(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`22 June 2006 (22.06.2006)
`
`
`
`(51) International Patent Classification:
`C07D 211/22 (2006.01)
`A61K 31/404 (2006.01)
`C07D 295/20 (2006.01)
`A61K 31/444 (2006.01)
`C07D 217/06 (2006.01)
`A61K 31/4523 (2006.01)
`C07C 271/44 (2006.01)
`A61K 31/472 (2006.01)
`C07D 217/24 (2006.01)
`A61K 31/496 (2006.01)
`C07C 311/08 (2006.01)
`A61P 35/00 (2006.01)
`C07C 271/58 (2006.01)
`C07D 211/66 (2006.01)
`C07D 211/60 (2006.01)
`C07D 243/08 (2006.01)
`C07D 215/08 (2006.01)
`C07D 209/08 (2006.01)
`C07D 471/04 (2006.01)
`C07D 215/20 (2006.01)
`A61K 31/325 (2006.01)
`C07D 401/12 (2006.01)
`A61K 31/4025 (2006.01)
`C07D 491/10 (2006.01)
`
`(21) International Application Number:
`PCT/US2005/042482
`
`(22) International Filing Date:
`23 November 2005 (23.11.2005)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/629,889
`60/633,738
`60/639,283
`
`23 November 2004 (23.11.2004)
`6 December 2004 (06.12.2004)
`27 December 2004 (27.12.2004)
`
`US
`US
`US
`
`(71) Applicant (for all designated States except US): PTC
`THERAPEUTICS, INC. [US/US]; 100 Corporate Court,
`Middlesex Business Center, South Plainfield, New Jersey
`07080 (US).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): CHOI, Soongyu
`
`(10) International Publication Number
`
`WO 2006/065479 A2
`
`[KR/US]; 44 Durham Road, Skillman, New Jersey 08558
`(US). MOON, Young-Choon [KR/US]; 11 Edgewood
`Drive, Belle Mead, New Jersey 08502 (US). TAMILA-
`RASU, Nadarajan [IN/US]; 67 Proctor Street, Edison,
`New Jersey 08817 (US).
`
`(74) Agents: ADELSON, Lisa A. et a1.; Arnold & Porter LLP,
`Attn:
`IP Docketing, 555 Twelfth SL, N.w., Washington,
`District Of Columbia 20004—1206 (US).
`
`(81) Designated States (unless otherwise indicated, for ever
`kind of national protection available): AE, AG, AL, AM,
`AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
`CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI,
`GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE,
`KG, KM, KN, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV,
`LY, MA, MD, MG, MK, MN, MW, MX, MZ, NA, NG, NI,
`NO, NZ, OM, PG, PH, PL, PT, RO, RU, SC, SD, SE, SG,
`SK, SL, SM, SY, TJ, TM, TN, TR, TT, T7,, UA, UG, US,
`UZ, VC, VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (unless otherwise indicated, for ever
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI,
`FR, GB, GR, HU, IE, IS, IT, LT, LU, LV, MC, NL, PL, PT,
`RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA,
`GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`— without international search report and to be republished
`upon receipt of that report
`
`For two—letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes and Abbreviations” appearing at the begin,
`ning of each regular issue of the PCT Gazette.
`
`(54) Title: SUBSTITUTED PHENOLS AS ACTIVE AGENTS INHIBITING VEGF PRODUCTION
`
`(57) Abstract: The present invention relates to methods, compounds, and compositions for inhibiting angiogenesis. More particu—
`larly, the present invention relates to methods, compounds, and compositions for inhibiting VEGF production.
`
`
`
`W02006/065479A2|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
`
`

`

`WO 2006/065479
`
`PCT/U82005/042482
`
`SUBSTITUTED PHENOLS AS ACTIVE AGENTS INHIBITING VEGF PRODUCTION
`
`RELATED APPLICATIONS
`
`The present application claims priority to and the benefit under 35 U.S.C. §1 19 of US.
`Provisional Application No. 60/639,283, filed December 27, 2004, which application is herein
`
`incorporated by reference in its entirety. The present application claims priority to and the
`
`benefit under 35 U.S.C. §119 of US. Provisional Application No. 60/629,889, filed November
`
`23, 2004, and US. Provisional Application No. 60/633,738, filed December 6, 2004.
`
`FIELD OF THE INVENTION
`
`10
`
`The present invention relates to methods, compounds, and compositions for inhibiting
`angiogenesis. More particularly, the present invention relates to methods, compounds, and
`
`compositions for inhibiting VEGF production.
`
`BACKGROUND OF THE INVENTION
`
`15
`
`2O
`
`Aberrant angiogenesis plays a critical role in the pathogenesis of numerous diseases,
`
`including malignant, ischemic, inflammatory and immune disorders (1, 2). The best-known of
`
`these disorders are cancer, exudative macular degeneration and diabetic retinopathy (DR), the
`
`last two of which are leading cause of blindness in the United States (3, 4). During the last
`
`decade our understanding of the molecular basis of angiogenesis has grown considerably.
`
`Numerous cytokines and growth factors that stimulate angiogenesis, such as VEGF, FGF-2,
`
`PDGF, IGF-l, TGF, TNFoc, G-CSF have been identified (5-7). Among these growth factors,
`Vascular Endothelial Growth Factor (VEGF) plays a central role in angiogenesis (2).
`VEGF, also known as VEGF-A, was initially identified for its ability to induce vascular
`
`permeability and to promote vascular endothelial cell proliferation (8—10). VEGF is encoded by
`a single gene that gives rise to four isoforms by alternative splicing (11). All four isoforms
`
`25
`
`share the same unusually long and GC rich 5’-UTR, as well as a 3’-UTR that includes multiple
`RNA stability determinants. The receptors VEGFR—Z (also known as KDR or Flk-l) and
`
`VEGFR-l (previously known as Fltl) recognize the dimeric form of VEGF (12, 13). The highly
`specific VEGFR-2 receptor is expressed on endothelial cells. VEGF binding to the VEGFR-2
`
`receptor activates the receptor’s tyrosine kinase activity, leading to endothelial cell proliferation,
`differentiation and primitive vessel formation (14). VEGFR-l inhibits growth either by acting
`as a decoy or by suppressing signaling pathways through VEGFR-2 (15).
`
`30
`
`Over 30 years ago, it was proposed that inhibition of tumor angiogenesis could be an
`1
`
`

`

`WO 2006/065479
`.
`.
`..
`n m
`_
`PCT/U82005/042482
`effeciivellappidad‘liidruthehtii'eliatirierri’tlbnf cancer (16). Subsequent studies have demonstrated that
`angiogenesis regulators, including VEGF, the FGFs, PDGF, TGF, EGF, IL—8, IL-6, and the
`angiopoietins, etc, are involved in tumor growth and metastasis (17, 18). VEGF and its receptor
`have been demonstrated to have a central role in tumor angiogenesis, especially in the early
`stages of tumor growth (19). Indeed, increased levels of VEGF expression have been correlated
`
`with microvessel density in primary tumor tissues (20). Moreover, increased levels of the
`
`VEGF transcript are found in virtually all of the common solid tumors (21).
`
`In general, tumor-
`
`bearing patients have higher levels of VEGF compared to those in tumor-free individuals, and
`
`high VEGF levels in serum/plasma are associated with poor prognosis (22). Consistent with the
`
`role of VEGF in tumor angiogenesis, VEGF null embryonic stem cells showed a dramatically
`reduced ability to form tumors in nude mice (23). Direct evidence for the involvement of
`
`VEGF in tumorigenesis was demonstrated by using specific antibodies against VEGF in human
`
`xenografts implanted in nude mice (24, 25). In these studies, the inhibition of tumor growth
`
`correlated positively with decreased vessel formation in the antibody-treated tumors.
`
`Subsequent experiments using the soluble receptors substantiated the importance of VEGF
`
`activity in tumor growth (26), and demonstrated that inactivation of VEGF by specific antibody
`treatment directly resulted in a nearly complete suppression of tumor-associated
`
`neovascularization (27, 28).
`
`In exudative macular degeneration and diabetic retinopathy, pre-clinical experiments
`
`and clinical trials have demonstrated that over production of VEGF is critical for aberrant
`
`retinal or choroidal neovascularization (reviewed in 3). Evidence has been obtained that intra—
`
`ocular VEGF levels are strongly correlated with active retinal/choroidal neovascularization
`
`(CNV) in patients with diseases such as diabetic retinopathy and wet form macular degeneration
`
`(29, ,30). In addition, studies using transgenic mice demonstrated that overexpression of VEGF
`
`in retinal pigment epithelial cells or photoreceptor cells results in choroidal or retinal
`
`neovascularization (31, 32). In recent studies neutralizing antibodies, soluble receptor, receptor
`antagonists, or siRNA have proven efficacious in reducing VEGF-mediated blood vessel
`
`formation in animal models and in the clinic (33, 34—37).
`
`VEGF expression is regulated by a number of factors and agents including cytokines,
`
`growth factors, steroid hormones and chemicals, and mutations that modulate the activity of
`oncogenes such as ras or the tumor suppressor gene VHL (38, 39). Nevertheless, hypoxia is the
`most significant physiologic signal for regulating VEGF expression. Hypoxia results in
`
`enhanced VEGF expression by increasing both the transcription rate and stability of the VEGF
`
`transcript (40-42). Hypoxia-inducible factor 1a (HIF-la) is a transcription factor that increases
`
`2
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 2006/065479
`PCT/U82005/042482
`u
`u...“ .::::nII...I!.f:':::n..-:‘ "villrim gulf-4r" "3‘
`VfiGh'gene expressmn in cells Myergoing hypoxia by binding to the hypoxia response element
`(HRE) located in the VEGF promoter (43, 44). The stability of VEGF mRNA is also greatly
`enhanced as a consequence of the binding of factors to elements in the 3’-UTR (45). In
`addition, the translation initiation of the VEGF transcript is uniquely regulated. Under hypoxic
`conditions, translation of most cellular transcripts mediated by cap-dependent translation
`initiation process is greatly impaired (46). Initiation of translation of the VEGF mRNA,
`however, is unique under hypoxic conditions in that it is mediated via an internal ribosome
`
`entry site (IRES) within the VEGF .5’UTR (41, 42, 47, 48).
`
`10
`
`15
`
`20
`
`25
`
`30
`
`There is a large body of experimental evidence indicating that tumor growth can be
`inhibited by the prevention of neovascularization (26, 49). Tumor vessels are generally
`immature and constantly undergo remodeling ( 1, 50). Active and aberrant angiogenesis is the
`result of a disruption in the normal balance of proangiogenic and anti-angiogenic factors,
`including various cytokines, growth factors and steroid hormones. Despite the complexity of
`the regulation of tumor angiogenesis, accumulated evidence indicates that targeting a single
`proangiogenic factor might be sufficient to inhibit tumor angiogenesis and suppress tumor
`growth (24, 51, 52). Among many angiogenesis targets, VEGF and its receptor are most
`
`attractive (1, 12). As noted above, treatment with a monoclonal antibody specifically targeting
`VEGF inhibited the growth of tumors in human xenografts implanted in nude mice.
`
`Subsequently, various approaches designed to inactivate VEGF have been tested in tumor
`
`models and have proven to be highly effective in a broad range of tumor cell lines including
`carcinomas, sarcomas and gliomas (21, 24, 51-53). In addition, inhibition of VEGF by anti-
`VEGF antibody did not result in significant side effects in fiilly developed rodents or primates
`(54, 55). Taken together, these results indicate that VEGF is a valid target for the development
`of tumor therapy. Indeed, a number of clinical trials are underway using VEGF inhibitors (17,
`25).
`
`Although several pro-angiogenic factors are implicated in the pathology of exudative
`
`age-related macular degeneration, VEGF appears to be the most critical in the pathogenesis and
`development of this disease (3, 56). Data from preclinical experiments and clinical trials have
`
`demonstrated that blockade of VEGF alone is sufficient to alleviate or stabilize disease
`
`progression (33, 34-37). For example, inhibition of VEGFR signaling by a specific tyrosine
`kinase inhibitor is sufficient to completely prevent retinal neovascularization in a murine
`
`retinopathy of prematurity model (5 7). Furthermore, it has recently been demonstrated that
`
`small interfering RNAs (siRNA) directed against murine VEGF significantly inhibited ocular
`
`neovascularization after laser photocoagulation in a mouse model (58). These results indicate
`
`3
`
`

`

`W9 29.96/99-54Z9rm..;.1
`:I: II
`PCT/U82005/042482
`that selective 1nh1b1t10n ofWGl':expiession1s achievable and offers validation ofthis approach
`for the treatment of ocular neovascular diseases such as exudative macular degeneration and
`diabetic retinopathy.
`
`Three approaches have been used to inhibit VEGF activity, including (1) neutralization
`of VEGF activity by using a specific antibody, soluble VEGF receptor or aptamer oligos against
`the VEGF/VEGFR interaction (24, 26, 27, 49, 51, 59, 60); (2) inhibition of VEGFR mediated
`signal transduction by specific small molecule tyrosine kinase inhibitors (52, 61, 62); and (3)
`inhibition of VEGF/VEGFR expression by using antisense, siRNA or ribozyme (58, 63-65).
`Although all of these approaches show significant inhibition of angiogenesis in viva, they all
`possess significant limitations. For example, therapeutic proteins (antibody and soluble
`receptors) or oligos (antisense, siRNA and ribozyme) are large molecules with poor
`permeability that usually require parenteral administration and are costly to produce. For
`treatment of chronic ocular neovascularization, multiple injections may be impractical due to
`potential complications such as retinal detachment and procedure related infection. Moreover,
`tyrosine kinase inhibitors have the potential for limited specificity. VEGF is constitutively
`' expressed at a low level in normal eyes and other tissues and thus it may be harmful to
`completely suppress VEGF function by administration of antibody or tyrosine kinase inhibitors
`systemically, especially for patients with AMD and RD many of whom are also hypertensive
`(66-69).
`
`Thus, there remains a need to develop characterize and optimize lead molecules for the
`development of novel anti-angiogenesis drugs. Accordingly, it is an object of the present
`invention to provide such compounds.
`
`The present invention relates to methods and compounds for inhibiting angiogenesis.
`More particularly, the present invention relates to methods and compounds for inhibiting VEGF
`production.
`
`10
`
`15
`
`20
`
`25
`
`SUMMARY OF THE INVENTION
`
`In accordance with the present invention, compounds that inhibit the expression of
`VEGF post—transcriptionally have been identified, and methods for their use provided.
`One embodiment of the present invention provides a compound of Formula (I):
`
`

`

`WO 2006/065479
`it" If" "i“ ll...“ {'55:}? it?“ .‘fz'ffii
`
`“ulluiifff? ”nil-ii”? if???
`R5
`
`R6
`
`3
`
`R4
`
`R1
`l
`l
`‘ \ T \R2
`/Y\R8 X
`
`PCT/U82005/042482
`
`5
`
`10
`
`1 5
`
`20
`
`25
`
`R7
`
`(1)
`
`wherein
`
`X is O or S;
`
`Y is C or N,
`
`with the proviso that when Y is N, R8 is absent;
`
`A and B are each, independently, O or N,
`
`with the proviso that when A is O, R3 is absent, and when B is O, R2 is
`
`absent;
`
`R1 and R2 are each, independently, selected from the group consisting of H,
`
`alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, alkylsulfonyl, -COR9, and -
`
`C02R9;
`
`wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, and
`
`alkylsulfonyl groups of R1 and R2 are each, independently, substituted or
`
`unsubstituted;
`
`R1 and R2, taken together with the atom to which they are attached, may
`
`optionally form a substitutedor unsubstituted heterocycle containing, including
`
`the heteroatom to which R1 and R2 are attached, one to three ring heteroatoms
`
`selected from the group consisting of N, O, and S; or
`
`R1 and R3, taken together with the atoms to which they are attached may
`
`optionally form a substituted or unsubstituted heterocycle containing, including
`
`the heteroatoms to which R1 and R3 are attached, two to three ring heteroatoms
`
`selected from the group consisting of N, O, and S;
`
`R3 is H, alkyl, aryl, or heterocycle,
`
`wherein said alkyl, aryl and heterocycle groups of R3 are each,
`
`independently, substituted or unsubstituted;
`
`R4, R5, R6, R7, and R8 are each, independently, selected from the group
`
`consisting of H, alkyl, alkenyl, alkoxy, alkynyl, aryl, cycloalkyl, heterocycle,
`
`alkylsulfonamido, -COR9, -0R9, —C02H, £02119, -C(O)NR1°R”, SR9, -NR1°R”,
`
`30
`
`and halogen;
`
`

`

`WO 2006/065479.
`u
`n...
`n
`w .::::nu..is1.'f:::u “nil-vim}! "amt?"
`whereln
`
`PCT/U82005/042482
`
`said alkyl, alkenyl, alkoxy, alkynyl, aryl, cycloalkyl, heterocycle,
`and alkylsulfonamido groups of R4, R5, R6, R7, and R8 are each,
`
`independently, substituted or unsubstituted;
`Rlo and R11 are selected from the group consisting of H, alkyl,
`alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, and alkylsulfonyl;
`Wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
`heterocycle, and alkylsulfonyl groups of R10 and R11 are
`
`each, independently, substituted or unsubstituted;
`
`each of the following pairs of the substituents: R4 with R5, R5 with R6, R6 with
`R7, and R7 with R8, independently, together with the atoms to which they are
`attached, may optionally form a substituted or unsubstituted monocyclic
`heterocycle having Zero to two ring heteroatoms selected from the group
`consisting of N, O, or S or a substituted or unsubstituted monocyclic aromatic
`
`ring, thereby forming a bicyclic ring system;
`R9 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,
`cycloalkyl, and heterocycle;
`
`wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocycle
`groups of R9 are each, independently, substituted or unsubstituted;
`or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or hydrate thereof.
`
`Another embodiment of the present invention provides a compound of Formula (II):
`R4
`T1
`
`/
`
`R15_
`R6 \
`
`l
`
`wherein
`
`\H/
`O
`
`(11)
`
`0
`
`N
`
`\ 2
`
`R
`
`R] and R2 are each, independently, selected from the group consisting ofH,
`alkyl, alkenyl, aryl, and cycloalkyl;
`
`wherein said alkyl, alkenyl, aryl, and cycloalkyl groups of R1 and R2 are
`
`each, independently, substituted or unsubstituted;
`R1 and R2, taken together with the atom to which they are attached, may
`optionally form a 5 to 7 membered substituted or unsubstituted heterocyclic ring,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`PCT/U82005/042482
`WO 2096/065479 ”I
`2
`1
`113" 11..... 11 11...11 '1:::1i 11.11.13711“ v‘..11..11 1.1.7.:"111711?"
`containing, ihcludingthe heteroatom to which R and R are attached, one to
`
`three ring heteroatoms selected from the group consisting of N, O, and S; and
`
`R4, R6, and R15 are each, independently, selected from the group consisting of H,
`
`substituted or unsubstituted alkyl, and halogen;
`
`5
`
`or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or hydrate thereof.
`
`Still another embodiment of the present invention provides a compound having the
`
`structure :
`
`“of.
`
`Yet another embodiment of the present invention provides a compound of Formula (I)
`
`10
`
`having the structure of Formula (111):
`
`5
`
`R
`R5
`
`R4
`
`R3
`R1
`1
`1
`\A\”/3\R2
`/Y\R8
`
`R7
`
`,
`
`(111)
`
`wherein RI and R2 are each, independently, selected from the group consisting of H,
`
`alkyl, aryl, cycloalkyl, heterocycle, alkylsulfonyl, -COR9, and -C02R9;
`
`1 5
`
`wherein
`
`said alkyl, aryl, cycloalkyl, heterocycle, and alkylsulfonyl groups of R1
`
`and R2 are each, independently, substituted or unsubstituted;
`
`R9 is selected from the group consisting of H, alkyl, alkenyl, alkynyl,
`
`aryl, cycloalkyl, and heterocycle;
`
`20
`
`wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl and
`
`heterocycle groups of R9 are each, independently, substituted or
`
`unsubstituted;
`
`or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or hydrate thereof.
`
`Another embodiment of the present invention provides compounds of Formula (IV):
`
`

`

`PCT/U82005/042482
`
`WQ 290.64.06.54? :::::n n..." :::::n
`
`""t’iuifiiff “xii-fl 17" R4
`R5
`
`R1
`R3
`El;
`I
`\ \2/ \R2
`
`|
`
`R6
`
`wherein
`
`X is O or S;
`
`Y is C or N,
`
`/"\R8 )li
`
`R7
`
`(IV)
`
`with the proviso that when Y is N, R8 is absent;
`
`Z is C or absent, with the proviso that when Z is absent, X, B, R1 and R2 are
`absent;
`5
`
`A and B are each independently O or N,
`
`with the proviso that when B is 0, R2 is absent;
`
`R1 and R2 are each independently selected from the group consisting of H; alkyl
`optionally substituted with cycloalkyl or halogen; aryl optionally substituted with alkyl,
`alkylsulfonylamido or halogen; and cycloalkyl; or
`
`R1 and R2, taken together with the atom to which they are attached, may
`optionally form a substituted or unsubstituted heterocycle containing, including the
`heteroatom to which R1 and R2 are attached, one to three ring heteroatoms selected from
`the group consisting of N, O, and S;
`
`.
`R3 is H;
`R4 is selected from the group consisting of H, -COR9, -NR10R“, and halogen,
`wherein R9 is alkyl and R10 and R11 are independently selected from the group consisting
`of H and alkylsulfonyl;
`
`R5 with R6, together with the atoms to which they are attached, is a monocyclic
`heterocycle optionally substituted with alkyl and having zero to two ring heteroatoms selected
`from the group consisting of N, O, or S, or R5 with R6 together with the atoms to which they are
`attached, is monocyclic aromatic ring optionally substituted with alkoxy or halogen, thereby
`forming a bicyclic ring system; or
`R5 is hydrogen and R6 is selected from the group consisting of H, alkyl, and halogen;
`R7 is a hydrogen or halogen; and
`
`R8 is a halogen;
`
`5
`
`10
`
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`
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`
`25
`
`

`

`WO 2006/065479
`5577’? it: "3' ..
`Ill'ru llHAM 'r'll I7”:fl‘-----
`or a pharmaceuticallyacceptables
`ali',"‘enantiomer, stereoisomer, or hydrate thereof.
`
`PCT/U82005/042482
`
`A further embodiment of the present invention provides a method of selectively
`
`inhibiting vascular endothelial cell growth, comprising the step of exposing cells exhibiting
`
`vascular endothelial cell growth to an effective amount of one or more compounds of Formula
`
`(I):
`
`5
`
`R
`R6
`
`R4
`
`R3
`R1
`|
`|
`\ATB\R2
`/Y\R8
`
`R7
`
`(1)
`
`wherein
`
`X is O or S;
`
`Y is C or N,
`
`with the proviso that when Y is N, R8 is absent;
`
`A and B are each, independently, O or N,
`
`with the proviso that when A is O, R3 is absent, and when B is O, R2 is
`
`absent;
`
`R1 and R2 are each, independently, selected from the group consisting of H,
`
`alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, alkylsulfonyl, -COR9, and -
`
`C02R9;
`
`wherein
`
`said alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, and
`
`alkylsulfonyl groups of R1 and R2 are each, independently,
`
`substituted or unsubstituted;
`
`R' and R2, taken together with the atom to which they are attached, may
`
`optionally form a substituted or unsubstituted heterocycle containing, including
`
`the heteroatom to which R1 and R2 are attached, one to three ring heteroatoms
`
`selected from the group consisting of N, O, and S; or
`
`RI and R3, taken together with the atoms to which they are attached may
`
`optionally form a substituted or unsubstituted heterocycle containing, including
`
`the heteroatoms to which RI and R3 are attached, two to three ring heteroatoms
`
`selected from the group consisting of N, O, and S;
`
`R3 is H, alkyl, aryl, or heterocycle,
`9
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`10.
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`W9 2996496547,?
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`PCT/U82005/042482
`
`m "m" “wheieilndsghid';gliyl, aryl and heterocycle groups ofR3 are each,
`independently, substituted or unsubstituted;
`R4, R5, R6, R7, and R8 are each, independently, selected from the group
`consisting of H, alkyl, alkenyl, alkoxy, alkynyl, aryl, cycloalkyl, heterocycle,
`alkylsulfonamido, -COR9, -OR9, -C02H, -C02R9, —C(0)NR‘°R' ‘, SR9, -NR‘°R“,
`and halogen;
`
`wherein
`
`said alkyl, alkenyl, alkoxy, alkynyl, aryl, cycloalkyl, heterocycle,
`and alkylsulfonamido groups of R4, R5, R6, R7, and R8 are each,
`independently, substituted or unsubstituted;
`R10 and R11 are selected from the group consisting of H, alkyl,
`alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, and alkylsulfonyl;
`wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl,
`
`heterocycle, and alkylsulfonyl groups of R10 and R11 are
`
`each, independently, substituted or unsubstituted;
`each of the following pairs of the substituents: R4 with R5, R5 with R6, R6 with
`R7, and R7 with R8, independently, together with the atoms to which they are
`attached, may optionally form a substituted or unsubstituted monocyclic
`heterocycle having zero to two ring heteroatoms selected from the group
`consisting of N, O, or S or a substituted or unsubstituted monocyclic aromatic
`ring, thereby forming a bicyclic ring system;
`R9 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl,
`cycloalkyl, and heterocycle;
`
`wherein said alkyl, alkenyl, alkynyl, aryl, cycloalkyl and heterocycle
`groups of R9 are each, independently, substituted or unsubstituted;
`or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or hydrate thereof.
`
`Still a further embodiment of the present invention provides a method of selectively
`inhibiting vascular endothelial cell growth, comprising the step of exposing cells exhibiting
`vascular endothelial cell growth to an effective amount of one or more compounds having the
`structure:
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`W0 299610.654]?
`
`.,...n u..." .;;;:u
`
`""IPiIIIIfI “"lf"ii:::li iii???
`
`PCT/U82005/042482
`
`R4
`
`R3
`
`R1
`
`R5
`R6
`
`\
`
`l
`/Y\R8 X
`
`l
`
`i
`
`\R2
`
`R7
`
`(Ia)
`
`wherein
`
`5
`
`X is O or S;
`
`Y is C or N,
`
`with the proviso that when Y is N, R8 is absent;
`
`A and B are each, independently, O or N,
`
`with the proviso that when A is O, R3 is absent, and when B is O, R2 is
`
`absent;
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`
`.
`
`R1 and R2 are each independently selected from the group consisting of H; alkyl
`optionally substituted with cycloalkyl or halogen; aryl optionally substituted with alkyl,
`alkylsulfonylamido, or halogen; and cycloalkyl; or
`
`15
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`20
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`25
`
`R1 and R2, taken together with the atom to which they are attached, may
`optionally form a substituted or unsubstituted heterocycle containing, including the
`heteroatom to which R1 and R2 are attached, one to three ring heteroatoms selected from
`the group consisting of N, O, and S;
`
`R3 is H;
`
`R4 is selected from the group consisting of H, -COR9, -NR10R”, and halogen,
`wherein R9 is alkyl and R10 and R11 are independently selected from the group consisting
`of H and alkylsulfonyl;
`
`R5 with R6, together with the atoms to which they are attached, is a monocyclic
`heterocycle optionally substituted with alkyl and having zero to two ring heteroatoms selected
`from the group consisting ofN, O, or S, or R5 with R6 together with the atoms to which they are
`attached, is‘ monocyclic aromatic ring optionally substituted with alkoxy or halogen, thereby
`forming a bicyclic ring system; or
`R5 is hydrogen and R6 is selected from the group consisting of H, alkyl, and halogen;
`R7 is hydrogen or halogen; and
`
`R8 is hydrogen or halogen;
`
`or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or hydrate thereof.
`
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`WQ 2QQ6/Q65479
`PCT/U82005/042482
`F” 'In another" fiéfi'éé'ct'oft efllhi/ention compounds of Formulas (I), (II), (III), and (IV) are
`provided which are useful in the inhibition of VEGF production,1n the inhibition of
`angiogenesis, and/or in the treatment of cancer, diabetic retinopathy, rheumatoid arthritis,
`psoriasis, atherosclerosis, obesity, chronic inflammation or exudative macular degeneration.
`In another aspect ofthe invention, pharmaceutical compositions comprising compounds
`of Formulas (I), (II), (III), and (IV) are provided which are useful in the inhibition of VEGF
`production, in the inhibition of angiogenesis, and/or in the treatment of cancer, diabetic
`retinopathy, rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammation or
`exudative macular degeneration.
`
`In another aspect of the invention, methods are provided for the inhibition of VEGF
`production, the inhibition of angiogenesis, and/or the treatment of cancer, diabetic retinopathy,
`rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammation or exudative
`macular degeneration using the compounds described herein.
`
`In one embodiment, the invention is directed to methods for inhibiting VEGF production
`comprising administering a VEGF-inhibiting amount of one or more compounds of the
`invention to a subject in need thereof.
`
`In another embodiment, methods for inhibiting angiogenesis are provided comprising
`administering an anti—angiogenic amount of one or more compounds of the invention to a
`subject in need thereof.
`
`In yet another embodiment, methods for treating cancer, diabetic retinopathy,
`rheumatoid arthritis, psoriasis, atherosclerosis, obesity, chronic inflammation or exudative
`macular degeneration are provided comprising administering a therapeutically effective amount
`of one or more compounds of the invention to a subject in need thereof.
`
`5
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`10
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`15
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`20
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`These and other aspects of the invention will be more clearly understood with reference
`to the following preferred embodiments and detailed description.
`
`25
`
`CERTAIN EMBODIMENTS
`
`Embodiment 1. A method for inhibiting VEGF production in a subject, comprising
`administering a VEGF-inhibiting amount of a compound selected from the group consisting of
`the compounds of Formula (I), Formula (II), Formula (III), or Formula (IV) or an enantiomer, a
`diastereomer, a pharmaceutically acceptable salt, a prodrug, a solvate or a mixture thereof to a
`subject in need thereof.
`
`30
`
`Embodiment 2. A method for inhibiting angiogenesis in a subject, comprising
`administering an anti-angiogenic amount of a compound selected from the group consisting of
`the compounds of Formula (I), Formula (II), or Formula (III) or an enantiomer, a diastereomer,
`12
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`

`

`PCT/U82005/042482
`.....,3,, ,,, ,3
`wo 2096/0q5479-,, 1..3,,
`a pharmaceutlcallyaccepta lesaitt,millprodrug, a solvate or a mixture thereof to a subject1n need
`
`thereof.
`
`Embodiment 3. A method for treating cancer in a subject, comprising administering a
`therapeutically effective amount of a compound selected from the grOUp consisting of the
`compounds of Formula (I), Formula (II), Formula (III), or Formula (IV) or an enantiomer, a
`diastereomer, a pharmaceutically acceptable salt, a prodrug, a solvate or a mixture thereof to a
`subject in need thereof.
`
`Embodiment 4. A method for treating diabetic retinopathy in a subject, comprising
`administering a therapeutically effective amount of a compound selected from the group
`consisting of the compounds of Formula (I), Formula (II), Formula (III), or Formula (IV) or an
`enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, a solvate or a mixture
`thereof to a subject in need thereof.
`
`Embodiment 5. A method for'treating exudative macular degeneration in a subject,
`comprising administering a therapeutically effective amount of a compound selected from the
`group consisting ofthe compounds of Formula (I), Formula (II), Formula (III), or Formula (IV)
`or an enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, a solvate or a
`mixture thereof to a subject in need thereof.
`
`Embodiment 6. A method for treating rheumatoid arthritis in a subject, comprising
`administering a therapeutically effective amount of a compound selected from the group
`consisting ofthe compounds of Formula (I), Formula (II), Formula (III), or Formula (IV) or an
`enantiomer, a diastereomer, a pharmaceutically acceptable salt, a prodrug, a solvate or a mixture
`thereof to a subject in need thereof.
`
`Embodiment 7. A method for treating psoriasis in a subject, comprising administering a
`therapeutically effective amount of a compound selected from the group consisting ofthe
`compounds of Formula (I), Formula (II), Formula (III), or Formula (IV) or an enantiomer, a
`diastereomer, a pharmaceutically acceptable salt, a prodrug, a solvate or a mixture thereof to a
`subject in need thereof.
`
`Embodiment 8. A method for atherosclerosis in a subject, comprising administering a
`therapeutically effective amount of a compound selected from the group consisting of the
`compounds of Formula (1), Formula (II), Formula (III), or Formula (IV) or an enantiomer, a
`diastereomer, a pharmaceutically acceptable salt, a prodrug, a solvate or a mixture thereof to a
`subject in need thereof.
`
`Embodiment 9. A method for treating obesity in a subject, comprising administering a
`therapeutically effective amount of a compound selected from the group consisting of the
`
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`WO 2006/065479
`Mi- i271". “wil- Iii“; 51??“
`Fifi M 59:33 EIIH Iii;
`compounds of Formula (I), Formula (II), Formula (III), or Formula (IV) or an enantiomer, a
`
`PCT/U82005/042482
`
`diastereomer, a pharmaceutically acceptable salt, a prodrug, a solvate or a mixture thereof to a
`
`subject in need thereof.
`
`Embodiment 10. A method for treating chronic inflammation in a subject, comprising
`administering a therapeutically effective amount of a compound selected from the group
`
`consisting of the compounds of Formula (1), Formula (II), Formula (III), or Formula