Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
  • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
  • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/428—Thiazoles condensed with carbocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
• • 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
• • 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
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • 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
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
  • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Definitions

• This invention relates to novel benzoisothiazole substituted compounds, pharmaceutical compositions, processes for their preparation, and use thereof in treating LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 mediated diseases.
• Interleukin-8 Interleukin-8
• NAP-1 neutrophil attractant/activation protein- 1
• MDNCF monocyte derived neutrophil chemotactic factor
• NAP 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, endotheliai and epithelial cells exposed to TNF, IL-l ⁇ , IL-l ⁇ or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP. M.
• GRO ⁇ , GRO ⁇ , GRO ⁇ and NAP-2 also belong to the chemokine ⁇ family. Like IL-8, these chemokines have also been referred to by different names. For instance GRO ⁇ , ⁇ , ⁇ have been referred to as MGSA ⁇ , ⁇ and ⁇ respectively
• 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.
• LL-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. 146.
• ELR chemokines (those containing the amino acids ELR motif just prior to the CXC motif) have also been implicated in angiostasis, see Strieter et al., Science 258, 1798 ( 1992).
• 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. Thomas et al., J. Biol. Chem. 266. 14839 (1991); and Holmes et al., Science 253. 1278 (1991).
• the development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research. Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993.
• the LL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
• IL-8R ⁇ which binds only IL-8 with high affinity
• LL-8R ⁇ which has high affinity for IL-8 as well as for GRO- ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
• IL-8R ⁇ which binds only IL-8 with high affinity
• LL-8R ⁇ which has high affinity for IL-8 as well as for GRO- ⁇ , GRO ⁇ , GRO ⁇ and NAP-2.
• This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and
• chemokine is IL-8.
• This invention also relates to a method of inhibiting the binding of IL-8 to its receptors in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of Formula (I) or (II).
• the present invention also provides for the novel compounds of Formula (I), and (II) and pharmaceutical compositions comprising a compound of Formula (I), and (II) and a pharmaceutical carrier or diluent.
• R is -NH -C(X 2 )-NH- (CR 13 R 14 ) V Z;
• Z is W, HET, TM n . optionally substituted Ci . JQ alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-10 alkynyl;
• X[ is independently hydrogen, halogen, Ci-io alkyl, NR4R5, C(O)NR4R5, optionally substituted Ci-io alkyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, hydroxy, aryl, aryl -4 alkyl, aryloxy, aryl Cj-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic Ci-4alkyl, or heteroaryl Ci-4 alkyloxy; provided that both of Xi are not hydrogen;
• A is CH 2 , C(O) or C(S);
• R 1 is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, azide, (CRgRg)q S(O) t R4, hydroxy, hydroxyCi-ioalkyl, aryl, arylCi-4 alkyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroarylalkyl, heterocyclic, heterocyclic C ⁇ _4alkyl, heteroaryl C ⁇ _4 alkyloxy, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)qNR4R5, C2-10 alkenyl C(O)NR4R5, (CR 8 R 8 )q C(O)NR4R 5 , (CR 8
• HET is an optionally substituted heteroaryl
• R4 and R5 are independently hydrogen, optionally substituted C1 -4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substimted heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic C1-4 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, Cj-io alkoxy, halosubstituted Ci-io alkoxy, azide, (CR 8 R 8 )q S(O) t R4, hydroxy, hydroxyCi-ioalkyl, aryl, aryl C1.4 alkyl, aryloxy, arylCi-4 alkyloxy, heteroaryl, heteroarylalkyl, heteroaryl C1-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl
• RlO is Ci-10 alkyl C(O) 2 R8;
• Rl l is hydrogen, Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl
• Ci-4alkyl optionally substituted heteroaryl, optionally substituted heteroarylC ⁇ _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 Cj-4 alkyl, or one of R13 and R14 may be an optionally substituted aryl;
• R15 and R 16 are independently hydrogen, or an optionally substituted Ci-4 alkyl;
• Rl7 is Cj-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclic, or heterocyclicC ⁇ _4alkyl ?
• Rl8 is hydrogen, Ci-4 alkyl, aryl, arylC .4 alkyl, heteroaryl, heteroarylC 1.4 alkyl, heterocyclic, or heterocyclicC 1.4 alkyl, all of which may be optionally substituted;
• R a is NR6R7, alkyl, arylC ⁇ .4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl- C ⁇ _4 alkyl. heteroarylC2-4 alkenyl, heterocyclic, or heterocyclicC 1.4 alkyl, wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted;
• the E containing ring is optionally selected from
• R is -NH -C(X 2 )-NH- (CR ⁇ 3 Ri4) v - Z;
• Z is W, HET, ( ⁇ )n , optionally substituted C i-io alkyl, optionally substituted C2-10 alkenyl, or optionally substituted C2-10 alkynyl;
• X is C(X ⁇ ) or N;
• Xl is hydrogen, halogen, Ci-io alkyl, NR4R5, C(O)NR4R5, optionally substituted Ci-io alkyl, Ci-io alkoxy, halosubstituted Ci-io alkoxy, hydroxy, aryl, aryl Ci-4 alkyl, aryloxy, aryl C1-4 alkyloxy, heteroaryl, heteroaryl -4 alkyl, heterocyclic, heterocyclic Cj-4alkyl, or heteroaryl C ⁇ -4 alkyloxy;
• A is CR ⁇ 8 ;
• Rl is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted C -io alkyl, Ci-io alkyl, C2-10 alkenyl, -io alkoxy, halosubstituted Ci-io alkoxy, azide, (CRgRg)q S(O) t R4, hydroxy, hydroxy Ci-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, aryl C i-4 alkyloxy, heteroaryl, heteroaryl Ci-4 alkyl, heterocyclic, heterocyclic C i-4alkyl, heteroaryl Ci-4 alkyloxy, aryl C2- 10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)qNR4R5, C2-IO alkenyl C(O)NR4R5, (CR 8 R 8 )q C(O)NR4R5, (CR 8 R
• NR4C(O)Rn (CR 8 R 8 )qC(NR 4 )NR 4 R 5 , (CR 8 Rg)q NR 4 C(NR 5 )Rn, (CRgR 8 )q NHS(O) 2 Ri7, or (CR 8 Rg)q S(O) 2 NR4R 5 , or two Rl moieties together may form O-(CH2)sO or a 5 to 6 membered saturated or unsaturated ring;
• m is an integer having a value of 1 to 3;
• n is an integer having a value of 1 to 3;
• p is an integer having a value of 1 to 3;
• q is 0, or an integer having a value of 1 to 10;
• s is an integer having a value of 1 to 3;
• t is 0, or an integer having a value of 1 or 2;
• v is 0, or an integer having a value of 1 to 4;
• HET is an optionally substituted heteroaryl
• R4 and R5 are independently hydrogen, optionally substituted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic C1-4 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 C ⁇ _ ⁇ o alkoxy, azide, (CR 8 R 8 )q S(O)tR4, hydroxy, hydroxyCi-ioalkyl, aryl, aryl C1-4 alkyl, aryloxy, arylCj-4 alkyloxy, heteroaryl, heteroaryl Ci-4 alkyl, heteroaryl Ci-4 alkyl, heteroaryl Ci-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)q NR4R5, C2-10 alkenyl C(O)NR4R5, (CR 8 Rg)q C(O)NR
• R 8 is independently hydrogen or Ci-4 alkyl; Rio is Ci-10 alkyl C(O)2R8;
• Rl 1 is hydrogen, Cj-4 alkyl, optionally substituted aryl, optionally substituted aryl
• Ci-4alkyl optionally substituted heteroaryl, optionally substituted heteroarylC i-4alkyl, optionally substituted heterocyclic, or optionally substituted heterocyclicC 1 _4alkyl
• R 12 is hydrogen, C i- 10 alkyl, optionally substituted aryl or optionally substituted arylalkyl
• Rl3 and R14 are independently hydrogen, optionally substituted C [-4 alkyl, or one of R13 and R14 may be an optionally substituted aryl
• Rl5 and Rig are independently hydrogen, or an optionally substituted Ci-4 alkyl
• Rj7 is Ci-4alkyl, aryl, arylalkyl.
• R[ 8 is hydrogen, Ci-4 alkyl, aryl. arylC ⁇ .4 alkyl, heteroaryl, heteroarylC 1.4 alkyl, heterocyclic, or heterocyclicC 1.4 alkyl, all of which may be optionally substituted;
• R a is NR6R7.
• alkyl arylC ⁇ .4 alkyl, arylC2-4 alkenyl, heteroaryl, heteroaryl- C ⁇ _4 alkyl, heteroarylC2-4 alkenyl, heterocyclic,or heterocyclicC 1.4 alkyl, wherein the aryl, heteroaryl and heterocyclic rings may all be optionally substituted;
• the E containing ring is optionally selected from
• the compounds of Formula (I) and (II) may also be used in association with the veterinary treatment of mammals, other than humans, in need of inhibition of
• Chemokine mediated diseases for treatment, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
• the difference between compounds of Formula (I) and (II) lies in the unsaturation of the A containing ring, and hence the substitutions on the X and A moieties.
• the remaining terms, defined below, are the same for both compounds of Formula (I) and (II) unless otherwise indicated.
• R l is independently selected from hydrogen; halogen; nitro; cyano; halosubstituted C i- io alkyl, such as CF3; C i- io alkyl, such as methyl, ethyl, isopropyl, or n-propyl; C2-10 alkenyl; Ci-io alkoxy, such as methoxy, or ethoxy; halosubstituted Ci-io alkoxy, such as trifluoro methoxy; azide; (CRgRg)q S(O) t R4, wherein t is 0, 1 or 2; hydroxy; hydroxy C i-ioalkyl, such as methanol or ethanol; aryl, such as phenyl or naphthyl; aryl C i-4 alkyl, such as benzyl; aryloxy, such as phenoxy; aryl C i-4 alkyloxy, such as benzyl
• Ri may form O-(CH2)s-O or a 5 to 6 membered saturated or unsaturated ring. All of the aryl, heteroaryl, and heterocyclic containing moieties above may be optionally substituted as defined herein below.
• Ri is other than azido for methods of use herein.
• Rj moiety may be substituted on the benzene ring or the A containing ring, if possible.
• s is an integer having a value of 1 to 3
• m is an integer having a value of 1 to 3.
• Ri forms a dioxybridge s is preferably 1.
• Ri forms an additional saturated or unsaturated ring it is preferably 6 membered ring, preferably resulting in a naphthylene ring system. These additional rings may be substituted independently, 1 to 3 times, by the other Ri moieties as defined above.
• Ri is hydrogen, halogen, cyano, nitro, CF3, (CR 8 R 8 )q C(O)NR4R5, C2-10 alkenyl C(O)NR4R5, (CR 8 R 8 )q C(O)R4R ⁇ o, C2-10 alkenyl
• R4 and R5 are independently hydrogen, optionally substimted Ci-4 alkyl, optionally substituted aryl, optionally substituted aryl Ci-4alkyl, optionally substituted heteroaryl, optionally substituted heteroaryl C ⁇ _4alkyl, heterocyclic, or heterocyclicC 1-4 alkyl, or R4 and R5 together with the nitrogen to which they are attached form a 5 to 7 member ring which may optionally comprise an additional heteroatom selected from O/N/S.
• R6 and R7 are independently hydrogen or a Ci-4 alkyl group, or R and R7 together with the nitrogen to which they are attached form a 5 to 7 member ring which ring may optionally contain an additional heteroatom which heteroatom is selected from oxygen, nitrogen or sulfur.
• Rg is independently hydrogen or C1-4 alkyl.
• RJO is Ci -io alkyl C(O)2R8, such as CH2C(O)2H or CH2C(O)2CH3.
• Ri l is hydrogen, Ci-4 alkyl, aryl, aryl -4 alkyl, heteroaryl, heteroaryl Ci-4alkyl, heterocyclic, or heterocyclic Ci-4alkyl.
• R12 is hydrogen, C J. IQ alkyl, optionally substituted aryl or optionally substituted aryl C ⁇ _4 alkyl.
• R13 and R14 are independently hydrogen, an optionally substituted
• Ci-4 alkyl which may be straight or branched as defined herein, or one of R13 and R 14 are an optionally substituted aryl; v is 0, or an integer having a value of 1 to 4.
• Rj3 or R14 are an optionally substituted alkyl, the alkyl moiety may be substituted one to three times independently by halogen; halosubstituted C1-4 alkyl such as trifluoromethyl; hydroxy; hydroxy Ci-4alkyl, Cj-4 alkoxy; such as methoxy, or ethoxy, halosubstituted C[.10 alkoxy, S(O)tR4; aryl; NR4R5; NHC(O)R4; C(O)NR4R5; or C(O)ORg.
• R17 is Ci-4alkyl, aryl, arylalkyl, heteroaryl, heteroarylC i-4alkyl, heterocyclic, or heterocyclicC i-4alkyl, wherein the aryl, heteroaryl and heterocyclic containing rings may all be optionally substituted.
• Y is independently selected from hydrogen, halogen, nitro, cyano, halosubstituted Ci-io alkyl, Ci-io alkyl, C2-10 alkenyl, Ci-io alkoxy, halosubstituted C l-io alkoxy, azide, (CRgRg)q S(O)tR4, hydroxy, hydroxyCi-ioalkyl, aryl, aryl Ci-4 alkyl, aryloxy, arylCi-4 alkyloxy, heteroaryl, heteroaryl C1-4 alkyl, heteroaryl Ci-4 alkyloxy, heterocyclic, heterocyclic Ci-4alkyl, aryl C2-10 alkenyl, heteroaryl C2-10 alkenyl, heterocyclic C2-10 alkenyl, (CRgRg)q NR4R5, C2-IO alkenyl C(O)NR4R5, (CR 8 R 8 )q C(O)NR4R5.
• (CR 8 Rg)q C(O)NR4Rl0, S(O) 3 Rg, (CRgRg)q C(O)R ⁇ 1 , C 2 -10 alkenyl C(O)R ⁇ 1, C 2 -10 alkenyl C(O)OR ⁇ 1, (CRgRg)q C(O)OR ⁇ 2 , (CR 8 R 8 )q OC(O) Rl l, (CRgRg)q NR4C(O)R ⁇ 1, (CRgRg)qC(NR4)NR 4 R5, (CRgRg)q NR 4 C(NR 5 )R ⁇ l t (CR 8 Rg)q NHS(O)2R a , or (CRgRg)q S(O)2 R4R5, or two Y moieties together may form O-(CH2)s -O or a 5 to 6 membered saturated or unsaturated ring.
• Y is other than azido for methods of use herein.
• n is an integer having a value of 1 to 3.
• s is preferably 1.
• the aryl, heteroaryl and heterocyclic containing moieties noted above for Y may all be optionally substituted as defined herein.
• Y forms an additional saturated or unsaturated ring, it is preferably 6 membered ring, more preferably resulting in a naphthylene ring system. These additional rings may be optionally substituted 1 to 3 times by other Y moieties as defined above.
• R a is NRgR7, alkyl, aryl C1.4 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 rings may all be optionally substituted.
• Y is preferably a halogen.
• Y is more preferably mono-substituted halogen, disubstituted halogen, mono-substituted alkoxy, disubstituted alkoxy, methylenedioxy, aryl, or alkyl. More preferably these groups are mono or di-substituted in the 2'- position or 2'-, 3'-position when Z is W and W is a phenyl ring (such as when no E group is present).
• Y may be substituted in any of the 5 ring positions when W is a phenyl moiety, Y is preferably mono-substituted in the 2'-position or 3'- position, with the 4'- preferably being unsubstituted. If the phenyl ring is disubstituted, the substituents are preferably in the 2' or 3' position of a monocyclic ring. While both R 1 and Y can both be hydrogen, it is preferred that at least one of the rings be substituted, preferably both rings are substituted.
• A is suitably CH2, C(S) or C(S). It is noted that in Formula (I) the A containing ring is saturated. In compounds of Formula (II), A is suitably CRjg. It is also noted that in Formula (II) the A containing ring contains unsaturation.
• Rig is hydrogen.
• R is suitably -NH -C(X 2 )-NH- (CR 1 3 R 14 ) v - Z. 00/05216
• Z is W, HET, alkyl. an optionally substituted C2-10 alkenyl, or an optionally substituted C2-10 alkynyl.
• p is an integer having a value of 1 to 3.
• W is or
• the E containing ring is optionally selected from
• Z is
• the E ring denoted by its point of attachment through the asterix (*) may optionally be present. If it is not present, the ring is a phenyl moiety which is substituted by the Y terms as shown above.
• the E ring may be substituted by the Y moiety in any ring, saturated or unsaturated, and is shown for purposes herein substituted only in the unsaturated ring(s).
• X is S(O) m' .
• Most preferably X is S(O) m ', and m' is 2, when A is CH2.
• both of X[ can not be hydrogen.
• one of X ⁇ is an electron withdrawing group such as a halosubstituted alkyl, such as CF3, or C(O)NR 4 R 5 .
• X is suitably C(X 1 ) or N, preferably C(X 1 ).
• Xi is independently hydrogen, halogen, NR4R5, C(O)NR4R , optionally substituted Ci-io alkyl, -io alkoxy, halosubstituted Ci- 10 alkoxy, aryl, aryl Ci-4 alkyl, aryloxy, aryl Ci-4 alkyloxy, heteroaryl, heteroaryl C ⁇ . alkyl, heterocyclic. heterocyclic Ci-4alkyl; or heteroaryl Cj-4 alkyloxy.
• the alkyl group may be optionally substituted one or more times by hydroxy, NR4R5, or halogen.
• Xj is hydrogen.
• XI is preferably hydrogen or an electron withdrawing group, such as a halosubstituted alkyl, such as CF3, or C(O)NR4R5 ) HET is an optionally substimted heteroaryl moiety, as defined below both for optional substituents and for particular heteroaryl moieties.
• R15 and Rig are independently hydrogen, or an optionally substituted C 1-4 alkyl as defined above for R13 and R14.
• 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 amino such as in the NR4R5 group; NHC(O)R4; C(O)NR4R5; C(O)OH; S(O)2NR4R5; NHS(O)2Rl9
• Ci-io alkyl such as methyl, ethyl, propyl, isopropyl, or t-butyl
• halosubstituted Ci-io alkyl such CF3; an optionally substituted Ci-io alkyl, such CF3; an optionally substituted
• Rl9 is suitably C 1-4 alkyl, aryl, aryl Ci-4alkyl, heteroaryl, heteroarylC 1 -4alkyl, heterocyclic, or heterocyclicC 1 -4alkyl.
• Suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of inorganic and organic acids, such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane sulphonic acid, ethane sulphonic acid, acetic acid, malic acid, tartaric acid, citric acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, benzoic acid, salicylic acid, phenylacetic acid and mandelic acid.
• pharmaceutically acceptable salts of compounds of Formula (I) may also be formed with a pharmaceutically acceptable cation, for instance, if a substituent group comprises a carboxy moiety.
• Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations.
• halo all halogens, that is chloro, fluoro, bromo and iodo.
• Ci-ioalkyl or "alkyl” - both straight and branched chain radicals of 1 to 10 carbon atoms, unless the chain length is otherwise limited, including, but not limited to, methyl, ethyl, n-propyl, iso-p ⁇ opyl, rc-butyl, sec-butyl, iso-butyl, tert- butyl, /i-pentyl and the like.
• cycloalkyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, including but not limited to cyclopropyl, cyclopentyl, cyclohexyl, and the like.
• alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2-10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1-butenyl, 2-butenyl and the like. • "aryl” - phenyl and naphthyl;
• heteroaryl (on its own or in any combination, such as “heteroaryloxy”, or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
• heterocyclic (on its own or in any combination, such as “heterocyclicalkyl”) - a saturated or partially unsaturated 4-10 membered ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O, or S; such as, but not limited to, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, or imidazolidine.
• arylalkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean Ci-io alkyl, as defined above, attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
• Ri moieties may together form a 5 or 6 membered saturated or unsaturated ring
• Exemplified compounds of Formula (I) include: N-(2-Bromophenyl) -N' -( 1, 3-Dihydro-2, 2-dioxo-2,l-benzisothiazol-7-yl-)urea N-[(l,3-dihydro-2.2-dioxo-4-floro-2,l-benzisothiazo)-7-yl]-N'-(2- bromophenyl)urea N-[(l,3-dihydro-2,2-dioxo-4-chloro-2,l-benzisothiazo)-7-yl]-N'-(2,3- dichlorophenyl)urea N-[(l,3-dihydro-2,2-dioxo-4-chloro-2,l-benzisothiazo)-7-yl]-N'-(2- chlorophenyl)urea N-[(l,3-dihydro-2,2-dioxo-4-chloro
• Additional exemplified compounds of Formula (I) include: N-(4-Bromophenyl) -N' -(1, 3-Dihydro-2, 2-dioxo-2,l-benzisothiazol-7-yl-)urea
• Exemplified compounds of Formula (II) include: N-(2-indazole)-N'-(2-bromophenyl)urea Methods of Preparation
• the corresponding heterocyclic sulfamide can be prepared from the commercially available compound 1 -scheme 1 with reduction of the nitro group using suitable reducing conditions such as SnCh, hydrogen and Pd/C or zinc metal in a suitable organic solvent such as, ethyl acetate and cyclization using triethylamine in methylene chloride.
• suitable reducing conditions such as SnCh, hydrogen and Pd/C or zinc metal
• a suitable organic solvent such as, ethyl acetate and cyclization using triethylamine in methylene chloride.
• Alternative reaction conditions for the cyclic sulfonamide 7_ scheme 1 can be achieved by cyclization of 2-chlorobenzylsulfonamide with potassium carbonate and copper-bronze powder in under pressure using a polar solvent or using a high boiling solvent such as 2, 3-dimethylaniline at 100-180°C, preferably about 180°C, or by reacting the 2-aminobenzylsulfonic acid sodium salt 0/05216
• the desired heterocyclic compound 2-scheme 2 is not commercially available then it can be prepared from the commercially available compound ]_ scheme 2 with triphenyl phosphine oxide, triethylamine, trifluoroacetic anhydride in an aprotic solvent such as 1, 2 - dichloroethane.
• the desired heterocyclic compound 2-scheme 4 is not commercially available then it can be prepared from the commercially available compound _ scheme 4 with aluminum amalgam in diethyl ether or THF.
• the desired heterocyclic compound 3-scheme 5 is not commercially available then it can be prepared from the commercially available compound l_ scheme 5 with nitrous acid to the diazonium salt, followed by treating with sodium sulfite to the hydrazine 2-scheme 5. Cyclization can be achieved with sulfuric acid to give 3-scheme 5.
• An alternative method to obtain 3-scheme 5 would be reduction of indazolinone with lithium aluminum hydride.
• the corresponding nitro compound can be prepared from 1 -scheme 6, under standard nitration conditions (using HNO3 or NaNO 3 ) at 0-100°C, preferably about 23°C, under acid conditions such as acetic acid, acetic anhydride, or under biphasic condition such as aqueous sulphuric acid and a chlorinated solvent such as methylene chloride.
• acid conditions such as acetic acid, acetic anhydride, or under biphasic condition such as aqueous sulphuric acid and a chlorinated solvent such as methylene chloride.
• suitable reducing agents such as H2t d in an organic solvent, such as
• MeOH, DMF or ethylacetate (alternately SnCb in EtOH, or LiAlH4 or zinc metal in acetic acid ) at 0-100°C.
• Other commercially available heterocylic compounds such as Indoline, Indole, Oxindole, Isatin, Indazole and Indazolinone can be converted to the desired anilines through this procedure.
• Ortho substituted heterocyclic phenyl ureas in 2-scheme 7 may be prepared by standard conditions involving the condensation of the commercially available optionally substituted aryl isocyanate(Aldrich Chemical Co., Milwaukee, Wi) with the corresponding aniline 1 -scheme 7 in an aprotic solvent such as DMSO, DMF, toluene or methylene chloride at room temperature or elevated temperature from 1 h to 24 h.
• an aprotic solvent such as DMSO, DMF, toluene or methylene chloride
• the desired isocyanates can be made by condensing the amine with triphosgene in the presence of base (such as potassium carbonate) or by reacting the carboxylic acid with diphenyl phosphoazide in the presence of a base (such as triethyl amine).
• base such as potassium carbonate
• diphenyl phosphoazide such as triethyl amine
• aromatic rings of the compounds can be further functionalized by conditions well known in the art such as bromination or other electrophilic substitution reactions. These substituents can be further manipulated using standard nucleophilic substitutions such as reaction with an anion (such as sodium methoxide), or in palladium catalyzed coupling reaction chemistry.
• an anion such as sodium methoxide
• Another aspect of the invention is the novel process for making compounds of Formula (I), in particularly when A is CH2 and X is S(O)m which process comprises a process for producing a compound of Formula (I), as defined above, wherein A is CH2 and X is S(O) m , which process comprises a) reacting a compound of the formula
• Another aspect of the present invention is the novel process of producing novel compounds of the formula: which process comprises reacting a compound of the formula
• Yet another aspect of the present invention is a process for producing a compound of the Formula (C), which process comprises reacting a compound of the formula
• N-[ l, 3-Dihydro-l, 2-benzisothiazole-3, 3-dioxide]-N'-[2-bromophenyl] urea was prepared from 4-amino- 1 , 3-Dihydro-l, 2-benzisothiazole-2, 2-dioxide (64mg, 0.35 mmol) according to the procedure in General Method B. The product was purified by chromatography of the resulting solid on silica gel(EtOAc/ hexane ( lequiv./lequiv.)). (45mg, 34%).
• Example 2 N-(l, 3-Dihydro-4-bromo-l, 2-benzisothiazole-3, 3-dioxide) N'- phenylurea
• Example 3 N-[( 1 ,3-dihydro-2,2-dioxo-4-floro-2, 1 -benzisothiazo)-7-yl]-N'-(2- bromophenyl)urea; (M ' : 398.1, 400.1)
• Example 4 N-[(l,3-dihydro-2,2-dioxo-4-chloro-2,l-benzisothiazo)-7-yl]-N'-(2,3- dichlorophenyl)urea; (M" : 403.9, 406.2, 408.0)
• Example 5 N-[(l,3-dihydro-2,2-dioxo-4-chloro-2, l-benzisothiazo)-7-yl]-N'-(2- chlorophenyl)urea;
• Example 7 N-[(l,3-dihydro-2,2-dioxo-4-chloro-2,l-benzisothiazo)-7-yl]-N'- isopropylurea; (M * : 304.1, 306.2)
• Example 8 N-[(l,3-Dihydro-2,2-dioxo-4-chloro-2,l-benzisothiazo)-7-yl]-N'- (2-bromophenyl)urea; (M- : 414, 416)
• Example 9 N-[(l,3-Dihydro-2,2-dioxo-4-cyano-2,l-benzisothiazo)-7-yl]-N'- (2-bromophenyl)urea; (M" : 404.9, 407.1)
• Example 10 N-[( 1 ,3-Dihydro-2,2-dioxo-4-bromo-2, 1 -benzisothiazo)-7-yl]-N'
• the compounds of Formula (I), and (II) or a pharmaceutically acceptable salt thereof can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of any disease state in a human, or other mammal, which is exacerbated or caused by excessive or unregulated 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.
• Formula (I) will also refer to compounds of Formula (II) unless otherwise indicated.
• the present invention provides a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the chemokines are LL-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 LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78 for instance in the context of the present invention constitute: (i) levels of free LL-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 LL-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.
• interleukin-8 and rhinovirus may be found in articles such as: Tumer.et al., Clin. Infect. Dis. (1998), 26(4), 840-846; Sanders, et al., J. Virol. ( 1998), 72(2), 934-942; Sethi, et al., Clin. Exp. Immunol. (1997), 110(3), 362-369; Zhu, et al., Am. J. Physiol.
• the ⁇ -chemokines but particularly, GRO ⁇ , GRO ⁇ , GRO ⁇ , or NAP-2, working through the IL-8 type I or II receptor can promote the neovascularization of tumors by promoting the directional growth of endothelial cells. Therefore, the inhibition of LL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.
• the present invention also provides for a means of treating, in an acute setting, as well as preventing, in those individuals deemed susceptible to, CNS injuries by the chemokine receptor antagonist compounds of Formula (I).
• CNS injuries as defined herein include both open or penetrating head trauma, such as by surgery, or a closed head trauma injury, such as by an injury to the head region. Also included within this definition is ischemic stroke, particularly to the brain area.
• Ischemic stroke may be defined as a focal neurologic disorder that results from insufficient blood supply to a particular brain area, usually as a consequence of an embolus, thrombi, or local atheromatous closure of the blood vessel.
• the role of inflammatory cytokines in this are has been emerging and the present invention provides a mean for the potential treatment of these injuries. Relatively little treatment, for an acute injury such as these has been available.
• TNF- ⁇ is a cytokine with proinflammatory actions, including endothelial leukocyte adhesion molecule expression.
• Leukocytes infiltrate into ischemic brain lesions and hence compounds which inhibit or decrease levels of TNF would be useful for treatment of ischemic brain injury. See Liu et al., Stoke, Vol. 25., No. 7, pp. 1481-88 (1994) whose disclosure is incorporated herein by reference.
• the compounds of Formula (I) are administered in an amount sufficient to inhibit IL-8, binding to the IL-8 alpha or beta receptors, from binding to these receptors, such as evidenced by a reduction in neutrophil chemotaxis and activation.
• the discovery that the compounds of Formula (I) are inhibitors of LL-8 binding is based upon the effects of the compounds of Formulas (I) in the in vitro receptor binding assays which are described herein.
• the compounds of Formula (I) have been shown to be inhibitors of type II 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 LL-8, GRO ⁇ , GRO ⁇ , GRO ⁇ , NAP-2 or ENA-78. This would include a disease state in which, IL-8 plays a role, either by production of IL-8 itself, or by IL-8 causing another monokine to be released, such as but not limited to IL- 1 , IL-6 or TNF.
• cytokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or h ; natopoietic 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 (LL-6), Interleukin-8 (LL-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, LL-8, GRO- ⁇ , GRO- ⁇ , GRO- ⁇ , NAP-2, ENA-78, IP- 10, MIP- 1 ⁇ , MlP- ⁇ , PF4, and MCP 1 , 2, and 3.
• a pharmaceutical composition comprising an effective, non- toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
• Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
• the compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures.
• the compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
• the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
• the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the pharmaceutical carrier employed may be, for example, either a solid or liquid.
• solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
• liquid carriers are syrup, peanut oil, olive oil, water and the like.
• the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
• 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 human recombinant
• Gro- ⁇ is obtained from NEN- New England Nuclear. All other chemicals are of analytical grade.
• High levels of recombinant human LL-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)). Except that the homogenization buffer is changed to lOmM Tris-HCL, ImM MgS04, 0.5mM EDTA (ethylene-diaminetetra- acetic acid), lm MPMSF ( ⁇ -toluenesulphonyl fluoride), 0.5 mg L Leupeptin, pH
• 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 125 ⁇ L .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 HCl buffers, pH 8.0, containing 1.2 mM MgSO4,
• EDTA 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS.
• drug or compound of interest is added which has been pre-dissolved in DMSO so as to reach a final concentration of between O.OlnM and 100 uM.
• the assay is initiated by addition of 12 ⁇ l-iL-8. After 1 hour at room temperature the plate is harvested using a Tomtec 96-well harvester onto a glass fiber filtermat blocked with 1% polyethylenimine/ 0.5% BSA and washed 3 times with 25 mM NaCl, 10 mM TrisHCl, 1 mM MgSO4,
• the filter is then dried and counted on the Betaplate liquid scintillation counter.
• the recombinant LL-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.
• Incubation is allowed to proceed for between about 45 and 90 min. at about 37°C in a humidified incubator with 5% CO2.
• 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.
• the plate is placed in a fluorescent 96 well plate reader (Cytofluor 2350, Millipore, Bedford, MA) and data collected at 3 min. intervals according to the method of Nakajima et al J. Biol Chem 2544027 (1979).
• the amount of Elastase released from the PMNs is calculated by measuring the rate of MeOSuc- Ala- Ala-Pro- Val-AMC degradation.
• TNF- ⁇ in Traumatic Brain Injury Assay This assay provides for examination of the expression of tumor necrosis factor mRNA in specific brain regions which follow experimentally induced lateral fluid- percussion traumatic brain injury (TBI) in rats. Since TNF- ⁇ is able to induce nerve growth factor (NGF) and stimulate the release of other cytokines from activated astrocytes, this post-traumatic alteration in gene expression of TNF- ⁇ plays an important role in both the acute and regenerative response to CNS trauma.
• a suitable assay may be found in WO 97/35856 or WO 97/49286 whose disclosures are incorporated herein by reference.
• CNS Injury model for IL- ⁇ mRNA This assay characterizes the regional expression of interleukin-l ⁇ (LL-l ⁇ ) mRNA in specific brain regions following experimental lateral fluid-percussion traumatic brain injury (TBI) in rats. Results from these assays indicate that following TBI, the temporal expression of IL-l ⁇ mRNA is regionally stimulated in specific brain regions. These regional changes in cytokines, such as IL-l ⁇ play a role in the post- traumatic pathologic or regenerative sequelae of brain injury.
• TBI lateral fluid-percussion traumatic brain injury
• In vivo - athereoschlerosis assay In vivo models for measuring atherosclerosis in mice is based on the assay of Paigen et al with small modifications as described below. See Paigen B, Morrow A, Holmes PA, Mitchell D, Williams RA. Quantitative assessment of atherosclerotic lesions in mice. Atherosclerosis 68: 231-240 (1987); and Groot PHE, van Vlijmen BJM, Benson GM, Hofker MH, Schiffelers R, Vidgeon-Hart M, Havekes LM. Quantitative assessment of aortic atherosclerosis in APOE*3 Leiden transgenic mice and its relationship to serum cholesterol exposure. Arterioscler Thromb Vase Biol. 16: 926-933 (1996). Sectioning and staining of the aortic sinus
• Cross-sections of the aortic root are taken as has been described previously (1,2). Briefly, the hearts are bisected just below the level of the atria and the base of the heart plus aortic root are taken for analysis. After equilibrating the tissue in OCT compound overnight the hearts are immersed in OCT compound on a cryostat chuck (Bright Instrument Company Ltd., UK) with the aorta facing the chuck. The tissue is frozen by surrounding the chuck with dry ice. The hearts are then sectioned perpendicular to the axis of the aorta, starting within the heart and working in the direction of the aorta.
• Ten alternate sections of the aortic root are imaged using an Olympus BH-2 microscope equipped with an 4x objective and a video camera (Hitachi, HV-C10). Twenty-four bit colour images are acquired and analysed using a PC (Datacell Pentium P5-133, Datacell, Berks, U.K.) fitted with a framegrabbing board (Snapper, Active Imaging Ltd, Berks. U.K.) and running Optimas software (version 5.1, Optimas Corp., WA, U.S.A.). The images are captured under identical lighting, microscope, camera and PC conditions. Quantification of the atherosclerotic lesion areas is performed by drawing around the lesions by hand using the Optimas software. Colour thresholds are set that quantify the areas that are stained red within the lesions. Absolute values for the cross-sectional areas of the lesions and the areas stained red are obtained by calibrating the software using an image of the grid on a haemocytometer slide.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Immunology (AREA)
• Pulmonology (AREA)
• Rheumatology (AREA)
• Epidemiology (AREA)
• Physical Education & Sports Medicine (AREA)
• Communicable Diseases (AREA)
• Neurosurgery (AREA)
• Neurology (AREA)
• Oncology (AREA)
• Biomedical Technology (AREA)
• Diabetes (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Transplantation (AREA)
• Hematology (AREA)
• Hospice & Palliative Care (AREA)
• Toxicology (AREA)
• Virology (AREA)
• Psychiatry (AREA)
• Urology & Nephrology (AREA)
• Pain & Pain Management (AREA)
• Heart & Thoracic Surgery (AREA)
• Dermatology (AREA)
• Cardiology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Peptides Or Proteins (AREA)

Priority Applications (13)

Applications Claiming Priority (1)

Publications (1)

Family

ID=22267562

Family Applications (1)

Country Status (13)

Cited By (2)

Citations (1)

Family Cites Families (6)

• 1998
  • 1998-07-23 IL IL14098398A patent/IL140983A0/xx unknown
  • 1998-07-23 BR BR9815951-8A patent/BR9815951A/pt not_active Application Discontinuation
  • 1998-07-23 HU HU0102863A patent/HUP0102863A3/hu unknown
  • 1998-07-23 KR KR1020017000923A patent/KR20010106415A/ko not_active Application Discontinuation
  • 1998-07-23 WO PCT/US1998/015533 patent/WO2000005216A1/en not_active Application Discontinuation
  • 1998-07-23 EP EP98937163A patent/EP1098884A4/en not_active Withdrawn
  • 1998-07-23 AU AU85941/98A patent/AU8594198A/en not_active Abandoned
  • 1998-07-23 TR TR2001/00219T patent/TR200100219T2/xx unknown
  • 1998-07-23 CN CN98814176A patent/CN1314893A/zh active Pending
  • 1998-07-23 PL PL98346178A patent/PL346178A1/xx not_active Application Discontinuation
  • 1998-07-23 JP JP2000561172A patent/JP2002521368A/ja active Pending
  • 1998-07-23 CA CA002338741A patent/CA2338741A1/en not_active Abandoned
• 2001
  • 2001-01-22 NO NO20010353A patent/NO20010353D0/no not_active Application Discontinuation

Patent Citations (1)

Also Published As

Similar Documents

Legal Events