri 1, C -10 alkenyl C(O)ORn, (CR8R8)q C(O)ORi2, (CR8R8)q OC(O) Rn, (CR8Rg)q NR4C(O)Rι 1, (CRgRg)qC(NR4)NR4R5, (CR Rg)q NR4C(NR5)Rn, (CR8Rg)q NHS(O)2Ra, or (CR8R8)q S(O)2NR4R5; or two Y moieties together may form O-(CH2)s-O or a 5 to 6 membered saturated or unsaturated ring; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted; R8 is hydrogen or Ci-4 alkyl;
RlO is C 1-10 alkyl C(O)2R8;
Rl 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 -4alkyl ;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; Rl3 and R 14 are independently hydrogen, optionally substituted Cj-4 alkyl, or one of Rι3 and R14 may be optionally substituted aryl; R17 is Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cj-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCι_4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl ; Rjg is hydrogen, optionally substituted Ci-io alkyl, Cj-io alkoxy, halosubstituted Ci- io alkoxy, hydroxy, arylCι.4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-
C i-4 alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC 1.4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted; Ra is NR4R5, alkyl, arylCι.4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl- C^alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC j .4 alkyl; and wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted; the E containing ring is optionally selected from
the asterix * denoting point of attachment of the ring; or a pharmaceutically acceptable salt thereof.
Ilustrative compounds of Formula (III) include:
N-(2-bromophenyl)-N'-(l,3-dihydro-2,2-dioxidoisothiazolo[4,3-c]pyridin-7- yl)urea; N'-(phenyl)-N'-( 1 ,3-dihydro-2,2-dioxidoisothiazolo[4,3-c]pyridin-7-yl)urea;
N'-(2-bromophenyl)-N'-(4-cyano-l,3-dihydro-2,2-dioxidoisothiazolo[4,3-c]pyridin-7- yl)urea; V"-(2-bromophenyl)-Λ'"-(4-bromo-l,3-dihydro-2,2-dioxidoisothiazolo[4,3-e]pyridin-7- yl)urea; Λ -(2-bromophenyl)-ΛT-(4-chloro-l,3-dihydro-2,2-dioxidoisothiazolo[4,3-c]pyridin-7- yl)urea; N-(4-cyano- 1 ,3-dihydro-2,2-dioxidoisothiazolo[4,3-c]pyridin-7-yl) N '-(2,3- dichlorophenyl)urea; Λ^-(4-chloro-l,3-dihydro-2,2-dioxidoisothiazolo[4,3-c]pyridin-7-yl) N-(2,3- dichlorophenyl)urea;
/V-(4-bromo-l,3-dihydro-2,2-dioxidoisothiazolo[4,3-c]pyridin-7-yl) N'-(2,3- dichlorophenyl)urea; or a pharmaceutically acceptable salt thereof.
METHODS OF PREPARATION
The compounds of Formulas (I), (II) and (III) 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 Formulas (I), (II) and (III) having a variety of different R, Ri, and Z 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.
Scheme 1
a) H2S04, Br2 b)fuming H2S04, 30%H2O2 c)NBS d)sodium thioacetate e) AcOH, sodium acetate, Cl2 f) ammonium hydroxide g) potassium carbonate, DMF 100° h) Pd/C, MeOH, H2 i) PHNCO, DMF 80°
If the desired aniline 5-scheme 1 is not commercially available then the corresponding commercially available compound 1 -scheme 1 is then brominated under standard conditions (H2SO4 and Br2). Compound 2-scheme 1 is then oxidized under standard conditions ( Fuming H2SO4/ 30% H2O2). Compound 3-scheme 1 can be treated with standard bromination conditions (NBS), followed by standard sulfamide formation via the thioacetate(sodium thioacetate, DMF), sulfonyl chloride(AcOH/sodium acetate/C^), and then sulfamide formation (ammonium hydroxide or ammonia gas) to give compound 4-scheme 1. The aniline 5-scheme 1 may be prepared by cyclization of compound 4-scheme 1, followed by standard reduction condition (Pd/C and H2 or SnCl2, thiol, or zinc in acetic acid). The ortho substituted phenyl urea in 6-scheme 1 may be prepared by standard conditions involving the condensation of the commercially available substituted aryl isocyanate (Aldrich Chemical Co., Milwaukee,Wi.) with the corresponding aniline 5-scheme 7 in an aprotic solvent such as (DMF or toluene). The bromo substituent on 4-6- scheme-1 can be further eleaborated using palladium catalyzed arylation, Heck reactions or carbonylation. Alternately the bromide can be displaced using nucleophilic conditions such as sodium alkoxides, azide, thiols or cyanide. These functional groups can then be further interconverted using conditions well known in the art.
The other pyridine cyclic sulfonamide derivatives of Formulas (II) and (III) can be synthesized following the procedure elaborated in Schemes 2 and 3 shown below.
Scheme 2
Starting with the 4-amino 2-chloro methyl pyridine 1 -scheme-2 which can be synthesized by the method elaborated in Ife, R. et. al. J. Med. Chem. 32(8), 1989 1970-7. This compound can then be oxidized to form the nitro pyridine n-oxide 2- scheme-2. The methyl can then be brominated under radical bromination conditions such as NBS. The bromide can be converted to the corresponding sulfonamide using the following three step procedure. The bromide can be reacted with sodium thioacetate. This thioacetate can be converted to the sulfonyl chloride using chlorine gas in aqueous acetic acid. If the sulfonyl chloride hydrolyses to the sulfonic acid it can be converted back to the sulfonyl chloride using POCl . The sulfonyl chloride can then be reacted with ammonium hydroxide or ammonia gas to form the sulfonamide 3-scheme-2. The sulfonamide can then be cyclized using potassium carbonate in an aprotic polar solvent such as DMF, DMSO or propionitrile to form the corresponding cyclic sulfonamide. The nitro can then be reduced using standard conditions such as Pd/C and H2 or SnCl2, thiol, or zinc in acetic acid to form the amine 4-scheme-2. The amine can be coupled with the commericially available isocyanate, 5-scheme-2.
Alternatively 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 phosphorazide in the presence of a base (such as triethyl amine). The aromatic rings can be further functionalized by halogenation using a halogen in the presence of an acid or lewis acid or a perhalogenated salt such as pyridinium bromide perbromide to form the brominated aromatic. It is recognized that a mixture of isomers may be produced in this reaction. The isomers can be separated by chromatography. The bromine can then be displaced by a nucleophile such as cupric cyanide or sodium methoxide in a polar aprotic solvent such as DMF or DMSO. Alternatively the bromide can be used for palladium-catalyzed coupling or carbonylation reactions.
Starting with the 4-amino-2-chloro methyl pyridine (which can be synthesized by the method elaborated in Brekiesz-Lewandowska, Barbara; Talik, Zofia. Rocz. Chem. (1967), 41(11), 1887-93), the amine can be converted the chlorine by diazotization with sodium nitrite in aqueous hydrochloric acid followed the addition of copper chloride to form the corresponding aromatic chloride.
Scheme 3
This compound can then be oxidized to form the nitro pyridine n-oxide to form 2-scheme-3. The methyl can then be brominated under radical bromination conditions such as NBS. The bromide can be converted to the corresponding sulfonamide using the following three step procedure. The bromide can be reacted with sodium thioacetate. This thioacetate can be converted to the sulfonyl chloride using chlorine gas in aqueous acetic acid. If the sulfonyl chloride hydrolyses to the sulfonic acid it can be converted back to the sulfonyl chloride using POCl3. The sulfonyl chloride can then be reacted with ammonium hydroxide or ammonia gas to form the sulfonamide 3-scheme-3. The sulfonamide can then be cyclized using potassium carbonate in an aprotic polar solvent such as DMF, DMSO or propionitrile to form the corresponding cyclic sulfonamide 3-scheme-3. The nitro can then be reduced using standard conditions such as Pd/C and H2 or SnCl2, thiol, or zinc in acetic acid to form the amine 4-scheme-3. The amine can be coupled with the commericially available isocyanate. Alternatively 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 phosphorazide in the presence of a base (such as triethyl amine) to form 5-scheme-3.
All of the aromatic rings can be further functionalized by halogenation using a halogen in the presence of an acid or lewis acid or a perhalogenated salt such as pyridinium bromide perbromide to form the brominated aromatic. It is recognized that a mixture of isomers may be produced in this reaction. The isomers can be separated by chromatography. The bromine can then be displaced by a nucleophile such as cupric cyanide or sodium methoxide in a polar aprotic solvent such as DMF or DMSO. Alternatively the bromide can be used for palladium-catalyzed coupling or carbonylation reactions.
Substitution on the methylene can be achieved by following the methodology elaborated in Scheme 4. This procedure is applicable to all three pyridine isomers described herein.
Scheme 4
The nitro pyridine n-oxide l-scheme-4 which was described previously can be alkylated with an allyl group to form 2-scheme-4 in the presence of a base such as potassium carbonate, or sodium hydride to form 2-scheme-4. The methylene of the cyclic sulfonamide can then be alkylated by an alkyl halide in the presence of sodium hydride or lithium heaxamethyldisilazine to form 3-scheme -4. The methylene can also be functionalized by reaction with an isocyanate or thio isocyanate in the presence of a base to form the corresponding amide or thio amide. Alternately the methylene can be halogenated using an electrophilic halogen source such as N-fluoro benzene-sulfonimide or N-bromosuccinimide in the presence of a base such as sodium hydride, triethyl amine or sodium heaxamethyl disilazine. This benzylic halide can be displaced by a variety of nucleophiles such as alcohols, thiols, or amines in the presence of a base such as sodium hydride, triethyl amine or sodium heaxamethyl disilazine. The allyl can be deprotected using a palladium catalyst in the presence of a reducing agent such as sodium borohydride and the nitro can be reduced by standard conditions such as conditions such as Pd/C' and H2 or SnCl2, thiol, or zinc in acetic acid to form the amine 4-scheme-4. The amine can be coupled with the commericially available isocyanate. Alternatively 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 phosphorazide in the presence of a base (such as triethyl amine).
Another aspect of the present invention is the novel process of making a compound of Formula (I) which process comprises condensing an isocyanate derivative of the formula
NCO - (CRι3Ri4)v - Z; wherein Rι3, R 4, v and Z are as defined for Formula (I); with a compound of the formula
wherein R\, and m are as defined for Formula (I) to yield a compound of Formula (I).
Similarly, another aspect of the present invention is the process of making a compound of Formula (II) which process comprises condensing an isocyanate derivative of the formula wherein Rι , R 4, v and Z are as defined for Formula (II); with a compound of the Formula (Ha) :
wherein Ri , and m are as defined for Formula (II) to yield a compound of Formula (II).
Similarly, another aspect of the present invention is the process of making a compound of Formula (III) which process comprises condensing an isocyanate derivative of the formula
NCO - (CR 3Ri4)v - Z; wherein R 3, R14, v and Z are as defined for Formula (III); with a compound of the Formula (Ilia) :
wherein Rj, and m are as defined for Formula (III) to yield a compound of Formula
(III).
Yet another aspect of the present invention are the novel intermediate compounds of Formula (la) represented by the formula:
wherein
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, (CRgRg)q S(O)tR4, hydroxy, hydroxy Cj-4alkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, heteroaryl Ci-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CRgRg)q C(O)NR4R5, (CR8R8)q C(O)NR4RlO, S(O)3R8, (CR8R8)q C(O)Ri 1, C2-10 alkenyl C(O)Ri 1, C2-10 alkenyl C(O)ORn, C(O)Rn, (CR8R8)q C(O)ORi2, (CRgRg)q OC(O) Rn, (CR8R8)q
NR4C(O)Rn, (CR8R8)qC(NR4)NR4R5, (CR8Rg)q NR4C(NR5)Rn, (CR8R8)q NHS(O) Ri7, or (CR8Rg)q S(O)2NR4R5; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted; m is an integer having a value of 1 to 3; q is 0, or an integer having a value of 1 to 10; s is an integer having a value of 1 to 3; t is 0, or an integer having a value of 1 or 2;
R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, heterocyclic Cι_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 hydrogen or Cj-4 alkyl;
RlO is C 1-10 alkyl C(O)2R8; Rl l i hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl; Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; and
Rl7 is Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cj-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCι_4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 -4alkyl.
Yet another aspect of the present invention is the novel intermediate compounds of Formula (II) and (III) which are the pyridine isomers of Formula (I) as described above.
Yet another aspect of the present invention is the novel process of making a compound of Formula (la) which process comprises cyclizing a compound of the formula: under standard conditions and then reducing under standard conditions to yield a compound of Formula (la).
Yet another aspect of the present invention is the novel process of making a compound of Formula (Ila) which process comprises cyclizing a compound of the formula:
under standard conditions and then reducing under standard conditions to yield a compound of Formula (Ila).
Yet another aspect of the present invention is the novel process of making a compound of Formula (Ilia) which process comprises cyclizing a compound of the formula:
under standard conditions and then reducing under standard conditions to yield a compound of Formula (Ilia).
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 temperatures are given in degrees centigrade, all solvents are highest available purity and all reactions run under anhydrous conditions in an argon atmosphere unless otherwise indicated.
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. ^H-NMR (hereinafter "NMR") spectra were recorded at 250 MHz using a Bruker AM 250 or Am 400 spectrometer. Multiplicities indicated are: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet and br indicates a broad signal. Sat. indicates a saturated solution, eq indicates the proportion of a molar equivalent of reagent relative to the principal reactant.
General Method: Synthesis of N, N'- phenyl urea To a solution of phenyl isocyanate(1.0 equiv.) in dimethyl formamide (1ml) the corresponding aniline (1.0 equiv.) was added. The reaction mixture was stirred at 80°C until complete (3-16 hrs.), then removed solvent under vacuum. The purification, yields and spectral characteristics for each individual compound are listed below.
Example 1
Preparation of N-r5-bromo 1,3-dihydro 2,2 dioxidoisothiazolor3,4-clpyridin-7-yl)- N'-phenylureal-N'-r2-bromophenyn urea a) Preparation of 2-amino-3,5-dibromo-4-methylpyridine
To a solution of 2-amino-4-methylpyridine(30.0g, 0.277 mol) in 72% sulfuric acid( 130ml) was stirred with addition of bromine(21.5ml, 0.416mol) at 0°
C. The mixture was then allowed to warm to 25° C for 18 hrs. The reaction was then poured into ice and the ph was adjusted to 10 with 50% NaOH. The desired product precipitated out of solution and the mixture was filtered. The filtrate was extracted with methylene chloride and the organic layer was dried with MgSO4. The combined solids were purified by flash chromatography( 2% MeOH/ CH2CI2) to give the desired product(42.7g, 58%). Η NMR (CDC13): δ 8.08 (s, 1H), 4.95 (bs,
2H), 2.51 (s, 3H). b) Preparation of 2-nitro-3,5-dibromo-4-methylpyridine
2-amino-3,5-dibromo-4-methylpyridine (8g, 30.0mmol) was cooled to 10° C, followed by the addition of concentrated sulfuric acid(lθml). The mixture was stirred, maintaining the temperature at 10° C for 2hrs, with the addition of a mixture of 30% hydrogen peroxide in 30% fuming sulfuric acid(25ml/50ml). The mixture was allowed to warm to room temperature and stirred for an additional 48 hrs. The reaction was then added to 300ml of water with cooling and made very slightly basic with dropwise addition of 505 NaOH solution while the temperature was maintained at 20-25o C. The product was extracted using ether(4x 150ml) and dried with
MgSO4. The solution was concentrated and purified by flash chromatography( 2%
MeOH/CH2Cl2) to give the desired product(2.94g, 33%). Η NMR (CDCI3): δ 8.45 (s, 1H), 2.68 (s, 3H).
c) Preparation of 2-nitro-3,5-dibromo-4-bromomethylpyridine
To a solution of 2-nitro-3,5-dibromo-4-methylpyridine(10.7g, 36.15mmol) in benzene(20ml) was added benzoyl peroxide(1.0g, 5.42mmol) and N- bromosuccinamide(7.75g, 42.18mmol). The mixture was stirred at 110° C and irradiated with a 150-W floodlight for 48 hrs. The solvent was evaporated and chromatography of the resulting solid on silica gel (10%EtOAc/ Hexane) gave the desired product(4.5g, 33%). Η NMR (CDCI3): δ 8.56 (s, 1H), 4.76 (s, 2H).
d) Preparation of 2-nitro-3,5-dibromo-4-methylenethioacetate pyridine
To a solution of 2-nitro-3,5-dibromo-4-bromomethylpyridine (0.45g, 1.20mmol) in DMF( 10ml) was added potassium thioacetate(0.14g, 1.44mmol). The mixture was stirred at 25° C for 48 hrs. The solvent was evaporated and chromatography of the resulting solid on silica gel (10%EtOAc/ Hexane) gave the desired product(370mg, 84%). Η NMR (CDC13): δ 8.52 (s, 1H), 4.60 (s, 2H), 2.42 (s, 3H).
e) Preparation of 2-nitro-3,5-dibromo-4-methylenesulfonylchloride pyridine
To a solution of 2-nitro-3,5-dibromo-4-methylenethioacetate pyridine
(160mg, 0.432mmol) in acetic acid/water(5/l, 5ml) was added sodium acetate(250mg, 3.02mmol). The mixture was stirred at 25° C with the addition of chlorine gas for 30 mins. The mixture was diluted with ethyl acetate washed with ice water and dried with Na2SO4 The solvent was evaporated to give the desired product(90mg, 53%). Η NMR (CDC13): δ 8.69 (s, 1H), 5.58 (s, 2H).
f) Preparation of 2-nitro-3,5-dibromo-4-methylenesulfonamide pyridine
To 2-nitro-3,5-dibromo-4-methylenesulfonylchloride pyridine(90mg, 0.228mmol) was added concentrated ammonium hydroxide(5ml). The mixture was stirred at 25° C for 24 hrs. The mixture was diluted with 10% HC1 and filtered to give the desired product(15mg, 17%). Η NMR (CDCI3): δ 8.52 (s, 1H), 5.03 (s, 2H), 4.90 (bs, 2H).
g) Preparation of 5-bromo 7-nitro-l,3-dihydro-2,2-dioxidoisothiazolo[3,4-c]pyridine To a solution of 2-nitro-3,5-dibromo-4-methylenesulfonylamide pyridine(15mg, 0.040mmol) in DMF(5ml)was added potassium carbonate(0.7mg,
0.040mmol). The mixture was stirred at 25° C for 24 hrs. The mixture was diluted with ethyl acetate, washed with water and dried with Na2SO4. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2C12) gave the desired product(10mg, 91%). 'H NMR (CD3SO2CD3): δ 7.46(s, 1H), 4.02 (s, 2H).
h) Preparation of 7-amino-5-bromo l,3-dihydro-2,2-dioxidoisothiazolo[3,4-c]pyridine
To a solution of 2-nitro-5-bromo-4-cyclicsulfonamide pyridine (lOmg, 0.034mmol) in methanol(20ml) was added 10% Pd/C (0.10g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure for 4 hrs. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5%MeOH/ CH2C12) gave the desired product(6.0mg, 96 %). Η NMR (CD3SO2CD3): δ 7.60
(d, 1H), 6.69 (d, 1H), 4.55 (s, 2H). i) N-[5-bromo 1,3-dihydro 2,2 dioxidoisothiazolo[3,4-c]pyridin-7-yl)-N'-[2- bromophenyl] urea
N-[pyrsulfonamide]-N'-[2-bromophenyl] urea is prepared from 2-amino-5- bromo-4-cyclicsulfonamide pyridine (wt, mol) according to the procedure in General
Method B. The product is purified by chromatography of the resulting solid on silica gel (EtOAc/ hexane(2equiv./3equiv.)). (yield) Η NMR (CD3SO2CD3): δ( proton nmr).
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 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 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 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, in particular IL-8, GROα, GROβ, GROγ, 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, GROα, GROβ, GROγ, 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, GROα, GROβ GROγ, NAP-2 or ENA-78 above normal physiological levels; or (iii) the presence of IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 above basal levels in cells or tissues in which IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 respectively, is produced.
There are many disease states in which excessive or unregulated IL-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, glomerulonephritis, thrombosis, graft vs. host reaction, Alzheimer's disease, allograft rejections, malaria, restinosis, angiogenesis or undesired hematopoietic stem cells release, rhinovirus infections, and various bone resorption indications.
These diseases are primarily characterized by massive neutrophil infiltration, T-cell infiltration, or neovascular growth, and are associated with increased IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 production which is responsible for the chemotaxis of neutrophils into the inflammatory site or the directional growth of endothelial cells. In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 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, NAP-2 or ENA-78, working through the IL- 8 type I or II receptor can promote the neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, the inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.
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).
Present evidence also indicates the use of IL-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. Additinal supporting references are: Apostolopoulos, et al., Arterioscler Thromb Vase Biol. 1996, 16: 1007-1012; Liu, et al., Arterioscler 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, 109-113.; and Terkeltaub et al., Arterioscler Thromb, 1994, 14:47-53. 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-α 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.
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) whose disclosure is incorporated 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 IL-8, binding to the IL-8 alpha or beta receptors, from binding to these receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation. The discovery that the compounds of Formula (I) are inhibitors of IL-8 binding is based upon the effects of the compounds of Formulas (I) in the in vitro receptor binding assays which are described herein. The compounds of Formula (I) have been shown to be inhibitors of type II IL-8 receptors.
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 IL-8, GROα, GROβ, GROγ, NAP-2 or ENA-78 themselves, or by IL-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 IL-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 IL-8 α or β receptor plays a role, such as but not limited to IL-8, GRO-α, GRO-β, GROγ, NAP- 2 or ENA-78. This would include a disease state in which, IL-8 plays a role, either by production of IL-8 itself, or by IL-8 causing another monokine to be released, such as but not limited to IL-1, IL-6 or TNF. A disease state in which, for instance, IL-1 is a major component, and whose production or action, is exacerbated or secreted in response to IL-8, would therefore be considered a disease stated mediated by IL-8.
As used herein, the term "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. 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, endothelial cells, brain astrocytes, bone marrow stromal cells, epideral keratinocytes and B -lymphocytes. Lymphokines are generally referred to as being produced by lymphocyte cells. Examples of cytokines include, but are not limited to, Interleukin-1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-alpha (TNF-α) and Tumor Necrosis Factor beta (TNF-β).
As used herein, the term "chemokine" 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. Examples of chemokines include, but are not limited to, IL-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 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. 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 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. Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic 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 carrier is used, the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form or in the form of a troche or lozenge. The amount of solid carrier will vary widely but preferably will be from about 25mg. to about lg. When a liquid carrier 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 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. 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 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.
For all methods of use disclosed herein for the compounds of Formula (I), and (II) 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. 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 IL-8, and Gro-α chemokine inhibitory effects of compounds of the present invention are determined by the following in vitro assay: Receptor Binding Assays:
[125τ] iL_g (human recombiήant) is obtained from Amersham Corp., Arlington Heights, IL, with specific activity 2000 Ci/mmol. Gro-α is obtained from NEN- New England Nuclear. All other chemicals are 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 homogenization buffer is changed to lOmM Tris-HCL, ImM MgS04, 0.5mM EDTA (ethylene-diaminetetra- acetic acid), lmMPMSF (α-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 25 jL_g (0.25 nM) or 125τ Gro-α and 0.5 μg/mL of IL-8Rα or 1.0 μg/mL of IL-8Rβ membranes in 20 mM Bis- Trispropane and 0.4 mM Tris HC1 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 is added which has been pre-dissolved in DMSO so as to reach a final concentration of between 0.0 InM and 100 uM. The assay is initiated by addition of 25ι_iL- _ 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,
0.5 mM EDTA, 0.03 % CHAPS, pH 7.4. The filter is then dried and counted on the Betaplate liquid scintillation counter. The recombinant IL-8 Rα, or Type I, receptor is also referred to herein as the non-permissive receptor and the recombinant IL-8 Rβ, or Type II, receptor is referred 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 IL-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, 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 IL-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
The present 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. Adult Sprague-Dawley rats (n=42) were anesthetized with sodium pentobarbital (60 mg kg, i.p.) and subjected to lateral fluid- percussion brain injury of moderate severity (2.4 atm.) centered over the left temporaparietal cortex (n=18), or "sham" treatment (anesthesia and surgery without injury, n=18). Animals are sacrificed by decapitation at 1, 6 and 24 hr. post injury, brains removed, and tissue samples of left (injured) parietal cortex (LC), corresponding area in the contralateral right cortex (RC), cortex adjacent to injured parietal cortex (LA), corresponding adjacent area in the right cortex (RA), left hippocampus (LH) and right hippocampus (RH) are prepared. Total RNA was isolated and Northern blot hybridization is performed and quantitated relative to an TNF-α positive control RNA (macrophage = 100%). A marked increase of TNF- α mRNA expression is observed in LH (104±17% of positive control, p < 0.05 compared with sham), LC (105±21%, p< 0.05) and LA (69±8%, p < 0.01) in the traumatized hemisphere 1 hr. following injury. An increased TNF- α mRNA expression is also observed in LH (46±8%, p < 0.05), LC (30±3%, p < 0.01) and LA (32±3%, p < 0.01) at 6 hr. which resolves by 24 hr. following injury. In the contralateral hemisphere, expression of TNF- α mRNA is increased in RH (46±2%, p < 0.01), RC (4±3%) and RA (22±8%) at 1 hr. and in RH (28±11%), RC (7±5%) and RA (26±6%, p < 0.05) at 6 hr. but not at 24 hr. following injury. In sham (surgery without injury) or naive animals, no consistent changes in expression of TNF- α mRNA are observed in any of the 6 brain areas in either hemisphere at any times. These results indicate that following parasagittal fluid-percussion brain injury, the temporal expression of TNF-α mRNA is altered in specific brain regions, including those of the non- traumatized hemisphere. Since TNF- α 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-α plays an important role in both the acute and regenerative response to CNS trauma.
CNS Injury model for IL-β mRNA
This assay characterizes the regional expression of interleukin-lβ (IL-1B) mRNA in specific brain regions following experimental lateral fluid-percussion traumatic brain injury (TBI) in rats. Adult Sprague-Dawley rats (n=42) are anesthetized with sodium pentobarbital (60 mg/kg, i.p.) and subjected to lateral fluid-percussion brain injury of moderate severity (2.4 atm.) centered over the left temporaparietal cortex (n=18), or "sham" treatment (anesthesia and surgery without injury). Animals are sacrificed at 1, 6 and 24 hr. post injury, brains removed, and tissue samples of left (injured) parietal cortex (LC), corresponding area in the contralateral right cortex (RC), cortex adjacent to injured parietal cortex (LA), corresponding adjacent area in the right cortex (RA), left hippocampus (LH) and right hippocampus (RH) are prepared. Total RNA is isolated and Northern blot hybridization was performed and the quantity of brain tissue IL-lβ mRNA is presented as percent relative radioactivity of IL-lβ positive macrophage RNA which was loaded on same gel. At 1 hr. following brain injury, a marked and significant increase in expression of IL-lβ mRNA is observed in LC (20.0±0.7% of positive control, n=6, p < 0.05 compared with sham animal), LH (24.5±0.9%, p < 0.05) and LA (21.5±3.1%, p < 0.05) in the injured hemisphere, which remained elevated up to 6 hr. post injury in the LC (4.0±0.4%, n=6, p < 0.05) and LH (5.0±1.3%, p < 0.05). In sham or naive animals, no expression of IL-lβ mRNA is observed in any of the respective brain areas. These results 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.
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 any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is Claimed Is:
1. A compound of the formula:
wherein
R is -NH -C(X)-NH- (CRι3Ri4)v - Z;
X is oxygen or sulfur;
Z is W, HET, (γ)n , an optionally substituted Cj. ιo alkyl, an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl; Rj 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, (CRgRg)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 Cj-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-IO alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR8R8)q C(O)NR4R5, (CR8R8)q C(O)NR4Rιo, S(O)3R8, (CR8Rg)q C(O)Rn, C2-10 alkenyl C(O)Rn , C2-10 alkenyl C(O)ORn, C(O)Ri 1, (CRgRg)q C(O)ORι2, (CRgRg)q OC(O) Rn, (CRgRg)q
NR4C(O)Rn, (CRgRg)qC(NR4)NR4R5, (CR8R8)q NR4C(NR5)Rn, (CR8R8)q NHS(O)2Ri7, or (CR8R8)q S(O)2NR4R5; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted; 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 Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, 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, -io alkyl, C2-10 alkenyl, -io alkoxy, halosubstituted Ci-io alkoxy, (CR8R8)q S(O)tR4, hydroxy, hydroxyCι_4alkyl, aryl, aryl Ci-4 alkyl, aryloxy, arylCi-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl Ci-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CR8R8)q NR4R5, C2-10 alkenyl C(O)NR4R5, (CR8Rg)q C(O)NR4R5, (CRgRg)q C(O)NR4RlO, S(O)3Rg;
(CRgRg)q C(O)Rn , C2-10 alkenyl C(O)Rn , C2-10 alkenyl C(O)ORn, (CR R )q C(O)ORi2, (CR8R8)q OC(O) Rn , (CR8R8)q NR4C(O)Rn, (CR8R8)qC(NR4)NR4R5, (CR8Rg)q NR4C(NR5)Rn , (CRgR )q NHS(O)2Ra, or (CRgRg)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 all be optionally substituted; R8 is hydrogen or Ci-4 alkyl;
RlO is Ci-10 alkyl C(O)2R8; Ri 1 is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Cι_4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylCi-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 -4alkyl;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl;
Rl3 and R14 are independently hydrogen, optionally substituted Cι_4 alkyl, or one of Rι3 and R14 may be optionally substituted aryl; Rl7 is 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 1 -4alkyl; R 8 is hydrogen, optionally substituted Ci-io alkyl, Ci-10 alkoxy, halosubstituted Ci-io alkoxy, hydroxy, arylCι_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; Ra is NR4R5, alkyl, arylCι.4 alkyl, arylC 2-4 alkenyl, heteroaryl, heteroaryl-
Cι_4alkyl, heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC .4 alkyl; and wherein the aryl, heteroaryl and heterocyclic containing moieties may all be optionally substituted;
the E containing ring is optionally selected from
the asterix * denoting point of attachment of the ring; or a pharmaceutically acceptable salt thereof.
2. The compound according to Claim 1 wherein Rj 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)NR .R5.
3. The compound according to Claim 1 wherein Z is W.
4. The compound according to Claim 3 wherein W is phenyl substituted by (Y)n.
5. The compound according to Claim 4 wherein Y is halogen, Cj-4 alkoxy, optionally substituted aryl, optionally substituted arylalkoxy, methylene dioxy, NR4R5, thioCι_4alkyl, thioaryl, halosubstituted alkoxy, optionally substituted Ci-4alkyl, or hydroxy alkyl.
6. The compound according to Claim 1 wherein X is oxygen.
7. A pharmaceutical composition comprising a compound according to any of Claims 1 to 6, and a pharmaceutically acceptable carrier or diluent.
8. A method of treating a chemokine mediated disease in a mammal in need thereof, wherein the chemokine binds to an IL-8 α or β receptor, which method comprises administering to said mammal an effective amount of a compound according to Claims 1.
9. The method according to Claim 8 wherein the mammal is afflicted with a chemokine mediated disease selected from psoriasis, 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, Alzheimer's disease, graft vs. host reaction, or allograft rejections.
10. A process of making a compound according to Claim 1 which process comprises condensing an isocyanate derivative of the formula
NCO - W wherein W is as defined for Formula (I) above, with a compound of the formula
wherein R\, and m are as defined above for Formula (I) to yield a compound of
Formula (I).
11. A compound of the formula
Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted
Ci-io alkyl, -io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, (CR R8)q S(O)tR4, hydroxy, hydroxy Cι_4alkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, heteroaryl Ci-4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CRgRg)q C(O)NR4R5, (CRgRg)q C(O)NR4RlO, S(O)3R8, (CR8R8)q C(O)Rι 1, C2-10 alkenyl C(O)Rn, C2-10 alkenyl C(O)ORn, C(O)Rn, (CR8R8)q C(O)ORi2, (CR8R8)q OC(O) Rn, (CR8R8)q
NR4C(O)Rn, (CR8R8)qC(NR4)NR4R5, (CR8R8)q NR4C(NR5)Rn, (CR8R8)q NHS(O)2Rπ, or (CR8Rg)q S(O)2NR4R5; and wherein the aryl, heteroaryl, and heterocyclic containing moieties may all be optionally substituted; m is an integer having a value of 1 to 3; q is 0, or an integer having a value of 1 to 10; s is an integer having a value of 1 to 3; t is 0, or an integer having a value of 1 or 2;
R4 and R5 are independently hydrogen, optionally substituted Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Cι_4alkyl, heterocyclic, 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; Rg is hydrogen or Ci-4 alkyl;
RlO is C 1-10 alkyl C(O)2R8;
Rl l 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 1 -4alkyl;
Rl2 is hydrogen, Ci-io alkyl, optionally substituted aryl or optionally substituted arylalkyl; and Rl7 is Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroarylC ι_4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC i _4alkyl.
12. A process of making a compound according to Claim 11 which process comprises cyclizing a compound of the formula:
under standard conditions and then reducing to yield a compound of Formula (la).
EP99956537A 1998-10-13 1999-10-12 Il-8 receptor antagonists Withdrawn EP1121360A4 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022457A1 (en) * 1996-11-19 1998-05-28 Amgen Inc. Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
WO1998032438A1 (en) * 1997-01-23 1998-07-30 Smithkline Beecham Corporation Il-8 receptor antagonists
WO1998034929A1 (en) * 1997-02-12 1998-08-13 Smithkline Beecham Corporation Il-8 receptor antagonists

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Publication number Priority date Publication date Assignee Title
EP0429341A3 (en) * 1989-11-20 1991-11-13 Rhone-Poulenc Sante Heterocyclic derivatives, their preparation and pharmaceuticals containing them

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998022457A1 (en) * 1996-11-19 1998-05-28 Amgen Inc. Aryl and heteroaryl substituted fused pyrrole antiinflammatory agents
WO1998032438A1 (en) * 1997-01-23 1998-07-30 Smithkline Beecham Corporation Il-8 receptor antagonists
WO1998034929A1 (en) * 1997-02-12 1998-08-13 Smithkline Beecham Corporation Il-8 receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO0021963A1 *

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