WO2000041505A2 - 4'heteroaryle diarylamines - Google Patents
4'heteroaryle diarylamines Download PDFInfo
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- WO2000041505A2 WO2000041505A2 PCT/US1999/030491 US9930491W WO0041505A2 WO 2000041505 A2 WO2000041505 A2 WO 2000041505A2 US 9930491 W US9930491 W US 9930491W WO 0041505 A2 WO0041505 A2 WO 0041505A2
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- Prior art keywords
- phenylamino
- methyl
- benzamide
- chloro
- difluoro
- Prior art date
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- OWISXYQFTOYGRO-UHFFFAOYSA-N Cc(c(C)c1)ccc1C#N Chemical compound Cc(c(C)c1)ccc1C#N OWISXYQFTOYGRO-UHFFFAOYSA-N 0.000 description 1
- 0 Cc1cc(-c2n[s]nc2*)ccc1Nc1cc(F)ccc1C(O)=O Chemical compound Cc1cc(-c2n[s]nc2*)ccc1Nc1cc(F)ccc1C(O)=O 0.000 description 1
- LGPVTNAJFDUWLF-UHFFFAOYSA-N Nc1cc(F)ccc1C(O)=O Chemical compound Nc1cc(F)ccc1C(O)=O LGPVTNAJFDUWLF-UHFFFAOYSA-N 0.000 description 1
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- C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
- C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
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- C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
- C07C229/58—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position having the nitrogen atom of at least one of the amino groups further bound to a carbon atom of a six-membered aromatic ring, e.g. N-phenyl-anthranilic acids
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- C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
- C07C317/34—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring
- C07C317/36—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having sulfone or sulfoxide groups and amino groups bound to carbon atoms of six-membered aromatic rings being part of the same non-condensed ring or of a condensed ring system containing that ring with the nitrogen atoms of the amino groups bound to hydrogen atoms or to carbon atoms
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- C07C323/31—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
- C07C323/33—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring
- C07C323/35—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group
- C07C323/36—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton having at least one of the nitrogen atoms bound to a carbon atom of the same non-condensed six-membered aromatic ring the thio group being a sulfide group the sulfur atom of the sulfide group being further bound to an acyclic carbon atom
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- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
Definitions
- This invention relates to 4' heteroaryl diarylamines having pharmaceutical activity.
- MEK enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis.
- Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins.
- Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade .
- the cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP.
- Ras leads in turn to the activation of a cascade of serine/threonine kinases.
- One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEK ⁇
- MEK e.g., MEK ⁇
- MAP kinase e.g., MEK ⁇
- Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation.
- Blockade of downstream Ras signaling for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants.
- Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism.
- Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, s218 and S ⁇ 22 j n he case of MEK-1 , which are the prerequisite for activation of MEK as a kinase.
- MEK in turn phosphorylates MAP kinase on both a tyrosine, Y 1 8 5 , and a threonine residue, T ' '83 j separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold.
- MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein.
- target protein such as a kinase, a transcription factor, or another cellular protein.
- other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase.
- MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase.
- MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins.
- the invention features a compound having the formula (I) below:
- W is OR1, NR20R!, NR A R B , NR 2 NR A RB, 0(CH 2 ) 1 - 4 NR A R B , or NR 2 (CH 2 ) ⁇ -4 NR A RB- RI is H, C ⁇ alkyl, C 3 - ⁇ alkenyl, C 3 . 8 alkynyl,
- C 3-8 cycloalkyl phenyl, (phenyl)C ⁇ . 4 alkyl, (phenyl)C 3 - 4 alkenyl, (phenyl)- C 3-4 alkynyl, (C 3 . 8 cycloalkyl)C 1-4 alkyl, (C 3- 8 cycloalkyl)C 3 -4 alkenyl, (C 3-8 cycloalkyl)C 3- alkynyl, C 3-8 heterocyclic radical, (C 3 -s heterocyclic radical)C 1-4 alkyl, (C 3-8 heterocyclic radical)C 3 -4 alkenyl, or (C 3-8 heterocyclic radical)C 3-4 alkynyl.
- Each of R 2 and R 3 is independently H, phenyl, C 1.4 alkyl, C 3-8 alkenyl, C 3 . 8 alkynyl, C 3 . 8 cycloalkyl, or (C 3 - 8 cycloalkyl)C 1- 4 alkyl.
- Each of R 4 , R5 and R 6 is independently H, F, Br, Cl, or NO 2 .
- RA is H, C ⁇ - 6 alkyl, C 3 . 8 alkenyl, C 3 - 8 alkynyl, C 3 - 8 cycloalkyl, phenyl, (C 3 - 8 cycloalkyl)C 1. 4 alkyl, (C 3 .
- J is SR C , OR c , SO 2 R c , SOR c , SO 2 NR D RE, C 1 - ⁇ alkyl, C 3 -s alkenyl, C 3 . 8 alkynyl, C 3 - ⁇ cycloalkyl, C 5 - ⁇ cycloalkenyl, phenyl, (C 3 - 8 cycloalkyl)C 1 - 4 alkyl, (C 3 . 8 cycloalkyl)C 3 .
- M' is O, SO, SO 2 , NR E , (CO)NR E , NR E (CO), SO 2 NR E , NR E S0 2 , or CH 2 .
- E' is absent (in other words, a covalent bond), (CH 2 ) ⁇ -4 or (CH 2 )m O(CH 2 ) p where 1 ⁇ (each of m and p independently) ⁇ 3 and 2 ⁇ (m + p) ⁇ 4.
- G' is OR 3 , SORc, SO 2 R C
- or NR F R G ; provided that where p 1 , then G' is H.
- R c , RD > RE, RF and RG is independently selected from H, C 1-6 alkyl, C 3 -4 alkenyl, C 3 - 4 alkynyl, C 3 - 6 cycloalkyl, C 3 .
- NRFRG and NRDR E can each also independently be selected from morpholinyl, pyrazinyl, piperazinyl, pyrrolidinyl, or piperadinyl.
- R 10 is H, C 1- 4 alkyl, halo, NO 2) or S0 2 NR H R
- Rn is H, halo, or NO 2 .
- Each hydrocarbon radical or heterocyclic radical above is optionally substituted with between 1 and 3 substituents independently selected from halo, C 1-4 alkyl, C 3 - 6 cycloalkyl, C 3 - 4 alkenyl, C 3 . 4 alkynyl, phenyl, hydroxy, amino, (amino)sulfonyl, and NO 2 , wherein each substituent alkyl, cycloalkyl, alkenyl, alkynyl or phenyl is in turn optionally substituted with between 1 and 3 substituents independently selected from halo, C 1 -2 alkyl, hydroxy, amino, and NO 2 .
- the invention also encompasses a pharmaceutically acceptable salt or C 1 . 7 ester of a compound of formula (I).
- the invention also relates to a pharmaceutical composition including (a) a compound of formula (I) and (b) a pharmaceutically-acceptable carrier.
- the invention further relates to a method for treating proliferative diseases, such as cancer, restenosis, psoriasis, autoimmune disease, and atherosclerosis.
- Other aspects of the invention include methods for treating MEK-related (including ras-related) cancers, whether solid or hematopoietic.
- cancers include colorectal, cervical, breast, ovarian, brain, acute leukemia, gastric, non-small cell lung, pancreatic, prostatic, and renal cancers.
- Further aspects of the invention include methods for treating or reducing the symptoms of xenograft (cell(s), llimb, skin, organ or bone marrow transplant) rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, complications of diabetes (including diabetic retinopathy and diabetic nephropathy), hepatomegaly, cardiomegaly, stroke (such as acute focal ischemic stroke and global cerebral ischemia), heart failure, septic shock, asthma, and Alzheimer's disease.
- xenograft cell(s), llimb, skin, organ or bone marrow transplant
- osteoarthritis rheumatoid arthritis
- cystic fibrosis cystic fibrosis
- complications of diabetes including diabetic retinopathy and diabetic nephropathy
- hepatomegaly such as acute focal ischemic stroke and global cerebral ischemia
- stroke such as acute focal ischemic stroke and global cerebral ischemia
- heart failure such as acute focal ischemic stroke
- Compounds of the invention are also useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV).
- B hepatitis virus
- HPV human papilloma virus
- CMV cytomegalovirus
- EBV Epstein-Barr virus
- These methods include the step of administering to a patient in need of such treatment, or suffering from such a disease or condition, a pharmaceutically-effective amount of a disclosed compound or pharmaceutical composition thereof.
- the invention also features methods of combination therapy, such as a method for treating cancer, wherein the method further includes providing radiation therapy or chemotherapy, for example, with mitotic inhibitors such as a taxane or a vinca alkaloid.
- mitotic inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine
- Other therapeutic combinations include a MEK inhibitor of the invention and an anticancer agent such as cisplatin, 5-fluoro-2-4(1 H,3H)-pyrimidinedione (5FU), flutamide, and gemcitabine.
- the chemotherapy or radiation therapy may be administered before, concurrently, or after the administration of a disclosed compound according to the needs of the patient.
- the invention further includes synthetic intermediates and methods disclosed herein.
- the invention features 4-heteroaryl diarylamine compounds, pharmaceutical compositions thereof, and methods of using such compounds and compositions.
- the compounds are MEK inhibitors.
- MEK inhibition assays include the in vitro MEK/MAP described at column 6, line 36 to column 7, line 4 of U.S. Patent Number 5,525,625 and the in vitro MEK assay described at column 7, lines 4-27 of the same patent, the entire disclosure of which is incorporated by reference (see also Examples 13 et seq.). A whole cell assay is described in Example 16.
- Alkyl groups include aliphatic (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures.
- Examples include methyl, ethyl, propyl, isopropyl, butyl, n-butyl, isobutyl, t-butyl, pentyl, isopentyl, 2,3-dimethylpropyl, hexyl, 2,3-dimethylhexyl, 1 ,1-dimethylpentyl, heptyl, and octyl.
- Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl.
- Alkyl groups can be substituted with 1 , 2, 3 or more substituents which are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy.
- substituents are independently selected from halo (fluoro, chloro, bromo, or iodo), hydroxy, amino, alkoxy, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, arylalkyloxy, heterocyclic radical, and (heterocyclic radical)oxy.
- Specific examples include fluoromethyl, hydroxyethyl, 2, 3-d i hydroxyethyl, (2- or 3-furanyl)methyl, cyclopropylmethyl, benzyloxyethyl, (3-pyridinyl)methyl, (2- or 3-furanyl)methyl, (2- thienyl)ethyl, hydroxypropyl, aminocyclohexyl, 2-dimethylaminobutyl, methoxymethyl, /V-pyridinylethyl, diethylaminoethyl, and cyclobutylmethyl.
- Alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp 2 carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond may be Mais (E), or sixteen (Z), cis, or trans. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). Unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a mixture thereof; like alkyl groups, unsaturated groups may be straight chain or branched, and they may be substituted as described both above for alkyl groups and throughout the disclosure by example.
- alkenyls, alkynyls, and substituted forms include cis-2-butenyl, trans-2-butenyl, 3-butynyl, 3-phenyl-2- propynyl, 3-(2'-fluorophenyl)-2-propynyl, 3-methyl(5-phenyl)-4-pentynyl, 2- hydroxy-2-propynyI, 2-methyl-2-propynyl, 2-propenyl, 4-hydroxy-3-butynyl, 3-(3- fluorophenyl)-2-propynyl, and 2-methyl-2-propenyl.
- alkenyls and alkynyls can be C 2 - ⁇ or C 2 .
- substituted hydrocarbon radicals include hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, and corresponding forms for the prefixes amino-, halo- (e.g., fluoro-, chloro-, or bromo-), nitro-, alkyl-, phenyl-, cycloalkyl- and so on, or combinations of substituents.
- halo- e.g., fluoro-, chloro-, or bromo-
- substituted alkyls include hydroxyalkyl, aminoalkyl, nitroalkyl, haloalkyl, alkylalkyl (branched alkyls, such as methylpentyl), (cycloalkyl)alkyl, phenylalkyl, alkoxy, alkylaminoalkyl, dialkylaminoalkyl, arylalkyl, aryloxyalkyl, arylalkyloxyalkyl, (heterocyclic radical)alkyl, and (heterocyclic radical)oxyalkyl.
- Ri thus includes hydroxyalkyl, hydroxyalkenyl, hydroxyalkynyl, hydroxycycloalkyl, hydroxyaryl, aminoalkyl, aminoalkenyl, aminoalkynyl, aminocycloalkyl, aminoaryl, alkylalkenyl,
- R A includes hydroxyalkyl and aminoaryl
- RB includes hydroxyalkyl, aminoalkyl, and hydroxyalkyl(heterocyclic radical)alkyl.
- Heterocyclic radicals which include but are not limited to heteroaryls, include: furyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, pyrrolyl, imidazolyl, 1 ,3,4- triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, 1 ,2,5-thiadiazolyl and their nonaromatic counterparts.
- heterocyclic radicals include piperidyl, quinolyl, isothiazolyl, piperidinyl, morpholinyl, piperazinyl, tetrahydrofuryl, tetrahydropyrrolyl, pyrrolidinyl, octahydroindolyl, thiadiazolyl, octahydrobenzothiofuranyl, and octahydrobenzofuranyl.
- Selective MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF receptor kinases, and C-src.
- a selective MEK 1 or MEK 2 inhibitor has an IC 50 for MEK 1 or MEK 2 that is at least one-fiftieth (1/50) that of its IC 50 for one of the above-named other enzymes.
- a selective inhibitor has an IC 50 that is at least 1/100, more preferably 1/500, and even more preferably 1/1000, 1/5000, or less than that of its IC 5 o or one or more of the above-named enzymes.
- Embodiments of the invention include compounds wherein: (a) R c is C ⁇ . 2 alkyl; (b) W is OH, or W is NHOR-i (c) Rio is methyl or chloro; (d) Rn is fluoro; (e) Rn is H; (f) J is trihalomethyl or methylthio; (g) J is SO 2 CH 3 ; (h) J is SOCH 3 ; (i) J is C 3 - ⁇ alkynyl where the triple bond is between the carbon atoms alpha and beta to the phenyl group; (j) Ri has at least one hydroxy substituent; (k) Ri is H, methyl, ethyl, propyl, isopropyl, isobutyl, benzyl, phenethyl, allyl, C 3 - 5 alkenyl, C 3 - 5 alkynyl, C
- R 2 is H, methyl, C 3 - 4 alkynyl, C 3 .
- R A is H, methyl, ethyl, isobutyl, hydroxyethyl, hydroxypropyl, cyclopropylmethyl, cyclobutylmethyl, C 3 - 4 alkynyl, phenyl, 2- piperjdin-1 -yl-ethyl, 2,3-dihydroxy-propyl, 3-[4-(2-hydroxyethyl)-piperazin-1-yl]- propyl, 2-pyrrolidin-1 -yl-ethyl, or 2-diethylamino-ethyl; and RB is H; or where R B is methyl and R A is phenyl; (0) each of R 4 and R ⁇ is H, and R 5 is F; (p) each of R 4 , R 5 , and R 6 is F; (q) R 5 is F; (r) each R 5 and R 6 is F and R 6 is
- Ri, R 2 , R A , RB, Rc, RD, RE, RF, and RG is an alkenyl or alkynyl group, its double or triple bond, respectively, is not adjacent the point of attachment.
- W is NR 2 OR ⁇
- R 2 is preferably prop-2-ynyl, or but-2 or 3-enyl, and less preferably prop-1-ynyl or but- 1-enyl.
- Examples of compounds of formula (I) include: 4-fluoro-2-(2-methyl-4- methylsulfanyl-phenylamino)-benzoic acid; 5-bromo-3,4-difluoro-2-(2-methyl-4- methylsulfanyl-phenylamino)-benzoic acid; 3,4-difluoro-2-(4-methanesulfinyl-2- methyl-phenylamino)-benzoic acid; 2-(4-methanesulfinyl-2-methyl-phenylamino)- 4-nitro-benzoic acid; 3,4,5-trifluoro-2-(4-methanesulfonyl-2-methyl-phenylamino)- benzoic acid; 3,4-difluoro-2-(2-methyl-4-methylsulfanyl-phenylamino)-benzoic acid; 2-(2-methyl-4-methylsulfanyl-phenylamino)-4-nitro-benzoic acid; 3,4, 5-
- Preferred examples of compounds of formula (I) are : 4-Fluoro-2-(4- methanesulfanyl-phenylamino)-benzoic acid (1); 4-Fluoro-2-(4-methanesulfinyl- phenylamino)-benzoic acid (2); 4-Fluoro-2-(4-methanesulfonyl-phenylamino)- benzoic acid (3); 4-Fluoro-2-(2-methyl-4-trimethylsilanylethynyl-phenylamino)- benzoic acid (6); 4-Fluoro-2-(2-methyl-4-ethynyl-phenylamino)-benzoic acid (7).
- Additional preferred compounds include the following: (a) 5-Bromo-2-(4- ethynyl-2-methyl-phenylamino)-3,4-difluoro-benzoic acid; N-Cyclopropylmethoxy- 2-(4-ethynyl-2-methyl-phenylamino)-3,4-difluoro-benzamide; 2-(4-Ethynyl-2- methyl-phenylamino)-3,4-difluoro-benzoic acid; N-Cyclopropylmethoxy-2-(4- ethynyl-2-methyl-phenylamino)-3,4,5-trifluoro-benzamide; 2-(4-Ethynyl-2-methyl- phenylamino)-3,4,5-trifluoro-benzoic acid; 5-
- Further preferred compounds include: (a) 5-bromo-2-(2-chloro-4- methylsulfanyl-phenylamino)-3,4-difluoro-benzoic acid; 2-(2-chloro-4- methanesulfinyl-phenylamino)-3,4-difluoro-benzoic acid; 2-(2-chloro-4- methanesulfonyl-phenylamino)-3,4,5-trifluoro-benzoic acid; 2-(2-chloro- methylsulfanyl-phenylamino)-3,4-difluoro-benzoic acid; 5-bromo-2-(2-chloro-4- methanesulfonyl-phenylamino)-3,4-difluoro-benzoic acid; 2-(2-Chloro-4- methanesulfonyl-phenylamino)-3,4-difluoro-benzoic acid; (b) 5-bromo-2
- the disclosed compounds can be synthesized according to the following five schemes, or variants thereof.
- PyBOP is (benzotriazolyl- oxy)-tripyrrolidino phosphonium hexafluorophosphate.
- compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions as provided in the Summary section, as well as diseases or conditions modulated by the MEK cascade.
- diseases or conditions modulated by the MEK cascade include stroke, heart failure, osteoarthritis, rheumatoid arthritis, organ transplant rejection, and a variety of tumors such as ovarian, non-small cell lung, pancreatic, brain, prostatic, renal, and colon.
- an effective amount will be between 0.1 and 1000 mg/kg per day, preferably between 1 and 300 mg/kg body weight, and daily dosages will be between 10 and 5000 mg for an adult subject of normal weight.
- Capsules, tablets or other formulations may be of between 5 and 200 mg, such as 10, 15, 25, 35, 50 mg, 60 mg, and 100 mg and can be administered according to the disclosed methods. 2.
- Dosage unit forms include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses. Dosage unit forms can also be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants. Administration methods include oral, rectal, parenteral (intravenous, intramuscular, subcutaneous), intracistemal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
- Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof.
- carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size.
- Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propellants.
- Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents.
- adjuvants such as preserving, wetting, emulsifying, and dispensing agents
- antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid
- isotonic agents such as a sugar or sodium chloride
- absorption-prolonging agents such as aluminum monostearate and gelatin
- absorption-enhancing agents such as aluminum monostearate and gelatin.
- the invention provides the disclosed compounds and closely related, pharmaceutically acceptable forms of the disclosed compounds, such as salts, esters, amides, hydrates or solvated forms thereof; masked or protected forms; and racemic mixtures, or enantiomerically or optically pure forms.
- Pharmaceutically acceptable salts, esters, and amides include carboxylate salts (e.g., C ⁇ . 8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic), amino acid addition salts, esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
- carboxylate salts e.g., C ⁇ . 8 alkyl, cycloalkyl, aryl, heteroaryl, or non-aromatic heterocyclic
- amino acid addition salts esters, and amides which are within a reasonable benefit/risk ratio, pharmacologically effective, and suitable for contact with the tissues of patients without undue toxicity, irritation, or allergic response.
- Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, iaurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate, and laurylsulfonate.
- alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium, as well as non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
- alkali metal and alkali earth cations such as sodium, potassium, calcium, and magnesium
- non-toxic ammonium, quaternary ammonium, and amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
- amine cations such as tetramethyl ammonium, methylamine, trimethylamine, and ethylamine.
- Representative pharmaceutically acceptable amides of the invention include those derived from ammonia, primary C -
- Secondary amines include 5- or 6-membered heterocyclic or heteroaromatic ring moieties containing at least one nitrogen atom and optionally between 1 and 2 additional heteroatoms.
- Preferred amides are derived from ammonia, C ⁇ 3 alkyl primary amines, and di (C ⁇ - 2 alkyl)amines.
- Representative pharmaceutically acceptable esters of the invention include C 1. 7 alkyl, C 5 - 7 cycloalkyl, phenyl, and phenyl(C ⁇ - 6 )alkyl esters.
- Preferred esters include methyl esters.
- the invention also includes disclosed compounds having one or more functional groups (e.g., hydroxyl, amino, or carboxyl) masked by a protecting group. Some of these masked or protected compounds are pharmaceutically acceptable; others will be useful as intermediates. Synthetic intermediates and processes disclosed herein, and minor modifications thereof, are also within the scope of the invention.
- one or more functional groups e.g., hydroxyl, amino, or carboxyl
- HYDROXYL PROTECTING GROUPS Hydroxyl protecting groups include: ethers, esters, and protection for 1 ,2- and 1 ,3-diols.
- the ether protecting groups include: methyl, substituted methyl ethers, substituted ethyl ethers, substituted benzyl ethers, silyl ethers and conversion of silyl ethers to other functional groups.
- Substituted Methyl Ethers include: methoxymethyl, methylthiomethyl, t- butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-ethoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, guaiacolmethyl, f-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloro- ethoxy)methyl, 2-(trimethylsilyl)- ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydro-pyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl, 4-methoxytetra
- Substituted ethyl ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1 -methyl- 1-methoxyethyl, 1-methyl-1 -benzyloxyethyl, 1 -methy 1-1 -benzyloxy-2- fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilyethyl, 2-(phenylselenyl)ethyl, f-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, and benzyl.
- Substituted Benzyl Ethers include: 1-ethoxyethyl, 1-(2,chloroethoxy)ethyl, 1 -methyl- 1-methoxyethyl, 1-methyl-1 -benzyloxyethyl, 1 -methy 1-1-1
- Substituted benzyl ethers include: p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- and 4-picolyl, 3-methyl-2-picolyl ⁇ /-oxido, diphenylmethyl, p, p -dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, ⁇ -naphthyl- diphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)- phenylmethyl, tri-(p-methoxyphenyl)methyl, 4-(4'-bromophenacyloxy)phenyl- diphenylmethyl, 4,4',4"-ths(4,5-dichlorophthalimid
- Silyl Ethers Silyl ethers include: trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylthexylsilyl, f-butyldimethylsilyl, f-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, and f-butylmethoxyphenylsilyl.
- Esters protecting groups include: esters, carbonates, assisted cleavage, miscellaneous esters, and sulfonates.
- protective esters include: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-P- phenylacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio) pentanoate, pivaloate, adamantoate,crotonate,4- methoxycrotonate, benzoate, p-phenylbenzoate, and 2,4,6-trimethylbenzoate (mesitoate).
- Carbonates include: methyl, 9-fluorenylmethyl, ethyl, 2,2,2-thchloroethyl, 2-(trimethylsilyl) ethyl, 2-(phenylsulfonyl) ethyl, 2-(triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl, and methyl dithiocarbonate.
- assisted Cleavage protecting groups include: 2-iodobenzoate, 4- azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2- formylbenzene-sulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate.
- 2-iodobenzoate 4- azido-butyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl) benzoate, 2- formylbenzene-sulfonate, 2-(methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) benzoate, and 2-(methylthiomethoxymethyl) benzoate.
- miscellaneous esters include: 2,6-dichloro-4- methylphenoxyacetate, 2,6-dichloro-4-(1 ,1 ,3,3-tetramethylbutyl) phenoxyacetate, 2,4-bis(1 ,1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (£)-2-methyl-2-butenoate (tigloate), o-(methoxycarbonyl) benzoate, p-P-benzoate, ⁇ -naphthoate, nitrate, alkyl N,N,N ',N '- tetramethylphosphorodiamidate, ⁇ /-phenylcarbamate, borate, dimethylphosphinothioyl, and 2,4-dinitrophenylsulfenate.
- Sulfonates Protective sulfates includes: sulfate, methan
- the protection for 1 ,2 and 1 ,3-diols group includes: cyclic acetals and ketals, cyclic ortho esters, and silyl derivatives.
- Cyclic Acetals and Ketals include: methylene, ethylidene, 1-f-butylethylidene, 1-phenylethylidene, (4-methoxyphenyl) ethylidene, 2,2,2-trichloroethylidene, acetonide (isopropylidene), cyclopentylidene, cyclohexylidene, cycloheptylidene, benzylidene, p-methoxybenzylidene, 2,4-dimethoxybenzylidene, 3,4- dimethoxybenzylidene, and 2-nitrobenzylidene.
- Cyclic ortho esters include: methoxymethylene, ethoxymethylene, dimethoxy- methylene, 1-methoxyethylidene, 1-ethoxyethylidine, 1 ,2-dimethoxyethylidene, ⁇ -methoxybenzylidene, 1-( ⁇ /, ⁇ /-dimethylamino)ethylidene derivative, ⁇ -( ⁇ /, ⁇ /- dimethylamino) benzylidene derivative, and 2-oxacyclopentylidene.
- Ester protecting groups include: esters, substituted methyl esters, 2-substituted ethyl esters, substituted benzyl esters, silyl esters, activated esters, miscellaneous derivatives, and stannyl esters.
- Substituted Methyl Esters include: 9-fluorenylmethyl, methoxymethyl, methylthiomethyl, tetrahydropyranyl, tetrahydrofuranyl, methoxyethoxymethyl, 2- (t methylsilyl)ethoxy-methyl, benzyloxymethyl, phenacyl, p-bromophenacyl, ⁇ - methylphenacyl, p-methoxyphenacyl, carboxamidomethyl, and N- phthalimidomethyl.
- 2-Substituted Ethyl Esters include: 2,2,2-trichloroethyl, 2-haloethyl, l-chloroalkyl, 2-(trimethylsily)ethyl, 2-methylthioethyl, 1 ,3-dithianyl-2-methyl, 2(p- nitrophenylsulfenyl)-ethyl, 2-(p-toluenesulfonyl)ethyl, 2-(2'-pyridyl)ethyl, 2-
- Substituted Benzyl esters include: triphenylmethyl, diphenylmethyl, bis(o-nitrophenyl)methyl, 9-anthrylmethyl, 2-(9,10-dioxo)anthrylmethyl, 5-dibenzo- suberyl, 1 -pyrenylmethyl, 2-(trifluoromethyl)-6-chromylmethyl, 2,4,6- thmethylbenzyl, p-bromobenzyl, o-nitrobenzyl, p-nitrobenzyl, p-methoxybenzyl, 2,6-dimethoxybenzyl, 4-(methylsulfinyl)benzyl, 4-sulfobenzyl, piperonyl, and 4-P- benzyl.
- Silyl esters include: trimethylsilyl, t ethylsilyl, f-butyldimethylsilyl, /- propyldimethylsilyl, phenyldimethylsilyl, and di- f-butylmethylsilyl.
- Miscellaneous Derivatives Miscellaneous derivatives includes: oxazoles, 2-alkyl-1 ,3-oxazolines, 4-alkyl-5- oxo-1 , 3-oxazolidines, 5-alkyl-4-oxo-1 ,3-dioxolanes, ortho esters, phenyl group, and pentaaminocobalt(lll) complex.
- Stannyl Esters examples include: triethylstannyl and tri-n-butylstannyl. AMIDES AND HYDRAZIDES
- Amides include: N,N -dimethyl, pyrrolidinyl, piperidinyl, 5,6-dihydrophen- anthridinyl, o-nitroanilides, ⁇ /-7-nitroindolyl, /V-8-nitro-1,2,3,4-tetrahydroquinolyl, and p-P-benzenesulfonamides.
- Hydrazides include: /V-phenyl, ⁇ /./V '-diisopropyl and other dialkyl hydrazides.
- CARBAMATES Carbamates include: carbamates, substituted ethyl, assisted cleavage, photolytic cleavage, urea-type derivatives, and miscellaneous carbamates.
- Carbamates include: methyl and ethyl, 9-fluorenylmethyl, 9-(2- sulfo)fluorenylmethyl, 9-(2,7-dibromo)fluorenylmethyl, 2,7-di- -butyl-[9-(10,10- dioxo-10, 10, 10, 10-tetrahydro- thioxanthyl)]methyl, and 4-methoxyphenacyl.
- Substituted Ethyl protective groups include: 2,2,2-trichloroethyl, 2- trimethylsilylethyl, 2-phenylethyl, 1-(1-adamantyl)-1-methylethyl, 1 ,1-dimethyl-2- haloethyl, 1 ,1dimethyl-2,2-dibromoethyl, 1 ,1-dimethyl-2,2,2-trichloroethyl, 1- methyl-1-(4-biphenylyl)ethyl, 1-(3,5-di-f-butylphenyl)-1-methylethyl, 2-(2'-and 4'- pyridyl)ethyl, 2-(/V, ⁇ /-icyclohexylcarboxamido)- ethyl, f-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, connam
- Assisted Cleavage Protection via assisted cleavage includes: 2-methylthioethyl, 2- methylsulfonylethyl, 2-(p-toluenesulfonyl)ethyl, [2-(1 ,3-dithianyl)]methyl, 4- methylthiophenyl, 2,4-dimethyl-thiophenyl, 2-phosphonioethyl, 2- triphenylphosphonioisopropyl, 1 ,1-dimethyl-2-cyanoethyl, m-chloro-p- acyloxy benzyl, p-(dihydroxyboryl)benzyl, 5-benzisoxazolyl-methyl, and 2- (trifluoromethyl)-6-chromonyimethyl.
- Photolytic Cleavage uses groups such as: m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o- nitrophenyl)methyl.
- groups such as: m-nitrophenyl, 3,5- dimethoxybenzyl, o-nitrobenzyl, 3,4-dimethoxy-6-nitrobenzyl, and phenyl(o- nitrophenyl)methyl.
- urea-type derivatives include: phenothiazinyl-(10)-carbonyl derivative, N '-p-toluenesulfonylaminocarbonyl, and N '-phenylaminothiocarbonyl.
- miscellaneous carbamates include: f-amyl, S-benzyl thiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxy-benzyl, diisopropylmethyl, 2,2- dimethoxycarbonylvinyl, o-( ⁇ /, ⁇ /-dimethyl-carboxamido)-benzyl, 1 ,1-dimethyl- 3( ⁇ /, ⁇ /-dimethylcarboxamido)propyl, 1 ,1-dimethyl-propynyl, di(2-pyridyl)methyl, 2- furanylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p(p - methoxyphenylazo)benzyl, 1-methylcyclobuty
- Amides includes: ⁇ /-formyl, ⁇ /-acetyl, ⁇ /-chloroacetyl, /V-trichloroacetyl, ⁇ /-trifluoroacetyl, /V-phenylacetyl, /V-3-phenylpropionyl, /V-picolinoyl, ⁇ /-3-pyridyl- carboxamide, ⁇ /-benzoylphenylalanyl derivative, ⁇ /-benzoyl, and ⁇ /-p- phenylbenzoyl.
- Assisted Cleavage Assisted cleavage groups include: /V-o-nitrophenylacetyl, N-o- nitrophenoxyacetyl, ⁇ /-acetoacetyl, ( ⁇ / -dithiobenzyloxycarbonylamino)acetyl, ⁇ /-3- (p-hydroxphenyl) propionyl, ⁇ /-3-(o-nitrophenyl)propionyl, ⁇ /-2-methyl-2-(o- nitrophenoxy)propionyl, ⁇ /-2-methyl-2-(o-phenylazophenoxy)propionyl, ⁇ /-4- chlorobutyryl, ⁇ /-3-methyl-3-nitrobutyryl, ⁇ /-o-nitrocinnamoyl, ⁇ /-acetylmethionine derivative, ⁇ /-o-nitrobenzoyl, ⁇ /-o-(benzoyloxymethyl)benzoyl, and 4,5-diphenyl-3- o
- Cyclic imide derivatives include: ⁇ /-phthalimide, ⁇ /-dithiasuccinoyl, ⁇ /-2,3-diphenyl-maleoyl, ⁇ /-2,5-dimethylpyrrolyl, ⁇ /-1 ,1 ,4,4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1 ,3-dimethyl-1 ,3,5-triazacyclohexan-2-one, 5-substituted 1 ,3-dibenzyl- 1 ,3,5-triazacyclohexan-2-one, and 1 -substituted 3,5-dinitro-4-pyridonyl.
- Protective groups for - NH include: ⁇ /-alkyl and ⁇ /-aryl amines, imine derivatives, enamine derivatives, and ⁇ /-hetero atom derivatives (such as /V-metal, N-N, N-P, N-Si, and N-S), /V-sulfenyl, and ⁇ /-sulfonyl.
- ⁇ /-Alkyl and ⁇ /-Aryl Amines ⁇ /-alkyl and ⁇ /-aryl amines include: ⁇ /-methyl, ⁇ /-allyl, ⁇ /-[2-(trimethylsilyl)ethoxyl]- methyl, ⁇ /-3-acetoxypropyl, ⁇ /-(1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, /V-benzyl, ⁇ /-di(4-methoxyphenyl)methyl, ⁇ /-5-dibenzosuberyl, /V-triphenylmethyl, ⁇ /-(4-methoxyphenyl)diphenylmethyl, ⁇ /-9-phenylfluorenyl, ⁇ /-2,7-dichloro-9-fluorenylmethylene, ⁇ /-ferrocenylmethyl, and ⁇ /-2-picolylamine N '-oxid
- Imine derivatives include: ⁇ /-1 ,1-dimethylthiomethylene, ⁇ /-benzylidene, ⁇ /-p-methoxybenzylidene, ⁇ /-diphenylmethylene, ⁇ /-[(2-pyridyl)mesityl]methylene, N-(N ',N '-dimethylaminomethylene), N,N '-isopropylidene, ⁇ /-p-nitrobenzylidene, ⁇ /-salicylidene, ⁇ /-5-chlorosalicylidene, ⁇ /-(5-chloro-2-hydroxyphenyl)phenyl- methylene, and ⁇ /-cyclohexylidene.
- Enamine Derivatives include: ⁇ /-1 ,1-dimethylthiomethylene, ⁇ /-benzylidene, ⁇ /-p-methoxybenzylidene, ⁇ /-diphenylmethylene, ⁇ /-
- An example of an enamine derivative is ⁇ /-(5,5-dimethyl-3-oxo-1-cyclohexenyl). ⁇ /-Hetero Atom Derivatives
- /V-metal derivatives include: ⁇ /-borane derivatives, ⁇ /-diphenylborinic acid derivative, ⁇ /-[phenyl(pentacarbonylchromium- or -tungsten)]carbenyl, and
- N-N derivatives include: ⁇ /-nitro,
- tV-P derivatives include:
- ⁇ /V-dialkyl phosphoryl examples include: ⁇ /-benzenesulfenyl,
- ⁇ /-sulfonyl derivatives include: /V-p-toluenesulfonyl, /V-benzenesulfonyl, N- 2,3,6-trimethyl- 4-methoxybenzenesulfonyl, ⁇ /-2,4,6-trimethoxybenzenesulfonyl, N-
- Disclosed compounds which are masked or protected may be prodrugs, compounds metabolized or otherwise transformed in vivo to yield a disclosed compound, e.g., transiently during metabolism.
- This transformation may be a hydrolysis or oxidation which results from contact with a bodily fluid such as blood, or the action of acids, or liver, gastrointestinal, or other enzymes.
- Example 4 to a solution of 2-methyl-4-trimethyl- silanylethynyl aniline (1.50 g, 0.008 mole) in THF (10 ml) at " 78°C, LDA (2 M in THF, 6 ml, 0.012 mole) was added and the mixture was stirred at " 78°C for 30 minutes. Solid 2,4-difluoro-benzoic acid (0.633 g, 0.004 mole) was added and the stirred for 16 hours while it warmed up to room temperature. The solvents were removed and water (30 ml) and Et 2 0 (50 ml) added to the oil residue.
- EXAMPLE 6 4-Fluoro-2-(2-methyl-4-ethvnyl-phenylamino)-benzoic acid (7). To a solution of 6 in CH 3 OH (30 ml), aqueous 1 N KOH (10 ml) was added.
- Incorporation of 32 P into myelin basic protein is assayed in the presence of a glutathione S-transferase fusion protein containing p44MAP kinase (GST-MAPK) and a glutathione S-transferase fusion protein containing p45MEK (GST-MEK).
- the assay solution contains 20 mM HEPES, pH 7.4, 10 mM MgCI 2 , 1 mM MnCI 2 , 1 mM EGTA, 50, ⁇ M [ ⁇ - 32 P]ATP, 10 ⁇ g GST-MEK, 0.5 ⁇ g GST-MAPK and 40 ⁇ g MBP in a final volume of 100 ⁇ L.
- Reactions are stopped after 20 minutes by addition of trichloroacetic acid and filtered through a GF/C filter mat. 32 P retained on the filter mat is determined using a 120S Betaplate. Compounds are assessed at 10 ⁇ M for ability to inhibit incorporation of 32 P.
- two additional protocols are employed. In the first protocol, compounds are added to tubes containing GST-MEK, followed by addition of GST-MAPK, MBP and [ ⁇ - 32 P]ATP. In the second protocol, compounds are added to tubes containing both GST-MEK and GST-MAPK, followed by MBP and [ ⁇ - 32 P]ATP. Compounds that show activity in both protocols are scored as MAPK inhibitors, while compounds showing activity in only the first protocol are scored as MEK inhibitors.
- Inhibitory activity can be confirmed in direct assays.
- MAP kinase 1 ⁇ g GST-MAPK is incubated with 40 ⁇ g MBP for 15 minutes at 30°C in a final volume of 50 ⁇ L containing 50 mM Tris (pH 7.5), 10 ⁇ M MgC1 2 , 2 ⁇ M EGTA, and 10 ⁇ M [ ⁇ - 32 P]ATP.
- the reaction is stopped by addition of Laemmli SDS sample buffer and phosphorylated MBP resolved by electrophoresis on a 10% polyacrylamide gel. Radioactivity incorporated into MBP is determined by both autoradiography, and scintillation counting of excised bands.
- GST-MEKi For evaluation of direct MEK activity, 10 ⁇ g GST-MEKi is incubated with 5 ⁇ g of a glutathione S-transferase fusion protein containing p44MAP kinase with a lysine to alanine mutation at position 71 (GST-MAPK-KA). This mutation eliminates kinase activity of MAPK, so only kinase activity attributed to the added MEK remains. Incubations are 15 minutes at 30°C in a final volume of 50 ⁇ L containing 50 mM Tris (pH 7.5), 10 ⁇ M MgCI 2 , 2 , ⁇ M EGTA, and 10 ⁇ M [ ⁇ - 32 P]ATP.
- the reaction is stopped by addition of Laemmli SDS sample buffer.
- Phosphorylated GST-MAPK-KA is resolved by electrophoresis on a 10% polyacrylamide gel. Radioactivity incorporated into GST-MAPK-KA is determined by autoradiography, and subsequent scintillation counting of excised bands.
- an artificially activated MEK containing serine to glutamate mutations at positions 218 and 222 (GST-MEK-2E) is used. When these two sites are phosphorylated, MEK activity is increased. Phosphorylation of these sites can be mimicked by mutation of the serine residues to glutamate.
- 5 ⁇ g GST-MEK-2E is incubated with 5 ⁇ g GST-MAPK-KA for 15 minutes at 30°C in the same reaction buffer as described above. Reactions are terminated and analyzed as above.
- Lysates are clarified by centrifugation at 13,000 x g for 10 minutes. Five to fifteen micrograms of protein from the resulting supematants are subjected to SDS/PAGE and Western blotting for phosphorylated MAP kinase levels.
- EXAMPLE 17 Monolaver growth Cells are plated into multi-well plates at 10 to 20,000 cells/mL. Forty-eight hours after seeding, test compounds are added to the cell growth medium and incubation is continued for 2 additional days. Cells are then removed from the wells by incubation with trypsin and enumerated with a Coulter counter. EXAMPLE 18 Growth in soft-agar
- Cells are seeded into 35-mm dishes at 5 to 10,000 cells/dish using growth medium containing 0.3% agar. After chilling to solidify the agar, cells are transferred to a 37°C incubator. After 7 to 10 days' growth, visible colonies are manually enumerated with the aid of a dissecting microscope.
- Type II collagen-induced arthritis in mice is an experimental model of arthritis that has a number of pathologic, immunologic, and genetic features in common with rheumatoid arthritis.
- the disease is induced by immunization of DBA/1 mice with 100 ⁇ g type II collagen, which is a major component of joint cartilage, delivered intradermally in Freund's complete adjuvant.
- the disease susceptibility is regulated by the class II MHC gene locus, which is analogous to the association of rheumatoid arthritis with HLA-DR4.
- a progressive and inflammatory arthritis develops in the majority of mice immunized, characterized by paw width increases of up to 100%.
- a test compound is administered to mice in a range of amounts, such as 20, 60, 100, and 200 mg/kg body weight/day. The duration of the test can be several weeks to a few months, such as 40, 60, or 80 days.
- a clinical scoring index is used to assess disease progression from erythema and edema (stage 1), joint distortion (stage 2), to joint ankylosis (stage 3). The disease is variable in that it can affect one or all paws in an animal, resulting in a total possible score of 12 for each mouse. Histopathology of an arthritic joint reveals synovitis, pannus formation, and cartilage and bone erosions. All mouse strains that are susceptible to CIA are high antibody responders to type II collagen, and there is a marked cellular response to CH.
- EXAMPLE 20 SCW-induced monoarticular arthritis
- Rats receive 6 ⁇ g sonicated SCW [in 10 ⁇ l Dulbecco's PBS (DPBS)] by an intraarticular injection into the right tibiotalar joint on day 0. On day 21 , the DTH is initiated with 100 ⁇ g of SCW (250 ⁇ l) administered i.v.
- SCW 250 ⁇ l
- SCW twice daily (10 ml/kg volume) beginning 1 hr prior to reactivation with SCW.
- Compounds are administered in amounts between 10 and 500 mg/kg body weight/day, such as 20, 30, 60, 100, 200, and 300 mg/kg/day. Edema measurements are obtained by determining the baseline volumes of the sensitized hindpaw before reactivation on day 21 , and comparing them with volumes at subsequent time points such as day 22, 23, 24, and 25. Paw volume is determined by mercury plethysmography.
- Each animal is anesthetized and an incision is made at the base of the recipient ear, cutting only the dorsal epidermis and dermis.
- the incision is spread open and down to the cartilage parallel to the head, and sufficiently wide to accommodate the appropriate tunneling for a rat or insertion tool for a mouse.
- a neonatal mouse or rat pup less than 60 hours old is anesthetized and cervically dislocated.
- the heart is removed from the chest, rinsed with saline, bisected longitudinally with a scalpel, and rinsed with sterile saline.
- the donor heart fragment is placed into the preformed tunnel with the insertion tool and air or residual fluid is gently expressed from the tunnel with light pressure. No suturing, adhesive bonding, bandaging, or treatment with antibiotics is required.
- Implants are examined at 10-20-fold magnification with a stereoscopic dissecting microscope without anesthesia. Recipients whose grafts are not visibly beating may be anesthetized and evaluated for the presence of electrical activity using Grass E-2 platinum subdermal pin microelectodes placed either in the pinna or directly into the graft and a tachograph. Implants can be examined 1-4 times a day for 10, 20, 30 or more days. The ability of a test compound to ameliorate symptoms of transplant rejection can be compared with a control compound such as cyciosporine, tacrolimus, or orally-administered lefluonomide.
- a control compound such as cyciosporine, tacrolimus, or orally-administered lefluonomide.
- mice Female C57BLJ6 mice are obtained from the Jackson Laboratory (Bar Harbor, ME). All animals are given food and water ad libitum. Mice are sensitized with a single i.p. injection of OVA (grade V, Sigma Chemical Company, St. Louis, MO) adsorbed to alum, (10 ⁇ g OVA + 9 mg alum in 200 ⁇ l saline) or vehicle control, (9 mg alum in 200 ⁇ l saline) on day 0. On day 14, the mice are challenged with a 12-minute inhalation of an aerosol consisting of 1.5% OVA (weight/volume) in saline produced by a nebulizer (small particle generator, model SPAG-2; ICN Pharmaceuticals, Costa Mesa, CA).
- OVA grade V
- vehicle control 9 mg alum in 200 ⁇ l saline
- mice are dosed with oral vehicle (0.5% hydroxypropylmethylcellulose / 0.25% TWEEN- 80), or a test compound at 10, 30, or 100 mg/kg in oral vehicle, 200 ⁇ l per mouse p.o. Dosing is performed once per day starting on day 7 or day 13, and extending through day 16. For determination of pulmonary eosinophilia, three days after the first
- mice are anesthetized with an i.p. injection of anesthetic (Ketamine/Acepromazine/Xylazine), and the tracheae is exposed and cannulated.
- anesthetic Ketamine/Acepromazine/Xylazine
- the lungs and upper airways are lavaged twice with 0.5 ml of cold PBS.
- a portion (200 ⁇ l) of the bronchoalveolar lavage (BAL) fluid is enumerated using a Coulter counter Model ZB1 (Coulter Electronics, Hialeah, FL).
- the remaining BAL fluid is then centrifuged at 300 x g for five minutes, and the cells are resuspended in 1 ml of HBSS (Gibco BRL) containing 0.5% fetal calf serum (HyClone) and 10 mM HEPES (Gibco BRL).
- the cell suspension is centrifuged in a cytospin (Shandon Southern Instruments, Sewickley, PA) and stained by Diff Quick (American Scientific Products, McGraw Park, IL) to differentiate BAL leukocytes into neutrophil, eosinophil, monocyte or lymphocyte subsets.
- the number of eosinophils in the BAL fluid is determined by multiplying the percentage of eosinophils by the total cell count.
- Transepithelial flux measurements were made by mounting the cell monolayers in a side-by-side diffusion chamber system (Precision Instrument Design, Tahoe City, CA). Temperature was maintained at 37°C with a circulating water jacket. The solutions were mixed with gas-lift circulation with 95% oxygen-5% carbon dioxide. Donor solutions with PD compounds, [ 14 C] mannitol (leakage marker) and [ 3 H] metoprolol (reference compound) were added to the apical chamber. Donor and receiver samples were collected at selected time intervals for up to 3 hours. Radiolabelled mannitol and metoprolol were analyzed using scintillation counting (TopCount, Packard Instruments, Downers Grove, IL).
- Step a Preparation of ⁇ /-Cvclopropylmethoxy-2,3,4-trifluoro-benzenesulfonamide
- a stirring suspension comprised of O-cyclopropylmethyl-hydroxylamine hydrochloride (5.40 g, 43.7 x 10 "3 mol) in dichloromethane (20 ml) at ambient temperature under a nitrogen atmosphere was added directly diisopropylethylamine (10.8 ml, 0.062 mol).
- a solution comprised of 2,3,4- trifluorobenzenesulfonyl chloride (1.00 g, 4.34 x 10 "3 mol) in dichloromethane (120 ml) was added as a slow steady stream over twelve minutes to the first solution.
- Step b Preparation of 2-(2-Chloro-4-iodo-phenylamino)- ⁇ /-cvclopropylmetho ⁇ y- 3,4-difluoro-benzenesulfonamide
- 2-chloro-4-iodoaniline (0.80 g, 3.2 x 10 "3 mol) in tetrahydrofuran (10 ml) at -78 °C under a nitrogen atmosphere was added 1.0 molar lithium b/ ' strimethylsilylamide solution in tetrahydrofuran (6.2 ml, 6.2 x 10 "3 mol) to form a green suspension.
- the suspension was stirred for five minutes before a stirring suspension comprised of lithiated N- cyclopropylmethoxy-2,3,4-trifluoro-benzenesulfonamide [prepared by adding 3.0 ml of the 1.0 molar lithium D/ ' strimethylsilylamide solution to a stirring solution comprised of 0.83 g (2.95 x 10 "3 mol) of ⁇ /-cyclopropylmethoxy-2,3,4-trifluoro- benzenesulfonamide in 10 ml of tetrahydrofuran at -78 °C] was added. The cold bath was removed and the reaction mixture was stirred for one hour.
- lithiated N- cyclopropylmethoxy-2,3,4-trifluoro-benzenesulfonamide prepared by adding 3.0 ml of the 1.0 molar lithium D/ ' strimethylsilylamide solution to a stirring solution comprised of 0.83 g (2.95
- Aqueous (10 %) hydrochloric acid 50 ml was added to the reaction mixture, and the biphasic mixture was concentrated in vacuo to an aqueous suspension that was extracted with diethyl ether (200 ml). The ether phase was dried (MgSO 4 ) and concentrated in vacuo to afford 2 g of a tan oil.
- the crude product was purified by flash silica chromatography.
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Priority Applications (5)
Application Number | Priority Date | Filing Date | Title |
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AU24834/00A AU2483400A (en) | 1999-01-13 | 1999-12-21 | 4'heteroaryl diarylamines |
CA002349180A CA2349180A1 (fr) | 1999-01-13 | 1999-12-21 | 4'heteroaryle diarylamines |
BR9916857-0A BR9916857A (pt) | 1999-01-13 | 1999-12-21 | 4 heteroaril diarilaminas |
JP2000593128A JP2002534446A (ja) | 1999-01-13 | 1999-12-21 | 4′ヘテロアリールジアリールアミン |
EP99968160A EP1150950A2 (fr) | 1999-01-13 | 1999-12-21 | Derives d'acide anthranilique |
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US11587699P | 1999-01-13 | 1999-01-13 | |
US12258399P | 1999-03-02 | 1999-03-02 | |
US60/122,583 | 1999-03-02 | ||
US60/115,876 | 1999-03-02 |
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WO2000041505A2 true WO2000041505A2 (fr) | 2000-07-20 |
WO2000041505A3 WO2000041505A3 (fr) | 2000-10-19 |
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PCT/US1999/030491 WO2000041505A2 (fr) | 1999-01-13 | 1999-12-21 | 4'heteroaryle diarylamines |
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EP (1) | EP1150950A2 (fr) |
JP (1) | JP2002534446A (fr) |
AU (1) | AU2483400A (fr) |
BR (1) | BR9916857A (fr) |
CA (1) | CA2349180A1 (fr) |
WO (1) | WO2000041505A2 (fr) |
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CA2349180A1 (fr) | 2000-07-20 |
BR9916857A (pt) | 2001-12-04 |
WO2000041505A3 (fr) | 2000-10-19 |
AU2483400A (en) | 2000-08-01 |
JP2002534446A (ja) | 2002-10-15 |
EP1150950A2 (fr) | 2001-11-07 |
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