WO2011060395A1 - Urées cycliques utilisées comme inhibiteurs du vih - Google Patents

Urées cycliques utilisées comme inhibiteurs du vih Download PDF

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Publication number
WO2011060395A1
WO2011060395A1 PCT/US2010/056767 US2010056767W WO2011060395A1 WO 2011060395 A1 WO2011060395 A1 WO 2011060395A1 US 2010056767 W US2010056767 W US 2010056767W WO 2011060395 A1 WO2011060395 A1 WO 2011060395A1
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pharmaceutically acceptable
ring
group
alkyl
compound according
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PCT/US2010/056767
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English (en)
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Gerald W. Shipps, Jr.
Cliff C. Cheng
Robert Jason Herr
Jinhai Yang
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Schering Corporation
Albany Molecular Research Institute
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds, to pharmaceutical compositions comprising these compounds and to their use in therapy, in particular for the blocking of HTV, or in treatment or prevention of inflammatory and immune disorders such as HIV infection.
  • Chemotaxis is a phenomenon in which movement of cells is directed by extracellular gradients of chemoattractant cytokines called chemokines (Jin et al., Eur. J. Cell Biol. 85, 905-913 (2006)). Chemotaxis plays critical roles in diverse physiological processes, including the initiation and maintenance of inflammation, trafficking of lymphocytes in the human body, and neuronal cell patterning in the development of the nervous system. More than 50 chemokines have been identified and classified in a family of small proteins (70 - 90 amino acids) that share conserved N-terminal cysteine motifs (Murphy, Pharmacol. Rev. 54, 227-229 (2002)).
  • Chemokines are further classified according to the number and spacing of cysteines in these motifs into C, CC, CXC and CX subfamilies. Most chemokines can also be classified as inflammatory or homeostatic (Moser et al., Nat. Immunol. 2, 123-128 (2001 )). Inflammatory chemokines are produced in response to pathological conditions, whereas homeostatic chemokines are involved in normal 'housekeeping' functions such as the maturation of leukocytes in the bone marrow.
  • chemokines The cellular receptors for chemokines are a subfamily of G-protein-coupled receptors (GPCRs). Receptor binding of chemokines results in the activation of associated heterotrimeric G-proteins, which stimulates a signaling cascade resulting in chemotaxis. To date 18 chemokine receptors have been identified and are responsible for the effects of the more than 50 known chemokines (Murphy, Pharmacol. Rev. 54, 227-229 (2002)).
  • CCR5 Two chemokine receptors CCR5 and CXCR4 have been shown to play essential roles in HIV infection (Alkhatib et al, Science 272, 1 55-1958 (1996), Feng et al., Science 272, 872-877 (1996)).
  • CCR5 normally functions in the inflammatory response to infection, and has 3 natural chemokine binding partners, CCL3 (MIP-1 alpha), CCL4 (MlP-lbeta) and CCL5 (RANTES) (Samson et al, Biochemistry 35, 3362-3367 (1 96)).
  • CCR5 function appears to be redundant as individuals that lack CCR5 do not have any apparent immunological defects (Liu et al., Cell 86, 367-377(1996)).
  • CXCR4 carries out essential roles in B-cell homeostasis, organ development and angiogenesis. To date CXCR4 has been shown to interact with only one chemokine CXCL12 (SDF- 1 ) (Bleul et al., 1996, Oberlin et al., 1996)). Short-term disruption of CXCL12 induced CXCR4 receptor function in humans by AMD3100 induces release of heamatopoetic stem cells and leukocytes from the bone marrow (Flomenberg et al., Blood 106, 1867- 1874 (2005)).
  • CXCR4 or CXCL2 knock-out mice have severe defects in organ vascularization, cardiogenesis and CNS development and die in utero (Zou et al., Nature, 393, 595-599 (1998); Tachibana et al, Nature 393, 591-594 (1998)).
  • HIV spikes consist of a trimer of heterodimers made up of one molecule of the viral g l20 envelope antigen non-covalently attached to a molecule of the gp41 transmembrane glycoprotein.
  • the primary receptor used by HIV for entry is CD4, which is expressed on the surface of a number of cell types that function in the immune system including T helper cells and macrophages.
  • CCR5 or CXCR4 are used as secondary receptors in the infection process and the preferential use of either CCR5 or CXCR4 by HIV strains is used to define HIV tropism (Wilkin et al, Clin. Infect. Dis. 44, 591-595 (2007)).
  • HIV cellular tropism was originally classified as T-cell line tropic (T-tropic) or macrophage tropic, based on the type of cells a virus was capable of infecting. It is now clear that viral tropism can be explained by differential expression of CCR5 and CXCR4 in these cell types.
  • viral tropism is defined as the preference of virus to mediate infection via either CCR5 alone (R5-tropic) or CXCR4 alone (X4- tropic).
  • dual tropic R5/X4 viruses that can use both CCR5 and CXCR4 have been reported.
  • dual tropic viruses are relatively rare and may represent transitional viruses that are evolving from CCR5 to CXCR4 tropism.
  • R5-tropic viruses are largely responsible for viral transmission and predominate in the early stages of the disease, but as HIV infection progresses X4-tropic viruses emerge in about 50% of patients. The majority of these patients are infected with a mixture of R5-tropic and X4-t.ropic and only about 2 percent are infected with X4- tropic virus exclusively. The emergence of X4 virus is often associated increased loss of CD4 cells and progression to AIDS, however it is not known if X4-tropic viruses are the cause or consequence of disease progression.
  • Enfuviritide is a 36 residue peptide mimic of the HR2 domain of gp41 (Wild ei al., Proc. Nat. Acad. Sci. USA 91, 9770-9774 (1994)). Fuzeon binds to the HR1 region of gp41 to prevent formation of the 6-helical bundle and fusion of the viral and cellular membranes.
  • Maraviroc is a member of a class of small molecule CCRS antagonists that inhibit receptor function and gpl20 binding (Westby el al., J. Virol. 80, 4909-4920 (2006)). Maraviroc and two other CCRS antagonists vicriviroc (Strizki et al., Antimicrob. Agents Chemother. 49, 491 1 -491 )) and aplaviroc do not directly compete with gpl20 for binding, but instead function as allosteric inhibitors that stabilize a confirmation of CCRS that is unfavorable for gpl 20 binding.
  • CXCR4 has also been targeted for antiviral therapy and several small molecule antagonists including, AMD3100, AMD070, KRH 1636 and KRH 3140 have been shown to have potent anti-viral activity in vitro.
  • AMD3100 has been tested in clinical trials that provided proof-of-concept for antagonism of CXCR4 as a treatment for HIV (Hendrix et al., J. Acquir. Immune Defic. Syndr. 37, 1253-1262 (2004)).
  • the unfavorable side effects of blocking CXCR4 receptor function have thus far limited the clinical development of CXCR4 antagonists for the HIV indication. This has prompted the need for novel CXCR4 antagonists for use as HIV inhibitors which block viral entry with pharmacologically acceptable abrogation of the signal transduction pathways activated following the CXCL12-CXCR4 interaction.
  • the present invention provides a compound of Formula I
  • X 1 and X 2 independently are N or S;
  • R1 is selected from the group consisting of:
  • each R independently is H or alkyl
  • each R 2 and R 2' is independently H, alkyl or cycloalkyl, or R 2 and R 2' together with the carbon or carbons to which they are shown bonded in formula 1 form a cycloalkyl;
  • a is an integer from 1 -3;
  • R3 is selected from the group consisting of H, alkyl, cycloalkyl, heteroacyclyl, aryl, and heteroaryl;
  • x 0, 1 , or 2;
  • each R5 independently is alkyl; is 0, l, or 2;
  • each R6 independently is alkyl
  • each Al ring independently is a five- or six-membered heterocyclyl or heteroaryl, whose ring heteroatoms consist only of 1-3 N atoms;
  • each A2 ring independently is a five- or six-membered heterocyclyl or heteroaryl, whose ring heteroatoms consist only of 1 -3 N atoms;
  • c is 1, 2, or 3;
  • Y1 and Y2 independently are C(R) or N;
  • d 0, 1, or 2;
  • Z' is O or S
  • Z2 is CR or N
  • R7 is -NR2
  • the present invention also provides pharmaceutical compositions and kits comprising the aforesaid compounds of Formula I, and methods of treating or preventing chemokine-mediated disorders such as HIV utilizing the aforesaid compounds of formula I.
  • X 1 and X 2 are both N.
  • ring A optionally with said aryl is selected from the group consisting of:
  • R is
  • R is
  • ring Al is a six-membered heterocyclyl.
  • R1 is
  • ring A 1 is piperidinyl
  • R1 is
  • R1 is
  • R 2 and R 2' are both H, and a is 2.
  • R3 is selected from the group consisting of H and aryl.
  • R3 aryl is phenyl which is unsubstituted or substituted with at least one halo.
  • the compound in formula I is selected from the group consisting of;
  • Patient includes both human and animals.
  • “Mammal” means humans and other mammalian animals.
  • Alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl” means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Alkenyl means an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • alkenyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl. aryl, cycloalkyl, cyano, alkoxy and -S(alkyl).
  • suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut- 2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • alkylene include methylene, ethylene and propylene.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • “Lower alkynyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • Alkynyl may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of alkyl, aryl and cycloalkyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • suitable aryl groups include phenyl and naphthyl.
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about. 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • heteroaryl may also include a heteroaryl as defined above fused to an aryl as defined above.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl.
  • 1,2,4- thiadiazolyl pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1,2- ajpyridinyl, imidazo[2,l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl,
  • heteroaryl also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl,
  • Alkyl or arylalkyl means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non- limiting examples of suitable aralkyl groups include benzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl, The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
  • Cycloalkylalkyl means a cycloalkyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl and the like.
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohept.a-l ,3-dienyl, and the like.
  • Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
  • Cycloalkenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like.
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Ring system substituent means a substituent attached to an aromatic or non- aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroaryl alkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylene dioxy, ethylenedioxy, - C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • Heteroarylalkyl means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • Heterocyclylalkyl means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
  • Heterocyclenyl means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • Non-limiting examples of suitable heterocyclenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2- dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6- tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4- dihydro-2H-pyranyl, dihydrofuranyl, fluorodihydrofliranyl, 7- oxabicyclo[2.2.1]heptenyl, di ydrothiophenyl, dihydrothiopyranyl, and the like.
  • Example of such moiety is pyrrolidinone:
  • Heterocyclenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • hetero-atom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • N, O or S there are no hydroxyl groups on carbon atoms adjacent to a N, O or S, as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl.
  • Heteroaralkyl means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin- 3-ylmethyl. The bond to the parent moiety is through the alkyl.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2-hydroxyethyl.
  • acyl means an H-C(O)-, alkyl-C(0)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl.
  • Preferred acyls contain a lower alkyl.
  • suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described, The bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent, moiety is through the ether oxygen,
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkyloxy means an aralkyl-O- group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio.
  • the bond to the parent moiety is through the sulfur.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio.
  • the bond to the parent moiety is through the sulfur.
  • Aralkylthio means an aralkyl-S- group in which the aralkyl group is as previously described.
  • Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
  • Alkoxycarbonyl means an alkyl-O-CO- group.
  • suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O-C(O)- group.
  • suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkoxycarbonyl means an aralkyl -O-C(O)- group.
  • a suitable aralkoxycarbonyl group is benzyloxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(02)- group. Preferred groups are those in which the alky] group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Alsulfonyl means an aryl-S(02)- group. The bond to the parent moiety is through the sulfonyl.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds,
  • stable compound or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • purified refers to the physical state of said compound after being isolated from a synthetic process (e.g., from a reaction mixture), or natural source or combination thereof.
  • purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan (e.g., chromatography, recrystallization and the like) in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • the present invention further includes the compound of formula I in all its isolated forms.
  • the compound of Formula I is intended to encompass all forms of the compound such as, for example, any solvates, hydrates, stereoisomers, tautomers etc.
  • the present invention further includes the compound of formula I in its purified form.
  • any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences. And any one or more of these hydrogen atoms can be deuterium.
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1 91), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • the term "prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (1) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-Cg)alkyl, (C2- Ci2)alkanoyloxymethyl, 1 -(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1- methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
  • alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1 -methyl- 1- (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1 -(N-
  • alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4- crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(C1-C2)alkylamino(C2-C3)alkyl (such as ⁇ -dimethylaminoethyl), carbamoyl-(C1-C2)alkyl, N,N-di (C1- C2)alkylcarbamoyl-(Cl-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2- C3)alkyl, and the like.
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (C1-CsJalkanoyloxvmethyl, l-((Cj- C6)alkanoyloxy)ethyl, 1 -methyl-1 -((C1-CeJalkanoyloxyJethyl, (C1- CeJalkoxycarbonyloxymethyl, N-(C1-C6)alkoxycarbonylaminomethyl, succinoyl, (Cp Cejalkanoyl, cc-amino(C1-C4)alkanyl, arylacyl and ⁇ -aminoacyl, or c -aminoacyl-a- aminoacyl, where each a-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (C1-C10)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl,— C(OH)C(0)OYJ wherein Y1 is H, (C1-C6)alkyl or benzyl,— C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (C1-C6)alkyl, carboxy (C1-Cfi)alkyl, amino(C1-C4)alkyl or mono-N— or di-N,N-(C1-C6)alkylaminoalkyl,
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H2O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sc , 930 ⁇ , 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the compounds of Formula I can form salts which are also within the scope of this invention.
  • Reference to a compound of Formula I herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions inner salts may be formed and are included within the term "salt(s)" as used herein.
  • Salts of the compounds of the Formula I may be formed, for example, by reacting a compound of Formula 1 with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates,
  • camphorsulfonates fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfbnates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quarternized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n- propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, CMalkyl, or Ci ⁇ alkoxy or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example,
  • phosphate esters may be further esterified by, for example, a C1.20 alcohol or reactive derivative thereof, or by a 2,3-di (C6.24)acyl glycerol.
  • Compounds of Formula I, and salts, solvates, esters and prodrugs thereof may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
  • the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a
  • diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral HPLC column.
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • salt is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 36 C1 and 123 I, respectively.
  • Certain isotopically-labelled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., 3H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • Certain isotopically-labelled compounds of Formula (I) can be useful for medical imaging purposes. E.g., those labeled with positron-emitting isotopes like UC or 18 F can be useful for application in Positron Emission Tomography (PET) and those labeled with gamma ray emitting isotopes like 123 I can be useful for application in Single photon emission computed tomography (SPECT).
  • PET Positron Emission Tomography
  • SPECT Single photon emission computed tomography
  • substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-li e or reduced dosage requirements) and hence may be preferred in some circumstances.
  • substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • isotopic substitution at a site where epimerization occurs may slow or reduce the epimerization process and thereby retain the more active or efficacious form of the compound for a longer period of time.
  • Isotopically labeled compounds of Formula (I), in particular those containing isotopes with longer half lives (Tl/2 >1 day), can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an appropriate isotopically labeled reagent for a non-isotopically labeled reagent.
  • the compounds of the present invention are useful in therapy.
  • the compounds of the present invention are useful in therapy in humans or animals.
  • the compounds of the present invention are useful in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by chemokines.
  • the compounds of the present invention are useful in the manufacture of a medicament for the treatment or prevention of inflammatory or immune diseases selected from neurodegenerative diseases, multiple sclerosis, systemic lupus, erythematosis, rheumatoid arthritis, ankylosing, spondylitis, psoriatic arthritis, juvenile rheumatoid arthritis, atherosclerosis, vasculitis, chronic heart failure, cerebrovascular ischemia, encephalitis, meningitis, hepatitis, nephritis, glomerulonephritis, sepsis, sarcoidosis, psoriasis, eczema, urticaria, type 1 diabetes, asthma, conjunctivitis, ophthalmic inflammation, otitis, allergic rhinitis, chronic obstructive pulmonary disease, sinusitis, dermatitis, inflammatory bowel disease, ulcerative colitis, Chron's disease. Behcet's syndrome,
  • the compounds of the present invention are also useful for the manufacture of a medicament for the treatment or prevention of cancer.
  • the compounds of the present invention are therefore useful for the manufacture of a medicament for the treatment or prevention of solid tumors and hemoatopoietic tumors associated with breast cancer, renal cancer, non-small cell lung cancer, non-hodgkins lymphoma, metastasis melanoma or leukemia.
  • the compounds of the present invention are also useful for the manufacture of a medicament for the treatment or prevention of a viral or bacterial infection.
  • the compounds of the present invention are also useful for the manufacture of a
  • the compounds of the present invention are also useful for the manufacture of a medicament for the treatment or prevention of a disease or condition selected from the group consisting of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allegies, and multiple sclerosis.
  • a disease or condition selected from the group consisting of solid organ transplant rejection, graft v. host disease, arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic dermatitis, psoriasis, asthma, allegies, and multiple sclerosis.
  • the present invention also includes a compound, for use in the treatment of any of the aforementioned diseases or disorders.
  • the present invention further includes a method for the treatment of a mammal, including a human, suffering from or liable to suffer from any of the aforementioned diseases or disorders, which method comprises administering an effective amount of a tricyclic compound according to the present invention or a pharmaceutically acceptable salt or solvate thereof.
  • a method of treatment may be oral, intravenous or subcutaneous.
  • Such a method of treatment may be oral, nasal, intravenous or subcutaneous, or other similar suitable method.
  • the amount of a compound of the present invention or a pharmaceutically acceptable salt, solvate, ester or prodrug thereof, also referred to herein as the active ingredient, which is required to achieve a therapeutic effect will, of course, vary with the particular compound, the route of administration, the age and condition of the recipient, and the particular disorder or disease being treated.
  • a suitable daily dose for any of the above mentioned disorders will be in the range of 0.001 to 50 mg per kilogram body weight of the recipient (e.g. a human) per day, preferably in the range of 0.01 to 20 mg per kilogram body weight per day.
  • the desired dose may be presented as multiple sub-doses administered at appropriate intervals throughout the day.
  • the present invention therefore also provides a composition comprising a compound according to the present invention in admixture with one or more acceptable excipients.
  • the present invention provides a pharmaceutical composition comprising a compound according to the present invention in admixture with one or more pharmaceutically acceptable excipients, such as the ones described in Gennaro et. al., Remmington: The Science and Practice of Pharmacy, 20th Edition, Lippincott, Williams and Wilkins, 2000; see especially part 5: pharmaceutical manufacturing.
  • pharmaceutically acceptable means being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. Suitable excipients are described e.g., in the Handbook of
  • compositions include those suitable for oral, nasal, topical (including buccal, sublingual and transdermal), parenteral (including subcutaneous, intravenous and intramuscular) or rectal administration or other suitable method.
  • the mixtures of a compound according to the present invention and one or more pharmaceutically acceptable excipient or excipients may be compressed into solid dosage units, such as tablets, or be processed into capsules or suppositories.
  • solid dosage units such as tablets
  • the compounds of the present invention can also be applied as an injection preparation in the form of a solution, suspension, emulsion, or as a spray, e.g., a nasal or buccal spray.
  • a spray e.g., a nasal or buccal spray.
  • dosage units e.g., tablets
  • the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated.
  • any pharmaceutically acceptable additive can be used.
  • the compounds of the present invention are also suitable for use in an implant, a patch, a gel or any other preparation for immediate and/or sustained release,
  • Suitable fillers with which the pharmaceutical compositions can be prepared and administered include lactose, starch, cellulose and derivatives thereof, and the like, or mixtures thereof used in suitable amounts,
  • aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol.
  • the present invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described.
  • the present invention provides a phannaceutical
  • composition as hereinbefore described, additionally comprising one or more anti-viral or other agents useful in the treatment of Human Immuno-deficiency Virus.
  • antiviral or other agents are well known in the art and include, but are not limited to: CCR5 antagonists (HIV entry inhibitor), nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, and other antiviral agents listed below not falling within these classifications.
  • the antiviral agent or agents may be combined with the presently claimed compounds that are CXCR4 antagonists in a single dosage form, or the CXCR4 antagonist and the antiviral agent or agents may be administered simultaneously or sequentially as separate dosage forms.
  • Antiretroviral Therapy are contemplated for use in combination with the CXCR4 antagonists of this invention or with the combination of the CXCR4 antagonists and CCR5 receptor antagonists.
  • CCR5 antagonist refers to CCR5 receptor antagonists that are well known those of ordinary skill in the art. Suitable CCR5 antagonists include Vicriviroc (Phase III, Schering-Plough), and Maraviroc (Selzentry; marketed by Pfizer).
  • nucleoside and nucleotide reverse transcriptase inhibitors as used herein means nucleosides and nucleotides and analogues thereof that inhibit the activity of HIV- 1 reverse transcriptase, the enzyme which catalyzes the conversion of viral genomic HIV-1 RNA into proviral HIV-1 DNA.
  • Typical suitable NRTIs include zidovudine (AZT) available under the
  • NRTP's non-nucleoside reverse transcriptase inhibitors
  • NNRTIs include nevirapine (BI-RG-587) available under the VIRAMUNE tradename from Boehringer Ingelheim, the manufacturer for Roxane Laboratories, Columbus, OH 43216; delaviradine (BHAP, U-90152) available under the RESCRIPTOR tradename from Pharmacia & Upjohn Co., Bridgewater NJ 08807; efavirenz (DMP-266) a benzoxazin-2-one disclosed in WO94/03440 and available under the SUSTIVA tradename from DuPont Pharmaceutical Co., Wilmington, DE 19880-0723; PNU-142721 , a fiiropyridine-thio-pyrimide under development by Pharmacia and Upjohn, Bridgewater NJ 08807; AG- 1549 (formerly Shionogi # S- 1 153); 5-(3,5-dichlorophenyl)- thio-4-isopropyl-1-(4-pyridyl)methyl-IH-imidazol-2- ylmethyl carbon
  • protease inhibitor means inhibitors of the HIV- 1 protease, an enzyme required for the proteolytic cleavage of viral polyprotein precursors (e.g., viral GAG and GAG Pol polyproteins), into the individual functional proteins found in infectious HIV-1.
  • HIV protease inhibitors include compounds having a peptidomimetic structure, high molecular weight (7600 daltons) and substantial peptide character, e.g. CRIXIVAN® (available from Merck) as well as nonpeptide protease inhibitors e.g., VIRACEPT® (available from Agouron).
  • Typical suitable Pis include saquinavir (Ro 31-8959) available in hard gel capsules under the INVIRASE® tradename and as soft gel capsules under the
  • nelfnavir available under the VIRACEPT® tradename from Agouron Pharmaceuticals, Inc., LaJolla CA 92037-1020; amprenavir (141 W94), tradename AGENERASE®, a non-peptide protease inhibitor under development by Vertex Pharmaceuticals, Inc., Cambridge, MA 02139-421 1 and available from Glaxo- Wellcome, Research Triangle, NC under an expanded access program; lasinavir (BMS-234475) available from Bristol-Myers Squibb, Princeton, NJ 08543 (originally discovered by Novartis, Basel, Switzerland (CGP-61755); DMP-450, a cyclic urea discovered by Dupont and under development by Triangle Pharmaceuticals; BMS- 2322623, an azapeptide under development by Bristol-Myers Squibb, Princeton, NJ 08543, as a 2nd -generation HIV-1 PI; ABT-378 under development by Abbott , Abbott Park, IL 60064; and AG- 1549 an
  • antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafuside and Yissum Project No. 11607.
  • Hydroxyurea Droxia
  • IL-2 a ribonucleoside triphosphate reductase inhibitor, the enzyme involved in the activation of T-cells, was discovered at the NCI is under development by Bristol-Myers Squibb; in preclinical studies, it was shown to have a synergistic effect on the activity of didanosine and has been studied with stavudine.
  • IL-2 is disclosed in Ajinomoto EP-0142268 , Takeda EP-0176299, and Chiron U. S. Patent Nos.
  • RE 33653, 4530787, 4569790, 4604377, 4748234, 752585, and 4949314 is available under the PROLEUKIN (aldesleukin) tradename from Chiron Corp., Emeryville, CA 94608-2997 as a lyophilized powder for IV infusion or sc administration upon reconstitution and dilution with water; a dose of about 1 to about 20 million IU/day, sc is preferred; a dose of about 15 million IU/day, sc is more preferred.
  • IL-12 is disclosed in W096/25171 and is available from Roche
  • Pentafuside DP-178, T-20
  • Pentafuside a 36-amino acid synthetic peptide,disclosed in U.S. Patent No.5,464,933 licensed from Duke University to Trimeris which is developing pentafuside in collaboration with Duke University; pentafuside acts by inhibiting fusion of HIV-1 to target membranes.
  • Pentafuside (3-100 mg /day) is given as a continuous sc infusion or injection together with efavirenz and 2 PI's to HIV-1 positive patients refractory to a triple combination therapy; use of 100 mg/day is preferred.
  • Yissum Project No. 1 1607 a synthetic protein based on the HIV -1 Vif protein, is under preclinical development by Yissum Research Development Co., Jerusalem 91042 , Israel.
  • Ribavirin, l-B-D-ribofuranosyl-1H-1,2,4-triazole-3- carboxamide, is available from ICN Pharmaceuticals, Inc., Costa Mesa, CA; its manufacture and formulation are described in U.S. Patent No. 4,21 1,771.
  • anti-HIV-1 therapy means any anti-HIV-1 drug found useful for treating HIV-1 infections in man alone, or as part, of multidrug combination therapies, especially the HAART triple and quadruple combination therapies.
  • Typical suitable known anti-HIV-1 therapies include, but are not limited to multidrug combination therapies such as (i) at least three anti-HTV-l drugs selected from two NRTls, one PI, a second PI, and one NNRTI; and (ii) at least two anti-HIV-1 drugs selected from , NNRTIs and Pis.
  • Typical suitable HAART - multidrug combination therapies include:
  • triple combination therapies such as two NRTIs and one PI ; or (b) two NRTIs and one NNRTI ; and (c) quadruple combination therapies such as two NRTIs , one PI and a second PI or one NNRTI.
  • triple combination therapies such as two NRTIs and one PI
  • two NRTIs and one NNRTI two NRTIs and one NNRTI
  • quadruple combination therapies such as two NRTIs , one PI and a second PI or one NNRTI.
  • the CD4 and HIV-1 -RN A plasma levels should be monitored every 3-6 months. Should viral load plateau, a fourth drug,e.g., one PI or one NNRTI could be added. See the table below wherein typical therapies are further described:
  • zidovudine + lamivudine zidovudine + didanosine
  • immune suppressants such as cyclosporine and Interleukin-10 (IL-10), tacrolimus, antilymphocyte globulin, OKT-3 antibody, and steroids;
  • IL-10 inflammatory bowel disease: IL-10 (see US 5,368,854), steroids and azulfidine;
  • rheumatoid arthritis methotrexate, azathioprine, cyclophosphamide, steroids and mycophenolate mofetil; and, multiple sclerosis: interferon-beta, interferon- alpha, and steroids.
  • a pharmaceutical composition comprising one or more anti-viral agents selected from zidovudine, lamivudine, zalcitabine, didanosine, stavudine, abacavir, adefovir dipivoxil, lobucavir, BCH-10652, emitricitabine, beta-L-FD4, DAPD, lodenosine, nevirapine, delaviridine, efavirenz, PNU-142721, AG-1549, MKC-442, (+)-calanolide A and B, saquinavir, indinavir, ritonavir, nelfinavir, lasinavir, DMP-450, BMS-2322623, ABT-378, amprenavir, hydroxyurea, ribavirin, IL-2, IL-12, pentafuside, Yissum No. 1 1607 and AG-1549.
  • the anti-viral agent component of said pharmaceutical selected from zidovudine
  • a further embodiment of the present invention is a method of inhibiting the replication of Human Immunodeficiency Virus, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a pharmaceutical composition of the present invention as hereinbefore described optionally comprising one or more anti-viral agents useful in the treatment of Human Immuno-deficiency Virus.
  • kits comprising in separate containers in a single package, pharmaceutical compositions for use in combination to treat Human Immunodeficiency Virus which comprises, in one container, a
  • composition comprising at least one compound according to the present invention, in one or more pharmaceutically acceptable carriers, and in a separate container, one or more pharmaceutical composition comprising one or more antiviral or other agents useful in the treatment of Human Immunodeficiency Virus in one or more pharmaceutically acceptable carriers.
  • Final compounds were purified by PrepLC using the column of Varian Pursuit XRs C 18 10m 250 x 21.2 mm and an eluent mixture of mobile phase A and B.
  • the mobile phase A is composed of 0.1% TFA in H2O and the mobile phase B is composed of CHjCN (95%) / H20 (5%) / TFA (0.1%).
  • the mixture of mobile phase A and B was eluted through the column at a flow rate of 20 mL/min at room temperature.
  • Acetic acid AcOH
  • N,N-Dimethylformamide DMF
  • dichloroethane DCE
  • dichloromethane DCM
  • dimethylsuphoxide DMSO
  • diphenylphosphoryl azide DPP A
  • ethanol EtOH
  • ethyl acetate EtOAc
  • HATU hexafluoro phosphate
  • HPLC high pressure liquid chromatography
  • DIPEA diisopropylethylamine
  • TAA triethylamine
  • TFA trifluoroacetic acid
  • water H20
  • the amine component (0, 14 mmol) (2-(5,6,7,8-tetrahydro-l ,8-naphthyridin-2- yl)ethanamine for Example 1.1) was weighed into a 4 mL scintillation vial and then dissolved in 0.5 mL of freshly opened anhydrous DMF. The vial was stirred until dissolved.
  • the isocyanate or thioisocyanate component (0, 1 mmol) (3- methylthiophenylisocyanate for Example 1.1 ) was weighed into a separate 4 mL scintillation vial and dissolved in 0.5 mL of freshly opened anhydrous DMF.
  • Step 1 A solution of tert-butyl 3-aminopropylcarbamate (418 mg, 2.4 mmol) in anhydrous methylene chloride (4 mL) was added dropwise to a solution of 3,4- dichlorobenzyl isocyanate (404 mg, 2.0 mmol) in anhydrous methylene chloride (2 mL) at room temperature under nitrogen and the mixture was stirred for 18 h.
  • Step 2 A solution of HC1 in dioxane (3.76 mL, 15 mmol, 4 M in dioxane) was added to a solution of tert-butyl 3-(3-(3,4-dichlorobenzyl)ureido)propylcarbamate (566 mg, 1.5 mmol) in anhydrous 1,4-dioxane (4 mL) at room temperature under nitrogen and the mixture was stirred for 16 h.
  • Step 4 A solution of HCl in dioxane (1.4 mL, 5.6 mmol, 4 M in dioxane) was added to a solution of tert-butyl l-(3,4-dichlorophenyl)-13, 13-dimethyl-3,l 1 -dioxo- 12-oxa- 2,4,8, 10-tetraazatetradecan-9-ylidenecarbamate (299 mg, 0.58 mmol) in anhydrous 1 ,4- dioxane (3 mL) at room temperature under nitrogen and the mixture was stirred for 18 h.
  • Silver(I) acetate 52 mg, 0.80 mmol was added to a solution of l-(3,4-dichlorobenzyl)- 3-(2-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)ethyl)thiourea (160 mg, 0.40 mmol) and sodium cyanamide (132 mg, 0.80 mmol) in anhydrous DMF (2 mL) at room temperature under nitrogen and the mixture was stirred for 12 h. Additional silver(I) acetate (52 mg, 0,80 mmol) and sodium cyanamide (132 mg, 0.80 mmol) were added and stirring was continued for a total of 40 h.
  • Step 1 3 -Fluorophenyl isocyanate (250 mg, 1.8 mmol) was added to a solution of 6,7,8,9-tetrahydropyrido[2,3-6][1,6]naphthyridine (405 mg, 2.2 mmol) in anhydrous methylene chloride (10 mL) at room temperature under nitrogen and the mixture was stirred for 18 h. The solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with
  • Step 2 A solution of HCl in dioxane (0.8 mL, 1 .6 mmol, 4 M in dioxane) was added to a solution of N-(3-fluorophenyl)-l )2,3,4,8,9-hexahydropyrido[2,3-b][1,6]naphthyridine- 7(6H)-carboxamide (109 mg, 0.33 mmol) in anhydrous methanol (5 mL) and anhydrous methylene chloride (5 mL) at room temperature under nitrogen and the mixture was stirred for 10 min.
  • Step 1 A solution of 9-BBN dimmer (8,0 mL, 4.0 mmol, 0.5 M solution in THF) was added dropwise to a solution of benzyl vinylcarbamate (850 mg, 4.8 mmol) in anhydrous THF (6 mL) at 0 °C under a nitrogen atmosphere after which the mixture was slowly warmed to room temperature, stirring for a total of 16 h. The mixture was cooled to 0 °C and 3 M NaOH (3.6 mL) was added dropwise, after which the mixture was warmed to room temperature, stirring for a total of 90 min.
  • Step 2 A mixture of benzyl 2-(6-(methylamino)pyridin-2-yl)ethylcarbamate (388 mg, 1.36 mmol) and 10% palladium on charcoal (300 mg) in ethanol (10 mL) was stirred under one atmosphere of hydrogen at room temperature for 24 h. The solids were removed by vacuum filtration and the filtrate solvents were removed under reduced pressure to provide 6-(2-aminoethyl)-N-methylpyridin-2-amine (200 mg, 97%) which was suitable for use without further purification: ESI MS m/z 152 [M + H]+. Step 3.
  • Step 2 A mixture of N-(2-nitrobenzyl)-2-(5,6,7,8-te1.rahydro-l ,8-naphthyridin-2- yl)ethanamine (100 mg, 0.32 mmol) and platinum(IV) oxide (35 mg) in ethanol (2 mL) and ethyl acetate (2 mL) was stirred under one atmosphere of hydrogen at room temperature for 2 h. The solids were removed by vacuum filtration and the filtrate solvents were removed under reduced pressure.
  • Step 3 Carbonyl diimidazole (32 mg, 0.20 mmol) was added to a solution of 2-((2- (5,6,7,8-tetrahydro-l ,8-naphthyridin-2-yl)ethylamino)methyl)ai.iline (60 mg, 0.20 mmol) in anhydrous methylene chloride (1 mL) at room temperature under nitrogen and the mixture was stirred for 12 h.
  • Step 1 Diisopropylethylamine (0.17 mL, 1.0 mmol) was added to a suspension of 2- (3-fluorophenylamino)acetic acid (85 mg, 0.50 mmol) PyBop (260 mg, 0.50 mmol) in anhydrous methylene chloride (3 mL) at room temperature under nitrogen and the resulting mixture was added immediately to a mixture of 2-(5,6,7,8-tetrahydro-l ,8- naphthyridin-2-yl)ethanamine hydrochloride (307 mg, 0.50 mmol) and
  • Step 2 A solution of borane in THF (2.43 mL, 2.43 mmol, 1 M solution in THF) was added solution of 2-(3-fluorophenylamino)-N-(2-(5,6,7,8-tetrahydro- 1 ,8-naphthyridin- 2-yl)ethyl)acetamide (267 mg, 0.81 mmol) in anhydrous THF (10 mL) at room temperature under nitrogen and the mixture was stirred for 12 h. The mixture was diluted with 2 HCl (5 mL) and stirred for 10 min, after which the mixture was neutralized by the addition of solid NaHCO 3 .
  • Step 4 A solution of N-(2-(3-fluorophenylamino)ethyl)-N-(2-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)ethyl)-lH-imidazole-l -carboxamide (24 mg, 0.059 mmol) in anhydrous chloroform (1 mL) was heated at 60 °C under nitrogen for 2 days.
  • CXCR4 that was isolated from a permanent mammalian cell line (HEK-293-EbNA) expressing an epitope-tagged recombinant form of CXCR4 at 10 pmol/mg of membrane in adherent growth mode and using the general screening and Iigand binding assays described in J. Biomol. Screening., 2006, 11, 194-207 and Comb. Chem. And High Throughput Screen, 2008,11, 427-438.
  • Luciferase reporter viruses (ADA, YU-2) were generated as described by Connor et al. (J. Virol, 1996, 70, 5206-531 1), Primary HIV-1 isolates were obtained from commercial sources. Viral Stocks were propagated in phytohemagglutinin (5
  • PBMC peripheral blood mononuclear cells
  • test compounds were added and incubated for and additional 1 hr period.
  • CXCR4-tropic HXB2 virus (3), or HIV-1 particles pseudotyped with the HXB2 envlelope ( 1 ), both of which were engineered to express the firefly luciferase gene were added to the test wells.
  • luciferase acitivity was measured using Glo Lysis buffer (Promega) and the Brightlite reagent (PerkinElmer).
  • Ficoll-purified PBMC were stimulated in vitro with 5 mg/ml phytohemagglutin and 50 units/ml IL-2 for 3 days.
  • the cells were resuspended at 4 x 106/ml in complete medium (RPMI, 10% FBS/50 units/ml IL-2), seeded into 96 well plates (2 x 10 5 well), incubated with inhibitor for lh at 37 °C and infected in triplicate with 25-100 tissue culture 50% ineffective dose (TCID5o) per well of an HIV-1 primary isolate for 3-4 h.
  • the cells were washed twice in PBS to remove residual vims and cultured in the presence of inhibitor for 4-6 days. HIV-1 replication was quantitatied by measurement of extracellular p24 antigen by EL1SA.
  • the IC 50 and IC 90 values for each virus were determined by using GRPAHPAD PRISM software.
  • the migrated cells were counted on a flow cytometer.
  • Many of the compounds of the invention had IC 50 values less than 25 ⁇ in the chemotaxis assay.
  • the "CXCR4 IC50” values refer to assay results that used a live virus.
  • the “CXCR4 PV IC50” values refer to assay results that used a pseudovirus. Listings in tables of SO indicate actual values of SO or greater.

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Abstract

L'invention concerne un composé représenté par la formule (I) dans laquelle les variables sont telles que définies dans la spécification. L'invention concerne également des compositions pharmaceutiques comprenant ces composés et leur utilisation en thérapie, en particulier pour traiter ou prévenir les troubles induits par la chimiokine, tels qu'une infection par le VIH.
PCT/US2010/056767 2009-11-16 2010-11-16 Urées cycliques utilisées comme inhibiteurs du vih WO2011060395A1 (fr)

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EP2627178A1 (fr) * 2010-10-11 2013-08-21 Merck Sharp & Dohme Corp. Composés de type quinazolinone convenant comme antagonistes de crth2
US20150057308A1 (en) * 2013-02-07 2015-02-26 Scifluor Life Sciences, Llc Fluorinated 3-(2-Oxo-3-(3-Arylpropyl)Imidazolidin-1-yl)-3-Arylpropanoic Acid Derivatives
US9388126B2 (en) 2012-07-19 2016-07-12 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US9518053B2 (en) 2013-02-07 2016-12-13 Scifluor Life Sciences, Inc. Fluorinated integrin antagonists
US11117870B2 (en) 2017-11-01 2021-09-14 Drexel University Compounds, compositions, and methods for treating diseases
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2627178A1 (fr) * 2010-10-11 2013-08-21 Merck Sharp & Dohme Corp. Composés de type quinazolinone convenant comme antagonistes de crth2
EP2627178A4 (fr) * 2010-10-11 2014-08-20 Merck Sharp & Dohme Composés de type quinazolinone convenant comme antagonistes de crth2
US8927559B2 (en) 2010-10-11 2015-01-06 Merck Sharp & Dohme Corp. Quinazolinone-type compounds as CRTH2 antagonists
US10314795B2 (en) 2012-07-19 2019-06-11 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US9889102B2 (en) 2012-07-19 2018-02-13 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US9388126B2 (en) 2012-07-19 2016-07-12 Drexel University Sigma receptor ligands and methods of modulating cellular protein homeostasis using same
US9717729B2 (en) 2013-02-07 2017-08-01 Scifluor Life Sciences, Inc. Fluorinated integrin antagonists
US9593114B2 (en) 2013-02-07 2017-03-14 Scifluor Life Sciences, Inc. Fluorinated 3-(2-oxo-3-(3-arylpropyl)imidazolidin-1-yl)-3-arylpropanoic acid derivatives
US9518053B2 (en) 2013-02-07 2016-12-13 Scifluor Life Sciences, Inc. Fluorinated integrin antagonists
US9802933B2 (en) 2013-02-07 2017-10-31 Scifluor Life Sciences, Inc. Fluorinated 3-(2-oxo-3-(3-arylpropyl)imidazolidin-1-yl)-3-arylpropanoic acid derivatives
US9266884B2 (en) * 2013-02-07 2016-02-23 Scifluor Life Sciences, Inc. Fluorinated 3-(2-oxo-3-(3-arylpropyl)imidazolidin-1-y1)-3-arylpropanoic acid derivatives
US10106537B2 (en) 2013-02-07 2018-10-23 Scifluor Life Sciences, Inc. Fluorinated integrin antagonists
US10155758B2 (en) 2013-02-07 2018-12-18 Scifluor Life Sciences, Inc. Fluorinated 3-(2-oxo-3-(3-arylpropyl)imidazolidin-1-yl)-3-arylpropanoic acid derivatives
US20150057308A1 (en) * 2013-02-07 2015-02-26 Scifluor Life Sciences, Llc Fluorinated 3-(2-Oxo-3-(3-Arylpropyl)Imidazolidin-1-yl)-3-Arylpropanoic Acid Derivatives
US11685737B2 (en) 2013-02-07 2023-06-27 Ocuterra Therapeutics, Inc. Fluorinated integrin antagonists
US11685738B2 (en) 2015-02-19 2023-06-27 Ocuterra Therapeutics, Inc. Fluorinated tetrahydronaphthyridinyl nonanoic acid derivatives and uses thereof
US11117870B2 (en) 2017-11-01 2021-09-14 Drexel University Compounds, compositions, and methods for treating diseases

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