Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • 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
  • A61P17/00—Drugs for dermatological disorders
• • 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
  • A61P31/12—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
• • 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
  • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
  • C07D209/04—Indoles; Hydrogenated indoles
  • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
  • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

• This invention relates to a novel group of indole compounds, processes for the preparation thereof, the use thereof in treating IL-8 mediated diseases and pharmaceutical compositions for use in such therapy.
• Interleukin-8 such as neutrophil attractant/activation protein- 1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor.
• NAP-1 neutrophil attractant/activation protein- 1
• MDNCF monocyte derived neutrophil chemotactic factor
• NAF neutrophil activating factor
• T-cell lymphocyte chemotactic factor T-cell lymphocyte chemotactic factor.
• Interleukin-8 is a chemoattractant for neutrophils, basophils, and a subset of T-cells.
• nucleated cells including macrophages, fibroblasts, endothelial and epithelial cells exposed to TNF, IL- 1 ⁇ , IL- 1 ⁇ or LPS, and by neutrophils themselves when exposed to LPS or chemotactic factors such as FMLP.
• IL-8 stimulates a number of functions in vitro. It has been shown to have chemoattractant properties for neutrophils, T-lymphocytes, and basophils. In addition it induces histamine release from basophils from both normal and atopic individuals as well as lysozomal enzyme release and respiratory burst from neutrophils. IL-8 has also been shown to increase the surface expression of Mac- 1 (CD 1 1 b/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.
• IL-8 As IL-8 promotes the accumulation and activation of neutrophils it has 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).
• IL-8 induces 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 of IL-8 receptors. Thomas et al., J. Biol. Chem. 266. 14839 (1991); and Holmes et al.. Science 253. 1278 (1991).
• the development of non-peptide small molecule antagonists for members of this receptor family has precedent. For a review see R. Freidinger in: Progress in Drug Research. Vol. 40, pp. 33-98, Birkhauser Verlag, Basel 1993.
• the IL-8 receptor represents a promising target for the development of novel anti-inflammatory agents.
• IL-8R ⁇ which binds only IL-8 with high affinity
• IL-8R ⁇ which has high affinity for IL-8 as well as for GRO- ⁇ and NAP-2.
• This invention relates to the novel compounds of Formula (I) and pharmaceutical compositions comprising a compound of Formula (I) and a pharmaceutically acceptable diluent or carrier.
• This invention provides for a method of treating a chemokine mediated disease, wherein the chemokine is one which binds to an IL-8 ⁇ or ⁇ receptor and which method comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
• the chemokine is IL-8.
• This invention also relates to a method of inhibiting the binding of 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).
• Ar is an optionally substituted phenyl or naphthyl group
• R is hydrogen, hydroxy, C .-8 alkoxy, or O-(CR8R9)n- 6
• R6 is an optionally substituted C3-7 cycloalkyl, optionally substituted C3-7 cycloalkenyl, or an optionally substituted aryl
• n is 0 or an integer having a value of 1, 2, 3 or 4;
• Rl is hydrogen, halogen, halosubstituted -8 alkyl, Ci-8 alkyl, hydroxy, Ci-8alkoxy, halosubstitutedC 1 -8 alkoxy, -(CH2)taryl, O-(CH2)t aryl, O-CH2-O-C 1 - ⁇ alkyl,
• Ri moieties may form a methylene dioxy ring system or together two Rl moieties may form a 6 membered saturated or unsaturated ring system which may be optionally substituted;
• s is an integer having a value of 1, 2, or 3;
• v is an integer having a value of 1 , 2, 3, or 4;
• m is 0 or an integer having a value of 1 or 2;
• t is 0 or an integer having a value of 1, 2; 3 or 4;
• R2 is an optionally substituted Cj-8 alkyl
• R3 is independently hydrogen, or C 1.4 alkyl, or together with the nitrogen to which they are attached form a 5 to 7 membered saturated or unsaturated ring
• R4 is independently hydrogen, or C1-4 alkyl
• R5 is hydrogen, optionally substituted Cj-8 alkyl, or Ci-8 alkoxy
• R8 and R9 are independently hydrogen or Ci-4 alkyl; or pharmaceutically acceptable salts thereof.
• novel compounds of Formula (I) 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, therapeutically or prophylactically, in animals include disease states such as those noted herein in the Methods of Treatment section.
• Novel compounds of Formula (I) are represented by the structure
• Ar is an optionally substituted phenyl or naphthyl group
• R is hydrogen, hydroxy, Ci-8 alkoxy, or O-(CR8R9)rr R6;
• R6 is an optionally substituted C3-7 cycloalkyl, optionally substituted C3-7 cycloalkenyl, or optionally substituted aryl; n is 0 or an integer having a value of 1, 2, 3 or 4; Ri is hydrogen, halogen, halosubstituted Cj- alkyl, Ci-8 alkyl, hydroxy, Ci-8alkoxy, halosubstitutedCi-8 alkoxy, O-CH2-O-Ci-8alkyl, -(CH2).aryl, O-(CH2)t aryl, - O-(CH2) v C(O)OCl-4alkyl, NO2, S(O) m R2, N(Ifc)2.
• NHC(O)R4, -C(O)R5, or together two Ri moieties may form a methylene dioxy ring system, or together two Rl moieties may form a 6 membered saturated or unsaturated ring system which may be optionally substituted;
• t is 0 or an integer having a value of 1, 2, 3, or 4;
• v is an integer having a value of 1, 2, 3, or 4;
• s is an integer having a value of 1, 2, or 3;
• m is 0 or an integer having a value of 1 or 2;
• R2 is an optionally substituted Ci-8 alkyl;
• R3 is independently hydrogen, or Ci-4 alkyl, or together with the nitrogen to which they are attached form a 5 to 7 membered saturated or unsaturated ring;
• R4 is independently hydrogen, or C alkyl;
• R5 is hydrogen, optionally substituted Ci-8 alkyl, or Ci-8 alkoxy;
• R8 and R9 are independently hydrogen or C1-.4 alkyl; provided that a) when R is hydrogen, and Ar is 4-methoxyphenyl, then Ri is not a (2-chloro-4,5- methylenedioxy), or a (4,5-methylenedioxy); b) when R is hydrogen, and Ar is 2-nitrophenyl, then Rj is not hydrogen; c) when R is hydrogen, and Ar is 2-hydroxymethyl-4-methoxyphenyl, then Ri is not (2-chloro-4,5-methylenedioxy); or pharmaceutically acceptable salts thereof.
• Ar is optionally substituted phenyl or naphthyl group.
• Ar is an unsubstituted naphthyl or an optionally substituted phenyl.
• the aryl ring may be substituted independently one or more times, suitably one to three times, by halogen, such a chlorine or fluorine; Ci-8 alkyl, such as methyl; halosubstituted Ci-8 alkyl, such as CF3; optionally substituted -(CH2)n aryl, such as phenyl; hydroxy; halosubstituted C 1-8 alkoxy, such as -OCF3; Ci-8 alkoxy, such as methoxy; optionally substituted O-(CH2)n aryl, such as phenoxy or benzyloxy; NO2; N(R3)2, amines and substituted amines, such as in N(R3)2 wherein the R3 moieties are independently hydrogen, or C 1.4 alkyl, or together with the nitrogen to which they
• the substituents are chlorine, fluorine, methyl, OCF3, CF3, amine, C(O)H, phenyl, methoxy, phenoxy, or phenyl. More specifically the substituents are chloro, such as 4-fluoro, 4-chloro; di-chloro, such as 2,4-dichloro, 3,5- dichloro, or 3-chloro-4-fluoro; CF3, such as 4-CF3; methoxy, such as 4-methoxy; phenoxy, such as 4-phenoxy; phenyl such as 4-phenyl; alkyl such as 4-methyl; amino such as 3-amino; or C(O)R5, such as 2-C(O)H or 4-C(O)H.
• chloro such as 4-fluoro, 4-chloro
• di-chloro such as 2,4-dichloro, 3,5- dichloro, or 3-chloro-4-fluoro
• CF3 such as 4-CF3
• methoxy such as 4-methoxy
• R is hydrogen, hydroxy, Ci- alkoxy, or O-(CR8R9)n- R6- R6 is an optionally substituted C3-7 cycloalkyl, optionally substituted C3-7 cycloalkenyl, or an optionally substituted aryl.
• R is Ci-8 alkoxy or an optionally substituted O-(CR8R9)n-aryl, wherein the aryl is phenyl, such as in a benzyloxy group.
• R6 ring may be optionally substituted one or more times independently by halogen; hydroxy; hydroxy substituted Ci-ioalkyl; Ci-io alkyl, such as methyl, ethyl, propyl, isopropyl, or t-butyl; halosubstituted -io alkyl, such CF3; Ci-io alkoxy, such as methoxy, ethoxy, isopropyloxy, or propyloxy; optionally substituted Ci-io alkoxy, such as methoxymethoxy or trifluoromethoxy; S-Ci- 10 alkyl, such as methyl thio; amino, mono & di-substituted amino, such as in the N(R3)2 group; N(R3)-C(O)Ci-ioalkyl, such as acetamido; C(O)Ci-ioalkyl
• R6 when two substituents form a methylene dioxy ring system it is preferably when R6 is an aryl group, more preferably a phenyl ring.
• R6 when R6 is a C3-7 cycloalkyl moiety it is preferably a cyclohexyl ring, such as in cyclohexylmethoxy.
• Rl is hydrogen, halogen, halosubstituted Cj-8 alkyl, Cj-8 alkyl, hydroxy, C 1 - ⁇ alkoxy, halosubstituted C 1 -8 alkoxy, O-CH2-O-C 1 - ⁇ alkyl, -(CH2)_aryl, O- (CH2)t aryl, -O-(CH2) v C(O)OC 1 -4alkyl, NO2, S(O) m R2, N(R3)2, NHC(O)R4, or - C(O)R5; or together two Ri moieties may form a methylenedioxy ring system; or together two Ri moieties may form a 6 membered saturated or unsaturated ring system which may be optionally substituted; and t is 0 or an integer having a value of 1 to 4. - 6 -
• the R i group is in the 4-position.
• the phenyl ring is substituted by a methylenedioxy group it is preferably in the 3,4-position; and more preferably the phenyl ring may also be additionally substituted by another Rj, such as halogen, preferably fluorine or chlorine.
• the two Ri moieties form a 6 membered saturated or unsaturated ring system, which may contain 0 to 2 double bonds, and is preferably an aromatic ring forming a naphthyl ring system, which ring may be optionally substituted as defined herein.
• Preferred substituents for Ri are NO2, OCF3, OCH3, CH3, benzyloxy, phenoxy, hydrogen or halogen, preferably fluorine or chlorine, more preferably chlorine.
• R2 is an optionally substituted Ci-8 alkyl; and R4 is independently hydrogen, or C 1-4 alkyl.
• R3 is independently hydrogen, or C1-.4 alkyl, or together with the nitrogen to which they are attached form a 5 to 7 membered saturated or unsaturated ring; such as such as pyrrole, piperidine, or pyridine.
• Exemplified compounds of Formula (I) include:
• Exemplified compounds of Formula (I) include: l-(2-chloro-4,5-methylenedioxyphenylmethyl)-3-(4-methoxyphenyl)indole-2- carboxylic acid 5-benzyloxy- 1 -(2-chloro-4,5-methylenedioxyphenylmethy 1)- 3-phenylindole-2- carboxylic acid 5-benzyloxy- 1 -(4-benzyloxybenzyl)-3-phenylindole-2-carboxylic acid 1 -(2-chloro-4,5-methylenedioxyphenylmethyI)-3-phenylindole-2-carboxylic acid
• a preferred salt form of the compounds of Formula (I) is the sodium salt.
• a preferred subgroup of compounds within Formula (I) are represented by the structure having the formula:
• Ar is an optionally substituted phenyl or naphthyl group
• R is hydrogen, hydroxy, Ci-8 alkoxy, or optionally substituted O-(CH2)n-phenyl; n is 0 or an integer having a value of 1, 2, 3 or 4;
• Rl is hydrogen, halogen, halosubstituted Ci-8 alkyl, Ci-8 alkyl, hydroxy, Ci-8alkoxy, halosubstituted C 1-8 alkoxy, aryl, aryl C 1-4 alkyl, aryloxy, arylCi-4alkyloxy,
• N(R3)2 N(R3)2
• s is an integer having a value of 1, 2 or 3;
• R2 is an optionally substituted Ci-8 alkyl
• R3 is independently hydrogen, or Cj-4 alkyl, or together with the nitrogen to which they are attached form a 5 to 7 membered saturated or unsaturated ring;
• R4 is independently hydrogen, or C i-4 alkyl; provided that when R is hydrogen, and Ar is 4-methoxyphenyl, then R ⁇ is not a (4-chloro- l,3-benzodioxol-5-yl)methyl, a (6-chloro- l,3-benzodioxol-5-yl)methyl or a (l,3-benzodioxol-5-yl)methyl; or pharmaceutically acceptable salts thereof.
• R, R i and Ar are as defined for Formula (I).
• Additional exemplified compounds of Formula (I) include:
• Specifically exemplified compounds of Formula (Ic) include: 1 1 -
• Another aspect of the present invention is the novel library of compounds of
• G-protein coupled receptors are a 7- transmembrane receptor which uses G-proteins as part of their signaling mechanism, including but not limited to IL-8 receptors, dopamine receptors muscarinic acetylcholine receptors and the like.
• "optionally substituted” unless specifically defined shall mean such groups as halogen, such as fluorine, chlorine, bromine or iodine; hydroxy; hydroxy substituted Ci-ioalkyl; Cj-io alkoxy, such as methoxy or ethoxy; S(O)m C ⁇ .
• Ci-io 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, wherein these aryl moieties may be substituted one to two times by halogen; hydroxy; hydroxy substituted alkyl; Cj-io alkoxy; S(O)m Ci-io alkyl; amino, mono & di-substituted amino, such as in the N(R3)2 group; Ci-io alkyl,
• 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 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, . ' .ro-propyl, «-bu ⁇ yl, sec-butyl, iso-butyl, tert-butyl, ⁇ -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.
• cycloalkenyl is used herein to mean cyclic radicals, preferably of 3 to 8 carbons, having one or more bonds which are unsaturated, including but not limited to cyclopentenyl, or cyclohexenyl.
• alkenyl is used herein at all occurrences to mean straight or branched chain radical of 2- 10 carbon atoms, unless the chain length is limited thereto, including, but not limited to ethenyl, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-butenyl and the like.
• heteroaryl (on its own or in any combination, such as “heteroaryloxy”, or “heteroaryl alkyl”) - a 5-10 membered aromatic ring system in which one or more rings contain one or more heteroatoms selected from the group consisting of N, O or S, such as, but not limited, to pyrrole, pyrazole, furan, thiophene, quinoline, isoquinoline, quinazolinyl, pyridine, pyrimidine, oxazole, thiazole, thiadiazole, triazole, imidazole, or benzimidazole.
• heterocyclic (on its own or in any combination, such as
• heterocyclylalkyl 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.
• aralkyl or “heteroarylalkyl” or “heterocyclicalkyl” is used herein to mean Ci-8 alkyl as defined above attached to an aryl, heteroaryl or heterocyclic moiety, as also defined herein, unless otherwise indicated.
• 3-Scheme 1 is arylated by treatment with a palladium (0) catalyst (such as Pd(PPh 3 ) 4 , ArPd(PPh 3 ) 2 I, Pd(OAc) 2 , [(allyl)PdCl] 2 or Pd 2 (dba) 3 ), an arylboronic acid (such as phenylboronic acid, 4-methoxyphenylboronic acid, 2,4- dimethoxyphenylboronic acid, 3,5-dichlorophenylboronic acid, 3-chloro-4- fluorophenylboronic acid or 1-naphthylboronic acid) and a base (such as sodium carbonate, potassium carbonate, potassium phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide or thallium hydroxide) in a mixture of toluene, ethanol and water.
• a palladium (0) catalyst such as Pd(PPh 3 ) 4 , ArPd(PPh 3 )
• a mixture of acetonitrile and water or DME and water may be substituted for this solvent mixture.
• the arylated product, 4-Scheme 1. is saponified by treatment with a hydroxide base (such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic acid 5-Scheme 1.
• a hydroxide base such as potassium hydroxide, sodium hydroxide or lithium hydroxide
• a palladium (0) catalyst such as Pd(PPh 3 ) 4 , ArPd(PPh 3 )2l, Pd(OAc)2, [(allyl)PdCl]2 or Pd2(dba) 3
• the arylated product, 3-Scheme 2. is alkylated by treatment with a strong base (such as sodium hydride or potassium hydride) in an aprotic solvent (such as DMF or THF) and an alkyl halide (such as 6- chloropiperonyl chloride or 4-benzyloxybenzyl chloride).
• a strong base such as sodium hydride or potassium hydride
• an aprotic solvent such as DMF or THF
• an alkyl halide such as 6- chloropiperonyl chloride or 4-benzyloxybenzyl chloride.
• 4- Scheme 2 is saponified by treatment with a hydroxide base (such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic acid 5-Scheme 2.
• 3-Scheme 3 may be prepared by treatment with a primary or secondary alcohol, triphenylphosphine and an azodicarboxylic ester (such as diethyl azodicarboxylate or diisopropylazodicarboxylate) in an aprotic solvent ) such as THF or N-methylmorpholine).
• 3-Scheme 3 may be saponified by treatment with a hydroxide base (such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic acid 4-Scheme 3.
• the library of compounds of Formula (II) may be obtained by applying synthetic procedures analogous to those as described in the scheme, Scheme 4, below.
• 1 -Scheme 4 is saponified by treatment with an alkali metal hydroxide (such as potassium hydroxide, sodium hydroxide or lithium hydroxide) to yield carboxylic acid
• an alkali metal hydroxide such as potassium hydroxide, sodium hydroxide or lithium hydroxide
• Example 1(c) The compound of Example 1(c) (125 mg, 0.23 mmol) was dissolved in 1.5 mL of 1: 1 T ⁇ F/ethanol and 3 N potassium hydroxide (0.8 mL) was added. The mixture was heated at reflux for 1.5 h then diluted with ethyl acetate and acidified with 3 N HC1. The organic layer was washed with saturated brine, dried (MgSO4), filtered and concentrated to provide the title compound (112 mg, 94%). mp 213-214 °C.
• Example 2 Preparation of 5-benzyloxy-l-(4-benzyloxybenzvP-3-phenylindole-2-carhoxylic acid Following the procedure of Example 1(a)- 1(d), except substituting 4- benzyloxybenzyl chloride for 6-chloropiperonyl chloride in step (c), the title compound was prepared (24% overall). mp(ethyl acetate/hexanes) 181-182 °C.
• Example 1(a)- 1(d) Following the procedure of Example 1(a)- 1(d), except substituting ethyl indole- 2-carboxylate for ethyl 5-benzyloxyindole-2-carboxylate in step (a) and 4- benzyloxybenzyl chloride for 6-chloropiperonyl chloride in step (c), the title compound was prepared (39% overall), mp 193- 194 °C.
• Example 1(a)- 1(d) Following the procedure of Example 1(a)- 1(d), except substituting ethyl indole- 2-carboxylate for ethyl 5-benzyloxyindole-2-carboxylate in step (a) and 4- methoxyphenylboronic acid for phenylboronic acid in step (b), the title compound was prepared (92% overall), mp 189-190 °C.
• Example 6(a)-6(d) Following the procedure of Example 6(a)-6(d), except substituting 3,5- dichlorophenylboronic acid for 1 -naphthylboronic acid in step (c), the title compound was prepared (51 % overall), mp 221 -222 °C.
• Example 8 Preparation of 3-(3-chloro-4-fluorophenyl .- 1 -(2-chloro-4.5-methylenedioxyphenyl- methvl .indole-2-carboxvlic acid Following the procedure of Example 6(a)-6(d), except substituting 3-chloro-4- fluorophenylboronic acid for 1 -naphthylboronic acid in step (c), the title compound was prepared (25% overall), mp 210-21 1 °C.
• Example 10 (d) (1.25g, ca. 0.6 mil) was slurried in dry DMF (30 ml) at room temperature. To this was added a slurry of NaH (140 mg of 60% oil dispersion, 3.5 mmol) in DMF (10 ml) and stirring continued for 18 h. To this was added a solution of 6- chloropiperonyl chloride (718 mg, 3.5 mmol) in DMF (5 ml) and stirring continued 20 h. The mixture was filtered and the resin was washed successively with DMF (3x 50 ml), methanol (3x 50 ml) water (3x 50 ml) and methanol (3x 50 ml) then dried at 50° C in vacuo. f) l-(2-chloro-4,5-methylenedioxyphenylmethyl)-3-arylindole-2-carboxylic acid ten member sublibrary
• Example 10 The mixture of Example 10 (e) (414 mg, ca. 0.2 mmol) was stirred in DMF (10 ml) with 5M aqueous sodium hydroxide solution (1 ml) at room temperature for 20 h. The mixture was filtered and the filtrate partitioned between 3N HCl and ethyl acetate. The organic extract was washed with water then brine, dried (sodium sulfate) and the solvent removed in vacuo to afford the title sublibrary (37 mg). MS m/e (M-H)-:404.0, 434.0, 438.0, 454.0, 455.8, 463.8, 471.8, 479.8, 495.8.
• Example 13 Preparation of 3-arvl-l-Dhenvlmethvlindole-2-carboxvlic acid ten member sublibrarv Following the procedure of Examples 10(a) - 10(f), with the exception of substitution of benzyl chloride for 6-chloropiperonyl chloride in step (e), the title sublibrary was prepared (31 mg). MS m e (M-H)-:326.0, 356.0, 360.0, 376.0, 377.8, 386.0, 394.0, 402.0, 418.0.
• Example 22 Preparation of 1 -(2-chloro-4.5-methvlenedioxvbenzvl .-5-(4-methoxvbenzyloxy .-3- phenylindole-2-carboxylic acid Following the procedure of Example 18(a)- 18(b), except substituting 4- methoxybenzyl alcohol for isopropanol in step (a), the title compound was prepared (0.060g, 50% overall). MS (MH-): 540.0
• Example 24 Preparation of 1 -(2-chloro-4.5-methvlenedioxvbenzvn-3-phenvl-5-(2- trifluoromethvlhenzvloxv.indole-2-carboxvlic acid Following the procedure of Example 18(a)- 18(b), except substituting 2- trifluoromethylbenzyl alcohol for isopropaonl in step (a), the title compound was prepared (0.03 lg, 24% overall). MS (MH-): 578.0
• Example 26(b) To the compound of Example 26(b) (0.1 lOg, 0.212mmol) in THF (2mL) was added potassium bis(trimethylsilyl)amide (0.636mL (0.5M in toluene), 0.316mmol). The solution stirred at room temperature for 1 hour when 4-trifluoromethoxybenzyl bromide (0.065g, 0.254mmol) was added and stirring continued for 4 hours. The solution was partitioned between ethyl acetate and water.
• Example 32 Preparation of l-(2-chloro-4.5-methylenedioxyphenylmethyl ,-5-(4- cvanophenylmethoxvV3-phenvlindole-2-carboxvlic acid Following the procedure of Example 26(c)-26(d), except substituting ethyl 1 -
• Example 37 Preparation of 5-henzloxy- l-(2-chloro-4.5-methylenedioxybenzyl V3-(4- fluorophenyl.indole-2-carhoxvl.c acid Following the procedure of Example 1 (a)- 1 (d), except substituting 4- fluorophenylboronic acid for phenylboronic acid in step (b), the title compound was prepared as a white solid (77% overall). MS (MH " ): 428.0
• Example 38 Preparation of 3-(3-aminophenyl)-5-benzloxy- 1 -(2-chloro-4.5-methylenedioxy- henzvl .indole-2-carhoxvlic acid
• 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 chemokine is IL-8.
• the compounds of Formula (I) are administered in an amount sufficient to inhibit cytokine function, in particular IL-8, such that it's 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 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; ( ⁇ ) any cell associated IL-8 above normal physiological levels; or (iii) the presence of IL-8 above basal levels in cells or tissues in which IL-8, respectively, is produced.
• IL-8 There are many disease states in which excessive or unregulated HL-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, allograft rejections, and malaria. These diseases are primarily characterized by massive neutrophil infiltration, and are associated with increased IL-8 production which is responsible for the chemotaxis of neutrophils into the inflammatory site.
• IL-8 In contrast to other inflammatory cytokines (IL-1, TNF, and IL-6), IL-8 has the unique property of promoting neutrophil chemotaxis and activation. Therefore, the inhibition of IL-8 induced chemotaxis or activation would lead to a direct reduction in the neutrophil infiltration.
• 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 dual inhibitors of both recombinant type I and type II IL-8 receptors.
• IL-8 mediated disease or disease state refers to any and all disease states 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.
• 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- ⁇ , or NAP-2. This would include a disease state in which, IL-8 plays a role, either by production of IL-8 itself, or by IL-8 causing another monokine to be released, such as but not limited to IL-1, IL-6 or TNF.
• cytokine refers to any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or hematopoietic response.
• a cytokine includes, but is not limited to, monokines and lymphokines, regardless of which cells produce them.
• a monokine is generally referred to as being produced and secreted by a mononuclear cell, such as a macrophage and/or monocyte.
• Lymphokines are generally referred to as being produced by lymphocyte cells.
• cytokines include, but are not limited to, Interleukin- 1 (IL-1), Interleukin-6 (IL-6), Interleukin-8 (D -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, IP- 10, MlP-l ⁇ , MlP- ⁇ , PF4, and MCP 1, 2, and 3.
• a pharmaceutical composition comprising an effective, non-toxic amount of a compound of Formula (I) and a pharmaceutically acceptable carrier or diluent.
• Compounds of Formula (I), pharmaceutically acceptable salts thereof and pharmaceutical compositions incorporating such may conveniently be administered by any of the routes conventionally used for drug administration, for instance, orally, topically, parenterally or by inhalation.
• the compounds of Formula (I) may be administered in conventional dosage forms prepared by combining a compound of Formula (I) with standard pharmaceutical carriers according to conventional procedures.
• the compounds of Formula (I) may also be administered in conventional dosages in combination with a known, second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.
• the form and character of the pharmaceutically acceptable character or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well-known variables.
• the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• the pharmaceutical carrier employed may be, for example, either a solid or liquid. 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.
• 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 sohd 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.
• systemic administration refers to oral, intravenous, intrapentoneal 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. 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.
• IL-8 human recombinant
• Amersham Corp., Arlington Heights, IL with specific activity 2000 Ci/mmol. All other chemicals were of analytical grade.
• High levels of recombinant human IL-8 type ⁇ and ⁇ receptors were individually expressed in Chinese hamster ovary cells as described previously (Holmes, et al., Science, 1991, 253, 1278).
• the Chinese hamster ovary membranes were homogenized according to a previously described protocol (Kraft, et al., Nature, 1983, 301, 621).
• Membrane protein concentration was determined using Pierce Co. micro- assay kit using bovine serum albumin as a standard. All assays were performed in a 96- well micro plate format.
• Each reaction mixture contained 125j JL-8 (0.25 nM), 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, 0.1 mM EDTA, 25 mM NaCl and 0.03% CHAPS plus peptide at relevant concentrations.
• the assay was initiated by addition of ⁇ $ ⁇ - __.-..
• 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.

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