AP813A - Urea derivatives as inhibitors of IMPDH enzyme. - Google Patents

Urea derivatives as inhibitors of IMPDH enzyme. Download PDF

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Publication number
AP813A
AP813A APAP/P/1997/000973A AP9700973A AP813A AP 813 A AP813 A AP 813A AP 9700973 A AP9700973 A AP 9700973A AP 813 A AP813 A AP 813A
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compound
substituents
agent
present
formula
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APAP/P/1997/000973A
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Inventor
David Armistead
Michael C Badia
Guy Bemis
Randy S Bethiel
Cathrine A Frank
Perry M Novak
Steven M Ronkin
Jeffrey Saunders
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Vertex Pharma
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Priority claimed from US08/636,361 external-priority patent/US5807876A/en
Priority claimed from US08/832,165 external-priority patent/US6054472A/en
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Abstract

A class of compounds which are IMPDH inhibitors, and pharmaceutical compositions comprising these compounds, of the formula: A is selected from (Ci-C6) alkyl, or (C2-C6)- alkenyl or alkynyl; B is a monocyclic or bicyclic ring system, D is selected from C(O), C(S), or S(0)2.

Description

TECHNICAL FIELD OF THF, T-NVF.NTION The present invention relates to a novel class of compounds which inhibit IMPDH. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting IMFDH enzyme activity and
1C consequently, may be advantageously used as therapeutic
-f.
-4 agents for IMPDH mediated processes. This invention also relates to metnods for inhibiting Lhe activlLy u£ IMPDH using the compounds of thio invention and related compounds.
BACKGROUND OF THE INVENTION The synthesis of nucleotides in organisms is required for the cells in those organisms to divide and replicate. . Nucleotide synthesis in mammals may be achieved through one of two pathways: the de novo
AP/P/ 97 / 0 0 9 7 3
AP000813
- 2 synthesis pathway or the salvage pathway. Different cell types use these pathways to a different extent.
Inosine-51 monophosphate dehydrogenase (IMPDH; EC 1.1.1.205) is an enzyme involved in the de novo synthesis of gusnosine nucleotides. IMPDH catalyses the NAD-dopondont oxidation of inosine-F’monophosphate (IMP) to xanthosine-5'-monophosphate (ΧΜΓ) [Jaokcon R.C. ot. al . , Nature, 256, pp. 331-733, (1975)].
IMPDH is ubiquitous in eukaryotes, bacteria and protozoa [Y. Natsumeda & S.F. Carr, Ann. N.Y.
Acad., 696, pp. 88-93 (1993)], The prokaryotic forms share 30-40% sequence identity with the human enzyme, *
Regardless of species, the enzyme follows an ordered
Bi-Bi reaction sequence of substrate and cofactor binding and product release. First, IMP binds to IMPDH. This is followed by the binding of the cofactor NAD. The reduced cofactor, NADH, is then released from the product, followed by the pi-oduoL, XMP [S.F. C<uj. et
Q 20 al., J. Biol. Chem., 268, pp. 27286-90 (1993); E.W.
Holmes et al·., Biochim. Blophys. Acta, 364, pp. 209-217 (1074)]. Thi s mor.haninm differs from that of most other known NAD^-dependent dehydrogenases-, which, -have, either a random order of substrate addition or require
NAD to bind-before the . substrate.
Two isoforms of human IMPDH, designated type
I and type II,'have been identified and sequenced [F.R. Collart and E. Huberman, J, Biol. Chem., 263, pp. 15769-15772, (1988); Y. Natsumeda et- al,, J. Biol.
Chem., Zb5, pp. ozyz-5zy5, (1990)]. nach is 514 amino’ acids, and they share 84% sequRnce identity. Roth IMPDH type I and type II form active tetramers in solution, with'subunit molecular weights of 56 kDa [Y.
AP/P/ 9 7 / 0 0 9 7 3
APO 0 0 8 1 3
- 3 Yamada et. al., Biochemistry, 27, pp. 2737-2745 (1988)].
The o’e novo synthesis of guanosine nucleotides, and thus the activity of IMPDH, is particularly important m b and T-lymphocytes. These cells depend on the de novo, rather than salvage pathway to generate sufficient levelς of nncl potirifts necessary to initiate a proliferaLive response to mitogen or antigen [A.C. Allison et. al,, Lancet II,
1179, (1975) and A.C. Allison et. al., Ciba Found.
Syrnp., 48, 207, (1977)]. Thus, IMPDH is an attractive target for selectively inhibiting the immune system without also inhibiting the proliferation of other cells.
immunosuppression has been achieved by inhibiting a variety of enzymes including for example, the phosphatase calcineurin (inhibited by cyclosporin and Fi< 505) ; dihydroorotate dehydrogenase, an enzyme i-ί? involved in the biosynthesis of pyrimidines (inhibited by leflunomide and brequinar); the kinase FRAP (inhibited by rapamycin); and the heat shock protein “hsp7O TinHibiited 'by deoxyspergualin) . [See Β. B. Kahan, Immunological Reviews, 136, pp. 29-4y (lyyjj; κ. b.
Morris, The Journal of Heart and Lung Transplantation, ’ 12(6), pp. S275-S286 (1993)].
Inhibitors of IMPDH are also known. United
States patents 5,380,879 and 5,444,072 and PCT publications WO 94/01105 and WO 94/12184 describe mycophenolic acid (MPA) and some of its derivatives as potent, uncompetitive, reversible inhibitors of human
IMPDH type I (Ki=33 nM) and type II (Kq=9 nM). MPA has been demonstrated to block the response of B and TAP/P/ 9 7 / 0 0 9 7 3
APO00813 cells to mitogen or antigen Ann. Ν. Y. Acad. Sci·, 696, [A, ¢. Allison et. al. 63, (19935 .
MPA
Immunosuppressants, such as MPA, are useful drugs in the treatment of transplant rejection and autoimmune diseases. [R. E, Morris, Kidney Inti., 49, Suppl. 53, 5-26, (1996)]. However, MPA is characterized by undesirable pharmacological properties, such as gastrointestinal toxicity and poor bioavail&bili-ty. [L. M. Chaw, ct. al. , Therapeutic Drug
Monitoring, 17, pp. 690-699, (1995)] .
Nucleoside analogs such as tiazofurin, ribavirin and mizoribine also inhibit IMPDH [L. Hedstrom, et. al. Biochemistry, 29, pp. Θ49-854 _(1990) These compounds, which are competitive inhibitors of IMPDH, suffer from lack of specificity to this enzyme.
Mycophenolate raofetil, a prodrug which quickly liberates free MPA in vivo, was recently approved to prevent acute renal allograft rejection following kidney transplantation. [L. M. Shaw, et. al., Therapeutic Drug Monitoring, 17, pp. 690-699, (1995); H. W. Sollinger, Transplantation, 60, pp. 225232 (1995)]. Several clinical observations, however, limit the therapeutic potential of this drug. [L. M. Shaw, et al , Therapeutic Driig Monitoring, 17, pp. 690-699, (1995)]. MPA is rapidly metabolized to the
AP/P/ 9 7 / 0 0 9 7 3
AP Ο ύ Ο 813
- 5 inactive glucuronide an vivo. [A.C., Allison and E.M. Eugill, immunological Reviews, 13G, yy. 5 20 ¢1093)] .
The glucuronide then undergoes enterohepatic recycling causing accumulation of MPA in the gastrointestinal tract where it cannot exert its IMPDH inhibitory activity on the immune system. This effectively lowers the drug’s in vivo potency/ while increasing its undesirable gastrointestinal side effects.
It is also known that IMPDH plays a role in other metabolic events. Increased IMPDH activity has been observed in rapidly proliferating human leukemic cell lines and other tumor ceil linco, indicating IMPDH as a target for anti-cancer as well as immunosuppressive chemotherapy [M. Nagai et. al.,
Cancer Res., 51, pp. 3886-3890, (1991)]. IMPDH has also been shown to play a role in the proliferation of smooth muscle cells, indicating that inhibitors of IMPDH, such as MPA or rapamycin, may be useful in preventing restenosis or other hyperproliferative vascular diseases [C. R, Crcgory ct al.,
Transplantation, 59, pp. 655-61 (1995); PCT publication WO 94/12184; andPCT publication ”WCT94701T05] .
Additionally, IMPDH has been shown to play a role in viral replication in some viral cell lines, [s.F. Carr, J. Biol, Chem., 266, pp. 27286-27290 (1993)]. Analogous to lymphocyte and tumor cell lines, the implication is that the de novor rather than the salvaye, pathway is critical in the process of vir&l replication.
The IMPDH inhibitor ribavirin is currently being evaluated for the treatment of hepatitis-C virus (HCV) and hepatitis-3 virus (HBV) infection and disease. Ribavirin enhances the sustained efficacy of
AP/P/ 9 7 / 0 0 9 7 3
ΑΡ ο Ο Ο 8 1 3
- 6 interferon in HBV and HCV treatment. However, the therapeutic potential of ribavirin is limited by its lack of a sustained response in monotherapy and broad cellular toxicity.
Thus, there remains a heed for potent IMPDH inhibitors with improved pharmacological properties. Such inhibitors would have therapeutic potential as immunosuppressants, anti-cancer agents, anti-vascular hyperproliferative agents, antiinflammatory agents, antifungal agents, antipsoriatic and anti-viral agents.
SUMMARY OF THE INVENTION The present invention provides compounds, and pharmaceutically acceptable derivatives thereof, that 15 are useful as inhibitors of IMPDH. These compounds can be used alone or in combination with other therapeutic or prophylactic agents, such as anti-virals, antiinflammatory agents, antibiotics, and immunosuppressants for the treatment or prophylaxis of 20 transplant rejection and autoimmune disease.
Additionally, these compounds are useful, alone or in combination with other agents, as therapeutic and prophylactic agents for antiviral, anti-tumor, anticancer, antiinflammatory agents, antifungal agents, antipsoriatic immunosuppressive chemotherapy and restenosis therapy regimens.
The invention also provides pharmaceutical compositions comprising the compounds of this invention, as well as multi-component compositions comprising additional IMPDH compounds together with an immunosuppressant. The invention also provides methods of using the compounds of this invention, rs wpI1 rs other related compounds, for the inhibition of IMPDH.
AP/P/ 9 7 / 0 0 9 7 3
AP Ο Ο Ο 813
The compounds of this invention, as well as those used in the methods of this invention demonstrate a different metabolic profile than MPA and its darivativoc. Because of this difference, methods^ Of this invention and the compounds used therein may offer advantages as therapeutics for IMPDH mediated disease. These advantages include increased overall therapeutic benexit and reduction in delcLcj-iuus side effects.
DETAILED DESCRIPTION OF THE INVENTION In order that the invention herein described may be more fully understood, the following detailed description is set forth. In the description, the following abbreviations are used:
Designation Reagent or Fragment
Ac
Me
Et
Bn
CDI
DIEA
DMAP
DMF
DM5 D
EDC
EtOAc
THF acetyl methyl ethyl benzyl carbonyldiimidazole dilsopropyle'thyTanilne dimethylaminopyridine dimethylformamide dimethylsulfoxide
1-(3-dimethylaminopropyl)-3ethylcarbodiimide hydrochloride ethyl acetate tetrahydrofuran
The following terms are employed herein: Unless expressly stated to the contrary, the terms -SO2- and -SiO^- used herein refer to a
AP/P/ 9 7 / 0 0 9 7 3
AP Ο Ο Ο 813
«.Μ/
- 8 sulfone or sulfone derivative (i.e., both appended groups linked to the S), and not a sulfinate ester.
The terms halo or halogen refer to a radical of fluorine, chlorine, bromine or iodine.
The term immunosuppieaaeniL to a compound or drug which possesses immune response inhibitory activity. Examples of such agents include cyclosporin A, KK506, rapamycin, lefluhomide, deoxyspergualin, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon and mizoribine.
The term interferon refers to all forms of interferons, including but not limited to alpha, beta and gamma forms .
lb iMFUh-mediated disease refers Lu any disec.Se state in which the IMPDH enzyme plays a regulatory role in the metabolic pathway of that disease. Examples of IMPDII mediated disease include transplant rejection and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, and inflammatory bowel disease, as well as inflammatory diseases, cancer, viral replication diseases and vascular diseases.
For example, the compounds, compositions and
L'b inetnoac OX using Lhem Of Lhla invauLluu way be uociJ Ήί the treatment of transplant rejection {e.g., kidney, liver, heart, lung, pancreas tisret cells), bone marrow, cornea, small bowel and skin allografts and liKrir I vrtlvt; abuuwin£Lq) qxxxJ. enifcoiiiimii·!*. diatases, ouch
3° as rlieLntiaLuid η ι thr Ί tin, multiple acleroulu, juvenile diabetes, asthma, inflammatory bowel disease (Crohn's disease, ulcerative colitus), lupus, diabetes, me!Titus myasthenia gravis, psoriasis,_dermatitis, eczema, seborrhoea, pulmonary inf lamination, eye uveitis,
AP/P/ 9 7 / 0 0 9 7 3
APO Ο Ο 813
- 9 hepatitis, Grave's disease, Hashimoto's thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolytic anaemia, idiopathic adrenal insufficiency, polyglandular autoimmune syndrome, and glomerulonephritis, scleroderma, lichen planus, viteligo (depignentation of the skin), autoimmune thyroiditis, and alveollLia, lull animat ory diseases such as osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma and adult respiratory distress syndrome, as we) 1 as in the treatment of cancer and tumors, such as solid tumors, lymphomas and leukemia, vascular diseases, such as restenosis, stenosis and artherosclerosis, and DNA and RNA viral replication diseases, such as retroviral diseases, and herpes.
Additionally, IMPDH enzymes are also known to he present in bacteria and thus may regulate bacterial growth. As such, the IMPDH-inhibitor compounds, compositions and methods described herein may be useful in treatment or prevention of bacterial infection, alone or in combination with other antibiotic agents.
The term treating as used herein refers to the alleviation of symptoms of a particular disorder in a patient or the improvement of an ascertainable measurement associated, with a particular disorder. As used herein, the term patient refers to a mammal, including a human.
The term thiocarbamates refers to compounds containing tho functional group N-SOg-^
The terms HBV, HCV and HGV refer to hepatitis-B virus, hepatitis-C virus and hepatitis-G virus, respectively.
AP/P/ 97/00973
APO 0 0 8 1 3
- 10 According to one embodiment/· the invention provides methods of. inhibiting IMPDH activity in a mammal comprising the step of administering to said mammal, a compound of formula I:
Η H (I) wherein:
A is selected from:
(C^-Cg)-straight or branched alkyl, or (CjCg)-straight or branched alkenyl or alkynyl; and A optionally comprises up to 2 substituents, wherein:
the first of said substituents, if present, io cslootad from P.1 or , ann the second of said substituents , if present, is R1;
is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, 0, or S and selected from the formulae:
X is the number of hydrogen atoms complete proper valence;
AP/P/ 9 7 / 0 0 9 7 3 wherein each necessary to r AP Ο Ο Ο 8 1 3
- ii and Β optionally comprises up to 3 substituents, wherein:
the first of said substituents, if present, is selected from R1, R2 , R4 orR5, the second of said substituents, if present, is selected from R1 or R4, and the third ot said substrtuents, xi preseni-, is R1; and
D is selected from C(O), C(S)’, or S(O)2/‘ wherein:
tach nl io indopandently selected from 1,7methylenedioxy, l,2-ethylenedioxy, Rs or (CH2)n,-Y;
wherein n is 0, 1 or 2; and
Y is selected from halogen, CN, N02, CF3, QCF3,
Oil, £r6z e(O)R5, SQ2R6, NH2, NHRfi, N(Rfi)2, NR6HS, COOH, COOR6 or OR6;
each R2 is independently selected from (C1-C4)straight or branched alkyl, or (C2“C4)-straight or branched alkenyl or alkynyl; and each R2 optionally · comprises up to 2 substituents, wherein:
the first of said substituents, if present, ____is selected from R1, R4 and R5' and_____ the second of-said substituents, if present, is R1; _ · . R3 is selected, from a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 hetp.rnatoms selected from N, o, or s, and wherein a CH2 • adjacent to any of said N, O, or S heteroatoms is optionally substituted with C (Ο) ; and each R3 optionally comprises up to 3 substituents, wherein:
AP/P/ 9 7 / 0 0 9 7 3
ΑΡθoo813
- 12 the first of said substituents, if present, is selected from R1, R2, R4 or R5/
Llie second of said Dubctituants, if prpfipnt, is selected from R1- or R4, and 5 the third of said substituents, if present, is R1;
each R4 is independently selected from OR5, OC(O)Re, 0C(0)R5, OC{O)0RS, OC(O)OR5, OC(O)N(R6)2, 0P(0) (OR6)2, SRS, SR5, S(O)R5, S(O)R5, SO2R6, SO2R5,
SO2N(RG)2, SO2NR5Re, SO3r6, C(O)R5, C(0)OR5, C(O)R6,
C(0)Or6, NC(0)C(0)R6, NC(0)C(0)R5, NO (0) c (0) orS , NC(O)C(O)N(R6)2, C(O)N(r6)2, C(0)N(0R6)Rs,
C (O)N (OR6) R5, C(NOR6)R6, C(NOR6)R5, N(Rs)2, NR6C(O)Rx, ' NR6C(O)R6, NR6C(O)r5, NRsC(O)0R6, NR6C(O)0R5,
NR6C(O)N(R5)2, NR6C(O)NR5R6, nrsso2r6, nr6so2r5, NR6SO2N(Re)2, NR6SO2NR5R5, N(0RS)R6, N(OR6)R5,
P (0) (OR6)N(R5) 2, and P(0) (0Rfe)2?
each R5 is a monocyclic or a bicyciic ring system consisting nF s im fi members per ring/ wherein said 20 _ ring system optionally comprises up to 4 heteroatoms selected from N, o, or S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C(O) ,- and each R5 optionally comprises 'up to 3 substituents, each of which, if present, is R1;
each R6 is independently selected from H, (C^-C^)straight or branched alkyl, or (C2-C4) straight or branched alkenyl; and each R6 optionally comprises a substituent that is R7;
R7 is a monocyclic or a bicyciic ring system consisting of 5 to 6 members per ring, wherein said
AP/P/ 9 7 / 0 0 9 7 3 $«
APO Ο Ο 813
- 13 ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C{0); and each R7 optionally comprises up to 2 substituents independently chosen from H, (04-04)-straight or branched alkyl, (C2C4) straight or branched alkenyl, 1,2-methylenedioxy,
1,2-ethylenedioxy, or (CH2)nz7 wherein n is 0, 1 or 2; and
Z is selected from halogen, CN, N02, CF3, OCF3,
OH, Ξ (C3.-C4} -alkyl, SO(C4-C4)-alkyl, SO2 (04-04) -alkyl, KH2, NH (04-04)-alkyl, x'T<<cx C4) -ilkyl) 2 , IT ( (Gx .0*) alkyl)Rn, COOK, C(0)0(C4-C4)-alkyl or O(C1-C4)-alkyl? and
R8 is an amino protecting group; and wherein any carbon atom in any A, R^ or R6 is optionally replaced by 0, S, SO, S02, NH, or N (C4-C4 )alkyl.
The term substituted refers to the replacement of one or more hydrogen radicals in a given sLrueLure with a ' radica1 3e1 ectea from'a sp0cifled group. When more than one hydrogen radical may be replaced with a substituent selected from the samp, specified group, the substituents may be either the same or different at every position.
The term monocyclic or bicyclic ring system consisting of 5 to 6 members per ring refers to 5 or 6 member monocyclic rings and 8, 9 and 10 membered bieiyclie ring otruoturac, whoroin each hnnrl in park ring may be possess any degree of saturation that is chemically feasible. When such structures contain substituents, those substituents may be at any position of the ring system, unless otherwise specified.
AP/P/ 9 7 / 0 0 9 7 3
AP O 0 0 8 1 3 » i
- 14 As specified, such ring systems may optionally comprise up Lu 4 heterottomo oclcutod from N, 0 or S. Those heteroatoms may replace any carbon atoms in these ring systems as long as the resulting compound is chemically stable.
The term wherein each X is the number of hydrogen atoms necessary to complete proper valence means that X is 0, 1 or ? hydrogen atom?, depending upon the identity of the ring atom to which X is bound (c, N, 0 or G), the identity of the two adjacent ring . atoms, and the nature of the bonds between the ring atom to which'X is bound and the two adjacent ring atoms (single, double or triple bond). In essence, this definition is meant to exclude from X any substituents other than hydrogen.
The term amino protecting group refers to a .Ύ suitable chemical group which may be attached to a „<α nitrogen atom. The term protected refers to when the designated functional group is attached to a suitable zu chemical group (piuLcuting group). Exomplco of suitable amino protecting groups and protecting groups are described in T.W. Greene and F.G.M. Wuts,
Pj.uLai.Lhe Groupg in OrquHiu Synthesis, 2d. Ed. , John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wilev and Sons (1334),· L. Paguette, ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and are exemplified in certain of the specific compounds used in this invention.
According to another embodiment, the invention provides mernocts or inhiblring IMPDH In mammalc by administering a compound of the formula (II) :
&PIPI 97/00973
APO Ο Ο 8 1 3 Β\
Η
Ν'
Η (II) wherein Β and D are as defined above.
More preferably, in methods employing the compounds of formulae (I) or (II), component B comprises from 0 to 2 substituents. According to an alternate embodiment, the invention provides methods for inhibiting IMPDH in a mammal employing compounds (I) or (II), wherein B comprises at least a single substituent selected from the group defined by R^. Preferably, in this embodiment, B is a monocyclic aromatic ring containing at least one substituent which is also a monocyclic aromatic ring.
The present invention also provides compounds which are useful in inhibiting IMPDH. .According to one embodiment, the IMPDH inhibitory compound has the formula (III):
AP/P/ 9 7 / 0 0 9 7 3 wherein A, B and D are as defined above;
E is oxygen or sulfur;’and
G and G’ are independently selected from Rl or hydrogen.
According to an alternate embodiment, the invention provides a compound of the formula (IV) :
APO 0 0 8 1 3
£3
wherein B, D, E, G and Gr are defined as above and B’ is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, 0, or S and selected from the formulae:
AP/P/ 9 7 / 0 0 9 7 3 wherein each X is the number of hydrogen atoms necessary to complete proper valence;
and B’ optionally comprises up to 3 substituents, wherein:
the first of said substituents, if present, is selected from R^, r2, p4 or the second of said substituents, if present, is selected from R1 or R4, and the third of said substituents, if present, ic Rl; wherein X, R^·., R2, R^ and R^ are defined as above.
Excluded him this invention are compounds of formula (IV) wherein B and B’ are simultaneously unsubstituted phenyl and compounds wherein B is
APO00813
- 17 unsubstituted- phenyl end B’ is tri-chloro-, tri-bromo or tri-iodo phenyl.
Preferably, in compounds of formula (IV), B and B' are phenvi groups cuuipj-iaing at lcaot one substituent each. These compounds are represented by formula (V):
(V) wherein K is selected from R1 or R4; and J is selected from R1, R2 or R4.
Preferred compounds of formula (V) are those wherein D is -0(0)-, those wherein E is oxygen; those wherein J is NR6C(O)R^ or NR6C(O)R6, preferably
NR6C(O)Re, more preferably N(CH3)C(0)R6, and more preferably N(CH3)C(Ο)CH3; those wherein K is (CH2)n_Y' preferably OCH3 (i.e., n is 0, Y is OR6, and R6 is ______________CH3); and those wherein G is hydrogen. More preferred
AP/P/ 97/00973 compounds of formula (V) are those wherein:
E is oxygen
J is-NRsC(O)R5 or NR6C(O)R6;
K is (ΟΗ2)χι-Υ; and G is hydrogen.
Even more preferred compounds of formula (V) are those 25 wherein:
D is -C(O)-;
E is oxygen; j is nr6c(o)r6,APO00813
- 18 Λ?’.
Κ is OCH3; and G is hydrogen.
Most preferably in such compounds, J is N(CH3}C(0)Re.
Alternate preferred compounds are those of formula V: wherein J is R2, those wherein D is -C (0)-, those wherein E is oxygen, those wherein J is R
4, 4 substituted with R preierably wherein R is NR.6c(o)OR.5 or NR6c(O)OR6, more preferably wherein R4 is
NR^C(0)0R5, more preferably wherein R4 is NHC'(0)0R^, ά and more preferably wherein R is MHC(0)0-3tetrahydrofuranyl, those wherein K is (Ci^n-Y, preferably wherein K is OCH3, those wherein G is hydrogen, and those wherein:
D is -0(0)
15 A E is oxygen;
_ J K is 0CH3' and
G is hydrogen.
AP/P/ 97/00973
Alternatively, other preferred compounds 20 include those of formula VI:
VI
AP Ο Ο Ο 8 1 3 <>
- 19 those compounds of formula VI wherein K is OCH3, and those compounds of formula VI wherein G is hydrogen.
An alternate embodiment of this invention is compounds of formula V wherein K is selected from rA or rA; and J is selected from R1, R2, R4, and R wherein,
R1, R2, and R^, are as defined above and R is independently selected from (C1-C4)-straight or branched alkyl, or (C2-C4) -straight or branched alkenyl or alkynyl; and each R^ optionally comprises up to 2 substituents selected from NR®C(O)OR-°, wherein R6 is' as defined above and R is selected from (02-05)* straight or branched alkyl optionally comprising up to two substituents selected from NReRe, SR6, SO2rS/
- (CE2)n_SR®, -(CH2)n-OR6, and OR®, wherein n, R® and
R8, are as defined above.
In another embodiment, preferred compounds are those of formula vii;
AP/P/ 97/00973 wlitsidii K ii selected from R^ and R^ · and
A, D, R1 and are each independently as defined in claim 1.
APO 0 0 8 1 3
- 20 More preferred compounds of formula VII are those wherein D is -C(0)-, those wherein A is a monocyclic aromatic ring substituted with 1-2 substituents selected from the group consisting of
NR6C(O)R6, NR5C(O)R5, CH2NRSC(O) OR6, and CH2NR6C(0)OR5, those wherein A is a monocyclic aromatic ring substituted with 1-2 substituents selected from the group consisting of CH2NR6C(0)OR6 and CH2NR®C(°)OR5' those A is a monocyclic aromatic ring substituted with
CH2NR5C(0)OR5' those wherein A is a monocyclic aromatic ring substituted wiLh (0) OR5' those wherein A is a monocyclic aromatic ring substituted with CH2NHC(O)O3-tetrahydrofuryi, those wherein K is (CH2)n-Y, those wherein K is OCH3, and those wherein:
A is a monocyclic aromatic ring substituted with CH2NHC(O)O-3-tetrahydrofuryl; and
K is OCH3.
Alternatively, other preferred compounds of 20 this invention include those compounds of formula Viii;
£/600//6 /d/dV wherein D and K are as defined in claim 1.
Another embodiment is those compounds of formula IX:
AP000813
-zi wherein:
D is
K is
J is selected from C(0), C (S) and S(0)2' selected .from rA and R^; and selected from rA, R^, and .
More preferred compounds of formula IX include 10 those wherein D is -C(0)-, those wherein J is NR6C(O)R5 or NR5C(O)R6' those wherein J is NR6C(O)r6/· those wherein J is N(CHq)C(0)R6' those wherein J is
N (CH3) C (0) CH3f those wherein K is (CH2)n-Y, those wherein K is OCH3, and those wherein:
K is OCH3; and
J is N (CH3)'C (0) CH3.
AP/P/ 9 7 / 0 0 9 7 3
Tables IA, IB and IIB list preferred individual compounds of the invention and preferred compounds employed in the compositions and methods of this invention. Table IIA lists preferred compounds employed in the methods of this invention.
APOO0813
- 22 Table IA
# G K A
1 H H benzyl
Table IB
AP/P/ 97/00973
# G K B’
2 H H 3-methoxyphenyl
3 H H 3-thienyl
4 ... H.................. ..............- 3,4-difluorophenyl -.-. ..
5 H H 2,5-dimethoxyphenyl
6 H H 3-methylthiophenyi
7 H H 3-bromophenyl
8· H H 3-cyanophenyl
9 H H 3-trifluoromethyl-4chlorophenyl
10 H I H 2-methyl-3-chlorophenyl
11 H H 2-methoxy-5-methyIphenyl
12 H H 2-methoxyphenyl
13 H H 3-methoxyphenyl
14 H H 2,5-dimethoxyphenyl
15 H H 3-nitrophenyl
16 H H 4-nitrophenyl
17 Η Ί H · 3-methyIphenyl
IB H H . 3-trifluoromethyIphenyl
19 H H 2-trifluoromethyIphenyl
20 H H 3-fluorophenyl
S ι H Ή ύ -nh pr vrsh on. vi
APO Ο Ο 813
# G Κ B’
23 H Κ 3-chloro-4-fluorophenyl
24 Η Η 3-aminophenyl
25 Η Η 3-(hydroxymethyl)phenyl
26 Η Η 3-acetylenylphenyl
27 Η Η 3-hydroxyphenyl
29 Η Η 3-pvridinyl
30 Η Η 4-pyridinyl
31 Η Η 2-(5-methyl)thiazolyl
39 Η Η 3,4-ethylenedioxyphenyl
40 Η Η 3-methyl-4-nitrophenyl
41 Η Η 3-trifluoromethyl-4- nitrophenyl
42 II 3 chloro phenyl
43 Η 3-chloro 3-methylphenyl
44 - - -
45 Η 3-fluoro phenyl
46 Η 3-flu.orc 3-methylpheny1
47 Η H 3-carbomethoxymethylphenyl
48 Η H 3-carboxyethylphenyl
49 Η H 3-dime thylaminophenyl
50 Η H 3-[2-(2- methyl)dioxolanyl)phenyl
51 Η H 3-aminocarbonylphenyl
53 Κ H 3-(3-furanyl)-phenyl
54 Η H 3-carboxymethylphenyl
55 Η 3-methoxy 3-methylpheny1
56 Η 3-methoxy 3-nitrophenyl
57 Η 3-chloro 3-carbomethoxymethylphenyl
—5-8“ Η -....... H ----------- 3-amino-5-methylphenyl
59 Η 3-methoxy 3-aminophfinyl
60 Η 3-bromo 3-methylphenyl
61 Η 3-chloro 3-chloro-4-(5oxazolyl)phenyl
62 Η - 3-chloro 4-(2-methylpyridyl)
63 Η . 3-chlor'o 3-carboxymethylphenyl
64 Η 3-bromo 3-nitrophenyl
65 Η 3-bromo 3-aminophenyl
66 Η H 3-[5-(2- methylpyrimidinyl)]phenyl
67 Η H 3-(5-oxazolyl)phenyl
68 Η 3-chloro • 2-thienyl
69 Η 3-cnioro 3-thienyi
71 Η 3-chloro 3-methoxycarbamoyl-phenyl
72 Η 3-chloro 3-acetamidophenyl
73 Η 3-chloro 3-iodophenyl
7 4 Η 3-methyl phenyl
ΑΡ/Ρ/ 9 7 / 0 0 9 7 3
AP Ο Ο Ο 8 1 3
# G K B’
75 H 3-methyl 3-methylphenyl
76 methyl 3-chloro 3-methylphenyl
77 methyl H 3-methylphenyl
78 H 3-chloro 3-nitrophenyl
79 H 3-chloro 3-aminophenyl
80 H H 3- (cyclohexvlsulfamoyl)phenyl
81 H H 3-(methylsuramoyl)phenyl
82 H H 3-(phenylsufamoyl)phenyl
83 H 3-methoxy 3-benzyloxycarbamoyl-phenyl
84 H 3-methoxy 3-acetamidophenyl
85 H 3-chloro 4-(2-methyl)furanyl
OC II 3-chloro 5- (2-methyl)fhi enyl
88 H 3-carbomethoxy 3-methylphenyl
89 H 3-carbome Lhuxy 3-nitrophenyl
91 H 3-chloro 4-(2-nitro)thienyl
92 H 3-chloro 4-(2-hydroxyamino)thienyl
93 H 3-chloro 3- (bi- methyl) trifluoroacetamidophenyl
54 H 3-chloro 3-(methylamino)phenyl
95 H 3-chloro 4-(2-amino)thienyl
96 H 3-methoxy 3-trifluoroacetamidophenvl
97 H 3-methoxy 3- (Ν'- methyl) trifluoroacetamidophenyl
98 H 3-methoxy 3—(3’— picolyloxycarbamoyl) phenyl
99 H 3-methoxy 3-(phenoxycarbamoyl)phenyl
TOO H - .....3-methoxy 3-difluoroacetamidophenyl
101 H 3- acetoxymethyl· 3-methylphenyl
102 H 3- hydroxyme thyl 3-methylphenyl
104 H ’ H 3-nitro-4-fluorophenyl
105 H 3-methoxy 3-(aminomethyl)phenyl [•TFA]
106 H 3-methoxy 5-(N-acetoxy)indolinyl
107 H 3“uiti LliuAy 3- (N-w«thyl) acetemidophenyl
108 H 3-methoxy 3-[ (2-OXO-2-(3,4,5-tri- methoxyphenyl) acetyl) amino]phenyl
109 H 3-aiLLJ.ilU □ -iftethylpHenyl
110 H 3-methoxy 3-benzamidopheny'l
111 H 3-methoxy 3-phenylacetamidophenyi
112 H 3-methoxy 3-phenvlureidophenyl
h 3-methoxy 3- (t-butoxycarbamcyl
ΑΡ/Ρ/ 9 7 / 0 0 9 7 3 '•I
APO Ο Ο 813
# G K B’
methyl) phenyl
114 H 3-methoxy 3-(cyolopentylacetamido) phenyl
115 H 3-methoxy 3-methylphenyl
Table IC
Compound L
116 NHC(O)O-t-butyl
117 NCH3C(0)O-t-butyl
118 NHC(OJO-methyl
119 NHC(0)O-phenyl
120 NHC(0)O-(S)-3-tetrahydrofuranyl
121 NHC ¢0)O-2-picolinyl
122 NHC(0)0-(S)-5-oxazolidinonylmethyl
123 NHC (0)0 4 carfoomcthoxyphcnyl
124 NHC(0)0-isobutyi
125 NHC(0)0-allyl
12 6 NHC(0)0-5-(1,3-dioxanyl)
--------127 .....- NHC(0)0-4-acetamidophenyl---------
128 NHC(0)0-2-furfuryl
129 NHC(0)0-2-thiofurfuryl
130 NHC(0)0-2-methoxyethyl
131 NHC(0)0-4-tetrahydropyranyl
132 NHC(0)O-cyclohexyl
133 NHC(0)O-cyclopentyl
134 NHC(0)0-2-hydroxyethyl
135 NHC(0)Q-cyclohexylmethyl
136 NHC (0) 0- (R, 5) -3-LeLraliydx'of uxaxiyl
137 NHC(0)0-3-pyridyl
138 NHC(0)0-benzyl
139 NHC(0)0-3 (tDOC amino)propyl
140 NHC(0)0-4-hydroxybutyi
141 NHC(0)0-5-hydroxypentyl
142-------- nhc(U)ο-(κ,5)-z-pyranyi
143 NHC(0)0-3-(N-tBOC)-piperidinyl
144 NHC(0)0-(R)-3-(2-ΟΧΟ-4,4-
AP/P/ 9 7 / 0 0 9 7 3
APO Ο ϋ 81 3
- 26 'Λ
- ?
Compound L
dimethyl)furanyl
145 NHC(0)O-3-methylthiopropyl
146 NEC(0)0-4-[(2, 2-dimethyl)-1, 3- dioxany1]methyl
147 NHC(0)O-2-di-(hydroxymethyl)ethyl
148 NHC(0)0-4-(N-tBOC)-piperidinylmethyl
149 NHC(0)0-3-(N-tBOC)-piperidinylmethyl
150 NHC(0)0-(dibenzyloxymethyl)methyl
151 NHC(0)O-di-(hydroxymethyl)methyl
152 NHC(0)0-2-(N-t30C)-piperidinylmethyl
153 NHC(0)0-3-piperidinyl-TFA
154 NHC(O)O- (R,S)-(2tetrahydropyranyl) methyl
155 NHC(0)0-4-piperidinylmethyl-TFA
156 NHC(0)0-(R,S)-tetrahydrofuranylmethyl
157 NHC(0)0-3-methylsulfonylpropyl
158 NHC(0)O-3-piperidinylmethyl-TFA
159 NHC(0)O-2-piperidinylmethyl-TFA
160 NHC(0)0-(R,S)-3-tetrahydrothiophenvl
161 NHC(0)0-(R,S)-3-tetrahydrothiopyranyl
162 nhc(0)o-3-methoxypropyl
Table ΙΙΑ
ΑΡ/Ρ/ 97/0097 3
Q1 Q2 B
28 3-methoxy 4-methoxy 3-methylphenyl
32 3-nitro H 3-methylphenyl
33 4-cyano H 3-me thyIpheny1
34 3-methoxy 4-methoxy 3-bromophenyl
35 3-methoxy 4-methoxy 2-methoxy-5chlorophenyl
36 3-methoxy 4-methoxy 3-fluorophenyl
37 3-methoxy 4-methoxy 3-ethylphenyl
38 3-methoxy 4-methoxy 3-methylthiophenyl
52 3-chloro 4-methoxy 3-nitrophenyl
70 4-cyano 3-chloro 3-methylphenyl
87 1-imidazolyl H 3-methylphenyl
AP 0 I) 0 8 I 3
90 3-hydroxymethyl 4-methoxy 3-methylphenyl
103 3-(t-butoxycarbamoyl methyl) H 3-(t-butoxycarbamoyl methyl)phenyl
Table IIB
AP/P/ 97/00973
# Qi 23
163 Cl N (Me) (Ac)
164 OMe N(Me) (AC)
165 SMe CH2NHC(0)0-(3S)- tetrahydrofuranyl
166 S(O)2Me N(Me) (Ac)
167 OMe N(Me) (Ac)
168 SMe CH2NHC(0)0-(3s)tetrahydrofuranyl
ί .1
The compounds of Table HA correspond to compounds of formula (II) wherein one of said B components is phenyl with two substituents, Ql and Q2 .
In accordance wi th formula (II) :-----------------------Ql is selected from R1, R2, R4 or and
Q2 is selected from R1 or R4 .
The compounds of this invention may contain one or more asymmetric carbon atoms and thus may occur 15 as racemaLfcjs and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or s configuration.
Combinations of substituents and variables envisioned bv this invention are only those that result
Ar Ο Ο ϋ 8 1 3
- 28 in the formation of stable compounds. The term stable, as used herein, refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a mammal or for use in affinity chromatography applications). Typically, such cumpoui-ids are stable at a temperature of 40 °C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
As used herein, the compounds of this invention, including the compounds of formulae I-IX, are defined to include pharmaceutically acceptable derivatives or prodrugs thereof. A pharmaceutically acceptable derivative cr prodrug means any pharmaceutically auucpLablc salt, ester, salt of an ester, or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention. Particularly favored derivatives and prodrugs are those that increase the
--------- bioavailability of the compounds cf this invention when such compounds are administered to a mammal (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Preferred prodrugs include derivatives where a group which enhances aqueous solubility or active transport through the gut membrane is appended to the structure of formulae I-IX.
AP/P/ 97/00973
Pharmaceutically acceptable salts of the compounds of this invention include those derived from pnarmaceunically aucepLetbls? inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfunate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydruiodide, 2-hydroxyethaneGulfonato, lactate, maleate, malonate, methanesulfonate, 2naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in '•nv ,,.-.2 themselves pharmaceutically acceptable, may be employed
Fp in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
------------------ Salts- derived- from appropriate-bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium. andN-(Ci_4 alkyl)4+ sails.
This invention also envisions the guaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.
The compounds of this invention may be synthesized using conventional techniques.
Advantageously, these. compounds are conveniently synthesized from readily available starting materials.
AP/P/ 9 7 / 0 0 9 7 3
AF* ν ύ U θ f jj t
I
- 30 In general, compounds of formula (I)-{IX) are conveniently obtained via methods illustrated in General Synthetic Schemes 1-3.
In General Synthetic Scheme 1 (see below), an 5 X-substituted aniline is reacted with a Y-substituted phenylisocyanate under standard conditions to give the besi red nrpa. In this process, X and Y may be one or ·& more independent substituents (or their suitably protected variants) as exemplified by the ring substituents listed for compounds of formulae I-IX above, at any position on the aromatic ring.
AP/P/ 9 7 / 0 0 9 7 3
APO 0-0 8 1 3
- 31 General Synthetic Scheme 1:
Ambient temp, 12 hours
General Synthetic Scheme 2:
Mei
-NC^ 1) Tosylmethyl Isocyanide K2CO3, MeOH, reflux • MeO.
3) m-tolyi isocyanate dlehloroethane
2) H2, Pd/C, EtOAc ambient temp, overnight
AP/P/ 9 7 / 0 0 9 7 3 toluene, reflux
AP ο Ο Ο δ 1 3
- 32 In General Synthetic Scheme 2 (see above), a substituted benzaldehyde (here, 2-methoxy-4-nitrosubstituted) is treated sequentially with tosylmethylisocyanide, to give the resulting oxazole, then reduced by catalytic hydrogenation to give the desired aniline. Reaction of this aniline with an isocyanate (here, m-tclylisocyanate) under standard conditions gives the desired urea.
An alternate synthetic route is j.11 u.strsferi 10 in General Synthetic Scheme 3 (see above). A subs Li Luted benzaldehyde (here 4-nitro cubetituted) is converted to the corresponding oxazolyi aniline as shown in General Synthetic Scheme 2. This aniline is treated with a substituted benzoic acid -(here, 315 methyl-substituted) and a carboxylic acid activating agent, such as diphenyiphosphoryl azide, under standard reaction conditions, to give the desired urea.
As can be appreciated by the skilled artisan, the above synthetic schemes are not intended to 20 comprise a comprehensive list of all means by which the compounds described and claimed in this application may be synthesized. Further methods will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps described above may be 25 performed in an alternate sequence or order to give the desired compounds .
The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological compartment (e.g., blood, lymphatic system,, central nervous system), increase oral availability,
VST?5
- 33 increase κηΐ ιιΐι i liLy to p.How udminictration by injection/ alter metabolism and alter rate of excretion.
The novel compounds of the present invention arc excellent ligands for ΙΜΡΤΊΗ Rr.rnrrii ng) y, these compounds are capable of targeting and inhibiting IMPDH enzyme. Inhibition can be measured by various methods/ including, fnr example, IM? dehydrogenase HPLC assays (measuring enzymatic production of XMP and NADH from IMP and NAD) and IMP dehydrogenase spectrophotometric . assays (measuring enzymatic production of NADH from RAJJ} . Ltcc C. Montaro «L <1., Cliuii.w Cl·, ί τηϊ ι~λ Ar:fn,
238, pp. 169-178 (1995)].
Pharmaceutical compositions of this invehtion comprise a compound of formulae (I), (II) or (VII) or a pharmaceutically acceptable salt thereof; an additional agent selected from an immunosuppressant, an anticancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an antivascular hyperproliferation compound; and any pharmaceutically acceptable carrier, adjuvant or vehicle. Alternate compositions of this invention comprise a compound of formulae (III)-(IX) or a_ pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, adjuvant or vehicle. Such composition may optionally comprise an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation compound.
The term pharmaceutically acceptable carrier or adjuvant refers to a carrier or adjuvant that may be administered to a·'patient, together with a compound
AP/P/ 97/00973
Al· U ν ϋ υ ί 3
- 34 of this invention, and which does not destroy the pharmacological activity thereof and is nontoxic when aaminlscered in duacs .Sufficient to deliver a therapeutic amount of the compound.
Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pliar mac eu.fi cal compos itionn of thic invention include, bur oro noL lj.iuj.Lwd Lu, inn i*-xrh«rifjr-ro, ηίπττ.ίηη., aluminum stearate, lecithin, self-emulsifying drug delivery systems {SEDDS) such as da-tocopherol polyethyleueglycol 1000 succinate, surfactants used in pharmaceutical cosage rorms such as Tweens or other similar polymeric delivery matrices, serum proteins, such as human scrum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty ariris, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, -waxes-,- poryethylene-polyoxypr-opylene-bldok-polymers, polyethylene glycol and wool fat. Cyclodextrins such as α-, β-, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcvclodextrins, including 2- and 3-hydroxypropyl-B-cyclodextrins, or other solubilized derivatives may also be advantageously used to enhance delivery of compounds of formulae I-IX.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasallv,
AP/P/ 97/00973
X buccally, vaginally.or via an implanted reservoir. We prefer oral administration or administration by injection. The pharmaceutical compositions of this invenLion may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueouc or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable
AP/P/ 9 7 / 0 0 9 7 3 dispersing or wetting agents (such as, for example,
Tween 80) and auspei-iding agenta. Tho ctorilo injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally· acceptable diluent or solvent, for example, as a solution xn 1,d-outanedlol. Among the awoepLetle vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of
AP Ο Ο Ο 8 1 3
- 36 injectables, as are. natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as those described in Pharmacopeia Helvetica, Ph._ Helv,, or a similar . alcohol, or carboxymethyl celluose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and or suspensions Other commonly used surfactants such as Tweens or Spans and/or other similar emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharaiaeeutically acocptablo solid, liquid, or other dosage forms may also be used for the purposes of formulation .
The pharmaccutioal oompocitionc of this invention may be orally administered in any orally
Ai acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions ana solutions, in the case of tablets fur oral use, carriers which are commonly used include lactase and corn starch. Lubricating agents, such as magnesium stearate, are.also typically added. For oral . administration in a capsule form, useful diluents include lactose and dried corn starch, when aqueous suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase is combined with emulsifying and/or suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions or this invention may also be administered in the form of
AP/P/ 97/00973
AP Ο Ο Ο 8 1 3
- 37 suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid nt room temperature but liquid at the rectal temperature 'and therefore will melt in the rectum to release the active components. Such . materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention .Λ include, but are not limited to, mineral oil, liquid · s*’ peLruleum, white petroleum, propylene glycol, polyoxy20 ethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition wan be; formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier with suitable emulsifying agents, . Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also bo topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable, enema formulation. Topic'ally-transdermal patches are also included in this invention. ·
AP/P/ 97/00973 *Ρ009813
- 38 The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. .Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable . preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art,
Dosage levels of between about 0.01 and about
100 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day of the IMPDH inhibitory compounds described herein are useful in a monotherapy and/or in combination therapy for the prevention and treatment of IMPDH mediated disease. Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 5 times per day or alternatively, as a continuous (3 infusion. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with the carrier materials to produce a
- ......—single dosage form will vary depending upon--the host--------------treated and the particular mode of administration. A typical preparation will contain from about 5¾ to about ' 95% active compound (w/w) . Preferably, 3uch preparations contain from about 20% to about 80% active compound.
When the compositions of this invention comprise a combination of an IMPDH inhibitor of formulae (I)-(IX) and one or more additional therapeutic'or prophylactic agents,· both the IMPDH inhibitor and the additional agent should be present at dosage levels of between about 10 to 100%, and more
AP/P/ 97/00973
·. J20
APO 0 0 8 1 3
- 39 preferably between about 10 to 80% of the dosage normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
According to one embodiment/ the pharmaceutical compositions of this invention comprise an additional immunosuppression agent. Examples of additional immunosuppression agents include, but are not limited tc, cyclosporin A, PK506, rapamycin,
p.flunomide. deoxysperqualin, prednisone, azathioprine, mycophenolate mofetil, OKT3, ATAG, interferon and mizoribine.
According to an alternate embodiment/ the pharmaceutical compositions of this invention may additionally comprise an anti-cancer agent. Examples of anti·cancer agents include, but are not limited to, cis-platin, actinomycin D, doxorubicin, vincristine, vinblastine, etoposide, amsacrine, mitoxantrone, tenipaside, taxol, colchicine, cyclosporin A, phenothiazines, interferon and thioxantheres.
According to another alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise an anti-viral agent. Examples of anti-viral agents include, but are not limited to, Cvtovene. Ganciclovir, trrsodium phosphonoformate, Ribavirin, d4T, ddl, AZT, and acyclovir.
According to yet another alternate embodiment, the pharmaceutical compositions of this invention may additionally comprise an anti-vascular hyperproliferative agent. Examples of anti-vascular
AP/P/ 9 7 / 0 0 9 7 3
AP Ο ο Ο 8 1 3
- 40 hyperproliferative agents include, but are not limited to, HMG Co-Ά reductase inhibitors such as lovastatin, thromboxane A2 synthetase inhibitors, eicosapentanoic acid, ciprostene, trapidil, ACE inhibitors, low molecular weight heparin, mycophenolic acid, rapamycin and 5-(3'-pyridinylmethyl)benzofuran-2-carboxylate.
Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. 'Subsequently, the dosage or frequency of administration, or both, may be reduced, as .a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
As the skilled artisan will appreciate, lower or higher doses than those recited above may be required. Specific dosage and treatment regimens for any par Liuulcu. patient will depend upon a variety of
.......-............. factors, -including the-activity-of the specific.............-........
compound employed, the age, body weight, general health status, sex, diet, time.of administration, rate of ' excretion, drug combination, the severity and course of the infection, the patient’s disposition to the infection and the judgment of the treating physician.
In an alternate embodiment, this invention provides methods of treating or preventing IMPDH mediated disease in a a mammal comprising the step, of administrating to said mammal any of the pharmaceutical compositions and combinations described above. If the pharmaceutical composition only comprises the IMPDH
AP/P/ 9 7 / 0 0 9 7 3
AP Ο Ο Ο 8 1 3
Λ,
- 41 inhibitor of this invention as the active component, such methods may additionally comprise tne step uf administering to said mammal an agent selected from an antiinflammatory agent, immunosuppressant, an anti5 cancer agent, an anti-viral agent, or an anti-vascular hyperproliferation compound. Such additional agent may bo edministareo rn rn? mnimual Lu, ^vu^urrii'itly
WiUi, ui fulluwiiiy Ll.n_ idai-sUetration of tho ΤΤ/ΡΤΊΚ inhibitor composition.
In a preferred embodiment, these methods are useful in suppressing an immune respuiise in a mammal.
Such methods are useful in treating or preventing diseases, including, transplant rejection (e.g., kidney, liver, heart, lung, pancreas (islet cells), bone marrow, cornea, small bowel and skin allografts and heart valvo xenografts), graft versus host disease, and autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, juvenile diabetes, asthma, inflammatory bowel, disease (Crohn's disease, ulcerative colitus), lupus, diabetes,- mellitus myasthenia gravis, psoriasis, dermatitis, eczema, seborrhoea, pulmonary inflammation, eye uveitis, hepatitis,·Grave's disease,----------Hashimoto's thyroiditis, Behcet's or Sjorgen's syndrome (dry eyes/mouth), pernicious or immunohaemolytic ‘ anaemia, idiopathic·adrenal insufficiency, polyglandular autoimmune syndrome, glomerulonephritis, scleroderma, lichen planus, viteligo (depigmentation of the skin), autoimmune thyroidiLis, and alveolitis.
These methods comprise the step of administering to the mammal a composition comprising a compound of any of formulio I-IX and a pharmaceutically acceptable adjuvant. In a preferred embodiment, this particular method comprises the additional step of
AP/P/ 97/00973
APO Ο 0 8 13
- 42 administering to said mammal a composition comprising an additional immunosuppressant and a pharmaceutically acceptable adjuvant.
Alternatively, this method comprises the step 5 of administering to said mammal a composition comprising a compound of formulae I-IX; an additional immunosuppressive agent and a pharmaceutically acceptable adjuvant.
In an alternate preferred embodiment, these methods are useful fui inhibiting vix-al replication in a mammal. Such methods are useful in treating or preventing, DMA and RNA viral diseases caused hy, for example, HTLV-1 and HTLV-2, HIV-1 and HIV-2, nasopharyngeal carcinoma virus, HBV, HCV, HGV, yellow fever virus, Jeuyua fever virus, Japanoco encephalitis virus, human papilloma virus, rhinoviruses and Herpes viruses, such as Epstein-Barr, cytomegaloviruses and Herpes Simplex, Types 1 and 2, or Type 6. [See, United States patent 5,380,879].
These methods comprise the step of administering-to the mammal a composition--comprising a compound of any of formulae I-IX, and a pharmaceutically acceptable adjuvant. In a preferred embodiment, this particular method comprises the additional step of administering to said mammal a.
composition comprising an additional anti-viral agent and a pharmaceutically acceptable adjuvant.
Alternatively, this method comprises the step u£ administering to said mammal a composition uuiupLising e. compound of fonr.ulac I-IX; an additional anti-viral agent and'a pharmaceutically acceptable adjuvant.
AP/P/ 97/0097 3
APOΟ 0813
- 43 In another alternate preferred embodiment, these methods are useful for inhibiting vascular cellular hyperproliferation in a mammal. Such methods arc useful in treating or preventing diseases, including, restenosis, stenosis, artherosclerosis and other hyperproliferative vascular disease.·
These methods comprise the step of admin i Tf-ori ng to the mammal a composition comprising a compound of any of formulae i-tx, and a pharmaceutically acceptable adjuvant. In a preferred embodiment, this particular method comprises the additional step of administering to said mammal a composition comprising an additional anti-vascular hyperproliferative agent and a pharmaceutically acceptable adjuvant.
Alternatively, this method comprises the step of administering to said mammal a composition comprising a compound of formulae I-IX; an additional anti-vascular hyperproliferative agent and a pharmaceutically acceptable adjuvant.
In another alternate preferred embodiment, these methods are useful for inhibiting tumors and cancer in a mammal. Such methods are useful in treating or preventing diseases, including, tumors and malignancies, such as lymphoma, leukemia and· other forms of cancer.
These methods comprise the step of administering to the mammal a composition comprising a compound of any of formulae I-IX, and a pharmaceutically acceptable adjuvant. In a preferred embodiment, this particular method comprises the additional step of administering to said mammal a composition comprising an additional anti-tumor or
AP/P/ 97/00973
ΑΡθθο813
( - 44 anti-cancer agent and a pharmaceutically acceptable adjuvant.
Alternatively, this method comprises the step of administering to said mammal a composition comprising a compound of formulae I-IX; an additional anti-tumor or anti-cancer agent and a pharmaceutically acceptable adjuvant.
In another alternate preferred embodiment, these methods are useful for inhibiting inflammation and inflammatory diseases in a mammal. Such methods are useful in treating or preventing diseases, including, osteoarthritis, acute pancreatitis, chronic pancreatitis, asthma and adult respiratory distress syndrome.
These methods comprise the step of administerino to the mammal a composition comprising a compound of any of formulae I-IX, and a
Mm pharmaceutically acceptable adjuvant. In a preferred embodiment, this particular method comprises the additional step of administering to said mammal a compo sition-compri s ing-an-anti inflammatory agent—and- a pharmaceutically acceptable adjuvant.
In order that this invention be more fully understood, the following examples are set forth.
These examples are for the purpose of illustration only and are not’to be construed as limiting the scope of the invention in any way.
General Materials and Methods
All temperatures are recorded in degrees
Celsius. Thin layer chromatography (TLC) was carried out using 0.25 mm thick E. Merck silica gel 60 F254 plates and elution with the indicated solvent sysuem.
AP/P/ 9 7 / 0 0 9 7 3
ΛΡΟ 0 0 8 13
t.
' ί t ·
I
- 45 Detection of the compounds was carried out by treating the plate with an appropriate visualizing agent, such as 10% solution of phosphomolybdic acid in ethanol or a 0.1% solution of ninhydrin in ethanol, followed by heating, and/or by exposure to UV light or iodine vapors when appropriate. Analytical HPLC was carried out using a Rainin Mycrosorb-MV, 5μ Cyano reverse phase column, 3.9mm x 150mm, with a flow rate of l.OmL/minute and a solvent gradient of 5-100% 'acetonitrile (0.1%
TFA) in water (0.1% TFA). HPLC retention times were recorded in minutes. NMR spectral data was acquired using a Bruker AMX50Q in the indicated solvent.
The IMP dehydrogenase HPLC assay follows our standard conditions for the enzymatic production of XMP and NADH from IMP and NAD, but utilizes high pressure liquid chromatography on a Cl8 column with ion pairing reagents to separate all four components - The extent * of reaction is then determined from the resulting kff? product peak areas. This assay is particularly useful for determining the inhibition profiles of compounds which have cignificant absorbance in the UV-visible
-----------region between 290 and 340 nM. ------------------------—-----------------The reaction mixture typically contains 0.1 M
KPi; pH 8.0, 0.1M KCI, 0.5 mM EDTA, 2 mM DTT, and 0.2 ' mM each of IMP and NAD. This solution is incubated at 37°c for 10 minutes. The reaction is started by the addition of enzyme to a final concentration of 20 to 100 nM, and is allowed to proceed for 10 minutes.
After the allotted time, the reaction is quenched by th* addition of aycophenolic floiri tn n firm!
concentration of 0.01 mM.
The extent of conversion is monitored by HPLC using a Rainin Microsorb CDS column C18-200 of
AP/P/ 9 7 / 0 0 9 7 3
APO 0 0 8 1 3
- 46 dimensions 4.6 X 10 'mm and a solvent system containing tetrabutylammonium sulfate (5mM) in 0.1 M KPi pH 6.0 -with a 0-30% methanol gradient over 15 minutes. A similar solvent system has been used previously for the purification of halo-IMP derivatives. [L. C. Antionio and J. C. Wu, Biochemistry, 33, 1753-1759 (1994),] A . UV-monicor set al 254 ιϊΜ io used to detect the four components, and the product peaks are integrated to determine the extent of conversion of the substrates.
For the analysis of inhibitors, the compound in question is dissolved in DM50 to a final . concentration of 20 mM and added to the initial assay mixture at the desired concentration in a volume of 25% (v/v). The reaction is started by the addition of enzyme and after 10 minutes is quenched as above.
After HPLC analysis, the product areas are used to determine the extent of conversion relative to a .3 control’ assay containing only DMSO and no test compound. ±050 or Ki values are determined from non 20 linear least squares fitting of conversion vs concentration curves to the tight-binding equations of ....................... Henderson. [?. J. F.---Henderson, Bio chem—C , 127 , 321 (1972) /J
We have measured the inhibition constants of 25 ' each compound against IMPDH using an adaptation of the method first repnrfprt by Magasanik. (R. Maqasanik, H,
S. Moyed, and L. B. Gehring J. Biol. Chem,, ??fi, p.339 (1957)]..
Insofar as compounds of formulae I-IX are 3 0 able to inhibit IMPDH, they are of evident clinical utility for the treatment of IMPDH mediated disease. These tests are predictive of the compounds ability to inhibit IMPDH in vivo.
AP/P/ 97/00973
APO 0 Q 813
Experimental Section
Synthesis of Representative Examples;
Example 1
Synthesis of Compound 1
(1)
To a solution of 25mg (156pmole) 4-(5oxazolvl)-aniline in 250μΣ CH2CI2 was added 50μΕ (400 t μηοΐβ) of benzyl isocyanate at ambient temperature. After stirring overnignt, 1 was isolated, in pure form, by filtration with a 3:1 hexanes/CH2Cl2 rinse in a
- 15------------yield of 21mg (46%) . 1H NMR.....(500MHz, CDCI3) δ - 7. 86 (s)·,
7.55(d), 7.38(d), 7.22-7.35 (hi) , 6.39(g), 5.0 (br c), 4.43(a). Rf 0.30 (5% MeOH/CI^Cls) .
AP/P/ 9 7 / 0 0 9 7 3
Example 2
Synthesis of Compound 43
Cl.
(AcO)2HC
.NO2
BI
APOο 08 13 .(
- 48 To a solution of glacial acetic acid (46ml), acetic anhydride (4 6mL, 485mmole) and 2-chloro-4nitrotoluene (5g, 29.lmmole) at 0 °C was added cone.
H2SO4 (6.9mL) in a dropwise fashion. Upon complete addition, CrOg (8,06g, 80.8mmole) was added portionwise over 60 mins. Following an additional 15 mins of stirring at 0 °C, the reaction mixture was poured over ice and the resulting precipitate was isolated by filtration, rinsing with cold H2O. Purification by flash chromatography, eluting with a gradient of 15-50% • EtOAc in hexanes, provided 2,Q2g (24%, 40% based on recovered starting material) BI as a white solid. The
-H NMR was consistent with that of the desired structure.
AP/P/ 9 7 / 0 0 9 7 3
Compound BI was dissolved in 1:1 ethanol/water (2QmL), treated with cane. H2SO4 (2mL) ' and refluxed for 1 hour. Upon cooling to ambient temperature, the reaction was extracted 3x’s with diethyl ether. The ethereal solution was washed twice with water, dried over and concentrated in vacuo to yield a yellow solid. Purified product was obtained through two recrystallizations from hot Et20/hexanes, yielding 620mg (47.6%)'32 as a lightly yellowed
AP Ο Ο β 8 1 3
- 49 crystalline solid. The NMR was consistent with that of the desired structure.
lki·'
A mixture of B2 (200mg, 1.2mmol), 'tosylmethyl isocyanide (236mg, 1.2mmol), and powdered
K2CO3 (172mg, 1.2mmol'e) in methanol (13iuL) was heated at reflux for 90 minutes and then stirred overnight at ambient temperature. Upon concentration to dryness, the mixture was partitioned between CH2CI2 and water. The organics were separated, washed with 0.5N HCI, water and brine and then dried over NajSO^. The solvent was removed in vacuo to provide a crude yellow
I· solid. Purified product B3 was obtained through flash ' chromatography, eluting with a gradient of 0-2.5% CH3OK in CH2CI2, and recrystallization (C^Clg/hexanes) in a yield of 3.3g (68%) as a light yellow..crystalline solid. The NMR was consistent with that of the desired structure.
AP/P/ 97/00973
A solution of B3 (150mg, 0.67mmole) in 25 ethanol (7.5mL) was treated with SnCl2*2H2O (excess;
APO00813
- 50 ca. 5 equivalents) and heated at reflux for 30 minutes. The mixture was cooled to ambient temperature, diluted with diethyl ether and partitioned with 2N NaOH. The organics were separated, washed with water and brine, dried over Na2SOd and concentrated in vacuo. Purified product B4 was obtained through flash chromatography, eluting with a gradient of 0-0.5% CH3OH in CH2CI2/ in a yield of 54mg (41.5%) as a light yellow oil. The NMR was consistent with that of the desired structure.
AP/P/ 97/00973 (43)
To a solution of 20mg (103|±mole) B4 in ImL 15 CH2CI2 was added 20pL m-tolylisocyanate at ambient temperature. After stirring overnight, 43 was isolated in pure form by filtration with an EtOAc/hexanes rinse in a yield of 25mg (74%) . ^H NMR (500MHz, dg-DMSO) δ
9.06 (5), 8.73 (s), 8.50 (s), 7.89 (s), 7.73 (d) , 7.67 (5), 7.42 (d), 7.31 (s), 7.23 (d), 7.18 (t), 6.82 (d),
2.27 (s). Rf 0.28 (5% MeOH/CH2Cl2)>
ΑΡ Ο ο Ο 8 1 3
- 51 Example 3
Synthesis of Compound 56
MeO.
(AcO)2HC' //
Cl
Cl (8.14g, 51%) was prepared from 2-methyl-5nitroanisole (10.Og, 60mmole) in a fashion directly analogous to the preparation of Bi as described above. Th'e NMR was consistent with that of the desired · structure.
AP/P/ 97/00973
A stirred suspension of Cl (81.94g, 307mmole) in dioxane (lOOmL) was treated with concentrated HCI (2 0mL) and heated at reflux overnight. Upon cooling to ambient temperature, the product C2 precipitated as a light yellow crystalline solid in a yield of 40.65g (73.1%). The filtrate was concentrated to a volume of ca. 80mL and a second crop of product crystals was driven from solution by the addition of hexanes, yielding 8.91g (16.0%). Both batches were identical by NMR and TLC analysis and were consistent with that
ΑΡ Ο Ο Ο 8 1 3
- 52 of the desired material. Tho total yield of C2 wag 49.56g (89.1%).
A solution of C2 (456mg, 2.51mmole), tosylmethyl isocyanide (490mg, 2.5lmmole) and K2CO3 (347mg, 251miriOle) were dissolved in methanol and heated 10 to reflux for 1.5 hours. The product mixture was then concentrated in vacuo, redissolved in CH2cl2' washed with water and brine, dried over NagSC^ and again concentrated in vacuo. Purified product C3 was obtained through recrystallization (Et20/hexanes) to
PA 15 yield 375mg (68%). The NMR was consistent with that of the desired structure.
AP/P/ 97/00973
A solution of C3 (4.214g, 19.1mmole) in EtOAc (150mL) was treated with 10%Pd/C (1.05g, 25 wt.% of C3) and subjected to 40psi (Parr Hydrogenation
Apparatus) overnight. The reaction mixture was filtered and concentrated in vaevo. Pure product C4
Λ-.-4
V ....
- 53 was obtained through flash chromatography, eluting with a gradient of 30-40.% EtQAc/hexanes, in a yield of 3.4g (93%) . The NMR was consistent with that of the desired structure.
To a solution of C4 (25mg, 0.13lmmole) in CHjClg (ImL) was added toll isocyanate (25gL,
0,197mmole) at ambient temperature. After stirring overnight, 56 was isolated in pure form by filtration
with a CH2CI2 rinse in a yield of 4 2mg (74%) -Id nmr
(500MHz, dg-DMSO) 6 8.87 is), 8 . 64 (s) , 8.37 (s), 7.60
(d), 7.46 (d), 7,42 (£) , 7.33 ( s), 7.23 (d), 7.16-7.19
(t), 7.05 (dd), 6.80 (d), 3,92 (s) , 2.28 (s) . Rf 0.46
(5% MeOH/CH2Cl2).
AP/P/ 97/00973
Ο Ο ο θ 1 3
C
- 54 Example 4
Synthesis of Compound 59
T,o a solution of C4 (75mg, 0.394mmole) in dichloroethane (5mL) was added 3-nitrophenyl isocyanate (97mg, 0.591mmole) at ambient temperature- After stirring overnight, DI was isolated in. pure form by filtration with a CHgClg rinse in a yield of 110.3mg (79%). The iK NMR was consistent with that of the desired structure.
AP/P/ 97/00973
To a stirred suspension of DI (95mg,
0.26Smmole) in EtOH (20mL) was added SnClg^HgO (302mg,
1.34mmole)- The reaction mixture was brought to reflux, at which time dissolution occurred, for 1.5 hours. The solution was cooled to ambient temperature, diluted with EtOAc, washed with 2N NaOH and brine, dried (NagSOg) and concentrated in vacuo. Pure product
-’5>
.4
ΑΡ ο Ο Ο 8 1 3 was obtained through flash chromatography (eluting with a gradient of 2.5-5% MeOH in CH2CI2), followed by selective crystallization of the desired material from slightly impure fractions in a yield of 15.7mg (18%). -HNMR (500MHZ, dg-DMSO) δ 8.83 (s) , 8.44 (s), 8.35 (s), 7.59 (d), 7.48 (d), 7.40 (s), 6.97-7.04 (dd), 6.86-6.92 (t), 6.83 (d), 6.54 (dd), 6.20 (dd), 5.05 (br s), 3-. 92 (s). Rf 0.20 (5% MeOH/CH2Cl2) .
Example 5
Synthesis of Compound 113
AP/P/ 9 7 / 0 0 9 7 3
A solution of 3-aminobenzylamine (826mg, 6.87mmole) and triethylamine (2.39mL, 17.18mmole) was treated'wTth’~di-t-butyldicarbonate (l.SOg, 6.87mmole) and the mixture was stirred at ambient temperature for 2 hours. The reaction was then diluted with CH2CI2, washed with NaHCO3(aq), water and brine, dried (M&2SO4) and concentrated in vacuo. Pure El was obtained by flash chromatography, eluting with 25% EtOAc in hexanes in a yield of 200mg (46%). The 1H NMR was consistent with that of the desired structure.
ΠΠ0813 po’v/k v *
(113)
A solution of C4 (150mg, 0.789mmole) and. 1,15 dicarbonylimidiazole (160mg, 0.986mmole) were combined in THF (5mL) and stirred for 5 hours at ambient temperature. The precipitation of imidazole was noted. To this was then added El (351mg, 1.58mmole) and 27,27dimethylaminopvridine (97mg, 0.789mmole) and the mixture was refluxed overnight, resulting in a homogenous solution. Upon cooling to ambient temperature, the reaction was diluted with EtOAc (20mL), washed with KHSO4 (aq), water, and brine, dried 'I (MgSC^band concentrated. Pure 113.was obtained through flash chromatography, eluting with a gradient of 20-30-35% acetone in hexanes in a yield of 164mg (47¾). 1h NMR (500MHz, dg-DMSO) 68.90 (s), 8.75 (s), Θ.38 (s), 7.60 (d), 7.51 (s), 7.3-7.46 (m) , 7,21-7.27 (t), 7.05 (dd), 6.8-7 (d) , 4.12 (d) , 3.93 (s) , 1,44 (s) .
Rf- 0.21 (5% MeOH/CH2Cl2) .
£/600//6 /d/dV
APO 00 8 1 3
- 57 Example 6
Synthesis of Compound 70
Η H
/7¾ (70)
A solution of 3-chloro-4-cyanoaniline (500mgf 7,76mmole) and m-tolylisocyanate (l.OmL, 3.17mmole) in CE2CI2 (3mL) was stirred overnight at ambient temperature. The reaction mixture was concentrated and pure 70 was obtained through MPLC, eluting with 1¾ MeOH in CH2CI2, in a yield of 285mg (31%). ΧΗ NMR (500MHz, dg-DMSO) δ 9.36 (s) , 8.88 (s) , 7.94 (s), 7.83 (d),
7.44 (d), 7.30 (5), 7.24 (d) , 7.15-7.20 (t), 6,82 (d), 2.29 (s). Rf 0.36 (5% MeOH/CH2Cl2).
AP/P/ 9 7 / 0 0 9 7 3
Example 7
Synthesis of Compound 108
Gl
To a solution of 3,4, 5-trimethoxyacetophenone (9.2g, 43.4 mmol) in pyridine (35mL) was added selenium, dioxide (6.3g, 56.7mmdl) and the resulting solution was heated at reflux overnight. The reaction mixture was cooled to ambient temperature, filtered through celite
AP Ο Ο Ο 8 1 3
-ϊ..
- 58 and concentrated to yield a dark brown oil which was dissolved into ethyl acetate and washed with 1.0 N HCl and Llien wiLli saturated WaHCO3. The basic aqueous layer was diluted with ether and acidified with concentrated HCl. The layers were separated and the organic phase was washed with brine and then dried (Ty (Na2SC>4) to give 8.4 g of a dark yellow solid.
Recrystallization of this material from ethyl acetatehexane then gave G1 (6,8 g) as a pale yellow solid.
The 1H NMR was consistent with that of the desired structure.
(108)
AP/P/ 97/00973
A mixture of 59 (64mg, 0.20mmole), G1 (30Qmg, 1.20mmole)_and_EDC (300mg-, l.Smmole)- in THF (5mL) was stirred overnight at ambient temperature. The reaction was diluted with EtOAc (150mL), washed with water, dried (MgSO^) and concentrated in vacuo. Pure 108 was obtained through MPLC, eluting with a gradient system of 0-l%MeOH in CH2CI2 , in a yield of 37.4mg (35%).
XH NMR (500MHz, dg-DMSO) 6 9.83 (s), 8.23 (s), 8,18 (s), 7.65 (s), 7.61 (s), 7.35 (d), 7.33 (s), 7.29 (s),
7.27 (s), 7.11 (s), 7.06-7.10 (t), 6.94-6.99 (t), 6.52 (d)3.68 (5), 3.63 (s) / 3.61(s). Rf 0.26 (5%
MeOH/CH2Cl2)(·
APO Ο 0θ13
- 59 Example 9
Synthesis of Compound 115
A solution of 59 (300mg, 1.58mmole) and mtoll isothiocyanate (2.0mL, 14.7mmole) in CHgClg (5mL) was stirred at ambient temperature overnight. To drive 10 the reaction to completion, additional m-toll isothiocyanate (l.OmL, 7.4mmole) was added and the mixture was heated to reflux for 3 hours. The reaction
3· was concentrated in vacuo and 115 was obtained in pure © form through MPLC, eluting with 0-5% EtOAc in CH2C12, in a yield of 210mg (39%). NMR (500MHz, dg-DMSO) δ
7.90 (Ξ), 7.89 (5), 7.82 (S), 7.75 (d), 7.64 (s) Ί.44 (s), 7.32-7.37 (t), 7.27 (5), 7.13-7.21 (m), 6.91 (dd),
3.98 (s) , 2.40 (s). Rf 0.36 (5% MeOH/CH2Cl2).
AP/P/ 9 7 / 0 0 9 7 3
Example 9
Synthesis of Compound 97
A solution of nitroaniline (l.Og, 7.13mmole) in Cri2Cl2 (25mL·) was created wirh pyridine (2.9mL,
APO ο ο813
- 60 c-.~J
36mmole) and trifluoroacetic anhydride (5mL, 36imnole) and stirred at ambient temperature for 3 hours. The reaction was diluted 'further with CH2C12, washed with IN HCI and brine, dried (MgSOzj) and concentrated in vacuo to yield II (l,61g, 95%) as a white solid. The
NMR was consistent with that of the desired structure.
To a slurry of NaH (60% oil dispersion; 34 mg, 1.42mmole) in THF (lOmL) at 0 °C was added a solution of II (200mg, 0.85rcmole) in THF (lOmL) and the mixture stirred, for 1 hour. To this was added methyl iodide (lOOpL, 1.7mmole) and the mixture was stirred overnight at ambient temperature. The reaction was poured into water and extracted with EtOAc. The organics were separated, dried (MgSOzj) and concentrated in vacuo. Pure 12 was obtained through flash chromatography, eluting, with 5% EtOAc in hexanes, in a yield of 163mg (66%). as a yellow solid. The NMR was consistent with that of the desired structure.
AP/P/ 97/0097 3 ,CF3
A solution of 12 (l63mg, 0.66mmole) in ethanol (5mL) was treated with Pd/C (20mg) and
- 61 subjected to Η2 (1 atm.) for 3 hours. The reaction was filtered and concentrated in vacuo to yield 13 (120mg, 84%) as a waxy solid. The NMR was consistent with that of the desired structure.
To a solution of triphosgene (31mg,
0.104mmole) in dichloroethane (lmL) was added in a dropwise fashion a solution of B4 (50mg, 0.260mmole) and diiscpropylethylamine (67mg, 518mmole) in dichloroethane (5mL). The reaction mixture was stirred
-¾ for an additional 1 hour at ambient temperature, j
psy 15 treated with 13 (50mg, 0.230 mmole) and stirred overnight. The entire reaction mixture was subjected to flash chromatography, eluting with 1% MeOH in
..................CH2CI2, to provide pure 97 in a yield of Smg (7%).- -¼ —
NMR (500MHz, dg-DMSO) 5'9.20 (s) , 8.98 (s), 8.39 (s),
7.67 (s), 7.63 (d), 7.48 (s), 7.38-7.45 (m) , 7.04-7.10 (t), 3.95 (s), 3.31 (S). Rf 0.37 (5% MeOH/CH2Cl2).
AP/P/ 9 7 / 0 0 9 7 3 ion η η Β Λ· 3
- 62 Example 10
S'/iitEccic of Compound. Ill
A solution of 59{50mg, 0,154mmole) and triethylamine (3lmg, 0.308mmole) in DMF (0.5mL) was treated in a dropwise fashion with phenylacetyl chloride (25mg, O.l69mmole) and the reaction stirred overnight at ambient temperature. The mixture was diluted with CH2C12, washed with NaHC03(aq) and water, dried over MgSC>4 and concentrated in vacuo. Pure 111 was isolated by flash chromatography, eluting with 2%
MeOH in CH2C12, in a yield of 42mg (62%). 1h NMR (500MHz, dg-DMSO) δ 10.20(s), 8,90 (s), 8.79 (s) , 8.39 (s), 7.68 (s), 7.63 (d), 7.53 (d), 7.44 (s), 7.25-7.40 (m), 7.22 (t), 7.14 (d), 7 0.5. (dd), 3.56 (5), 3.66 (s) .
Rf 0.31 (5% MeOH/CH2Cl2)Example 11
Synthesis of Compound 102
AP/P/ 97/00973
A solution of 2-methyl-5-nitroben2oic acid (15g, 82.8mmole) in DMF (75mL) was treated with methyl
...
til
APS 5 03 13
- 63 iodide (6,7mL, 107.64mmole) followed by powdered K2CO3 (17.2g, 124-2mmole) (extreme exotherm) and the suspension Stirred at ambient temperature overnight.
The reaction mixture was partitioned between EtOAc and water, the organics separated and washed with water and brine, dried (i^SO^) and concentrated in vacuo to yield Kl (15.86g, 96%) in pure form as an off-white solid. Tho 1h NMR was consistent with that of tho desired structure.
K2 (4.09g, 16.2%) was prepared from Kl 15 (15.86g, 81„3mmole) in a fashion analogous to the preparation of BI as described above. The NMR was consistent with that of the desired structure.
AP/P/ 97 /00973
A. solution of K2 (2.5g, 8.03mmole) in dioxane (lOmL) was treated with cone, HCl (O.SmL) and the mixture was heated to reflux for 2 hours. Additional cone. HCl (O.SmL) was added and the reaction refluxed for 3 hours longer. The mixture was diluted with
EtOAc, washed with water and brine, dried (N^SQz)) and concentrated in vacuo. Pure K3 was obtained through
AFO G O 8 1 3 r
- 64 flash chromatography, eluting with a gradient of 20-3050% EtgO in hexanes, in a yield of 1.14g (68%). Also isolated was 215mg (11.8%) of the hydrated aldehyde.
The !h NMRs were consistent with that of the desired structures.
A solution of K3 (300mg, 1.43mmole) in benzene (5mL) was treated with 1,3-propane diol (114qL, l,573mmole) and p-TsOH*H2O (27mg, 0.14mmole) and the mixture was refluxed with Dean-Stark removal of water for 4.5 hours. The reaction was cooled to ambient
5 temperature, partitioned between EtOAc and dilute
NaHCC>3, the organics separated, washed with brine, dried (NagSC^) and concentrated in vacuo. Pure K4 was obtained through flash chromatography, eluting with a gradient of 20-25% Et2O in hexanes, in a yield of
324mg (84.5%) as an off-white crystalline solid. The ^H NMR was consistent with that of the desired structure .
K5
AP/P/ 9 7 / 0 0 9 7 3.
APO 0 0 8 1 3
- 65 A solution of K4 (289mg, 1.08mmole) in THF (5mL) at 0 °C was treated dropwise with a solution of DIBAL (1.0M in CHgClg; 2.7mL, 2.7mmole) and stirred for 40 minutes. The reaction was quenched by addition of saturated Rochelle's salt solution (lOmL), diluted with EtOAc and stirred for 30 minutes. The organics were collected, washed with brine, dried (NapSO^j) and concentrated in vacuo to give 250mg (97%) of K5 a's a white crystalline solid. The NMR was consistent with that of the desired structure,
£ L 6 0 0 / L 6 /d/dV ;u-at
3:-. -Tr
A solution of K5 (250mg, l.Oommole) in CH2CI2
J4mL) at 0 °C was treated with pyridine (11OuL, . ______
1.37mmole), benzoyl chloride (146pL, 1.26mmole) and 4DMAP (catalytic), and stirred at ambient temperature overnight. The reaction mixture was diluted, with
CH2CI2, washed with 0.5N HCI, water and brine, dried (Na2SO4> and concentrated in vacuo. Pure K6 was obtained through flash chromatography, eluting with 10% EtOAc in hexanes, in a yield of 340mg (99%) as a white solid. The 1β NMR was consistent with that of the desired structure.
Ar G G δ & 1 3
OHv
K7
A solution of K6 (326mg, 0.99mmcle) in dioxane (7mL) was treated with 2. ON HCl (5mL) and the mixture heated at 80 °C overnight. The reaction mixture was diluted with EtOAc and washed with saturated NaHCO3(aq), water and brine, dried (Na2SOd) and concentrated in vacuo. Pure K7 was obtained through flash chromatography, eluting with·30¾ Et20 in hexanes, in a yield of 208mg (77.5¾) as a white solid. The NMR was consistent with that of the desired structure.
HO
ΚΘ
AP/P/ 9 7 / 0 0 9 7 3
A solution of K7 (208mg, 0.729mmole) in MeOH (6mL) was treated with K2CO3 (lOlmg, 0.765mmole) and TosMIC (14Smg, 0..?65mmole) and the solution heated at
60 °C for one hour. The reaction was concentrated in vacuo, redissolved in CH2CI2 and washed with 1.0N NaOH (diluted with saturated NaHCO3). The aqueous portion wac baok-eittraetcd with CII^Cl^, the organici combined and washed with water and brine, dried (Na2SO4) and
APO00813
- 67 concentrated in vacuo. Pure K8 was obtained through flash chromatography, eluting with a gradient of 1050% acetone in hexanes, in a yield of 70mg (44%). The 1K NMR was consistent with that of the desired structure .
A solution of K8 (70mg, 0.318) in acetic anhydride (1.5mL) and pyridine (l.OmL) was treated with 4-DMAP (catalytic) and stirred at ambient temperature for 3 hours. The mixture was diluted with CH2CI2, washed with 1.0N HCI, water and brine, dried (Na2SC>4) and concentrated in vacuo to provide K9 in a yield of
82mg (98%) as a pale yellow solid. The 1H NMR was consistent with that of the desired structure.
AP/P/ 9 7 / 0 0 9 7 3
A solution or K9 (80mg, 0.305mmole) in dry :CH (4mL) was treated with SnCl2-2H2O (24lmg,
ΚΡΟ Ο 0 8 13
- 68 1.07mmole) and the mixture heated at 60 °C for 50 minutes, The reaction was diluted with EtOAc, washed with saturated NaHCC>3, water and brine, dried (Na2SO<2) and concentrated in vacuo. Pure K10 was obtained through flash chromatography, eluting with a gradient of 20-30% acetone in hexanes, in a yield of 52mg (73.4%) as a pale yellow oil. The NMR was consistent with that of the desired structure.
A solution of K10 (52mg, 0,224mmole) in dichloroethane (2mL) was treated with m-tolyl isocyanate (43l±L, 0.336mmole) and stirred overnight at ambient temperature. The mixture was diluted with CH2CI2:hexanes (2:1), filtered and rinsed with the same
AP/P/ 9 7 / 0 0 9 7 3 solvent system to provide Kll (67mg, 82%) as a white solid. The !h NMR was consistent with that of the desired structure.
(102)
Γ'
- 69 A solution of Kll (33mg, 0.09mmole) in MeOH (2mL) was treated with 1.0N NaOH (135 μΕ, 0.135rnmole) and stirred at ambient temperature for 1.5 hours. The reaction was neutralized by addition of 1.0N HCI (135 pL) and concentrated in vacuo. The white solid was rinsed with water end CHgClg:hexanes (2:1) and dried in vacuo to provide 102 (20mg, 68%) as a white solid, ~H NMR (500MHz, dg-DMSO) δ 9.29 (s), 9.00 (s), 8.42 (s) ,
7.69 (s), 7.55 (m), 7.37 (s) , 7.33 (s), 7.27 (d), 7.16 (t), 6.80 (d) , 5.39 (t), 4.58 (s) , 2.28 <s) , Rf 0.13 (1:1 hexanes/acetone).
Example 12
Synthesis of Compound 106
AP/P/ 9 7 / 0 0 9 7 3
A solution of C4 (50mg, 0.263mmole) in THF · (2mL) was treated with CDI (53mg, 0.33Qmmole) and stirred at ambient temperature for 4 hours. To this was added l-acetyl-6-aminoindole (93mg, 0.526mmole, Sigma Chemical Co.) and 4-DMAP (35mg, 0,289mmole) and the mixture refluxed overnight. Diluted with EtOAc (lOOmL), washed with 51 KHSO4, water and brine, dried (NagSC^) and concentrated in v&cuo. Redissolved in
EtOAc and filtered to removed insoluble materials and /tr ο ο ο δ 1 3
- 70 reconcentrated in vacuo. Pure 106 was obtained through flash chromatography, eluting with a gradient of 5060% acetone in hexanes, in a yield of 37mg (36%) as a
white solid. iH NMP. (500MHz, dg-DMSO) δ 8.79 <e) , 8.74
5 (s), 8,37 (5), 8,11 (s), 7.62 (d), 7.47 (s), 7,43 (s),
7.30 (d), 7.13 (d), 7.14 (d), 4,11 (t), 3.94 (s) , 3.07
(t), 2.17 (s) . Rf 0.14 (1:1 hexanes/acetone ) -
A suspension of 113 (from Example 5) (250mg, 5.7 6mmol) in CK2CI2 (lml) was treated in a dropwise fashion at ambient temperature with several equivalents of 15 trifluoroacetic acid and stirred for SOmin. The resulting solution was stripped in vacuo and tritrated with CK2CI2 and methanol. Pure product 168 was isolated by filtration in a yield of 253ng. (99%) ......-The
NMR was consistent with that of the desired product,
AP/P/ 97/00973
A suspension of 168 (250mg, 0.55mmol) in 21mL of
CH2cl2/Di4F (20:1 by volume) was treated with triethyl
APO00813 •A ί ;
- 71 smi ne (l93pL, l,38mmol) and stirred at ambient temperature until homogeneity was reached. The solution was cooled to 0 C, treated with (5) 3tetrahydrofuranyl-N-oxysuccinimidyl carbonate (635mg,
0.608mmol) and allowed to stir overnight with warming to ambient temperature. The mixture was poured into ethyl acetate (500mL), washed with NaHCOgiao)( 2x),
Fl water (2x), and brine(lx), dried over N&2SO4 and stripped in vacuo. Pure product 120 was isolated by tritration (30mL CH2Cl2r lOOmL ether) in a yield of
212mg (B5%). The NMR was consistent with that of the desired product.
Example 14
IMPDH Activity Inhibition Assay
We measured the inhibition constants of the j!
~ 20 compounds listed in Table III utilizing the following protocol:
IMP dehydrogenase activity was assayed following an adaptation of the method first reported by Magasanik. [Magasanik, B. Moyed, H. S- and Gehring L, 25 B. (1957) J. Biol. Chem·. 226, 339). Enzyme activity was measured spectrophotometrically, by monitoring the increase in absorbance at 340 nm due to the formation of NADH (ε340 is 6220 M“~ cm”l). The reaction mixture contained 0.1 M Tris pH 8.0, 0.1 M KCI, 3 mM EDTA, 2 mM
DTT, 0.1 M IMP and enzyme (IMPDH human type II) at a concentration of.15 to 50 nM. This solution is incubated at 37°c for 10 minutes. The reaction is started by adding NAD- to a final concentration cf 0.1M and the initial rate is measured by following the
AP/P/ 9 7 / 0 0 9 7 3 ρ 9 Ο Ο Β 1 3
- 72 linear increase in absorbance at 340 nm for 10 minutes. For reading in a standard spectrophotometer (path length 1 cm) the final volume in the cuvette is 1.0 ml. The assay has also been adapted to a 9S well microtiter plate format; in this case the concentrations of all the reagents remain the same and the final volume is decreased to 200 μϊ.
For the analysis of inhibitors, the compound in question is dissolved in DMSO to a final concentration of 20 mM and added to the initial assay mixture for preincubation with the enzyme at a final volume of 2.5% (v/v) . The reactinn is started hy the addition of NAD, and the initial rates measured as above.
determinations are made by measuring the initial velocities in the presence of varying amounts of inhibitor and fitting the data using the tight-binding equations of Henderson (Henderson, P. J, F. (1972) Biochem. J. 127, 321].
These results are shown in Table III. Ks values are expressed in nM. Category A indicates
0.01 to 50 nm activity, category B indicates 51-1000 nm activity, category C indicates 1001 to 10,000 nm activity, categoryD indicates greater than 10,000 nm activity. The 'designation ND is used where a given compound was not tested.
AP/P/ 97/00973
AP O 0 0 8 1 3
- 73 Table III
Cmpd K± Cmpd Ki Cmpd Ki
# (nM) # (nM) # (nM)
1 C 40 C 78 B
2 c 41 c 79 B
3 B 42 B 80 C
4 D 43 B 81 C
5 C 44 — 82 c
6 C 45 C 83 B
7 B 46 B 84 B
8 C 47 B 85 B
9 C 48 C 86 C
10 C 49 c 87 D
11 c 50 D 8B C
12 c 51 D 89 C
13 c 52 C 90 C
14 c 53 c 91 C
15 c 54 c 92 C
16 c 55 A 93 A
17 B 56 B 94 B
18 C 57 B . 95 C
19 C 58 C 96 B
20 c 5 9 A 97 A
21 c 60 B 98 B
22 c 61 D 99 A
23 c 62 C 100 D
24 B 63 C 101 C
25 C 64 B 102 c
26 c 65 B 103 c
27 c 66 C 104 c
28 c 67 C 105 B
29 D 68 B 106 B
30 c 69 B 107 A
31 D 70 · C 108 B
32 D 71 C 109 B
33 D 72' C 110 B
34 C 73 B 111 A
35 c 74 B 112 B
36 c 75 B 113 A
37 c 76 C 114 B
38 D 77 B 115 B
39 D
AP/P/ 9 7 / 0 0 9 7 3
A? ο Ο Ο 8 1 3
Cmpd Ki Cmpd Ki Cmpd Ki Cmpd K±
# (nM) (nM) (nM) # (nM)
116 A 129 A 142 A 155 A
117 B 130 A 143 B 156 A
118 C 131 A 144 B 157 B
119 A 132 A 145 A 158 B
120 A 133 A 146 A 159 A
121 A 134 A 147 A 160 A
122 A 135 A 148 A 161 A
123 A 136 A 149 A 162 A
124 A 137 B, 150 A 163 B
125 A 138 A 151 B 164 B
126 A 139 B 152 B 165 A
127 A 140 A 153 A 166 D
128 A 141 A 154 A 167 B
169 Β
Example 15
Anti-Viral Assays 5
The anti-viral efficacy of compounds may be evaluated in various in vitro and in vivo assays. For example, compounds may be tested in in vitro viral replication assays. In vitro assays may employ whole cells or isolated cellular components. In vivo assays include animal models for viral diseases. Examples of such animal models include, but are not limited to, rodent models for HBV or HCV infection, the Woodchuck model for H3V infection, and chimpanzee model for HCV infection.
While we have described a number of embodiments of this invention, it is apparent that our basic constructions may be altered to provide other embodiments which utilize the products and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims, rather than by the specific
AP/P/ 9 7 / 0 097 3
APO Ο Ο 8 1 3
- 75 embodiments which have been presented by way of example.

Claims (13)

1. A method of inhibiting IMPDH activity in a mammal comprising the step of administering to said mammal a compound of formula:
B (i) wherein:
A is selected from:
(C1-C6)-straight or branched alkyl, or (C2C6)-straight or branched alkenyl or alkynyl; and A optionally comprises up to 2 substituents, wherein:
the first of said substituents, if present, is selected from R1 or R3, and the second of said substituents , if present, is R1;
.-¾
B is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, 0, or S and selected from the formulae:
AP/P/ 9 7 / 0 0 97 3
X
X
AP 0 0 0 8 1 3
- 77 wherein each X is the number of hydrogen atoms necessary to complete proper valence;
and B optionally comprises up to 3 substituents, wherein:
the first of said substituents, if present, is selected from R1, R2, R4 or R5, the second of said substituents, if present, is selected from R1 or R4, and the third of said substituents, if present, is R1; and
D is selected from C(0), C(S), or S(0)2; wherein:
each R1 is independently selected from 1,2methylenedioxy, 1,2-ethylenedioxy, R6 or (CH2)n-Y;
' wherein n is 0, 1 or 2; and
Y is selected from halogen, CN, NO2, CF3, OCF3, OH, SR6, S(O)R6, SO2R6, NH2, NHR5, N(R6)2, NRSR8, COOH, COOR6 or OR6;
each R2 is independently selected from (C1-C4)straight or branched alkyl, or (C2-C4)-straight or branched alkenyl or alkynyl; and each R2 optionally comprises up to 2 substituents, wherein:
the first of said substituents, if present, is selected from R1, R4 and R5, and the second of said substituents, if present, is R1;
R3 is selected from a monocyclic or a bicyciic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH2 adjacent to any of said N, 0, or S heteroatoms is optionally substituted with C(0); and each R3 optionally
AP/P/ 97/00 973
AP 0 0 0 8 1 3
- 78 comprises up to 3 substituents, wherein:
the first of said substituents, if present, is selected from R1, R2, R4 or R5, the second of said substituents, if present, is selected from R1 or R4, and the third of said substituents, if present, is R1;
each R4 is independently selected from OR5,
OC(O)R6, OC(O)R5, 0C(0)OR6, OC(O)OR5, OC(O)N(R6)2,
OP (0) (OR6) 2, SR6, SR5, S(O)R6, S(O)R5, SO2R6, SO2R5, SO2N(R6)2, SO2NR5R6, SO3R6, C(0)R5, 0(0) OR5, C(0)R6, C(0)0R6, NC(O)C(O)R6, NC(O)C(O)R5, NC (0) C (0) OR6,
NC (0) C (0) N (R6) 2, C(O)N(R6)2, C (0) N (OR6) R5, C (0) N (OR6) R5, C(NOR6)R6, C(NOR6)R5, N(R6)2, NR6C(O)R!, NR6C(O)R6, NR6C(O)R5, NR6C(O)OR6, NR6C(O)OR5, NR6C (0) N (R6) 2,
NR6C (O)NR5R6, nr6so2r6, nrso2r5, NR6S02N(R6) 2, NR6S02NR5R6, N(0R6)R6, N(0R6)R5, P(0) (OR6)N(R6) 2, and P (0) (OR6) 2;
each R5 is a monocyclic or a bicyciic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with 0(0); and each R5 optionally comprises up to 3 substituents, each of which, if present, is R1;
each R6 is independently selected from H, (C1-C4)straight or branched alkyl, or (C2-C4) straight or branched alkenyl; and each R6 optionally comprises a substituent that is R7;
R7 is a monocyclic or a bicyciic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, 0, or S, and wherein a CH2 adjacent to said N, 0 or S maybe substituted with C(0); and each R7 optionally comprises up to 2 substituents independently
AP/P/ 9 7/00973
APO 0 0 8 1 3
- 79 chosen from H, (Ch-CJ-straight or branched alkyl, or (C2-C4) straight or branched alkenyl, 1,2methylenedioxy, 1,2-ethylenedioxy, or (CH2)n-Z;
wherein n is 0, 1 or 2; and
Z is selected from halogen, CN, NO2, CF3, OCF3, OH, S (Cx-C4)-alkyl, SO (Cx-C4)-alkyl, SO2 (Cx-C4)-alkyl, NH2, NH (Cx-C4)-alkyl, N ( (Cx-C4)-alkyl) 2, N ( (Cx-C4)-alkyl) R8, COOH, C (0) O(CX-C4)-alkyl or 0 (Cx-C4)-alkyl; and
R8 is an amino protecting group; and wherein any carbon atom in any A, R2 or R6 is optionally replaced by 0, S, SO, SO2, NH, or N (Cx-C4)alkyl.
2. The method according to claim 1, wherein • in said compound, B has from 0 to 2 substituents.
3. The method according to claim 1 or 2, wherein in said compound, B comprises at least a first substituent and wherein said first substituent is R5.
4. The method according to claim 3, wherein in said compound, B is a monocyclic aromatic ring and said first substituent of B is a monocyclic aromatic ring.
5. A method of inhibiting IMPDH activity in a mammal comprising the step of administering to said mammal a compound of the formula:
£/600//6 /d/dV (II)
ΑΡ Ο Ο Ο 8 1 3 wherein:
D and Β are as defined in claim 1.
6. The method according to claim 5, wherein in said compound, at least one B has from 0 to 2 substituents .
7. The method according to claims 5 or 6, wherein in said compound, one B comprises at least a first substituent and wherein said first substituent is R5.
8. The method according to claim 7, wherein in said compound, said B is a monocyclic aromatic ring and said first substituent of said B is a monocyclic aromatic ring.
9. A compound of the formula:
£ L 6 0 0 i L 6 /d/dV wherein:
A, D, and B are as defined in claim 1;
E is 0 or S; and
G and G' are independently selected from R1 or H.
10. A compound of the formula:
AP ο Ο Ο β 1 3 wherein:
Β and D are as defined in claim 5;
E, G and G’ are as defined in claim 9;
B' is a saturated, unsaturated or partially saturated monocyclic or bicyclic ring system optionally comprising up to 4 heteroatoms selected from N, 0, or S and selected from the formulae:
AP/P/ 9 7 / 0 0 9 7 3 and B’ optionally comprises up to 3 substituents, wherein:
the first of said substituents, if present, is selected from R1, R2, R4 or R5, the second of said substituents, if present,
AP Ο Ο Ο 8 1 3
- 82 is selected from R1 or R4 and the third of said substituents, if present, is R1;
wherein X, R1, R2, R4 or R5 are as defined in claim 5; wherein if B is unsubstituted phenyl and all of said substituents present are on B' are R1, then at least one of said R1 substituents is not chloro, bromo or iodo; and wherein B and B' are not simultaneously unsubstituted phenyl.
η '-ϋ'
11 .
the formula:
The compound according to claim 9 having
E L 6 0 0 1 L 6 /d/dV wherein:
K is J is selected selected from R1 and R4; and from R1, R2, and R4.
12. The compound according to claim 11, wherein D is -C(0)-.
13 The compound according to claim 11, wherein E is oxygen. 14 The compound according to claim 11, wherein J is NR6C(O)R5 or NR 6C (0) R6.
15. The, compound according to claim 14
ΑΡ ο Ο Ο 8 1 3
wherein J is NR6C(O)R6. wherein J 16. The compound is N(CR3)C(O)R6. according to claim 15, wherein K 17. The compound is (CH2)n-Y. according to claim 11, wherein K 18. The compound is OCH3. according to claim 17, wherein G 19. The compound is hydrogen. according to claim 11, wherein: 20. The compound D is -C(O)-; E is oxygen; K is OCH3; and G is hydrogen. according to claim 16, wherein J 21. The compound is R2. according to claim 11, wherein E 22. The compound is oxygen. according to claim 21, wherein J 23. The compound is R2 substituted according with R4. to claim 21, wherein R4 24. The compound is NReC(O)OR5 or j according MR6C (0) OR6. to claim 23,
AP/PI 97/00973
25. The.compound according to claim 21
AP 0 0 0 8 13
- 84 ».-JF
wherein K is ( CH2)n-Y. 26. The compound according to claim 25, wherein K is 0CH3. 27 . The compound according to claim 21, wherein: D is -C(0) E is oxygen; K is OCH3 and G is hydrogen.
28. A compound of the formula:
AP/P/ 9 7/ 00973 wherein K is selected from R1 and R4; and
B, D, R1 and R4 are each independently as defined in claim 1.
29. The compound according to claim 28, wherein D is -C(0)-.
30. The compound according to claim 28, wherein B is a monocyclic aromatic ring substituted with 1-2 substituents selected from the group consisting of NR6C(O)R5, NR5C(O)R5, CH2NR6C (0) OR6, and CH2NR6C (0) OR5.
APO 0 0 8 1 3
- 85 31. The compound according to claim 30, wherein B is a monocyclic aromatic ring substituted with 1-2 substituents selected from the group consisting of CH2NR6C (0) OR6 and CH2NR6C (0) OR5 .
32. The compound according to claim 28, wherein K is (CH2)n-Y.
33. The compound according to claim 32, wherein K is OCH3.
34. A compound according to the formula:
K .CN wherein:
AP/P/ 97/00973
is selected from C(0), C(S) and S (O)2; is selected from R1 and R4; and is selected from R1, R2, and R4. 35. The compound according to claim 34, D is -C(O)- 36. The compound according to claim : 34, J is NR6C(O)R5 or NR6C(O)R6. 37. The compound according to claim 34, K is (CH2)n· -Y.
38. The, compound according to claim 37,
AP Ο Ο Ο 8 1 3
- 86 wherein Κ is OCH3.
39. The compound according to claim 10 selected from the group consisting of compounds 1-27, 29-31, 39-51, 53-69, 71-86, 88-89, 91-102 and 104-162 in Tables IA, IB and IC.
40. The compound according to claim 34 selected from the group consisting of compounds 163-168 in Table IIB.
41. A pharmaceutical composition comprising: a. a compound of the formula:
or
AT (I) £4600//6 /d/dV (II) in an amount effective to inhibit IMPDH activity, wherein A, B and D are as defined in claim 1;
b. an additional agent selected from an immunosuppressant, an anti-cancer agent, an antiviral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation agent;
AP O θ Ο β13
- 87 c. a pharmaceutically acceptable adjuvant.
42. The composition according to claim 41, wherein in said compound, at least one B comprises at least a first substituent and wherein said first substituent is R5.
43.
the formula:
A compound according to claim 11 having
44. A pharmaceutical composition comprising:
a. a compound according to claim 43 in an amount effective to inhibit IMPDH activity; and
b. a pharmaceutically acceptable adjuvant.
45. A pharmaceutical composition comprising:
a. a compound according to any one of claims 8 to 32 in an amount effective to inhibit IMPDH activity; and
b. a pharmaceutically acceptable adjuvant.
46. The pharmaceutical composition according to either of claims 44 or 45, additionally comprising an additional agent selected from an immunosuppressant,
AP/P/ 9 7 /0097 3
AF000813
- 88 an anti-cancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation agent.
47. A method of use of a composition according to claim 41 for treating or preventing IMPDH mediated disease in a mammal, comprising the step of administering said composition to said mammal, wherein said composition comprises from about 0.01 mg/kg to about 100 mg/kg body weight per day of said compound of formula (I) or formula (II).
48. A method of use of a composition according to either of claims 44 or 45 for treating or preventing IMPDH mediated disease in a mammal, comprising the step of administering said composition to said mammal, wherein said composition comprises from about 0.01 mg/kg to about 100 mg/kg body weight per day of said compound of formula (I) or formula (II).
49. The method of use according to claim 48, wherein said composition additionally comprises an agent selected from an immunosuppressant, an anticancer agent, an anti-viral agent, an anti-inflammatory agent, an anti-fungal agent, an antibiotic, or an antivascular hyperproliferation agent.
50. The method of use according to any one of claims 47 to 49, wherein said method is used to suppress an immune response and wherein said additional agent, if present, is an immunosuppressant.
51. The method of use according to claim 50, wherein said IMPDH mediated disease is an autoimmune £ L 6 0 0 / L 6 /d/dV
APO00813
- 89 disease.
52. The method of use according to any one of claims 47 to 49, wherein the IMPDH mediated disease is a viral disease, and wherein said additional agent, if present, is an anti-viral agent.
53. The method of use according to any one of claims 47 to 49, wherein the IMPDH mediated disease is a vascular disease, and wherein said additional agent, if present, is an anti-vascular hyperproliferation agent.
54. The method of use according to any one of claims 47 to 49, wherein the IMPDH mediated disease is cancer, and wherein said additional agent, if present, is an anti-cancer agent.
55. The method of use according to any one of claims 47 to 49, wherein the IMPDH mediated disease / is an inflammatory disease, and wherein said additional agent, if present, is an anti-inflammatory agent.
APAP/P/1997/000973A 1996-04-23 1997-04-23 Urea derivatives as inhibitors of IMPDH enzyme. AP813A (en)

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US08/636,361 US5807876A (en) 1996-04-23 1996-04-23 Inhibitors of IMPDH enzyme
US08/801,780 US6344465B1 (en) 1996-04-23 1997-02-14 Inhibitors of IMPDH enzyme
US08/832,165 US6054472A (en) 1996-04-23 1997-04-02 Inhibitors of IMPDH enzyme

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Families Citing this family (159)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69709671T2 (en) * 1996-10-18 2002-08-22 Vertex Pharmaceuticals Inc., Cambridge INHIBITORS OF SERINE PROTEASES, ESPECIALLY NS3 PROTEASE OF THE HEPATITIS C VIRUS
WO1998024785A1 (en) * 1996-12-02 1998-06-11 Fujisawa Pharmaceutical Co., Ltd. Indole-urea derivatives with 5-ht antagonist properties
EP1366766A1 (en) * 1997-03-14 2003-12-03 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme
US6093742A (en) * 1997-06-27 2000-07-25 Vertex Pharmaceuticals, Inc. Inhibitors of p38
JP4555468B2 (en) * 1997-10-31 2010-09-29 アベンテイス・フアルマ・リミテツド Substituted anilide
WO1999032106A1 (en) * 1997-12-22 1999-07-01 Bayer Corporation Inhibition of raf kinase using substituted heterocyclic ureas
US7329670B1 (en) 1997-12-22 2008-02-12 Bayer Pharmaceuticals Corporation Inhibition of RAF kinase using aryl and heteroaryl substituted heterocyclic ureas
DK1043995T3 (en) * 1997-12-22 2007-03-05 Bayer Pharmaceuticals Corp Inhibition of p38 kinase activity using aryl- and heteroaryl-substituted heterocyclic ureas
US7517880B2 (en) 1997-12-22 2009-04-14 Bayer Pharmaceuticals Corporation Inhibition of p38 kinase using symmetrical and unsymmetrical diphenyl ureas
EP1076641A1 (en) * 1998-04-29 2001-02-21 Vertex Pharmaceuticals Incorporated Inhibitors of impdh enzyme
DE69915472T2 (en) * 1998-06-04 2004-08-19 Kumiai Chemical Industry Co., Ltd. PHENYL ACETYLENE DERIVATIVES AND BACTERICIDES FOR AGRICULTURE AND GARDENING
EP1514867A3 (en) * 1998-10-22 2005-03-23 NeuroSearch A/S Substituted phenyl derivatives, their preparation and use
AU764479B2 (en) 1998-10-29 2003-08-21 Bristol-Myers Squibb Company Compounds derived from an amine nucleus that are inhibitors of IMPDH enzyme
WO2000026197A1 (en) * 1998-10-29 2000-05-11 Bristol-Myers Squibb Company Novel inhibitors of impdh enzyme
US6420403B1 (en) 1998-10-29 2002-07-16 Edwin J. Iwanowicz Inhibitors of IMPDH enzyme
US6596747B2 (en) 1998-10-29 2003-07-22 Bristol-Myers Squibb Company Compounds derived from an amine nucleus and pharmaceutical compositions comprising same
GB9823873D0 (en) 1998-10-30 1998-12-30 Pharmacia & Upjohn Spa 2-ureido-thiazole derivatives,process for their preparation,and their use as antitumour agents
RU2233269C2 (en) * 1998-11-02 2004-07-27 Авентис Фарма Лимитед Substituted anilides, pharmaceutical composition and method for treatment
TR200101597T2 (en) * 1998-12-09 2001-10-22 American Home Products Corporation Thyurea inhibitors of herpes viruses.
US6201013B1 (en) 1998-12-09 2001-03-13 American Home Products Corporation Heterocyclic carboxamide-containing thiourea inhibitors of herpes viruses containing a substituted phenylenediamine group
US6166028A (en) 1998-12-09 2000-12-26 American Home Products Corporation Diaminopuridine-containing thiourea inhibitors of herpes viruses
ES2221470T3 (en) * 1998-12-09 2004-12-16 Wyeth VIRUS HERPES INHIBITORS DERIVED FROM ALFA-METHYLBENCIL-THIOUREA CONTAINING A PHENYLENEODIAMINE GROUP.
US6262090B1 (en) 1998-12-09 2001-07-17 American Home Products Corporation Aminopyridine-containing thiourea inhibitors of herpes viruses
US6337338B1 (en) 1998-12-15 2002-01-08 Telik, Inc. Heteroaryl-aryl ureas as IGF-1 receptor antagonists
CN1337941A (en) * 1998-12-22 2002-02-27 三菱化学株式会社 Amide derivatives
IL144144A0 (en) 1999-01-13 2002-05-23 Bayer Ag Omega-carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors
ME00275B (en) 1999-01-13 2011-02-10 Bayer Corp ?-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7928239B2 (en) 1999-01-13 2011-04-19 Bayer Healthcare Llc Inhibition of RAF kinase using quinolyl, isoquinolyl or pyridyl ureas
US8124630B2 (en) 1999-01-13 2012-02-28 Bayer Healthcare Llc ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
WO2000042012A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
HK1043127B (en) * 1999-03-12 2004-12-24 贝林格尔‧英格海姆药物公司 Compounds useful as anti-inflammatory agents
CN1196687C (en) * 1999-03-19 2005-04-13 沃泰克斯药物股份有限公司 Inhibitors of IMPDH enzyme
US6653309B1 (en) 1999-04-26 2003-11-25 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme technical field of the invention
WO2000073288A1 (en) * 1999-05-28 2000-12-07 Vertex Pharmaceuticals Incorporated Method for preparing 5-substituted oxazoles
US6107052A (en) * 1999-06-09 2000-08-22 Roche Diagnostics Corporation Enzymatic measurement of mycophenolic acid
MXPA02000294A (en) * 1999-06-25 2002-06-21 Vertex Pharma Prodrugs of carbamate inhibitors of impdh.
JP2001011060A (en) * 1999-06-28 2001-01-16 Nippon Synthetic Chem Ind Co Ltd:The Novel oxazole compound and method for producing the same
JP2001011059A (en) * 1999-06-28 2001-01-16 Nippon Synthetic Chem Ind Co Ltd:The Method for producing 5- (2-substituted-4-nitrophenyl) -oxazole
TWI262185B (en) * 1999-10-01 2006-09-21 Eisai Co Ltd Carboxylic acid derivatives having anti-hyperglycemia and anti-hyperlipemia action, and pharmaceutical composition containing the derivatives
US6867299B2 (en) 2000-02-24 2005-03-15 Hoffmann-La Roche Inc. Oxamide IMPDH inhibitors
AU5553801A (en) 2000-04-24 2001-11-07 Bristol Myers Squibb Co Heterocycles that are inhibitors of impdh enzyme
SV2003000617A (en) 2000-08-31 2003-01-13 Lilly Co Eli INHIBITORS OF PROTEASA PEPTIDOMIMETICA REF. X-14912M
US6423849B1 (en) * 2000-09-01 2002-07-23 The Nippon Synthetic Chemical Industry Co., Ltd. Process of preparing 5-(2-substituted-4-nitrophenyl)-oxazole, novel oxazole compound, and process of preparing the same
US7235576B1 (en) 2001-01-12 2007-06-26 Bayer Pharmaceuticals Corporation Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors
US7371763B2 (en) 2001-04-20 2008-05-13 Bayer Pharmaceuticals Corporation Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas
US6593362B2 (en) * 2001-05-21 2003-07-15 Guilford Pharmaceuticals Inc. Non-peptidic cyclophilin binding compounds and their use
TW200301698A (en) 2001-12-21 2003-07-16 Bristol Myers Squibb Co Acridone inhibitors of IMPDH enzyme
EP1478358B1 (en) 2002-02-11 2013-07-03 Bayer HealthCare LLC Sorafenib tosylate for the treatment of diseases characterized by abnormal angiogenesis
ATE529406T1 (en) 2002-02-11 2011-11-15 Bayer Healthcare Llc ARYL UREAS AS KINASE INHIBITORS
EP1402887A1 (en) * 2002-09-18 2004-03-31 Jerini AG New compounds for the inhibition of undesired cell proliferation and use thereof
CA2510006C (en) * 2002-12-06 2012-02-07 Vertex Pharmaceuticals Incorporated Compositions comprising a combination of diphenyl urea impdh inhibitors and apoptosis-inducing anti-cancer agents
DE60331367D1 (en) 2002-12-30 2010-04-01 Angiotech Int Ag ACTIVE COMPOSITION OF FAST GELING POLYMERIC COMPOSITION
US7220768B2 (en) * 2003-02-11 2007-05-22 Wyeth Holdings Corp. Isoxazole-containing thiourea inhibitors useful for treatment of varicella zoster virus
US8796250B2 (en) 2003-05-20 2014-08-05 Bayer Healthcare Llc Diaryl ureas for diseases mediated by PDGFR
DE602004010407T2 (en) 2003-07-23 2008-10-16 Bayer Pharmaceuticals Corp., West Haven FLUORO-SUBSTITUTED OMEGA-CARBOXYARYLDIPHENYL-UREA FOR THE TREATMENT AND PREVENTION OF DISEASES AND SUFFERING
TWI359147B (en) 2003-09-05 2012-03-01 Vertex Pharma Inhibitors of serine proteases, particularly hcv n
CN101857631A (en) 2003-10-10 2010-10-13 沃泰克斯药物股份有限公司 Serine protease, the particularly inhibitor of HCV NS3-NS4A proteolytic enzyme
AR045870A1 (en) * 2003-10-11 2005-11-16 Vertex Pharma COMBINATION THERAPY FOR HEPATITIS C VIRUS INFECTION
JP4890254B2 (en) 2003-10-27 2012-03-07 バーテックス ファーマシューティカルズ インコーポレイテッド HCVNS3-NS4A protease resistant mutant
EP1944042A1 (en) 2003-10-27 2008-07-16 Vertex Pharmceuticals Incorporated Combinations for HCV treatment
CA2554999A1 (en) 2004-02-04 2005-08-25 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases, particularly hcv ns3-ns4a protease
US7317030B2 (en) 2004-02-26 2008-01-08 4Sc Ag Compounds as inhibitors of cell proliferation and viral infections
EP1568696A1 (en) * 2004-02-26 2005-08-31 4Sc Ag Compounds as inhibitors of cell proliferation and viral infections
US20110104186A1 (en) 2004-06-24 2011-05-05 Nicholas Valiante Small molecule immunopotentiators and assays for their detection
ES2314690T3 (en) 2004-08-12 2009-03-16 Pfizer, Inc. DERIVATIVES OF TRIAZOLOPIRIDINILSULFANILO AS INHIBITORS OF MAP QUINASA P38.
SG155967A1 (en) * 2004-10-01 2009-10-29 Vertex Pharma Hcv ns3-ns4a protease inhibition
TWI437990B (en) 2004-10-29 2014-05-21 Vertex Pharma Medical use of vx-950
CN102267978A (en) * 2005-01-14 2011-12-07 Cgi药学股份有限公司 1,3-diaryl substituted ureas as modulators of kinase activity
US7625931B2 (en) * 2005-01-14 2009-12-01 Cgi Pharmaceuticals, Inc. Certain substituted diphenyl ureas, as modulators of kinase activity
US20060235009A1 (en) * 2005-02-08 2006-10-19 Richard Glickman Treatment of vascular, autoimmune and inflammatory diseases using low dosages of IMPDH inhibitors
EP1917010A2 (en) * 2005-02-08 2008-05-07 Aspreva Pharmaceuticals SA Compositions and methods for treating vascular, autoimmune and inflammatory diseases
AU2006222365B2 (en) 2005-03-07 2011-07-14 Bayer Healthcare Llc Pharmaceutical composition comprising an omega- carboxyaryl substituted diphenyl urea for the treatment of cancer
US7777040B2 (en) * 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
EP1891062A2 (en) * 2005-05-09 2008-02-27 Vertex Pharmaceuticals, Inc. Polymorphic forms of (s)- tetrahydrofuran-3-yl-3-(3-(3-methoxy-4-(oxazol-5-yl) phenyl) ureido) benzylcarbamate
CN101175718A (en) 2005-05-09 2008-05-07 沃泰克斯药物股份有限公司 Processes for preparing biaryl ureas and analogs thereof
EP1912996B1 (en) 2005-07-29 2012-06-20 Janssen R&D Ireland Macrocyclic inhibitors of hepatitis c virus
JP5171624B2 (en) 2005-07-29 2013-03-27 テイボテク・フアーマシユーチカルズ Macrocyclic inhibitor of hepatitis C virus
CN101273028B (en) 2005-07-29 2013-08-21 泰博特克药品有限公司 Macrocyclic inhibitors of hepatitis C virus
SI1919898T1 (en) 2005-07-29 2011-05-31 Tibotec Pharm Ltd Macrocyclic inhibitors of hepatitis c virus
JO2768B1 (en) 2005-07-29 2014-03-15 تيبوتيك فارماسيوتيكالز ليمتد Macrocylic Inhibitors Hepatitis C Virus
PE20070210A1 (en) 2005-07-29 2007-04-16 Tibotec Pharm Ltd MACROCYCLIC COMPOUNDS AS INHIBITORS OF HEPATITIS C VIRUS
AR057704A1 (en) 2005-07-29 2007-12-12 Tibotec Pharm Ltd MACROCICLIC INHIBITORS OF HEPATITIS C VIRUS, PHARMACEUTICAL COMPOSITION AND COMPOSITE PREPARATION PROCESS
HRP20110885T1 (en) 2005-07-29 2011-12-31 Tibotec Pharmaceuticals MACROCYCLIC HEPATITIS VIRUS INHIBITORS C
PE20070211A1 (en) 2005-07-29 2007-05-12 Medivir Ab MACROCYCLIC COMPOUNDS AS INHIBITORS OF HEPATITIS C VIRUS
EP2402331A1 (en) * 2005-08-02 2012-01-04 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases
US7964624B1 (en) * 2005-08-26 2011-06-21 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases
AR055395A1 (en) * 2005-08-26 2007-08-22 Vertex Pharma INHIBITING COMPOUNDS OF THE ACTIVITY OF SERINA PROTEASA NS3-NS4A OF HEPATITIS C VIRUS
US7705138B2 (en) 2005-11-11 2010-04-27 Vertex Pharmaceuticals Incorporated Hepatitis C virus variants
EP2392589A3 (en) 2005-11-11 2012-06-20 Vertex Pharmaceuticals Incorporated Hepatitis C virus variants
WO2007098270A2 (en) 2006-02-27 2007-08-30 Vertex Pharmaceuticals Incorporated Co-crystals comprising vx-950 and pharmaceutical compositions comprising the same
NZ571280A (en) 2006-03-16 2011-10-28 Vertex Pharma Deuterated hepatitis C protease inhibitors
US7825152B2 (en) 2006-04-11 2010-11-02 Novartis Ag Organic compounds and their uses
EP2066642A1 (en) * 2006-09-25 2009-06-10 Arete Therapeutics, INC. Soluble epoxide hydrolase inhibitors
JP5616063B2 (en) 2006-10-04 2014-10-29 ヤンセン・アールアンドデイ・アイルランド Carboxamide 4-[(4-pyridyl) amino] pyrimidine useful as an HCV inhibitor
EA200970493A1 (en) 2006-11-17 2009-10-30 Тиботек Фармасьютикалз Лтд. MACROCYCLIC INHIBITORS OF HEPATITIS C VIRUS
CN101687856A (en) * 2007-02-27 2010-03-31 弗特克斯药品有限公司 Co-crystal and pharmaceutical composition comprising same
US8575208B2 (en) * 2007-02-27 2013-11-05 Vertex Pharmaceuticals Incorporated Inhibitors of serine proteases
AU2008242720A1 (en) * 2007-04-20 2008-10-30 Deciphera Pharmaceuticals, Llc Kinase inhibitors useful for the treatment of myleoproliferative diseases and other proliferative diseases
AU2008248116A1 (en) 2007-05-04 2008-11-13 Vertex Pharmaceuticals Incorporated Combination therapy for the treatment of HCV infection
CN101835774B (en) * 2007-08-30 2014-09-17 弗特克斯药品有限公司 Co-crystals and pharmaceutical compositions comprising the same
PT2238142E (en) 2007-12-24 2012-09-24 Janssen R & D Ireland Macrocyclic indoles as hepatitis c virus inhibitors
TWI454476B (en) 2008-07-08 2014-10-01 Tibotec Pharm Ltd Macrocyclic indole derivatives useful as hepatitis c virus inhibitors
CN102124012B (en) 2008-08-14 2014-07-02 泰博特克药品公司 Macrocyclic indole derivatives useful as hepatitis C virus inhibitors
BRPI0922364A2 (en) 2008-12-03 2017-08-29 Presidio Pharmaceuticals Inc COMPOUND, PHARMACEUTICAL COMPOSITION AND USE OF A COMPOUND
WO2010065674A1 (en) 2008-12-03 2010-06-10 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
EP2396028A2 (en) 2009-02-12 2011-12-21 Vertex Pharmceuticals Incorporated Hcv combination therapies comprising pegylated interferon, ribavirin and telaprevir
US8969342B2 (en) 2009-03-20 2015-03-03 Brandeis University Compounds and methods for treating mammalian gastrointestinal microbial infections
AU2010229795A1 (en) 2009-03-27 2011-10-13 Presidio Pharmaceuticals, Inc. Fused ring inhibitors of hepatitis C
US8512690B2 (en) 2009-04-10 2013-08-20 Novartis Ag Derivatised proline containing peptide compounds as protease inhibitors
US20110182850A1 (en) 2009-04-10 2011-07-28 Trixi Brandl Organic compounds and their uses
WO2011014882A1 (en) 2009-07-31 2011-02-03 Medtronic, Inc. CONTINUOUS SUBCUTANEOUS ADMINISTRATION OF INTERFERON-α TO HEPATITIS C INFECTED PATIENTS
UA108211C2 (en) 2009-11-04 2015-04-10 Янссен Рід Айрленд Benzimidazole imidazole derivatives
AU2011210795A1 (en) 2010-01-29 2012-08-02 Vertex Pharmaceuticals Incorporated Therapies for treating Hepatitis C virus infection
WO2011112516A1 (en) 2010-03-08 2011-09-15 Ico Therapeutics Inc. Treating and preventing hepatitis c virus infection using c-raf kinase antisense oligonucleotides
CA2800509A1 (en) 2010-05-24 2011-12-01 Presidio Pharmaceuticals, Inc. Inhibitors of hcv ns5a
EP2575818A4 (en) 2010-06-03 2013-11-06 Pharmacyclics Inc USE OF INHIBITORS OF BRUTON TYROSINE KINASE (BTK)
WO2011156545A1 (en) 2010-06-09 2011-12-15 Vertex Pharmaceuticals Incorporated Viral dynamic model for hcv combination therapy
MX2012015198A (en) 2010-06-24 2013-02-11 Janssen R & D Ireland PREPARATION OF 13-CYCLOHEXYL-3-METHOXY-6-[METHYL-(2-{2-[METHYL-(S ULPHAMOYL)-AMINO]-ETHOXY}-ETHYL)-CARBAMOYL]-7<i>H</i>-INDOLO-[2, 1-a]-[2]-BENZAZEPINE-10-CARBOXYLIC ACID.
EP2593105A1 (en) 2010-07-14 2013-05-22 Vertex Pharmaceuticals Incorporated Palatable pharmaceutical composition comprising vx-950
WO2012020036A1 (en) 2010-08-13 2012-02-16 F. Hoffmann-La Roche Ag Hepatitis c virus inhibitors
WO2012109646A1 (en) 2011-02-11 2012-08-16 Vertex Pharmaceuticals Incorporated Treatment of hcv in hiv infection patients
CN102985104A (en) 2011-02-25 2013-03-20 麦德托尼克公司 Methods and systems for using pharmacokinetic and pharmacodynamic profiles in interferon-alpha treatment regimens
WO2012123298A1 (en) 2011-03-11 2012-09-20 F. Hoffmann-La Roche Ag Antiviral compounds
BR112013032188A2 (en) 2011-06-23 2016-12-20 Digna Biotech Sl composition, product and method for treating patients with chronic hepatitis C
WO2012175581A1 (en) 2011-06-24 2012-12-27 F. Hoffmann-La Roche Ag Antiviral compounds
HK1199454A1 (en) 2011-10-10 2015-07-03 F. Hoffmann-La Roche Ag Antiviral compounds
CN103987723B (en) 2011-12-16 2017-03-01 弗·哈夫曼-拉罗切有限公司 Inhibitors of HCV NS5A
CA2856179C (en) 2011-12-20 2017-02-28 F. Hoffmann-La Roche Ag 2',4'-difluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication
PT2794628T (en) 2011-12-20 2017-07-05 Riboscience Llc 4'-azido-3'-fluoro substituted nucleoside derivatives as inhibitors of hcv rna replication
AU2012360905B2 (en) 2011-12-28 2017-04-27 Janssen Sciences Ireland Uc Hetero-bicyclic derivatives as HCV inhibitors
US20130195797A1 (en) 2012-01-31 2013-08-01 Vertex Pharmaceuticals Incorporated High potency formulations of vx-950
CN104185624B (en) 2012-02-24 2016-10-12 弗·哈夫曼-拉罗切有限公司 Antiviral compound
US8461179B1 (en) 2012-06-07 2013-06-11 Deciphera Pharmaceuticals, Llc Dihydronaphthyridines and related compounds useful as kinase inhibitors for the treatment of proliferative diseases
US20140010783A1 (en) 2012-07-06 2014-01-09 Hoffmann-La Roche Inc. Antiviral compounds
EP3550031A1 (en) 2012-07-24 2019-10-09 Pharmacyclics, LLC Mutations associated with resistance to inhibitors of bruton's tyrosine kinase (btk)
WO2014028931A2 (en) 2012-08-17 2014-02-20 Brandeis University Compounds and methods for treating mammalian gastrointestinal microbial infections
US20140205566A1 (en) 2012-11-30 2014-07-24 Novartis Ag Cyclic nucleuoside derivatives and uses thereof
BR112015017414A2 (en) 2013-01-23 2017-07-11 Hoffmann La Roche antiviral triazole derivatives
RU2015136256A (en) 2013-03-05 2017-04-10 Ф. Хоффманн-Ля Рош Аг ANTI-VIRAL COMPOUNDS
MX2015015782A (en) 2013-05-16 2016-06-02 Riboscience Llc 4'-fluor0-2'-methyl substituted nucleoside derivatives.
US20180200280A1 (en) 2013-05-16 2018-07-19 Riboscience Llc 4'-Fluoro-2'-Methyl Substituted Nucleoside Derivatives as Inhibitors of HCV RNA Replication
MX2015015781A (en) 2013-05-16 2016-06-02 Riboscience Llc 4'-azido, 3'-deoxy-3'-fluoro substituted nucleoside derivatives.
BR112016009200A8 (en) 2013-10-25 2020-03-24 Pharmacyclics Llc use of a btk inhibitor and a checkpoint immune inhibitor
JP2017509336A (en) 2014-03-20 2017-04-06 ファーマサイクリックス エルエルシー Mutations associated with phospholipase C gamma 2 and resistance
US10682369B2 (en) 2017-09-21 2020-06-16 Riboscience Llc 4′-fluoro-2′-methyl substituted nucleoside derivatives as inhibitors of HCV RNA replication
BR112020015572A2 (en) 2018-01-31 2021-02-02 Deciphera Pharmaceuticals, Llc combination therapy for the treatment of mastocytosis
WO2019152711A1 (en) 2018-01-31 2019-08-08 Diciphera Pharmaceuticals Llc. Combination therapy for the treatment of gastrointestinal stromal tumors
WO2019191032A1 (en) 2018-03-26 2019-10-03 Clear Creek Bio, Inc. Compositions and methods for inhibiting dihydroorotate dehydrogenase
CN109970675A (en) * 2018-05-28 2019-07-05 中国医学科学院医药生物技术研究所 A group of thiourea compounds and their preparation method and application
MY201990A (en) 2018-06-19 2024-03-27 Novartis Ag N-substituted tetrahydrothienopyridine derivatives and uses thereof
US12098117B2 (en) * 2018-12-11 2024-09-24 Duke University Compositions and methods for the treatment of cancer
CN114615982A (en) 2019-08-12 2022-06-10 德西费拉制药有限责任公司 Ripoctinib for treating gastrointestinal stromal tumor
TWI878335B (en) 2019-08-12 2025-04-01 美商迪賽孚爾製藥有限公司 Methods of treating gastrointestinal stromal tumors
CN110590535A (en) * 2019-10-12 2019-12-20 重庆医药高等专科学校 Method for preparing aromatic glyoxylic acid by oxidizing aromatic ethyl ketone with selenium dioxide
IL293866A (en) 2019-12-30 2022-08-01 Deciphera Pharmaceuticals Llc Compositions of amorphous kinase inhibitors and methods of using them
FI4084779T3 (en) 2019-12-30 2024-12-16 Deciphera Pharmaceuticals Llc Compositions of 1-(4-bromo-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-phenylurea
US20210308117A1 (en) 2020-03-20 2021-10-07 Clear Creek Bio, Inc. Methods of treating viral infections using inhibitors of nucleotide synthesis pathways
WO2021209563A1 (en) 2020-04-16 2021-10-21 Som Innovation Biotech, S.A. Compounds for use in the treatment of viral infections by respiratory syndrome-related coronavirus
US11779572B1 (en) 2022-09-02 2023-10-10 Deciphera Pharmaceuticals, Llc Methods of treating gastrointestinal stromal tumors

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5380879A (en) * 1994-02-18 1995-01-10 Syntex (U.S.A.) Inc. Derivatives of mycophenolic acid

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1171904A (en) 1965-10-21 1969-11-26 Unilever Ltd Anilinobenzimidazoles having Antibacterial Properties
IL39336A0 (en) 1971-05-04 1972-07-26 Lilly Co Eli Substituted 2-anilinobenzoxazoles
DE2928485A1 (en) * 1979-07-14 1981-01-29 Bayer Ag USE OF UREA DERIVATIVES AS A MEDICINAL PRODUCT IN THE TREATMENT OF FATTY METABOLISM DISORDERS
US5283257A (en) 1992-07-10 1994-02-01 The Board Of Trustees Of The Leland Stanford Junior University Method of treating hyperproliferative vascular disease
WO1994012184A1 (en) 1992-11-24 1994-06-09 Syntex (U.S.A.) Inc. Use of mycophenolic acid, mycophenolate mofetil or derivate thereof to inhibit stenosis
US5444072A (en) 1994-02-18 1995-08-22 Syntex (U.S.A.) Inc. 6-substituted mycophenolic acid and derivatives

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5380879A (en) * 1994-02-18 1995-01-10 Syntex (U.S.A.) Inc. Derivatives of mycophenolic acid

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