WO2008059238A1 - Benzenesulfonamide compounds as edg-1 antagonists useful in the treatment of cancer - Google Patents
Benzenesulfonamide compounds as edg-1 antagonists useful in the treatment of cancer Download PDFInfo
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- WO2008059238A1 WO2008059238A1 PCT/GB2007/004342 GB2007004342W WO2008059238A1 WO 2008059238 A1 WO2008059238 A1 WO 2008059238A1 GB 2007004342 W GB2007004342 W GB 2007004342W WO 2008059238 A1 WO2008059238 A1 WO 2008059238A1
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- 0 CC(*)(CC*1*2*)CC[C@@]1[C@@](*)[C@]2C(*)(*)NS(C1CCCC(C)(*)CCCCC1)(=O)=O Chemical compound CC(*)(CC*1*2*)CC[C@@]1[C@@](*)[C@]2C(*)(*)NS(C1CCCC(C)(*)CCCCC1)(=O)=O 0.000 description 1
- KTCLMTXBVMYKRR-UHFFFAOYSA-O CC(C(N(C)OC)=O)NC[SH+]c(cc1)ccc1Cl Chemical compound CC(C(N(C)OC)=O)NC[SH+]c(cc1)ccc1Cl KTCLMTXBVMYKRR-UHFFFAOYSA-O 0.000 description 1
- FCFZSRJWRQXWKK-UHFFFAOYSA-N CCC(C(C(Cc1ccccc1)NC(OC(C)(C)C)=O)=O)C(OCC)=O Chemical compound CCC(C(C(Cc1ccccc1)NC(OC(C)(C)C)=O)=O)C(OCC)=O FCFZSRJWRQXWKK-UHFFFAOYSA-N 0.000 description 1
- ZJJSJMVZEITPOR-UHFFFAOYSA-N CCNc1cc(C(F)(F)F)ncc1C#CC(C)O Chemical compound CCNc1cc(C(F)(F)F)ncc1C#CC(C)O ZJJSJMVZEITPOR-UHFFFAOYSA-N 0.000 description 1
- VXKJLKDDBOJNDN-UHFFFAOYSA-O CCc1c(CCCC2)[n]2nc1C(C)N[SH+]c(cc1)ccc1Cl Chemical compound CCc1c(CCCC2)[n]2nc1C(C)N[SH+]c(cc1)ccc1Cl VXKJLKDDBOJNDN-UHFFFAOYSA-O 0.000 description 1
- GEEGDKYOKNWIHL-UHFFFAOYSA-N CCc1c(cccc2)[n]2nc1C(C)NC(OC(C)(C)C)=O Chemical compound CCc1c(cccc2)[n]2nc1C(C)NC(OC(C)(C)C)=O GEEGDKYOKNWIHL-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
Definitions
- the present invention relates to novel substituted heterocycles, their pharmaceutical compositions and methods of use.
- the present invention relates to therapeutic methods for the treatment and prevention of cancers.
- Edg endothelial differentiation gene receptors belong to a family of closely related, lipid activated G-protein coupled receptors.
- Edg-1, Edg-3, Edg-5, Edg-6, and Edg-8 are identified as receptors specific for sphingosine-1 -phosphate (SIP).
- Edg-2, Edg-4, and Edg-7 are receptors specific for lysophosphatidic (LPA).
- Edg-1, Edg-3 and Edg-5 are widely expressed in various tissues, whereas the expression of Edg-6 is confined largely to lymphoid tissues and platelets, and that of Edg- 8 to the central nervous system.
- Edg receptors are responsible for signal transduction and are thought to play an important role in cell processes involving cell development, proliferation, maintenance, migration, differentiation, plasticity and apoptosis. Certain Edg receptors are associated with diseases mediated by the de novo or deregulated formation of vessels — for example, for diseases caused by ocular neovascularisation, especially retinopathies (diabetic retinopathy, age-related macular degeneration); psoriasis; and haemangioblastomas such as "strawberry- marks”.
- retinopathies diabetic retinopathy, age-related macular degeneration
- psoriasis psoriasis
- haemangioblastomas such as "strawberry- marks”.
- Edg receptors are also associated with various inflammatory diseases, such as arthritis, especially rheumatoid arthritis, arterial atherosclerosis and atherosclerosis occurring after transplants, endometriosis or chronic asthma; and, especially, tumor diseases or by lymphocyte interactions, for example, in transplantation rejection, autoimmune diseases, inflammatory diseases, infectious diseases and cancer.
- An alteration in Edg receptor activity contributes to the pathology and/or symptomology of these diseases. Accordingly, molecules that themselves alter the activity of Edg receptors are useful as therapeutic agents in the treatment of such diseases.
- the applicants have hereby discovered novel compounds that are Edg-1 antagonists. These compounds of the present invention provide a method for treating a variety of angiogenesis-related diseases that may be characterized by any abnormal, undesirable or pathological angiogenesis, for example, tumor- related angiogenesis.
- the compounds may be used to produce an anti-cancer effect mediated alone or in part by antagonism of Edg-1.
- Such a compound of the invention is expected to possess a wide range of activity in angiogenesis-related diseases including, but not limited to, non-solid tumors such as leukemia, multiple myeloma, hematologic malignancies or lymphoma, and also solid tumors and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostrate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, esophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumors.
- the compounds of the invention are accordingly useful for their anti-angiogenic (such as anti-cancer)
- the invention also relates to processes for the manufacture of said compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-cancer effect, for example an antiproliferative effect, in warm-blooded animals such as man.
- the present invention includes pharmaceutically acceptable salts of such compounds. Also in accordance with the present invention applicants provide pharmaceutical compositions and a method to use such compounds in the treatment of cancer.
- Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 7 ;
- R 1 is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, Ci -6 alkanoyl, Ci -6 alkanoyloxy, N,N-(C 1-6 alkyl) 2 amino, Ci- 6 alkanoylamino, /V-(Ci -6 alkyl)carbamoyl, N,/V-(Ci -6 alkyi) 2 carbarnoyl, Ci -6 alkylS(O) a wherein a is 0 to 2, Ci -6 alkoxycarbonyl, N-(Ci -6 alkyl)sulphamoyl,
- R 9 is 0-5; wherein the values of R 1 may be the same or different;
- R 2 is selected from Ci- 6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, carbocyclyl or heterocyclyl; wherein R 2 may be optionally substituted on carbon by one or more R 10 ; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 11 ;
- R 3 is selected from hydrogen, C ⁇ alkyl, C 2-6 alkenyl or C 2-6 alkynyl; wherein R 3 may be optionally substituted on carbon by one or more R 12 ; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 13 ;
- R 4 is absent or selected from hydrogen, Ci -6 alkyl or carbocyclyl; wherein R 4 may be optionally substituted on carbon by one or more R 14 ;
- X and Y are independently selected from CH, C or N;
- Ring B is a 5-membered ring and is a single or double bond
- Ring D is fused to Ring B of formula (I) and is a 5-7 membered ring; wherein if said ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 15 ;
- R 5 is a substituent on carbon or nitrogen and is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, Ci- ⁇ alkanoyl, Ci -6 alkanoyloxy, TV-(C i -6 alkyl)amino, /V,/V-(Ci- 6 alkyl) 2 amino, Ci -6 alkanoylamino, /V-(Ci -6 alkyl)carbamoyl, N,N-(Ci -6 alkyl) 2 carbamoyl, Ci -6 alkylS(O) a wherein a is 0 to 2, Ci -6 alkoxycarbonyl, /V-(Ci -6 alkyl)sulphamoyl, N,/V-(Ci -6 alky
- R 6 is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, Ci -6 alkanoyl, Ci- ⁇ alkanoyloxy, N-(Ci - 6 alkyl)amino, N,N-(Ci -6 alkyl)2amino, Ci -6 alkanoylamino, N-(Ci -6 alkyl)carbamoyl, N,N-(Ci- 6 alkyl) 2 carbamoyl, C i -6 alky IS(O) 3 wherein a is 0 to 2, Ci -6 alkoxycarbonyl, N-(Ci -6 alkyl)sulphamoyl, N,N-(C 1-6 alkyl) 2 sulphamoyl or Ci -6 alky
- R 8 , R 14 , R 16 and R 18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci -6 alkoxy, Ci -6 alkanoyl, Ci -6 alkanoyloxy, N-(Ci -6 alkyl)amino, N,N-(Ci -6 alkyl) 2 amino, Ci -6 alkanoylamino, N-(Ci -6 alkyl)carbamoyl, N,N-(Ci -6 alkyl) 2 carbamoyl, Ci -6 alkylS(O) a wherein a is 0 to 2, Ci -6 alkoxycarbonyl, N-(Ci -6 alkyl)sulphamoyl,
- R 10 and R 12 are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, Ci -6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, Ci ⁇ alkoxy, Ci -6 alkanoyl, C 1-6 alkanoyloxy, N-(Ci -6 alkyl)amino, N,N-(Ci -6 alkyl) 2 amino, Ci -6 alkanoylamino, N-(C 1-6 alkyl)carbamoyl, N,N-(Ci -6 alkyl) 2 carbamoyl, C i -6 alky IS(O) 3 wherein a is 0 to 2, N-(Ci -6 alkyl)sulphamoyl, N,N-(Ci -6 alkyl) 2 sulphamoyl, Ci -6 alkylsulphonylamino, carbocyclyl or hetero
- R 7 , R 9 , R", R 13 , R 15 , R 17 , R 19 , R 21 and R 23 are independently selected from C, -6 alkyl, Ci -6 alkanoyl, Ci -6 alkylsulphonyl, Ci -6 alkoxycarbonyl, carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
- R 20 and R 22 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, iV-methylcarbamoyl, N-ethylcarbamoyl,
- the compounds of the invention are directed to enantiomers of the compounds of formula (I) depicted by formula (Ia)
- alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only.
- "Ci -6 alkyl” and include methyl, ethyl, propyl, isopropyl and /-butyl.
- references to individual alkyl groups such as 'propyl' are specific for the straight-chained version only and references to individual branched chain alkyl groups such as 'isopropyF are specific for the branched chain version only.
- references to individual alkyl groups such as 'propyl' are specific for the straight-chained version only and references to individual branched chain alkyl groups such as 'isopropyF are specific for the branched chain version only.
- a similar convention applies to other radicals.
- a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH 2 - group can optionally be replaced by a -C(O)-, a ring nitrogen atom may optionally bear a Ci -6 alkyl group and form a quaternary compound or a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides.
- heterocyclyl examples and suitable values of the term "heterocyclyl” are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, TV-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide.
- a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH 2 - group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides.
- a “carbocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH 2 - group can optionally be replaced by a -C(O)-. Particularly “carbocyclyl” is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms.
- Suitable values for "carbocyclyl” include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1 -oxoindanyl.
- Ring B is fused to Ring D of formula (I) or formula (Ia) and is a 5-membered heterocyclic ring containing 0, 1 or 2 nitrogen atoms wherein is a single or double bond and the remaining atoms are carbon;
- Ring D is fused to Ring B of formula (I) or formula (Ia) and is a 5-7 membered ring" said ring including the carbon-carbon or nitrogen-carbon bond of Ring B and, apart from said double bond, comprises 3-5 additional ring atoms selected from C, N, O or S joined by single or double bonds.
- Ring D fused to Ring B of formula (I) include indole; pyrazolo[l,5- ⁇ ]pyridine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyridine; 6,7-dihydro-5H- pyrazolo[5,l- ⁇ ][l,3]oxazine; 6-methyl-2,3-dihydropyrazolo[5,l- ⁇ ][l,3]oxazole; 2-methyl- 5,6,7,8-tetrahydropyrazolo[5,l-6][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ jpyrimidine; and pyrazolo[l,5- ⁇ ]pyrimidine.
- Ring D fused to Ring B of formula (I) or formula (Ia) include pyrrolo[3,2-c]pyridine; 2,3-dihydropyrazolo[5,l- 6][l,3]oxazole; 5,6,7,8-tetrahydropyrazolo[5,l-&][l,3]oxazepine. Any of these may be substituted as indicated in formula (I) or formula (Ia) if such substitution is not already indicated.
- Ci- ⁇ alkanoyloxy is acetoxy.
- Examples of “Ci -6 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl.
- Examples of “Ci -6 alkoxy” include methoxy, ethoxy and propoxy.
- Examples of “Ci -6 alkanoylamino” include formamido, acetamido and propionylamino.
- Examples of "Ci- 6 alkylS(O) a wherein a is 0 to 2" include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl.
- Examples of "Ci -6 alkanoyl” include propionyl and acetyl.
- Examples of 'W-(Ci -6 alkyl)amino” include methylamino and ethylamino.
- Examples of 'W,N-(C 1-6 alkyl) 2 amino include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino.
- Examples of “C 2-6 alkenyl” are vinyl, allyl and 1-propenyl.
- Examples of “C 2-6 alkynyl” are ethynyl, 1-propynyl and 2-propynyl.
- Examples of 'W-(Ci -6 alkyl)sulphamoyl” are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl.
- Examples of "N, N-(Ci. 6 alkyl) 2 sulphamoyl” are N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl.
- Examples of 'W-(Ci -6 alkyl)carbamoyl are methylaminocarbonyl and ethylaminocarbonyl.
- Examples of "N, N-(Ci -6 alkyl) 2 carbamoyl” are dimethylaminocarbonyl and methylethylaminocarbonyl.
- Examples of "Ci -6 alkylsulphonylamino” include methylsulphonylamino, isopropylsulphonylamino and /-butylsulphonylamino.
- Examples of "Ci -6 alkylsulphonyl” include methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl.
- Some compounds of the formula (I) or formula (Ia) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess Edg-1 antagonistic activity.
- the invention relates to any and all tautomeric forms of the compounds of the formula (I) or formula (Ia) that possess Edg-1 antagonistic activity.
- Ring A is carbocyclyl
- Ring A is heterocyclyl wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R 7 .
- Ring A is phenyl
- Ring A is phenyl or pyridinyl.
- Ring A is pyridinyl
- R 1 is halo, cyano or carbamoyl.
- R 1 is halo
- R 1 is chloro. n is 1.
- R 2 is d- 6 alkyl.
- R is Ci- 6 alkyl wherein R may be independently optionally substituted on carbon by one or more R 10 wherein R 1 is carbocyclyl.
- R 2 is Ci- 6 alkyl wherein R 2 may be independently optionally substituted on carbon by one or more R 10 ; wherein R 10 is carbocyclyl which may be independently optionally substituted on carbon by one or more R .
- R 2 is C
- R 2 is Ci- 6 alkyl wherein R 2 may be independently optionally substituted on carbon by one or more R 10 wherein R 10 is heterocyclyl.
- R is methyl wherein R may be independently optionally substituted on carbon by one or more R 10 wherein R 10 is phenyl.
- R 3 is hydrogen
- R 3 is Ci -6 alkyl.
- R 3 is methyl
- R 4 is absent or selected from Ci -6 alkyl wherein R 4 may be optionally substituted on carbon by one or more R 1 .
- R 4 is selected from Ci -6 alkyl wherein R 4 may be optionally substituted on carbon by one or more R 14 .
- R 4 is methyl
- R 4 is ethyl
- R 4 is absent.
- R 4 is carbocyclyl wherein R 4 may be optionally substituted on carbon by one or more
- X is N.
- Y is N.
- X and Y are both N.
- X is C.
- X is CH.
- Y is C.
- Y is CH.
- X is CH and Y is C.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms indole; pyrazolo[l,5- ⁇ ]pyridine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyridine; 6,7-dihydro-5H-pyrazolo[5,l- 6][l,3]oxazine; 6-methyl-2,3-dihydropyrazolo[5,l-6][l,3]oxazole; 2-methyl-5,6,7,8- tetrahydropyrazolo[5,l- ⁇ ][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyrimidine; or pyrazolo[ 1 ,5- ⁇ ]pyrimidine.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms indole; pyrazolo[l,5- ⁇ ]pyridine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyridine; 6,7-dihydro-5H-pyrazolo[5,l- 6][l,3]oxazine; 6-methyl-2,3-dihydropyrazolo[5,l- ⁇ ][l,3]oxazole; 2-methyl-5,6,7,8- tetrahydropyrazolo[5, 1-Z)][1, 3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyrimidine; pyrazolo[l,5-fl]pyrimidine or pyrrolo[3,2-c]pyridine.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms pyrazolo[l,5- ⁇ ]pyridine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyridine; 6,7-dihydro-5H-pyrazolo[5,l- ⁇ ][l,3]oxazine; 2,3- dihydropyrazolo[5,l-£][l,3]oxazole; 5,6,7,8-tetrahydropyrazolo[5,l-6][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyrimidine; or pyrazolo[l,5- ⁇ ]pyrimidine.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms pyrazolo[l,5- ⁇ ]pyridine.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms 4,5,6,7- tetrahydropyrazolo[l,5- ⁇ ]pyridine.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms 6,7-dihydro-5H- pyrazolo[5,l-6][l,3]oxazine.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms 6-methy 1-2,3- dihydropyrazolo[5, 1 -b] [1 ,3]oxazole.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms 2-methyl-5,6,7,8- tetrahydropyrazolo[5, 1 -b] [1 ,3]oxazepine.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms 4,5,6,7- tetrahydropyrazolo[ 1 ,5- ⁇ ]pyrimidine.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms pyrazolo[l,5- fljpyrimidine.
- Ring D fused to Ring B of formula (I) or formula (Ia) forms pyrrolo[3,2-c]pyridine.
- R 5 is halo, Ci -6 alkyl or Ci -6 alkoxy wherein R 5 may be optionally substituted on carbon by one or more R 16 .
- R 5 is Ci -6 alkyl wherein R 5 may be optionally substituted on carbon by one or more halo.
- R 5 is trifluoromethyl.
- n 0, 1 or 2. m is 1. m is O.
- R 6 is selected from hydrogen, halo, cyano, Ci ⁇ alkyl and Ci -6 alkoxy wherein R 6 may be optionally substituted on carbon by one or more R 18 .
- R 6 is selected from hydrogen, halo, cyano, Ci -6 alkyl and Ci -6 alkoxy.
- R 6 is hydrogen.
- R 6 is halo.
- R 6 is bromo or fluoro.
- R 6 is selected from Ci -6 alkyl and Ci -6 alkoxy wherein R may be optionally substituted on carbon by one or more R .
- R 6 is Ci -6 alkyl wherein R 6 may be optionally substituted on carbon by one or more
- R 6 is ethyl
- R 6 is Ci -6 alkoxy wherein R 6 may be optionally substituted on carbon by one or more
- R 6 is methoxy
- Ring A is carbocyclyl or heterocyclyl
- R 1 is halo, cyano or carbamoyl; n is 1;
- R 2 is Ci- 6 alkyl; wherein R 2 may be independently optionally substituted on carbon by one or more R 10 ;
- R 3 is hydrogen
- R 4 is absent or Ci -6 alkyl wherein R 4 may be optionally substituted on carbon by one or more R 14 ;
- Ring D fused to Ring B of formula (I) forms indole; pyrazolo[l,5- ⁇ ]pyridine; 4,5,6,7- tetrahydropyrazolo[l,5- ⁇ ]pyridine; 6,7-dihydro-5H-pyrazolo[5,l-6][l,3]oxazine; 6-methyl- 2,3-dihydropyrazolo[5 , 1 -b] [ 1 ,3]oxazole; 2-methyl-5,6,7,8-tetrahydropyrazolo[5, 1 - Z?][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyrimidine; pyrazolo[l,5-o]pyrimidine; or pyrrolo[3,2-c]pyridine; m is 0 or 1 ;
- R 6 is selected from hydrogen, halo, cyano, Ci -6 alkyl and Ci -6 alkoxy wherein R 6 may
- X and Y are independently selected from C and N provided at least one of X and Y is N; or a pharmaceutically acceptable salt thereof. Therefore in a further aspect of the invention there is provided a compound of formula (I) or formula (Ia) (as depicted above) wherein:
- Ring A is carbocyclyl
- R 1 is halo; n is 1;
- R 2 is Ci- 6 alkyl; wherein R 2 may be independently optionally substituted on carbon by one or more R 10 ;
- R 3 is hydrogen or Ci- 6 alkyl
- R 4 is absent or Ci -6 alkyl wherein R 4 may be optionally substituted on carbon by one or more R 14 ;
- Ring D fused to Ring B of formula (I) forms indole; pyrazolo[l,5- ⁇ ]pyridine; 4,5,6,7- tetrahydropyrazolo[l,5- ⁇ ]pyridine; 6,7-dihydro-5H-pyrazolo[5,l- ⁇ ][l,3]oxazine; 6-methyl- 2,3-dihydropyrazolo[5,l-6][l,3]oxazole; 2-methyl-5,6,7,8-tetrahydropyrazolo[5,l- &][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyrimidine; or pyrazolo[l,5- ⁇ ]pyrimidine; m is O;
- R 6 is selected from hydrogen, halo, cyano, Ci ⁇ alkyl and Ci -6 alkoxy wherein R 6 may be optionally substituted on carbon by one or more R ;
- X and Y are independently selected from C and N provided at least one of X and Y is N; or a pharmaceutically acceptable salt thereof.
- Ring A is phenyl or pyridinyl
- R 1 is halo, cyano or carbamoyl; n is 1;
- R 2 is Ci- 6 alkyl; wherein R 2 may be independently optionally substituted on carbon by carbocyclyl;
- R 3 is hydrogen
- R 4 is absent or Ci -6 alkyl
- X and Y are selected from N or C provided at least one of X and Y is N;
- Ring D fused to Ring B of formula (I) forms pyrazolo[l,5- ⁇ ]pyridine; 4,5,6,7- tetrahydropyrazolo[l,5- ⁇ ]pyridine; 6,7-dihydro-5H-pyrazolo[5,l-6][l,3]oxazine; 2,3- dihydropyrazolo[5,l-6][l,3]oxazole; 5,6,7,8-tetrahydropyrazolo[5,l-6][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyrimidine; or pyrazolo[l,5- ⁇ ]pyrimidine; m is 0 or 1 ;
- R 6 is selected from hydrogen, halo, Ci -6 alkyl and Ci -6 alkoxy wherein R 6 may be
- Ring A is carbocyclyl
- R 1 is halo; n is 1;
- R 2 is Ci- 6 alkyl; wherein R 2 may be independently optionally substituted on carbon by one or more R 10 ;
- R 3 is hydrogen
- R 4 is absent
- X and Y are both N;
- Ring D fused to Ring B of formula (I) forms pyrazolo[l, 5 -a] pyridine; 4,5,6,7- tetrahydropyrazolo[l ,5- ⁇ ]pyridine; 6,7-dihydro-5H-pyrazolo[5, 1 -b][l ,3]oxazine; 6-methyl- 2,3-dihydropyrazolo[5,l-6][l,3]oxazole; 2-methyl-5,6,7,8-tetrahydropyrazolo[5,l- 6][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5- ⁇ ]pyrimidine; or pyrazolo[l,5- ⁇ ]pyrimidine; m is O;
- R 6 is selected from Ci ⁇ alkyl and Ci -6 alkoxy wherein R 6 may be optionally substituted on carbon by one or more R 18 ; or a pharmaceutically acceptable salt thereof.
- R 2 is methyl wherein R 2 may be optionally substituted on carbon by R 10 ;
- R 3 is hydrogen;
- R 4 is ethyl;
- X is N
- Y is C
- Ring D fused to Ring B of formula (I) forms indole; m is 0;
- R 6 is selected from hydrogen, halo, cyano, Ci -6 alkyl and Ci -6 alkoxy wherein R 6 may be optionally substituted on carbon by one or more R 18 ;
- R 10 is carbocyclyl; or a pharmaceutically acceptable salt thereof.
- preferred compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt thereof.
- Another aspect of the present invention provides processes a and b for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof which processes (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprise the following: Process a) reacting compounds of formula (IV), (V) and (VI):
- M is a metal atom, for example Mg;
- Z is a halo, for example Cl or Br and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.
- L is a displaceable group, for example, halo e.g. chloro or bromo.
- aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
- modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
- a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
- the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
- an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
- a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
- an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
- a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
- a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
- the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
- an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
- a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
- an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
- a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
- a base such as sodium hydroxide
- a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
- the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
- Compounds of the present invention may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
- the dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician, when determining the individual regimen and dosage level as the most appropriate for a particular patient.
- An effective amount of a compound of the present invention for use in therapy of infection is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of infection, to slow the progression of infection, or to reduce in patients with symptoms of infection the risk of getting worse.
- inert, pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
- a solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
- the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
- the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
- Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
- Some of the compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention.
- acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulf
- Base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth.
- basic nitrogen- containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; aralkyl halides like benzyl bromide and others.
- Non-toxic physiologically-acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product.
- the salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
- a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
- the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
- composition is intended to include the formulation of the active component or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier.
- this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
- Liquid form compositions include solutions, suspensions, and emulsions.
- Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration.
- Liquid compositions can also be formulated in solution in aqueous polyethylene glycol solution.
- Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired.
- Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
- the pharmaceutical compositions can be in unit dosage form.
- the composition is divided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
- a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
- the compounds defined in the present invention are effective anti-cancer agents which property is believed to arise from their Edg-1 antagonistic properties. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by Edg-1, i.e. the compounds may be used to produce an Edg-1 antagonistic effect in a warm-blooded animal in need of such treatment.
- the compounds of the present invention provide a method for treating cancer characterized by the antagonistic effect of Edg-1, i.e. the compounds may be used to produce an anti-cancer effect mediated alone or in part by the antagonistic effect of Edg-1.
- the compounds of the present invention provide a method for treating a variety of angiogenesis-related diseases that may be characterized by any abnormal, undesirable or pathological angiogenesis, for example tumor-related angiogenesis.
- the compounds may be used to produce an anti-cancer effect mediated alone or in part by antagonism of Edg-1.
- Such a compound of the invention is expected to possess a wide range of activity in angiogenesis-related diseases including, but not limited to, non-solid tumors such as leukemia, multiple myeloma, hematologic malignancies or lymphoma, and also solid tumors and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostrate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, esophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumors.
- non-solid tumors such as leukemia, multiple myeloma, hematologic
- Excessive vascular growth also contributes to numerous non-neoplastic disorders for which the compounds of the invention may be useful in treating.
- These non-neoplastic angiogenesis-related diseases include: atherosclerosis, haemangioma, haemangioendothelioma, angiofibroma, vascular malformations (e.g.
- HHT Hereditary Hemorrhagic Teleangiectasia
- warts warts, pyogenic granulomas, excessive hair growth, Kaposis' sarcoma, scar keloids, allergic oedema, psoriasis, dysfunctional uterine bleeding, follicular cysts, ovarian hyperstimulation, endometriosis, respiratory distress, ascites, peritoneal sclerosis in dialysis patients, adhesion formation result from abdominal surgery, obesity, rheumatoid arthritis, synovitis, osteomyelitis, pannus growth, osteophyte, hemophilic joints, inflammatory and infectious processes (e.g.
- hepatitis hepatitis, pneumonia, glomerulonephritis
- asthma nasal polyps
- liver regeneration pulmonary hypertension
- retinopathy of prematurity diabetic retinopathy
- age-related macular degeneration leukomalacia
- neovascular glaucoma corneal graft neovascularization
- trachoma thyroiditis
- thyroid enlargement and lymphoproliferative disorders.
- a method for producing a Edg-1 antagonistic effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
- a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
- a method of treating pathologically angiogenic diseases, thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations or infections which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein before.
- a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a Edg-1 antagonistic effect in a warm-blooded animal such as man.
- a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
- a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of pathologically angiogenic diseases, thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations or infections in a warm-blooded animal such as man.
- anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
- chemotherapy may include one or more of the following categories of anti-tumor agents:
- antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); anti-tumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and tax
- cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride;
- antioestrogens for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene
- agents which inhibit cancer cell invasion for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function;
- inhibitors of growth factor function include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [HerceptinTM] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluor
- antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin);
- vascular endothelial growth factor for example the anti-vascular endothelial cell growth factor antibody bevacizumab [AvastinTM]
- vastinTM anti-vascular endothelial cell growth factor antibody bevacizumab
- compounds that work by other mechanisms for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin
- vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
- antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
- gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
- immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies.
- cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor
- Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
- Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
- the following assay can be used to measure the effects of the compounds of the present invention as SlPl/Edgl inhibitors.
- This cell-based assay was designed to assess the ability of small molecule antagonists to inhibit activation of the GPCR SlPl in the presence of its cognate ligand SlP.
- the assay used technology initially developed by Norak Biosciences (Xsira Pharmaceutical) and presently owned by Molecular Devices.
- a human osteogenic sarcoma (U2OS) cell line overexpressing the Edg-1 /SlPl) receptor as well as a beta-arrestin/green fluorescent protein (GFP) construct hereafter termed Edg-1 Transfluor U2OS WT Clone #37 was employed.
- Edg-1 Transfluor U2OS WT Clone #37 cells were plated at a density of 6250 cells in 40 ⁇ L medium per well in 384 well plastic bottomed microtiter plates (BD Falcon) and incubated overnight at 37°C/5% CO 2 . Prior to screening, compounds were dissolved in 100% dimethyl sulfoxide (DMSO) to a final stock concentration of 10 mM. Compounds were then serially diluted at 3OX final concentration in Edg-1 Transfluor cell growth medium containing 30% DMSO using the Tecan Genesis instrument.
- DMSO dimethyl sulfoxide
- compounds of the invention generally exhibit EC 50 values ⁇ 100 ⁇ M.
- the compound of Example 11 exhibited an EC 50 value of 1.17 uM
- the compound of Example 5 exhibited an EC 50 value of 0.240 uM
- the compound of Example 11 exhibited an EC 50 value of 1.17 uM
- temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C;
- organic solutions were dried over anhydrous sodium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30mmHg) with a bath temperature of up to 60 °C;
- Example 4 was prepared starting from example 3 as described below: A test tube equipped with a stir bar was charged with N-[l-(3-bromo-l-ethyl-lH-indol-2- yl)ethyl]-4-chlorobenzenesulfonamide (Example 3, 238 mg, 0.54 mmol), CuCN (157 mg, 1.75 mmol), and anhydrous DMF (1.0 mL). The resulting mixture was heated at 140°C for 53 h. On cooling, the mixture was diluted with EtOAc (10 mL) and was filtered through a plug of diatomaceous earth.
- This material was dissolved in MeOH (3.0 mL) and was treated with hydrazine monohydrate (65 ⁇ l, 1.34 mmol). The solution was allowed to stir at room temperature for 4 h and was then treated with K 2 CO 3 (362 mg, 2.62 mmol) and was heated to reflux. After heating overnight, the MeOH was removed in vacuo. The residue was partitioned between CH 2 Cl 2 and H 2 O, and the aqueous layer was further extracted with CH 2 Cl 2 .
- the aqueous phase was extracted with CH 2 Cl 2 , and the combined organics were washed with brine, dried (MgSO 4 ), filtered, and concentrated.
- the mixture was concentrated under reduced pressure, and the residue purified by silica gel chromatography (R/ 0.32, 40% ethyl acetate in hexanes) to give the desired product as a racemic mixture.(0.239 mg, 72%)
- the enantiomers are resolved by chiral SFC using AD-H 4.6x100 column with 20% isopropanol in CO 2 at the flow rate of 5 mL/min. The active enantiomer was identified based on its activity in the biological assay.
- Examples 15 -17 listed in Table 3, were made using a procedure similar to that for Example 14 but using the intermediates indicated.
- the aqueous layer was further extracted with CH 2 Cl 2 , and the combined organic layers were washed with brine, dried (MgSO 4 ), filtered, and concentrated.
- the aqueous layer was extracted with EtOAc, and the combined organics were washed with H 2 O, brine, dried (MgSO 4 ), filtered, and concentrated.
- the oil thus obtained was resubjected to the reaction conditions (474 mg, K 2 CO 3 , 210 ⁇ L 1,2-dibromoethane, 3.0 mL DMF, 80 °C overnight) before repeating the aqueous workup described above.
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Abstract
This invention relates to novel compounds of formula (I) and to their pharmaceutical compositions and to their methods of use. These novel compounds possess Edg-1 antagonistic activity and are accordingly useful in the treatment and/or prophylaxis of cancer.
Description
BENZENESULFONAMIDE COMPOUNDS AS EDG-I ANTAGONISTS USEFUL IN THE TREATMENT OF CANCER
Field of the invention
The present invention relates to novel substituted heterocycles, their pharmaceutical compositions and methods of use. In addition, the present invention relates to therapeutic methods for the treatment and prevention of cancers.
Background of the invention
Edg (endothelial differentiation gene) receptors belong to a family of closely related, lipid activated G-protein coupled receptors. Edg-1, Edg-3, Edg-5, Edg-6, and Edg-8 (also known as SlPl, S1P3, S1P2, S1P4, and S1P5) are identified as receptors specific for sphingosine-1 -phosphate (SIP). Edg-2, Edg-4, and Edg-7 (known also as LPAl, LPA2, and LP A3, respectively) are receptors specific for lysophosphatidic (LPA). Among the SIP receptor isotypes, Edg-1, Edg-3 and Edg-5 are widely expressed in various tissues, whereas the expression of Edg-6 is confined largely to lymphoid tissues and platelets, and that of Edg- 8 to the central nervous system.
Edg receptors are responsible for signal transduction and are thought to play an important role in cell processes involving cell development, proliferation, maintenance, migration, differentiation, plasticity and apoptosis. Certain Edg receptors are associated with diseases mediated by the de novo or deregulated formation of vessels — for example, for diseases caused by ocular neovascularisation, especially retinopathies (diabetic retinopathy, age-related macular degeneration); psoriasis; and haemangioblastomas such as "strawberry- marks". Edg receptors are also associated with various inflammatory diseases, such as arthritis, especially rheumatoid arthritis, arterial atherosclerosis and atherosclerosis occurring after transplants, endometriosis or chronic asthma; and, especially, tumor diseases or by lymphocyte interactions, for example, in transplantation rejection, autoimmune diseases, inflammatory diseases, infectious diseases and cancer. An alteration in Edg receptor activity contributes to the pathology and/or symptomology of these diseases. Accordingly, molecules that themselves alter the activity of Edg receptors are useful as therapeutic agents in the treatment of such diseases.
Summary of the invention
In accordance with the present invention, the applicants have hereby discovered novel compounds that are Edg-1 antagonists. These compounds of the present
invention provide a method for treating a variety of angiogenesis-related diseases that may be characterized by any abnormal, undesirable or pathological angiogenesis, for example, tumor- related angiogenesis. The compounds may be used to produce an anti-cancer effect mediated alone or in part by antagonism of Edg-1. Such a compound of the invention is expected to possess a wide range of activity in angiogenesis-related diseases including, but not limited to, non-solid tumors such as leukemia, multiple myeloma, hematologic malignancies or lymphoma, and also solid tumors and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostrate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, esophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumors. The compounds of the invention are accordingly useful for their anti-angiogenic (such as anti-cancer) activity and are therefore useful in methods of treatment of the human or animal body.
The invention also relates to processes for the manufacture of said compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an anti-cancer effect, for example an antiproliferative effect, in warm-blooded animals such as man.
The present invention includes pharmaceutically acceptable salts of such compounds. Also in accordance with the present invention applicants provide pharmaceutical compositions and a method to use such compounds in the treatment of cancer.
Detailed Description of the Invention
Accordingly, the present invention provides a compound of formula (I):
(D wherein:
Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R7;
R1 is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy, Ci-6alkanoyl, Ci-6alkanoyloxy,
N,N-(C1-6alkyl)2amino, Ci-6alkanoylamino, /V-(Ci-6alkyl)carbamoyl, N,/V-(Ci-6alkyi)2carbarnoyl, Ci-6alkylS(O)a wherein a is 0 to 2, Ci-6alkoxycarbonyl, N-(Ci-6alkyl)sulphamoyl,
N,/V-(Ci-6alkyl)2sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl, heterocyclyl; wherein R1 may be optionally substituted on carbon by one or more R ; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from
R9; n is 0-5; wherein the values of R1 may be the same or different;
R2 is selected from Ci-6alkyl, C2-6alkenyl or C2-6alkynyl, carbocyclyl or heterocyclyl; wherein R2 may be optionally substituted on carbon by one or more R10; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R11;
R3 is selected from hydrogen, C^alkyl, C2-6alkenyl or C2-6alkynyl; wherein R3 may be optionally substituted on carbon by one or more R12; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R13;
R4 is absent or selected from hydrogen, Ci-6alkyl or carbocyclyl; wherein R4 may be optionally substituted on carbon by one or more R14;
X and Y are independently selected from CH, C or N;
Ring B is a 5-membered ring and is a single or double bond;
Ring D is fused to Ring B of formula (I) and is a 5-7 membered ring; wherein if said ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R15;
R5 is a substituent on carbon or nitrogen and is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy, Ci-δalkanoyl, Ci-6alkanoyloxy, TV-(C i-6alkyl)amino, /V,/V-(Ci-6alkyl)2amino, Ci-6alkanoylamino, /V-(Ci-6alkyl)carbamoyl, N,N-(Ci-6alkyl)2carbamoyl, Ci-6alkylS(O)a wherein a is 0 to 2, Ci-6alkoxycarbonyl, /V-(Ci-6alkyl)sulphamoyl, N,/V-(Ci-6alkyl)2Sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R5 may be optionally substituted on carbon by one or more R16; and
wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R17; m is 0-5; wherein the values of R5 may be the same or different;
R6 is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy, Ci-6alkanoyl, Ci-όalkanoyloxy, N-(Ci -6alkyl)amino, N,N-(Ci-6alkyl)2amino, Ci-6alkanoylamino, N-(Ci-6alkyl)carbamoyl, N,N-(Ci-6alkyl)2carbamoyl, C i-6alky IS(O)3 wherein a is 0 to 2, Ci-6alkoxycarbonyl, N-(Ci-6alkyl)sulphamoyl, N,N-(C1-6alkyl)2sulphamoyl or Ci-6alkylsulphonylamino; wherein R6 may be optionally substituted on carbon by one or more R18;
R8, R14, R16 and R18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,
C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy, Ci-6alkanoyl, Ci-6alkanoyloxy, N-(Ci-6alkyl)amino, N,N-(Ci-6alkyl)2amino, Ci-6alkanoylamino, N-(Ci-6alkyl)carbamoyl, N,N-(Ci-6alkyl)2carbamoyl, Ci-6alkylS(O)a wherein a is 0 to 2, Ci-6alkoxycarbonyl, N-(Ci-6alkyl)sulphamoyl,
N, N-(C i-6alky I)2 sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R8, R14, R16 and R18 may be independently optionally substituted on carbon by one or more R20; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R ;
R10 and R12 are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci^alkoxy, Ci-6alkanoyl, C1-6alkanoyloxy, N-(Ci-6alkyl)amino, N,N-(Ci-6alkyl)2amino, Ci-6alkanoylamino, N-(C1-6alkyl)carbamoyl, N,N-(Ci-6alkyl)2carbamoyl, C i-6alky IS(O)3 wherein a is 0 to 2, N-(Ci-6alkyl)sulphamoyl, N,N-(Ci-6alkyl)2sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R10 and R12 may be independently optionally substituted on carbon by one or more R22; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R23;
R7, R9, R", R13, R15, R17, R19, R21 and R23 are independently selected from C,-6alkyl, Ci-6alkanoyl, Ci-6alkylsulphonyl, Ci-6alkoxycarbonyl, carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
R20 and R22 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl,
ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, iV-methylcarbamoyl, N-ethylcarbamoyl,
N, JV-dimethylcarbamoyl, N, iV-diethylcarbamoyl, iV-methyl-iV-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxy carbonyl, iV-methylsulphamoyl, N-ethylsulphamoyl, N, ./V-dimethylsulphamoyl,
N, N-diethylsulphamoyl or N-methyl-jV-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof; with the proviso that said compound is not:
4-chloro-JV-[2,2,2-trichloro- 1 -(1 ,3 -dimethyl- 1 ,4,5,6,7,8-hexahydrocyclohepta[ό]pyrrol-2- yl)ethyl]benzenesulfonamide; ^
4-chloro-N-[2,2,2-trichloro-l -(I -methyl- l,4,5,6,7,8-hexahydrocyclohepta[δ]pyrrol-2- yl)ethyl]benzenesulfonamide;
4-chloro-N-[2,2,2-trichloro-l-(l-methyl-4,5,6,7-tetrahydro-lH-indol-2- yl)ethyl]benzenesulfonamide;
4-methyl-N-[l-(3-methyl-lH-indol-2-yl)ethyl]benzenesulfonamide;
N-[l-(lH-inden-2-yl)ethyl]-4-nitrobenzenesulfonamide;
N- [ 1 -( 1 H-inden-2-y l)ethy l]-4-methy lbenzenesulfonamide;
N-[l-(2,3-dihydro-lH-inden-2-yl)-2-hydroxyethyl]-5-chlorothiophene-2-sulfonamide; or
N-[(3-methyl-lH-indol-2-yl)(phenyl)methyl]pyridine-2-sulfonamide.
In another embodiment, the compounds of the invention are directed to enantiomers of the compounds of formula (I) depicted by formula (Ia)
Formula (Ia) wherein A, B, D, R1, R2, R3, R4, R5, R6, n and m are as defined in formula (I), and pharmaceutically acceptable salts thereof.
In this specification the term "alkyl" includes both straight and branched chain alkyl groups but references to individual alkyl groups such as "propyl" are specific for the straight chain version only. For example, "Ci-6alkyl" and
include methyl, ethyl, propyl,
isopropyl and /-butyl. However, references to individual alkyl groups such as 'propyl' are specific for the straight-chained version only and references to individual branched chain alkyl groups such as 'isopropyF are specific for the branched chain version only. A similar convention applies to other radicals.
Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.
A "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH2- group can optionally be replaced by a -C(O)-, a ring nitrogen atom may optionally bear a Ci-6alkyl group and form a quaternary compound or a ring nitrogen and/or sulphur atom may be optionally oxidised to form the N-oxide and or the S-oxides. Examples and suitable values of the term "heterocyclyl" are morpholino, piperidyl, pyridyl, pyranyl, pyrrolyl, isothiazolyl, indolyl, quinolyl, thienyl, 1,3-benzodioxolyl, thiadiazolyl, piperazinyl, thiazolidinyl, pyrrolidinyl, thiomorpholino, pyrrolinyl, homopiperazinyl, 3,5-dioxapiperidinyl, tetrahydropyranyl, imidazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, TV-methylpyrrolyl, 4-pyridone, 1-isoquinolone, 2-pyrrolidone, 4-thiazolidone, pyridine-N-oxide and quinoline-N-oxide. In one aspect of the invention a "heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 5 or 6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, it may, unless otherwise specified, be carbon or nitrogen linked, a -CH2- group can optionally be replaced by a -C(O)-and a ring sulphur atom may be optionally oxidised to form the S-oxides.
A "carbocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic carbon ring that contains 3-12 atoms; wherein a -CH2- group can optionally be replaced by a -C(O)-. Particularly "carbocyclyl" is a monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable values for "carbocyclyl" include cyclopropyl, cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1 -oxoindanyl.
"Ring B" is fused to Ring D of formula (I) or formula (Ia) and is a 5-membered heterocyclic ring containing 0, 1 or 2 nitrogen atoms wherein is a single or double bond and the remaining atoms are carbon;
"Ring D is fused to Ring B of formula (I) or formula (Ia) and is a 5-7 membered ring" said ring including the carbon-carbon or nitrogen-carbon bond of Ring B and, apart from said double bond, comprises 3-5 additional ring atoms selected from C, N, O or S joined by single or double bonds. Suitable examples of Ring D fused to Ring B of formula (I) include indole; pyrazolo[l,5-α]pyridine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyridine; 6,7-dihydro-5H- pyrazolo[5,l-ό][l,3]oxazine; 6-methyl-2,3-dihydropyrazolo[5,l-ό][l,3]oxazole; 2-methyl- 5,6,7,8-tetrahydropyrazolo[5,l-6][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5- αjpyrimidine; and pyrazolo[l,5-α]pyrimidine. Additional examples of Ring D fused to Ring B of formula (I) or formula (Ia) include pyrrolo[3,2-c]pyridine; 2,3-dihydropyrazolo[5,l- 6][l,3]oxazole; 5,6,7,8-tetrahydropyrazolo[5,l-&][l,3]oxazepine. Any of these may be substituted as indicated in formula (I) or formula (Ia) if such substitution is not already indicated.
An example of "Ci-όalkanoyloxy" is acetoxy. Examples of "Ci-6alkoxycarbonyl" include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of "Ci-6alkoxy" include methoxy, ethoxy and propoxy. Examples of "Ci-6alkanoylamino" include formamido, acetamido and propionylamino. Examples of "Ci-6alkylS(O)a wherein a is 0 to 2" include methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl and ethylsulphonyl. Examples of "Ci-6alkanoyl" include propionyl and acetyl. Examples of 'W-(Ci-6alkyl)amino" include methylamino and ethylamino. Examples of 'W,N-(C1-6alkyl)2amino" include di-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examples of "C2-6alkenyl" are vinyl, allyl and 1-propenyl. Examples of "C2-6alkynyl" are ethynyl, 1-propynyl and 2-propynyl. Examples of 'W-(Ci-6alkyl)sulphamoyl" are N-(methyl)sulphamoyl and N-(ethyl)sulphamoyl. Examples of "N, N-(Ci.6alkyl)2sulphamoyl" are N,N-(dimethyl)sulphamoyl and N-(methyl)-N-(ethyl)sulphamoyl. Examples of 'W-(Ci -6alkyl)carbamoyl" are methylaminocarbonyl and ethylaminocarbonyl. Examples of "N, N-(Ci -6alkyl)2carbamoyl" are dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of "Ci-6alkylsulphonylamino" include methylsulphonylamino, isopropylsulphonylamino and /-butylsulphonylamino. Examples of "Ci-6alkylsulphonyl" include methylsulphonyl, isopropylsulphonyl and t-butylsulphonyl.
Some compounds of the formula (I) or formula (Ia) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention
encompasses all such optical, diastereoisomers and geometric isomers that possess Edg-1 antagonistic activity.
The invention relates to any and all tautomeric forms of the compounds of the formula (I) or formula (Ia) that possess Edg-1 antagonistic activity.
It is also to be understood that certain compounds of the formula (I) or formula (Ia) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess Edg-1 antagonistic activity.
Particular values of variable groups are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.
Ring A is carbocyclyl.
Ring A is heterocyclyl wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R7.
Ring A is phenyl.
Ring A is phenyl or pyridinyl.
Ring A is pyridinyl.
R1 is halo, cyano or carbamoyl.
R1 is halo.
R1 is chloro. n is 1.
R2 is d-6alkyl.
R is Ci-6alkyl wherein R may be independently optionally substituted on carbon by one or more R10 wherein R1 is carbocyclyl.
R2 is Ci-6alkyl wherein R2 may be independently optionally substituted on carbon by one or more R10; wherein R10 is carbocyclyl which may be independently optionally substituted on carbon by one or more R .
R2 is C|-6alkyl; wherein R2 may be independently optionally substituted on carbon by one or more R10 wherein R10 is carbocyclyl which may be independently optionally substituted on carbon by one or more R and wherein R is halo.
R2 is Ci-6alkyl wherein R2 may be independently optionally substituted on carbon by one or more R10 wherein R10 is heterocyclyl.
R is methyl wherein R may be independently optionally substituted on carbon by one or more R10 wherein R10 is phenyl.
R3 is hydrogen.
R3 is Ci-6alkyl.
R3 is methyl.
R4 is absent or selected from Ci-6alkyl wherein R4 may be optionally substituted on carbon by one or more R1 .
R4 is selected from Ci-6alkyl wherein R4 may be optionally substituted on carbon by one or more R14.
R4 is methyl.
R4 is ethyl.
R4 is absent.
R4 is carbocyclyl wherein R4 may be optionally substituted on carbon by one or more
R 14
X is N.
Y is N.
X and Y are both N. X is C. X is CH.
Y is C.
Y is CH.
X is CH and Y is C.
Ring D fused to Ring B of formula (I) or formula (Ia) forms indole; pyrazolo[l,5- α]pyridine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyridine; 6,7-dihydro-5H-pyrazolo[5,l- 6][l,3]oxazine; 6-methyl-2,3-dihydropyrazolo[5,l-6][l,3]oxazole; 2-methyl-5,6,7,8- tetrahydropyrazolo[5,l-ό][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyrimidine; or pyrazolo[ 1 ,5-α]pyrimidine.
Ring D fused to Ring B of formula (I) or formula (Ia) forms indole; pyrazolo[l,5- α]pyridine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyridine; 6,7-dihydro-5H-pyrazolo[5,l- 6][l,3]oxazine; 6-methyl-2,3-dihydropyrazolo[5,l-ό][l,3]oxazole; 2-methyl-5,6,7,8- tetrahydropyrazolo[5, 1-Z)][1, 3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyrimidine; pyrazolo[l,5-fl]pyrimidine or pyrrolo[3,2-c]pyridine.
Ring D fused to Ring B of formula (I) or formula (Ia) forms pyrazolo[l,5-α]pyridine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyridine; 6,7-dihydro-5H-pyrazolo[5,l-ό][l,3]oxazine; 2,3- dihydropyrazolo[5,l-£][l,3]oxazole; 5,6,7,8-tetrahydropyrazolo[5,l-6][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyrimidine; or pyrazolo[l,5-α]pyrimidine.
Ring D fused to Ring B of formula (I) or formula (Ia) forms pyrazolo[l,5-α]pyridine.
Ring D fused to Ring B of formula (I) or formula (Ia) forms 4,5,6,7- tetrahydropyrazolo[l,5-α]pyridine.
Ring D fused to Ring B of formula (I) or formula (Ia) forms 6,7-dihydro-5H- pyrazolo[5,l-6][l,3]oxazine.
Ring D fused to Ring B of formula (I) or formula (Ia) forms 6-methy 1-2,3- dihydropyrazolo[5, 1 -b] [1 ,3]oxazole.
Ring D fused to Ring B of formula (I) or formula (Ia) forms 2-methyl-5,6,7,8- tetrahydropyrazolo[5, 1 -b] [1 ,3]oxazepine.
Ring D fused to Ring B of formula (I) or formula (Ia) forms 4,5,6,7- tetrahydropyrazolo[ 1 ,5-α]pyrimidine.
Ring D fused to Ring B of formula (I) or formula (Ia) forms pyrazolo[l,5- fljpyrimidine.
Ring D fused to Ring B of formula (I) or formula (Ia) forms pyrrolo[3,2-c]pyridine.
R5 is halo, Ci-6alkyl or Ci-6alkoxy wherein R5 may be optionally substituted on carbon by one or more R16.
R5 is Ci-6alkyl wherein R5 may be optionally substituted on carbon by one or more halo.
R5 is trifluoromethyl.
m is 0, 1 or 2. m is 1. m is O.
R6 is selected from hydrogen, halo, cyano, Ci^alkyl and Ci-6alkoxy wherein R6 may be optionally substituted on carbon by one or more R18.
R6 is selected from hydrogen, halo, cyano, Ci-6alkyl and Ci-6alkoxy. R6 is hydrogen. R6 is halo.
R6 is bromo or fluoro.
R6 is selected from Ci-6alkyl and Ci-6alkoxy wherein R may be optionally substituted on carbon by one or more R .
R6 is Ci-6alkyl wherein R6 may be optionally substituted on carbon by one or more
R 18
R6 is ethyl.
R6 is Ci-6alkoxy wherein R6 may be optionally substituted on carbon by one or more
R IS
R6 is methoxy.
Therefore in a further aspect of the invention there is provided a compound of formula (I) or formula (Ia) (as depicted above) wherein:
Ring A is carbocyclyl or heterocyclyl;
R1 is halo, cyano or carbamoyl; n is 1;
R2 is Ci-6alkyl; wherein R2 may be independently optionally substituted on carbon by one or more R10;
R3 is hydrogen;
R4 is absent or Ci-6alkyl wherein R4 may be optionally substituted on carbon by one or more R14;
Ring D fused to Ring B of formula (I) forms indole; pyrazolo[l,5-α]pyridine; 4,5,6,7- tetrahydropyrazolo[l,5-α]pyridine; 6,7-dihydro-5H-pyrazolo[5,l-6][l,3]oxazine; 6-methyl- 2,3-dihydropyrazolo[5 , 1 -b] [ 1 ,3]oxazole; 2-methyl-5,6,7,8-tetrahydropyrazolo[5, 1 - Z?][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyrimidine; pyrazolo[l,5-o]pyrimidine; or pyrrolo[3,2-c]pyridine; m is 0 or 1 ;
R6 is selected from hydrogen, halo, cyano, Ci-6alkyl and Ci-6alkoxy wherein R6 may
1 SI be optionally substituted on carbon by one or more R ;
X and Y are independently selected from C and N provided at least one of X and Y is N; or a pharmaceutically acceptable salt thereof.
Therefore in a further aspect of the invention there is provided a compound of formula (I) or formula (Ia) (as depicted above) wherein:
Ring A is carbocyclyl;
R1 is halo; n is 1;
R2 is Ci-6alkyl; wherein R2 may be independently optionally substituted on carbon by one or more R10;
R3 is hydrogen or Ci-6alkyl;
R4 is absent or Ci-6alkyl wherein R4 may be optionally substituted on carbon by one or more R14;
Ring D fused to Ring B of formula (I) forms indole; pyrazolo[l,5-α]pyridine; 4,5,6,7- tetrahydropyrazolo[l,5-α]pyridine; 6,7-dihydro-5H-pyrazolo[5,l-ό][l,3]oxazine; 6-methyl- 2,3-dihydropyrazolo[5,l-6][l,3]oxazole; 2-methyl-5,6,7,8-tetrahydropyrazolo[5,l- &][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyrimidine; or pyrazolo[l,5-α]pyrimidine; m is O;
R6 is selected from hydrogen, halo, cyano, Ci^alkyl and Ci-6alkoxy wherein R6 may be optionally substituted on carbon by one or more R ;
X and Y are independently selected from C and N provided at least one of X and Y is N; or a pharmaceutically acceptable salt thereof.
Therefore in a further aspect of the invention there is provided a compound of formula (I) or formula (Ia) (as depicted above) wherein:
Ring A is phenyl or pyridinyl;
R1 is halo, cyano or carbamoyl; n is 1;
R2 is Ci-6alkyl; wherein R2 may be independently optionally substituted on carbon by carbocyclyl;
R3 is hydrogen;
R4 is absent or Ci-6alkyl;
X and Y are selected from N or C provided at least one of X and Y is N;
Ring D fused to Ring B of formula (I) forms pyrazolo[l,5-α]pyridine; 4,5,6,7- tetrahydropyrazolo[l,5-α]pyridine; 6,7-dihydro-5H-pyrazolo[5,l-6][l,3]oxazine; 2,3-
dihydropyrazolo[5,l-6][l,3]oxazole; 5,6,7,8-tetrahydropyrazolo[5,l-6][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyrimidine; or pyrazolo[l,5-α]pyrimidine; m is 0 or 1 ;
R6 is selected from hydrogen, halo, Ci-6alkyl and Ci-6alkoxy wherein R6 may be
18 optionally substituted on carbon by one or more R ; or a pharmaceutically acceptable salt thereof.
Therefore in a further aspect of the invention there is provided a compound of formula (I) or formula (Ia) (as depicted above) wherein:
Ring A is carbocyclyl;
R1 is halo; n is 1;
R2 is Ci-6alkyl; wherein R2 may be independently optionally substituted on carbon by one or more R10;
R3 is hydrogen;
R4 is absent;
X and Y are both N;
Ring D fused to Ring B of formula (I) forms pyrazolo[l, 5 -a] pyridine; 4,5,6,7- tetrahydropyrazolo[l ,5-α]pyridine; 6,7-dihydro-5H-pyrazolo[5, 1 -b][l ,3]oxazine; 6-methyl- 2,3-dihydropyrazolo[5,l-6][l,3]oxazole; 2-methyl-5,6,7,8-tetrahydropyrazolo[5,l- 6][l,3]oxazepine; 4,5,6,7-tetrahydropyrazolo[l,5-α]pyrimidine; or pyrazolo[l,5-α]pyrimidine; m is O;
R6 is selected from Ci^alkyl and Ci-6alkoxy wherein R6 may be optionally substituted on carbon by one or more R18; or a pharmaceutically acceptable salt thereof.
Therefore in a further aspect of the invention there is provided a compound of formula (I) or formula (Ia) (as depicted above) wherein: Ring A is phenyl; R1 is chloro; n is 1;
R2 is methyl wherein R2 may be optionally substituted on carbon by R10; R3 is hydrogen;
R4 is ethyl;
X is N; and
Y is C;
Ring D fused to Ring B of formula (I) forms indole; m is 0;
R6 is selected from hydrogen, halo, cyano, Ci-6alkyl and Ci-6alkoxy wherein R6 may be optionally substituted on carbon by one or more R18;
R10 is carbocyclyl; or a pharmaceutically acceptable salt thereof.
In another aspect of the invention, preferred compounds of the invention are any one of the Examples or a pharmaceutically acceptable salt thereof.
Another aspect of the present invention provides processes a and b for preparing a compound of formula (I) or a pharmaceutically acceptable salt or an in vivo hydrolysable ester thereof which processes (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprise the following: Process a) reacting compounds of formula (IV), (V) and (VI):
(IV)
(V)
R2-M-Z (VI)
wherein:
M is a metal atom, for example Mg;
Z is a halo, for example Cl or Br and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.
Process b) reacting a compound of formula (II):
(H) with an amine of formula (III):
(III)
and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.
L is a displaceable group, for example, halo e.g. chloro or bromo.
Specific reaction conditions for the above reactions are as follows. Process a) Compounds of formula (IV), (V) and (VI) can be reacted together in the presence of a suitable Lewis Acid e.g. Ti(ZOPr)4 and a solvent such as DCM. Process b) Compounds of formula (II) and (III) can be reacted together in the presence of a suitable solvent such as DCM and a base such as triethylamine. The reaction may require thermal conditions.
Compounds of formula (II) are commercially available, or they may be prepared by processes known in the art.
The above processes a and b may also apply to the preparation of compounds of formula (Ia) wherein appropriate chiral starting materials are used, or by resolving the final racemic compound and separating the enantiomers using a method described herein or a method well-known in the art.
It will be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T. W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.
A suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection
conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
Compounds of the present invention may be administered orally, parenteral, buccal, vaginal, rectal, inhalation, insufflation, sublingually, intramuscularly, subcutaneously, topically, intranasally, intraperitoneally, intrathoracially, intravenously, epidurally, intrathecally, intracerebroventricularly and by injection into the joints.
The dosage will depend on the route of administration, the severity of the disease, age and weight of the patient and other factors normally considered by the attending physician,
when determining the individual regimen and dosage level as the most appropriate for a particular patient.
An effective amount of a compound of the present invention for use in therapy of infection is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of infection, to slow the progression of infection, or to reduce in patients with symptoms of infection the risk of getting worse.
For preparing pharmaceutical compositions from the compounds of this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets, and suppositories.
A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, or tablet disintegrating agents; it can also be an encapsulating material.
In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
For preparing suppository compositions, a low-melting wax such as a mixture of fatty acid glycerides and cocoa butter is first melted and the active ingredient is dispersed therein by, for example, stirring. The molten homogeneous mixture is then poured into convenient sized molds and allowed to cool and solidify.
Suitable carriers include magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin, dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, a low-melting wax, cocoa butter, and the like.
Some of the compounds of the present invention are capable of forming salts with various inorganic and organic acids and bases and such salts are also within the scope of this invention. Examples of such acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate,
sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen- containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates like dimethyl, diethyl, dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; aralkyl halides like benzyl bromide and others. Non-toxic physiologically-acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.
In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment (including prophylactic treatment) of mammals including humans, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
In addition to the compounds of the present invention, the pharmaceutical composition of this invention may also contain, or be co-administered (simultaneously or sequentially) with, one or more pharmacological agents of value in treating one or more disease conditions referred to herein.
The term composition is intended to include the formulation of the active component or a pharmaceutically acceptable salt with a pharmaceutically acceptable carrier. For example this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions, suspensions, emulsions, creams, ointments, gels, nasal sprays, suppositories, finely divided powders or aerosols or nebulisers for inhalation, and for parenteral use (including intravenous, intramuscular or infusion) sterile aqueous or oily solutions or suspensions or sterile emulsions.
Liquid form compositions include solutions, suspensions, and emulsions. Sterile water or water-propylene glycol solutions of the active compounds may be mentioned as an example of liquid preparations suitable for parenteral administration. Liquid compositions can
also be formulated in solution in aqueous polyethylene glycol solution. Aqueous solutions for oral administration can be prepared by dissolving the active component in water and adding suitable colorants, flavoring agents, stabilizers, and thickening agents as desired. Aqueous suspensions for oral use can be made by dispersing the finely divided active component in water together with a viscous material such as natural synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, and other suspending agents known to the pharmaceutical formulation art.
The pharmaceutical compositions can be in unit dosage form. In such form, the composition is divided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of the preparations, for example, packeted tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, cachet, or tablet itself, or it can be the appropriate number of any of these packaged forms.
According to a further aspect of the present invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a method of treatment of the human or animal body by therapy.
We have found that the compounds defined in the present invention, or a pharmaceutically acceptable salt thereof, are effective anti-cancer agents which property is believed to arise from their Edg-1 antagonistic properties. Accordingly the compounds of the present invention are expected to be useful in the treatment of diseases or medical conditions mediated alone or in part by Edg-1, i.e. the compounds may be used to produce an Edg-1 antagonistic effect in a warm-blooded animal in need of such treatment.
Thus the compounds of the present invention provide a method for treating cancer characterized by the antagonistic effect of Edg-1, i.e. the compounds may be used to produce an anti-cancer effect mediated alone or in part by the antagonistic effect of Edg-1.
Thus the compounds of the present invention provide a method for treating a variety of angiogenesis-related diseases that may be characterized by any abnormal, undesirable or pathological angiogenesis, for example tumor-related angiogenesis. The compounds may be used to produce an anti-cancer effect mediated alone or in part by antagonism of Edg-1.
Such a compound of the invention is expected to possess a wide range of activity in angiogenesis-related diseases including, but not limited to, non-solid tumors such as leukemia, multiple myeloma, hematologic malignancies or lymphoma, and also solid tumors and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular
(liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostrate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, esophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumors.
Excessive vascular growth also contributes to numerous non-neoplastic disorders for which the compounds of the invention may be useful in treating. These non-neoplastic angiogenesis-related diseases include: atherosclerosis, haemangioma, haemangioendothelioma, angiofibroma, vascular malformations (e.g. Hereditary Hemorrhagic Teleangiectasia (HHT), or Osier- Weber syndrome), warts, pyogenic granulomas, excessive hair growth, Kaposis' sarcoma, scar keloids, allergic oedema, psoriasis, dysfunctional uterine bleeding, follicular cysts, ovarian hyperstimulation, endometriosis, respiratory distress, ascites, peritoneal sclerosis in dialysis patients, adhesion formation result from abdominal surgery, obesity, rheumatoid arthritis, synovitis, osteomyelitis, pannus growth, osteophyte, hemophilic joints, inflammatory and infectious processes (e.g. hepatitis, pneumonia, glomerulonephritis), asthma, nasal polyps, liver regeneration, pulmonary hypertension, retinopathy of prematurity, diabetic retinopathy, age-related macular degeneration., leukomalacia, neovascular glaucoma, corneal graft neovascularization, trachoma, thyroiditis, thyroid enlargement, and lymphoproliferative disorders.
Thus according to this aspect of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use as a medicament.
According to a further aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of a Edg-1 antagonistic effect in a warm-blooded animal such as man.
According to this aspect of the invention there is provided the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
According to a further feature of the invention, there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in the manufacture of a medicament for use in the treatment of pathologically angiogenic diseases,
thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations or infections in a warm-blooded animal such as man.
According to a further feature of this aspect of the invention there is provided a method for producing a Edg-1 antagonistic effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
According to a further feature of this aspect of the invention there is provided a method for producing an anti-cancer effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined above.
According to an additional feature of this aspect of the invention there is provided a method of treating pathologically angiogenic diseases, thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations or infections, in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined herein before.
In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of a Edg-1 antagonistic effect in a warm-blooded animal such as man.
In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
In a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as defined herein before in association with a pharmaceutically-acceptable diluent or carrier for use in the treatment of pathologically angiogenic diseases, thrombosis, cardiac infarction, coronary heart diseases, arteriosclerosis, tumors, osteoporosis, inflammations or infections in a warm-blooded animal such as man.
The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or
chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents:
1. antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); anti-tumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
2. cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), oestrogen receptor down regulators (for example fulvestrant), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride;
3. agents which inhibit cancer cell invasion (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
4. inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (for example the anti-erbb2 antibody trastuzumab [Herceptin™] and the anti-erbbl antibody cetuximab [C225]) , farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD 1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro- 4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;
5. antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, (for example the anti-vascular endothelial cell growth factor antibody bevacizumab [Avastin™], compounds such as those disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and compounds that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin);
6. vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;
7. antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense;
8. gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and
9. immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies.
Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range. Biological Activity
The following assay can be used to measure the effects of the compounds of the present invention as SlPl/Edgl inhibitors.
In Vitro Cell Based Receptor Activation Assay-Transfluor Assay
This cell-based assay was designed to assess the ability of small molecule antagonists to inhibit activation of the GPCR SlPl in the presence of its cognate ligand SlP. The assay used technology initially developed by Norak Biosciences (Xsira Pharmaceutical) and
presently owned by Molecular Devices. A human osteogenic sarcoma (U2OS) cell line overexpressing the Edg-1 /SlPl) receptor as well as a beta-arrestin/green fluorescent protein (GFP) construct hereafter termed Edg-1 Transfluor U2OS WT Clone #37 was employed.
Using a high content screening approach (Cellomics Arrayscan), receptor activity was measured by assessment of the relocalization of beta-arrestin GFP in response to stimulation of Edg-1 by SlP. Specifically, Edg-1 Transfluor U2OS WT Clone #37 cells were plated at a density of 6250 cells in 40 μL medium per well in 384 well plastic bottomed microtiter plates (BD Falcon) and incubated overnight at 37°C/5% CO2. Prior to screening, compounds were dissolved in 100% dimethyl sulfoxide (DMSO) to a final stock concentration of 10 mM. Compounds were then serially diluted at 3OX final concentration in Edg-1 Transfluor cell growth medium containing 30% DMSO using the Tecan Genesis instrument. These 30X plates were then diluted to 6X final concentration with Edg-1 Transfluor growth medium just prior to dosing. Cells were then dosed with 10 μL per well of 6X compound dilutions or 6% DMSO and pre-incubated for 15 minutes at room temperature. Cell plates were dosed with 10 μL per well 6X SlP Edg-1 Transfluor growth medium, then incubated for 45 minutes at 37°C/5% CO2. Final concentration in the well of DMSO was 1%, compound was IX (3-fold,
9 point IC50 dilutions starting at 100 μM final concentration), and either 375 nM or 750 nM SlP ligand. Cell plates were then fixed by adding 50 μL per well of 5% formaldehyde in IX Dulbecco's phosphate buffered saline (DPBS) directly and incubating for 30 minutes at room temperature in darkness. Fixative was removed and replaced with 50 μL per well of IX DPBS, after which cells were stained with 10 μg/mL final concentration of Hoechst 33342 (Molecular Probes) for 15 minutes at room temperature in darkness. Stain was then removed from the plates and replaced with 50 μL per well of IX DPBS using the BioTek ExL405 plate washer. Plates were then sealed and analysed on the Cellomics Arrayscan using the GPCR signalling algorithm. EC50 values were then calculated using IDBS ActivityBase software.
In this assay, compounds of the invention generally exhibit EC50 values <100 μM. For example, the compound of Example 11 exhibited an EC50 value of 1.17 uM; the compound of Example 5 exhibited an EC50 value of 0.240 uM; and the compound of Example
10 exhibited an EC50 value of 3.97 uM.
It should be understood that for compounds of formula (I) which possess a chiral center, when resolved into the individual enantiomers, generally only one of the enantiomers possesses activity in the above-described assay.
Percentage inhibition values were also calculated using IDBS ActivityBase software and are indicated for Examples 1-13 in the experimental section below. The % inhibition at a dose of 3.7μM is reported with the exception of Example 5 which was measured at 3.54μM. The differences in these absolute concentrations reflect differences in the top concentration for the corresponding dilution series. Hence, compounds listed as 3.7μM were titrated from a top concentration of lOOμM whereas the compound of Example 5 listed as 3.54μM was run with 3.54μM as the top concentration.
Examples
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (°C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25°C; (ii) organic solutions were dried over anhydrous sodium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30mmHg) with a bath temperature of up to 60 °C;
(iii) in general, the course of reactions was followed by TLC and/or LC-MS (liquid chromatography -mass spectrum) and reaction times are given for illustration only; (iv) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data;
(v) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; (vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 400 MHz using deuterated solvent as indicated; (vii) chemical symbols have their usual meanings; SI units and symbols are used; (viii) solvent ratios are given in volume: volume (v/v) terms; and (ix) mass spectra were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is (M/Z);
(x) where a synthesis is described as being analogous to that described in a previous example the amounts used are the millimolar ratio equivalents to those used in the previous example; and
(xi) the following abbreviations have been used:
THF tetrahydrofuran;
DMF N, 7V-dimethy lformamide;
EtOAc ethyl acetate;
RT room temperature;
DCM dichloromethane ;
DMSO dimethylsulphoxide;
AcOH or HOAc Acetic acid;
NaH Sodium hydride;
MgSO4 Magnesium sulfate;
EtOH Ethanol;
Et3N Triethylamine;
LDA Lithium diisopropyl amide;
LiHMDS Lithium hexamethyldisilazide
MeCN Acetonitrile;
Ti(OiPr)4 Titanium Isopropoxide;
CuCN Copper cyanide;
«-BuLi normal-Butyl lithium;
Boc-Phe-OCH3 tert-Butyloxy phenylalanine methyl ester;
Selectfluor l-(Chloromethyl)-4-Fluoro-l,4-Diazoniabicyclo[2.2.2]Octane
Bis(Trifluromethanesulfonate);
Boc-Ala-OH t-Butyloxycarbonyl-alanine;
PyBOP Benzotriazole- 1 -yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate ;
(PPh3)2PdCl2 trαn5-Dichlorobis(triphenylphosphine)palladium(II)
POCl3 Phosphorus Oxychloride
N(Et)3 triethylamine
TEA triethylamine; and
DIEA diisopropyl ethylamine.
Non-commercial sulfonyl chlorides were prepared as outlined below in the experimental section.
Example 1
4-chloro-ΛMl-(l-ethyl-l/f-indol-2-v0ethyllbenzenesulfonamide
A 25 mL round bottom flask was charged with 1 -ethyl- 1 H- indole-2-carbaldehyde (Intermediate 1, 210 mg, 1.21 mmol), 4-chlorobenzenesulfonamide (264 mg, 1.38 mmol), and CH2Cl2 (4.0 mL). Ti(OZPr)4 (360 μL, 1.22 mmol) was added, and the resulting mixture was allowed to stir at room temperature for 90 min. The volatile components were removed in vacuo, and the resulting residue was dissolved in anhydrous THF (4.0 mL). The solution was cooled to 0 °C, and then methyl magnesium chloride (3.0 M in THF; 2.50 mL, 7.50 mmol) was added dropwise. After 90 min, the reaction was quenched with glacial AcOH (1.0 mL). EtOAc and H2O were added, forming a gelatinous reaction mixture. This was suction- filtered through a pad of diatomaceous earth, which was thoroughly washed with EtOAc and H2O. The filtrate layers were separated, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 80:20 hexanes:EtOAc = 0.32) to give a colorless solid (243 mg, 55%). 1H NMR (400 MHz, DMSO-d6) δ 1.20 (t, J=7.20 Hz, 3 H) 1.30 (d, J=6.57 Hz, 3 H) 4.11 - 4.22 (m, 2 H) 4.65 - 4.76 (m, 1 H) 6.29 (s, 1 H) 6.97 (m, 1 H) 7.09 (m, 1 H) 7.35 (m, 1 H) 7.43 (m, 1 H) 7.51 - 7.59 (m, 2 H) 7.72 - 7.82 (m, 2 H) 8.29 (m, 1 H). M/Z = 362. 85.69 % inhibition at 3.70 μM
The compounds of Examples 2 and 3 were prepared by a procedure analogous to that of Example 1, using the Intermediate (INT) indicated in Table 1 and prepared hereinafter.
TABLE 1
Example 4 4-Chloro-ΛMl-(3-cvano-l-ethyl-l/y-indol-2-ylkthyllbenzenesulfonamide
Example 4 was prepared starting from example 3 as described below: A test tube equipped with a stir bar was charged with N-[l-(3-bromo-l-ethyl-lH-indol-2- yl)ethyl]-4-chlorobenzenesulfonamide (Example 3, 238 mg, 0.54 mmol), CuCN (157 mg, 1.75 mmol), and anhydrous DMF (1.0 mL). The resulting mixture was heated at 140°C for 53 h. On cooling, the mixture was diluted with EtOAc (10 mL) and was filtered through a plug of diatomaceous earth. The filtrate was concentrated, and the residual oil was purified by silica gel chromatography (gradient elution; Rf in 70:30 hexanes:EtOAc = 0.26) to give a
yellow oil. Lyophilization afforded the title compound as a pale yellow solid (74 mg, 35%). 1H NMR (400 MHz, DMSO-D6) δ 1.27 (t, J=7.20 Hz, 3 H) 1.49 (d, J=7.07 Hz, 3 H) 4.17 - 4.27 (m, 1 H) 4.27 - 4.37 (m, 1 H) 4.74 (m, 1 H) 7.23 (m, 1 H) 7.30 (m, 1 H) 7.47 (m, 2 H) 7.51 (s, 1 H) 7.56 (m, 1 H) 7.63 - 7.70 (m, 2 H) 8.79 (m, 1 H). M/Z =387. 70.84 % inhibition at 3.70 μM
Example 5 iy-H-fS-EthylpyrazoloH^-glpyridin-l-vDethyll^-methvIbenzenesulfonamide
A 50 mL round bottom flask was charged with tert-butyl [l-(3-ethylpyrazolo[l,5-α]pyridin-2- yl)ethyl]carbamate (Intermediate 4, 122 mg, 0.42 mmol) and 4N HCl/dioxane (5 mL). The resulting solution was allowed to stir at room temperature overnight. The volatile components were then removed in vacuo, and the residue was treated with Et3N (700 μL, 5.0 mmol) and CH2Cl2 (5 mL). 4-Chlorobenzenesulfonyl chloride (123 mg, 0.58 mmol) was added, and the reaction was allowed to stir at room temperature for 90 min. The mixture was then partitioned between CH2Cl2 and H2O, and the aqueous layer was further extracted with CH2Cl2. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 60:40 hexanes:EtOAc = 0.40) to give a colorless to pale yellow solid (113 mg, 74%). 1H NMR (400 MHz, DMSO-d6) δ 1.05 (t, J=7.58 Hz, 3 H) 1.38 (d, J=7.07 Hz, 3 H) 2.50 - 2.60 (m, 2 H) 4.55 - 4.66 (m, 1 H) 6.74 (m, 1 H) 7.00 - 7.11 (m, 1 H) 7.33 (m, 2 H) 7.45 (m, 1 H) 7.52 - 7.59 (m, 2 H) 8.28 (m, 1 H) 8.34 (m, 1 H). M/Z = 363. 88.24 % inhibition at 3.54 μM
The compounds of Examples 6 - 10 were prepared by a procedure analogous to that of Example 5, using the Intermediate (INT) indicated in Table 2 and prepared hereinafter.
TABLE 2
Example 11
4-Chloro-iV-[l-(3-ethyl-4,5,6J-tetrahvdropyrazolofl,5-fllpyridin-2- vDethyll benzenesulfonamide
An oven dried 50 mL round-bottom flask was evacuated while hot and was allowed to cool under N2. The flask was charged with anhydrous diisopropylamine (0.22 mL, 1.57 mmol) and anhydrous THF (3.0 mL). The solution was cooled to 0 °C, and then H-BuLi (2.5 M in hexanes; 0.60 mL, 1.50 mmol) was added dropwise. The solution was allowed to stir at 0 0C
for 30 min and was then cooled to -78 °C. Meanwhile, a separate oven-dried 25 mL round bottom flask was evacuated while hot and was allowed to cool under N2. The flask was charged with 4-chloro-N-(l-methyl-2-oxopentyl)benzenesulfonamide (Intermediate 5, 149 mg, 0.51 mmol), and was evacuated and back filled with N2. Anhydrous THF (1.0 mL) was added, and the resulting solution was added dropwise to a cold solution of LDA. This mixture was allowed to stir at -78 °C for 40 min. Meanwhile, a separate oven-dried 25 mL round bottom flask was evacuated while hot and was allowed to cool under N2. The flask was charged with l-(5-chloropentanoyl)-lH-imidazole (Intermediate 6, 141 mg, 0.76 mmol) and was evacuated and backfilled with N2. Anhydrous TΗF (1.0 mL) was added, and this solution was added dropwise to the cold enolate solution. After 1 h at -78 °C, the reaction was quenched with AcOH (0.2 mL) and was allowed to warm to room temperature. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was further extracted with EtOAc. The combined organics were washed with H2O, brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 70:30 hexanes:EtOAc = 0.57) to give a viscous oil that was contaminated with unreacted starting ketone (138 mg total). This material was dissolved in MeOH (3.0 mL) and was treated with hydrazine monohydrate (65 μl, 1.34 mmol). The solution was allowed to stir at room temperature for 4 h and was then treated with K2CO3 (362 mg, 2.62 mmol) and was heated to reflux. After heating overnight, the MeOH was removed in vacuo. The residue was partitioned between CH2Cl2 and H2O, and the aqueous layer was further extracted with CH2Cl2. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. The crude solid was recrystallized from EtOH/EtOAc to give a colorless solid (25 mg, 13% over 2 steps). 1H NMR (400 MHz, DMSO-d6) δ 0.89 (t, J=7.58 Hz, 2 H) 1.26 (d, J=6.82 Hz, 2 H) 1.67 (m, 2 H) 1.83 (m, 2 H) 2.07 - 2.19 (m, 2 H) 2.42 (m, 2 H) 3.68 (m, 1 H) 3.78 - 3.87 (m, 1 H) 4.36 (m, 1 H) 7.47 - 7.51 (m, 2 H) 7.51 - 7.56 (m, 2 H) 8.05 (m, 1 H). M/Z=367. 75.03 % inhibition at 3.70 μM
Example 12
4-ChIoI-Q-AM l-(3-ethyl-4,5,6,7-tetrahvdropyrazolo[l,5-alpyrimidin-2-yl)-2- phenylethyl I benzenesulfonam itle
A test tube equipped with a stir bar was charged with tert-Butyl [l-(5-amino-4-ethyl-lH- pyrazol-3-yl)-2-phenylethyl]carbamate (Intermediate 12, 210 mg, 0.64 mmol), Cs2CO3 (592 mg, 1.82 mmol), 1,3-dibromopropane (130 μL, 1.28 mmol), and anhydrous DMF (1.5 mL). The mixture was heated at 80 °C for 24 hours, and was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc, and the combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 20:80 hexanes:EtOAc = 0.38) to give a pale yellow foam (34 mg, 14%). This was subsequently dissolved in 4N HCl/dioxane (1.5 mL) and the solution was allowed to stir for 1.5 hours. At this point, the reaction was concentrated under reduced pressure, and the residue was treated with NEt3 (200 μL, 1.4 mmol), CH2Cl2 (3 mL), and 4-chlorobenzenesulfonyl chloride (30 mg, 0.14 mmol). After the reaction had stirred for 1 h, the reaction was partitioned between CH2Cl2 and H2O. The aqueous phase was extracted with CH2Cl2, and the combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 20:80 hexanes:EtOAc = 0.48) to give an oil. This was lyophilized (MeCN/H2O) to give colorless solid (26 mg, 63%). 1H NMR (400 MHz, DMSO-d6) δ 0.70 (t, 3 H) 1.88 - 1.92 (m, 2 H) 1.92 - 1.99 (m, 2 H) 2.91 (d, 2 H) 3.03 (m, 2 H) 3.62 (m, 1 H) 3.77 (m, 1 H) 4.27 - 4.37 (m, 1 H) 5.42 (broad s, 1 H) 7.07 - 7.15 (m, 3 H) 7.17 - 7.21 (m, 2 H) 7.39 - 7.50 (m, 4 H) 8.15 (s, 1 H). M/Z =445. 41.19 % inhibition at 3.70 μM
Example 13
4-Chloro-7V-[l-(3-ethylpyrazolo[l,5-fllpyrimidin-2-yl)-2-phenylethyll benzenesulfonamide
A round-bottom flask was charged with tert-Butyl [l-(5-amino-4-ethyl-lH-pyrazol-3-yl)-2- phenylethyl]carbamate (Intermediate 12, 257 mg, 0.78 mmol), 1,1,3,3-tetramethoxypropane (510 μL, 3.10 mmol), and THF (3 mL). The solution was treated with 4N HCl/dioxane solution (2 mL) and was allowed to stir at room temperature for 1 hour. At this point, the volatile components were removed under reduced pressure, and the residue was treated with Et3N (1.00 mL, 7.2 mmol) and CH2Cl2 (5 mL). 4-Chlorobenzenesulfonyl chloride (423 mg, 2.00 mmol) was added, and the mixture was allowed to stir at room temperature for 1 hour. The reaction was then partitioned between CH2Cl2 and H2O. The aqueous phase was extracted with CH2Cl2, and the combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 70:30 hexanes:EtOAc = 0.08) to give a pale yellow solid (58.5 mg, 17%) of 90% purity. 1H NMR (400 MHz, DMSO-D6) δ 0.83 (t, 3 H) 2.38 - 2.49 (m, 2 H) 3.08 - 3.19 (m, 2 H) 4.68 (m, 1 H) 6.89 (m, 1 H) 7.02 - 7.08 (m, 2 H) 7.10 - 7.15 (m, 2 H) 7.15 - 7.20 (m, 2 H) 7.33 - 7.43 (m, 2 H) 8.36 (m, 1 H) 8.61 (m, 1 H) 8.76 (m, 1 H). M/Z = 440. 90.9 % inhibition at 3.54 μM
Example 14
N-(lR-(l-Ethyl-6-(trifluoromethyl)-lH-pyrrolo[3,2-c]pyridin-2-yl)ethyl)-4- fluorobenzenesulfonamide
A round bottom flask was charged with l-(l-ethyl-6-(trifluoromethyl)-lH-pyrrolo[3,2- c]pyridin-2-yl)ethanamine (INT 13, 207 mg, 0.80 mmols)), CH2CI2 (5 mL per mmol
substrate), and NEt3 (0.5 mL, 3.59 mmols). The solution was treated with 4- flourophenylsulfonyl chloride (197 mg, 1.01 mmols) and allowed to stir at room temperature until reaction was complete by TLC or LC analysis. The mixture was concentrated under reduced pressure, and the residue purified by silica gel chromatography (R/ 0.32, 40% ethyl acetate in hexanes) to give the desired product as a racemic mixture.(0.239 mg, 72%) The enantiomers are resolved by chiral SFC using AD-H 4.6x100 column with 20% isopropanol in CO2 at the flow rate of 5 mL/min. The active enantiomer was identified based on its activity in the biological assay. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.23 (t, J=7.20 Hz, 3 H) 1.34 (d, J=6.82 Hz, 3 H) 4.27 - 4.37 (m, 2 H) 4.71 - 4.83 (m, 1 H) 6.59 (s, 1 H) 7.22 - 7.33 (m, 2 H) 7.76 (m, 2 H) 7.97 (m, 1 H) 8.42 (m, 1 H) 8.82 (m, 1 H). M/Z = 415.
Examples 15 -17, listed in Table 3, were made using a procedure similar to that for Example 14 but using the intermediates indicated.
TABLE 3
l-Ethyl-l//-indoIe-2-carbaldehyde
An oven-dried 250 mL round-bottom flask was evacuated while hot and was allowed to cool under N2. The flask was charged with 1 -ethyl- lH-indole (Starting Material 1, 2.90 g, 19.97 mmol) and was evacuated and back-filled with N2. Anhydrous TΗF (30 mL) was added and the solution was cooled to 0 °C. ra-BuLi (2.5 M in hexanes; 10.0 mL, 25.0 mmol) was added dropwise and the resulting solution was allowed to warm to room temperature. After 90 min, the solution was cooled to -78 °C and was treated with anhydrous DMF (2.50 mL, 32.3 mmol) dropwise. The mixture was allowed to stir at -78 °C for 1 hour and was then quenched with aqueous NaHCO3 before warming to room temperature. The mixture was
partitioned between EtOAc and H2O, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 95:5 hexanes:EtOAc = 0.39) to give a pale yellow solid (2.51 g, 73%). IH NMR (400 MHz, CDCl3) δ ppm 1.38 (t, J=7.07 Hz, 3 H) 4.60 (q, J=7.07 Hz, 2 H) 7.13 - 7.20 (m, 1 H) 7.24 (s, 1 H) 7.38 - 7.46 (m, 2 H) 7.73 (m, 1 H) 9.87 (s, 1 H). M/Z 173.
Intermediate 2 l-Ethyl-3-fluoro-l//-indole-2-carbaldehyde
A 50 mL round bottom flask was charged with 1 -ethyl- 1 H- indole-2-carbaldehyde (Intermediate 1, 524 mg, 3.03 mmol) and Selectfluor (1.29 g, 3.64 mmol). MeCN (6.0 mL) was added, and the mixture was allowed to stir at room temperature. After 90 min, the solvent was removed in vacuo, and the residue was partitioned between EtOAc and H2O, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 95:5 hexanes:EtOAc = 0.42) to give a colorless solid (191 mg, 33%) of 90% purity (remainder is unreacted starting material). 1H NMR (400 MHz, CDCl3) δ 1.31 - 1.39 (m, 3 H) 4.52 (q, J=7.07 Hz, 2 H) 7.16 (m, 1 H) 7.34 (m, 1 H) 7.38 - 7.45 (m, 1 H) 7.70 (m, 1 H) 10.08 (s, 1 H). M/Z 191.
Intermediate 3 3-Bromo-l-ethyl-l/y-indole-2-carbaldehvde
A 250 mL round bottom flask containing 1 -ethyl- lH-indole-2-carbaldehyde (Intermediate 1, 1.34 g, 7.74 mmol) was charged with CH2Cl2 (10 mL). N-bromosuccinimide (1.58 g, 8.88 mmol) was added, and the reaction was allowed to stir at room temperature for 3h. The
mixture was then partitioned between CH2Cl2 and H2O. The aqueous layer was further extracted with CH2Cl2, and the combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The crude solid material was purified by silica gel chromatography (gradient elution; Rf in 95:5 hexanes:EtOAc = 0.40) to give a pink oil that solidified on standing (1.56 g, 80%) of 90% purity. This was used without further purification. M/Z 252.
Intermediate 4
A 100 mL round bottom flask containing tert-butyl (l-methyl-2-oxo-3-pyridin-2- ylpentyl)carbamate (Starting Material 2, 309 mg, 1.06 mmol) was charged with O-(2,4- dinitrophenyl)hydroxylamine (prepared as described in J Org. Chem. 2003, 68, 7119; 251 mg, 1.26 mmol) and MeCN (5 mL). The resulting mixture was heated to reflux overnight. On cooling, the solvent was removed in vacuo and the residue was partitioned between CH2Cl2 and saturated aqueous NaHCO3. The aqueous layer was further extracted with CH2Cl2, and the combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The crude solid material was purified by silica gel chromatography (gradient elution; Rf in 80:20 hexanes:EtOAc = 0.37) to give a colorless solid (131 mg, 43%). 1H NMR (400 MHz, DMSO-d6) δ 1.08 - 1.19 (m, 3 H) 1.35 (s, 9 H) 1.42 (d, J=7.07 Hz, 3 H) 2.70 (m, 2 H) 4.92 (m, 1 H) 6.74 (m, 1 H) 7.05 - 7.13 (m, 1 H) 7.18 (m, 1 H) 7.54 (m, 1 H) 8.51 (m, 1 H). M/Z=289.
Intermediate 5 4-Chloro-iV-(l-inethyl-2-oxopentyl)benzenesuIfonamide
0 1 1 under N2. The flask was charged with N -[(4-chlorophenyl)sulfonyl]-/V -methoxy-N - methylalaninamide (Starting material 3, 3.13 g, 10.20 mmol) and was evacuated and backfilled with N2. Anhydrous THF (20 mL) was added, and the solution was cooled to 0 °C. n- Propyl magnesium chloride (2.0 M in diethyl ether; 12.0 mL, 24.0 mmol) was added drop wise, and the solution was slowly allowed to warm to room temperature. After stirring at room temperature overnight, the reaction was quenched with saturated aqueous NH4Cl (5 mL). The mixture was partitioned between EtOAc and H2O, and the aqueous layer was further extracted with EtOAc. The combined organics were washed with H2O, brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 70:30 hexanes:EtOAc = 0.36) to give a pale yellow solid (1.99 g, 67%). 1H NMR (400 MHz, CDCl3) δ 0.79 (t, J=7.45 Hz, 3 H) 1.34 (d, J=7.33 Hz, 3 H) 1.42 - 1.53 (m, 2 H) 2.23 (m, 1 H) 2.42 (m, 1 H) 3.88 - 3.96 (m, 1 H) 5.61 (m, 1 H) 7.45 (m, 2 H) 7.76 (m, 2 H). M/Z=289.
Intermediate 6
1 -(5-ChIo ropen tanovD- IH-im idazole
A 50 mL round bottom flask was charged with imidazole (420 mg, 6.17 mmol) and was evacuated and back-filled with N2. Anhydrous THF (3.0 mL) was added, and the resulting solution was treated with 5-chlorovaleroyl chloride (390 μL, 3.02 mmol). After stirring at room temperature overnight, the slurry was diluted with a few mL Of CH2Cl2 and was filtered through a pad of MgSO4. The filtrate was concentrated to a colorless oil that solidified on standing (552 mg, 98%). 1H NMR (400 MHz, CDCl3) δ 1.87 - 1.99 (m, 4 H) 2.91 (t, J=7.07 Hz, 2 H) 3.58 (t, J=6.19 Hz, 2 H) 7.08 (s, 1 H) 7.46 (s, 1 H) 8.16 (s, 1 H).
Intermediate 7 tert-But\l [l-(7-ethyl-2J-dihvdropyrazolo[5J-61[131oxazol-6-v0ethyl1earbamate
A 25 ml round bottom flask was charged with tert-Butyl [l-(4-ethyl-5-oxo-2,5-dihydro-l//- pyrazol-3-yl)ethyl]carbamate (Starting Material 4, 209 mg, 0.82 mmol), K2CO3 (468 mg, 3.39 mmol), and anhydrous DMF (3.0 mL). 1,2 Dibromoethane (140 μL, 1.62 mmol) was added, and the reaction was placed in an 80 °C oil bath. After heating overnight, LC-MS analysis indicated incomplete conversion of the starting pyrazolone. The reaction was allowed to cool and was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organics were washed with H2O, brine, dried (MgSO4), filtered, and concentrated. The oil thus obtained was resubjected to the reaction conditions (474 mg, K2CO3, 210 μL 1,2-dibromoethane, 3.0 mL DMF, 80 °C overnight) before repeating the aqueous workup described above. The crude oil was purified by silica gel chromatography (Rf in 95:5 CH2Cl2:Me0H = 0.30) to give a colorless oil (239 mg, M/Z 281) that contained some residual DMF. This was used without further purification.
Intermediates 8 - 10 were prepared in an analogous manner to that described for Intermediate 7 using ter/-Butyl 3-(4-ethyl-5-oxo-2,5-dihydro-lH-pyrazol-3-yl)-4- phenylbutanoate (Starting material 5) instead of Starting Material 4 and the halide indicated in Table 3.
TABLE 3
Intermediate 11 ter/-ButvUl-(3-methoxy-6,7-dihvdro-5H-pyrazolo[5,l-6in<31oxazin-2- vDethyll carbamate
A 50 niL round bottom flask containing Methyl 4-[(tørt-butoxycarbonyl)amino]-4,5-dideoxy- 2-O-methylpent-3-ulosonate (Starting Material 6, 279 mg, 1.01 mmol) was treated with MeOH (3 mL). The resulting solution was treated with hydrazine monohydrate (200 μL, 4.12 mmol), and was allowed to stir at room temperature for 7 hours. The volatile components were evaporated, and the crude residue was treated with Cs2CO3 (1.16 g, 3.56 mmol), 1,3-
dibromopropane (400 μL, 3.94 mmol) and anhydrous DMF (3 mL). The suspension was heated at 80 °C for 24 hours, at which point the reaction was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc, and the combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. This material was used without further purification.
Intermediate 12 tert-Butyl fl-(5-amino-4-ethyl-l//-pyrazol-3-vD-2-phenylethyllearbamate
A 50 mL round-bottom flask was charged with tert-butyl (l-benzyl-3-cyano-2- oxopentyl)carbamate (Starting Material 7, 1.07 g, 3.38 mmol) and absolute EtOH (10 mL). Hydrazine monohydrate (330 μL, 6.80 mmol) was added and the reaction was heated at reflux for 15 hours. On cooling, the solvent was removed under vacuum and the residue was purified by silica gel chromatography (gradient elution; Rf in 90:10 CH2Cl2:Me0H = 0.29) to give a colorless oil (641 mg, 57%). M/Z = 330. 1H NMR (400 MHz, DMSO-d6) δ 0.81 (t, 3 H) 1.28 (s, 9 H) 2.10 - 2.22 (m, 2 H) 2.93 (m, 2 H) 4.27 (broad s, 2 H) 4.63 - 4.74 (m, 1 H) 6.92 (s, 1 H) 7.11 - 7.24 (m, 5 H) 10.90 (s, 1 H). Intermediate 13 l-(l-Ethyl-6-(trifluoromethyl)-lH-pyrrolof3,2-clpyridin-2-vnethanamine
A 250 mL round bottom flask containing 2-(l-azidoethyl)-l-ethyl-6-(trifluoromethyl)-lH- pyrrolo[3,2-c]pyridine (Starting Material 8, 0.939 g, 3.32 mmol) was charged with 10% Pd/C (143 mg), and the flask was evacuated and backfilled with H2 via a filled balloon. Absolute
EtOH (12 mL) was added, and the reaction was allowed to stir at room temperature under 1 atm H2. After 1 hour total, the reaction was concentrated under reduced pressure and was
diluted with CH2CI2 (10 niL). The mixture was suction-filtered through a pad of diatomaceous earth, and the reaction flask and filter were thoroughly washed with Ct^C^-
The combined filtrates were concentrated to a grey-colored solid. M/Z = 257. This material was used directly without further purification. Starting Material 1 1-Ethyl-ljy-indole
A 250 mL round bottom flask was charged with indole (4.71 g, 40.2 mmol). Anhydrous DMF (30 mL) was added, and the resulting solution was cooled to 0 °C. NaH (60% dispersion in mineral oil; 1.95 g, 48.8 mmol) was cautiously added in small portions (gas evolution), followed by additional DMF (10 mL). The resulting slurry was allowed to stir at 0 0C for 15 min, and then ethyl iodide (4.80 mL, 60.0 mmol) was added. The reaction was allowed to slowly warm to room temperature overnight. The mixture was then partitioned between EtOAc and H2O, and the aqueous layer was further extracted with EtOAc (2 times). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (hexanes as eluent; Rf = 0.31) to give a pale yellow oil (5.51 g, 94%). 1H NMR (400 MHz, CDC13) δ 1.59 (t, J=7.33 Hz, 3 H) 4.30 (q, J=7.33 Hz, 2 H) 6.63 (m, 1 H) 7.21 - 7.26 (m, 2 H) 7.30 - 7.37 (m, 1 H) 7.48 (m, 1 H) 7.77 (m, 1 H). M/Z=145.
Starting Material 2 fer/-Butyl (l-methyl-2-oxo-3-pyridin-2-ylpentyl)carbamate
An oven-dried 50 mL round bottom flask was evacuated while hot and was allowed to cool under N2. The flask was charged with 2-«-propylpyridine (0.60 mL, 2.26 mmol) and anhydrous THF (6 mL). The solution was cooled to 0 °C, and rø-BuLi (2.5 M in hexanes; 1.80 mL, 4.50 mmol) was added drop wise, forming a dark red solution. This was allowed to stir
at to 0 °C, for 30 min. Meanwhile, a separate 50 mL round-bottom flask was evacuated while hot and was allowed to cool under N2. The flask was charged with JV-methyl-N-methoxy-2- [(ter/-butoxycarbonyl)amino]-propanamide (prepared as described in J Org. Chem. 2001, 66, 3613; 464 mg, 2.00 mmol), was evacuated and back-filled with N2, and was treated with anhydrous THF (3.0 mL). The resulting suspension was cooled to -78 °C, and the solution of lithiated pyridine was added dropwise. Additional THF (2 x 0.5 mL) was used to transfer remaining lithiated pyridine, and the mixture was allowed to stir at -78 °C for 1.5 h prior to being quenched with glacial HOAc (0.5 mL) and warming to room temperature. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was further extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 70:30 hexanes:EtOAc = 0.28) to give a yellow oil (489 mg, 84%). M/Z=292. IH NMR was complex, suggesting a mixture of keto/enol tautomers and/or enol E/Z isomers. This material was used without further purification.
Starting Material 3 iV--[(4-Chlorophenvπsulfonyll-7V--inethoxy-Λ^-methylalaninamide
A 250 mL round bottom flask containing iV-[(4-chlorophenyl)sulfonyl]alanyl chloride (Starting Material 4b, 32.9 mmol) was charged with N,O-dimethylhydroxylamine hydrochloride (3.94 g, 40.39 mmol) and CH2Cl2 (70 mL). The suspension was cooled to 0 0C, and then Et3N (12.0 mL, 86.1 mmol) was added drop wise over 10 min. After slowly warming to room temperature over the course of 4 h, the mixture was partitioned between CH2Cl2 and H2O. The aqueous layer was further extracted with CH2Cl2, and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated. The crude material was recrystallized from MeOH to give a crystalline solid (6.79 g, 67%). 1H NMR (400 MHz, CDCl3) δ 1.31 (d, J=7.07 Hz, 3 H) 2.99 (s, 3 H) 3.58 (s, 3 H) 4.35 (m, 1 H) 5.55 (m, 1 H) 7.45 (m, 2 H) 7.77 (m, 2 H). M/Z = 306.
Starting Material 3b 7V-[(4-ChlorophenvDsulfonvHalanyl chloride
A 250 mL round bottom flask was charged with N-[(4-chlorophenyl)sulfonyl]alanine (Starting Material 3a prepared as described in Jack et al, J. Pharm. Sci.; 76; 2; 1987; 149- 152 8.69 g, 32.95 mmol) and SOCl2 (30 mL). The mixture was heated at 80 °C overnight. On cooling, the excess SOCl2 was removed under reduced pressure to give a solid material. The material was used without further purification. 1H NMR (400 MHz, CDCl3) δ 1.52 (d, J=7.33 Hz, 3 H) 4.34 (m, 1 H) 5.21 - 5.31 (m, 1 H) 7.50 (m, 2 H) 7.79 (m, 2 H).
Starting Material 4 tert-Butyl [l-(4-ethyl-5-oxo-2,5-dihvdro-l//-pyrazol-3-yl)ethyll carbamate
An oven-dried 250 mL round bottom flask was evacuated while hot and was allowed to cool under N2. The flask was twice further evacuated and back-filled with N2, and was charged
with anhydrous diisopropylamine (8.50 niL, 60.6 mmol) and anhydrous THF (60 mL). This solution was cooled to 0 0C and «-BuLi (2.5 M solution in hexanes; 24.0 mL, 60.0 mmol) was added drop wise. The resulting solution was allowed to stir at 0 °C for 30 min, and was then cooled to -78 °C. Isopropyl butyrate (9.10 mL, 60.0 mmol) was added drop wise and the resulting suspension was allowed to stir at -78 °C for 1 h. A separate, oven-dried 100 mL round bottom flask was evacuated and allowed to cool under N2. The flask was charged with racemic BOC-alanine (3.41 g, 18.02 mmol) and was evacuated and back-filled with N2. Anhydrous THF (20 mL) was added, and the resulting solution was treated with 1,1 '- carbonyldiimidazole (3.24 g, 20.0 mmol). This solution was allowed to stir at room temperature for 30 min and was then added drop wise to the cold suspension of the ester enolate. After an additional hour, the reaction was quenched with glacial AcOH (6.0 mL) and was allowed to warm to room temperature. The mixture was partitioned between EtOAc and H2O and the aqueous layer was further extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (Rf in 80:20 hexanes:EtOAc = 0.18) to give a colorless oil (3.95 g, 73%). 1H NMR (400 MHz, DMSO d6) δ 0.77 - 0.89 (m, 3 H) 1.12 - 1.23 (m, 9 H) 1.37 (d, 9 H) 1.63 - 1.74 (m, 2 H) 3.64 - 3.74 (m, 1 H) 4.06 - 4.17 (m, 1 H) 4.88 (dt, 6.28 Hz, 1 H) 7.29 (d, 1 H). M/Z=301. Starting Material 5 fer/-ButvI 3-(4-ethyl-5-oxo-2,5-dihvdro-l/-r-pyrazol-3-yl)-4-phenylbutanoate
A 100 mL round bottom flask was charged with 6-tert-Butyl 1 -ethyl 4-benzyl-2-ethyl-3- oxohexanedioate (Starting Material 6a, 1.48 g, 4.07 mmol) and MeOH (15 mL). Hydrazine monohydrate (1.00 mL, 20.6 mmol) was added, and the solution was allowed to stir at room temperature overnight. MeOH and excess hydrazine were removed in vacuo, and the residue was partitioned between CH2Cl2 and H2O. The aqueous layer was further extracted with CH2Cl2 and the combined organics were washed with brine, dried (MgSO4), filtered, and concentrated to give a viscous oil (1.03 g, 76%). This was used without further purification.
Starting Material 5a
6-tert-Butyl 1-ethyl 4-benzyl-2-ethyl-3-oxohexanedioate
An oven dried 250 mL round bottom flask was evacuated while hot and was allowed to cool under N2. The flask was charged with anhydrous diisopropylamine (4.30 mL, 30.7 mmol) and anhydrous THF (30 mL). The solution was cooled to 0 °C, and then H-BuLi (2.5 M in hexanes; 12.0 mL, 30.0 mmol) was added drop wise. The solution was allowed to stir at 0 0C for 30 min and was then cooled to -78 °C. Ethyl butyrate (4.00 mL, 30.1 mmol) was added drop wise, and the solution was allowed to stir at -78 °C for 1 h. Meanwhile, a separate oven- dried 100 mL round-bottom flask was evacuated while hot and was allowed to cool under N2. The flask was charged with racemic BOC-Phe-OH (2.66 g, 10.0 mmol) and 1,1'- carbonyldiimidazole (1.77 g, 10.9 mmol). The flask was evacuated and backfilled with N2, and anhydrous THF (15 mL) was added. The resulting solution was allowed to stir at room temperature for 25 min, and was then added drop wise to the cold enolate solution. This mixture was then allowed to stir at -78 °C for 25 min before being quenched with glacial HOAc (3.5 mL). Upon warming, the reaction was partitioned between EtOAc and H2O and the aqueous layer was further extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 90:10 hexanes:EtOAc = 0.16) to give a colorless oil (2.75 g, 75%). 1H NMR is complex due to keto-enol tautomers as well as enol E/Z isomers. M/Z=363.
Starting material 6
Methyl 4-[(fer^butoxycarbonvOaminol-4,5-dideoxy-2-0-methylDent-3-ulosonate
An oven-dried round bottom flask was evacuated while hot and was allowed to cool under N2. The flask was charged with anhydrous THF (40 mL), and was cooled to -78 °C. «-BuLi (2.5 M solution in hexanes, 20.0 mL, 50.0 mmol) was added. The resulting cold solution was treated drop wise with butyronitrile (4.40 mL, 50.6 mmol) and this mixture was allowed to stir at -78 0C for 1 hour. At this point, BOC-Phe-OMe (4.34 g, 15.5 mmol) was added, and the resulting mixture was allowed to warm to - 50 °C. After 90 min at this temperature, the reaction was quenched with glacial AcOH, and was allowed to warm to room temperature. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was further extracted with EtOAc. The combined organics were washed with brine, dried (MgSO4),
filtered, and concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 80:20 hexanes:EtOAc = 0.35) to give a pale yellow oil that crystallized on standing (3.90 g, 79%). By 1H NMR, appears to be a ~2:1 mixture of tautomers (keto and enol). 1H NMR for major tautomer: 1H NMR (400 MHz, CDCl3) δ 1.03 (m, 3 H) 1.39 (s, 9 H) 1.81 - 1.89 (m, 1 H) 1.90 - 1.97 (m, 1 H) 2.90 - 3.00 (m, 1 H) 3.12 (m, 1 H) 3.39 (m, 1 H) 4.58 (m, 1 H) 5.01 (m, 1 H) 7.17 - 7.36 (m, 5 H). M/Z = 316.
Starting Material 8 l-(l-Ethyl-6-rtrifluoromethyl)-lH-pyrrolo[3,2-clpyridin-2-vnethanol:
A 250 niL round bottom flask containing crude 4-(4-(ethylamino)-6-(trifluoromethyl)pyridin- 3-yl)but-3-yn-2-ol (Starting Material 8b, 1.18 g, 4.56 mmol) was charged with CH2Cl2 (15 mL), THF (5 mL), and 3,4-dihydro-2H-pyran (2.40 mL, 26.3 mmol), resulting in a homogeneous solution. p-TsOH*H2O (94 mg, 11 mol%) was added, and the reaction was allowed to stir at room temperature.
After stirring overnight, the volatile components were evaporated under reduced pressure, and the residue was dissolved in THF (15 mL). Potassium t-butoxide (671 mg, 6.0 mmol) was added, and the resulting dark solution was allowed to stir at room temperature. After 90 minutes, the reaction was quenched with saturated NH4CI (aq), and the mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted with EtOAc, and the combined organics were concentrated to a brown oil.
The crude material was dissoved in MeOH (15 mL), and the solution was treated with /7- toluenesulfonic acid monohydrate (90 mg, 10.4 mol%), and the reaction was allowed to stir at 60 °C for 48 hours. The acid catalyst was quenched with NEtβ (-0.5 mL), and the mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient elution; Rf in 60:40 hexanes:EtOAc = 0.27) to give a colorless to pale yellow solid (930 mg, 79% over 2 steps from starting material 8c). M/Z = 258. 1H NMR
(400 MHz, DMSO-D6) δ ppm 1.30 (t, J=7.07 Hz, 3 H) 1.55 (d, J=6.32 Hz, 3 H) 4.35 - 4.47 (m, 2 H) 4.99 (m, 1 H) 5.48 (d, J=6.32 Hz, 1 H) 6.65 (s, 1 H) 8.03 (s, 1 H) 8.88 (s, 1 H).
Starting material 8b 4-(4-(EthyIamino)-6-(trifluoromethyI)pyridin-3-yl)but-3-yn-2-oI:
A 250 mL roundbottom flask containing N-ethyl-5-iodo-2-(trifluoromethyl)pyridin-4-amine (Starting Material 8c, 1.44 g, 4.56 mmol) was charged with (PPh3^PdCl2 (64 mg, 2.0 mol%) and CuI (95 mg, 10.9 mol%). The flask was evacuated and backfilled with N2 (2x), and anhydrous MeCN (10 mL) was added. The orange solution was treated with but-3-yn-2-ol (0.80 mL,10.2 mmol) and DIPEA (1.75 mL, 10.1 mmol), forming a bright yellow heterogeneous suspension. Additional MeCN (5 mL) was added, and the mixture was placed in an 80 0C oil bath, quickly becoming a dark brown solution. After 2 hours, the reaction was allowed to cool and the volatiles were evaporated under reduced pressure. The residue was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried (MgSO^, filtered, and concentrated to a grey/brown solid. M/Z =: 258. This material was used directly.
Starting material 8c N-Ethyl-5-iodo-2-(trifluoromethyl)pyridin-4-amine:
A 500 mL roundbottom flask containing 5-iodo-2-(trifluoromethyl)pyridin-4-ol (Starting Material 8d, 2.74 g, 9.48 mmol) was charged with POCI3 (15 mL), and the resulting mixture was placed in a 100 0C oil bath. After 90 minutes, the reaction was allowed to cool and the
POCI3 was evaporated under reduced pressure. The residue was treated with crushed ice, and then was carefully quenched with K2CO3 until basic. The mixture was extracted with EtOAc
(2x), and the combined organics were concentrated in vacuo to give a brown oil. This was dissolved in DMF (10 mL) and the solution was treated with aqueous ethylamine (70%; 3.2 mL, 40.3 mmol). The resulting mixture was placed in a 100 0C oil bath. After 90 minutes, the reaction was allowed to cool and was diluted with H2O (40 mL). The mixture was extracted with EtOAc (2x), and the combined organics were concentrated. The crude material was purified by silica gel chromatography (gradient elution; Rf in 90 : 10 hexanes:EtOAc =
0.29) to give a pale yellow solid (1.66 g, 55%). M/Z = 316. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.13 (t, J=7.07 Hz, 3 H) 3.33 (m, 2 H) 6.29 (m, 1 H) 6.84 (s, 1 H) 8.53 (s, 1 H).
Starting material 8d 5-Iodo-2-(trifluoromethyl)pyridin-4-ol:
A 250 mL round bottom flask was charged 2-(trifluoromethyl)pyridin-4-ol (prepared as described in Tyvorskii, V. I., Bobrov, D. N. Chemistry of Heterocyclic Compounds 1997, 33, 1138-9; 42.7 mmol). MeOH (45 mL) was added, and the solution was cooled to 0 0C. Potassium carbonate (6.55 g, 47.4 mmol) was added, and the resulting mixture was treated with iodine (11.37 g, 44.8 mmol) in portions over 5 minutes. The resulting mixture was allowed to stir at 0 0C, with slow warming to room temperature. After stirring at room temperature overnight, the reaction was quenched with aqueous NaS2θ3, was acidifed with
HOAc (10 mL), and was extracted with EtOAc (4x). The combined organics were washed with brine, concentrated, and purified by silica gel chromatography (gradient elution; Rf in
70:30 hexanes:EtOAc = 0.30) to give a pale yellow solid (2.74 g, 22%) of -90% purity. M/Z = 288. 1H NMR (400 MHz, DMSO-D6) δ ppm 7.19 (m, 1 H) 8.80 (m, 1 H) 12.43 (s, 1 H).
Preparation of non-commercial sulfonyl chlorides (SC): SC l:
A 250 mL round bottom flask was charged with water (30 mL) and cooled to 0 0C. Thionyl chloride (6.0 mL, 82.3 mmol) was added dropwise over a period of 2 hours. The mixture was slowly allowed to warm to room temperature overnight. CuCl (72 mg, 0.73 mmol) was added, and the yellow solution cooled to 0 0C. Meanwhile, a separate 100 mL round bottom flask was charged with 5-aminopyridine-2-carbonitrile (1.78 g, 15.0 mmol) and concentrated HCl (20 mL). The solution was cooled to 0 0C, and then a solution of sodium nitrite (1.49 g, 21.6 mmol) in H^O (15 mL) was added dropwise over 10 minutes. This mixture was allowed to stir at 0 0C for an additional 15 minutes, and then added dropwise (keeping the bulk of the diazonium mixture at 0 0C) to the water/thionyl chloride solution over 10 minutes. After 1 hour at 0 0C, the mixture was extracted with CH2CI2 (2x), and the combined organics were washed with brine, dried (MgSC^), filtered, and concentrated to give the sulfonyl chloride which wasused without any further purification. 1H NMR (CDCl3) δ ppm 7.97 (m, 1 H) 8.45 -
8.52 (m, 1 H) 9.32 (m, 1 H)
SC 2:
6-Carbamoyl-pyridine-3-sulfonyl chloride
O n
JTTSCI
NH2
Thionyl chloride (31.4 mL, 0.47 mol) was added to water (182 mL) at O0C over a period of Ih maintaining the reaction temperature below 50C. The reaction mixture was allowed to warm to 180C over a period of 2Oh. To this mixture was added copper (I) chloride (0.14 g, 0.001 mol) and the resulting yellow-green solution was cooled to -50C. In parallel, 5-amino-2- cyano pyridine (10.0 g, 0.08 mol) was dissolved slowing in concentrated HCl (98 mL) and allowed to stir at room temperature over the weekend. To this mixture was added dropwise over a period of Ih a solution Of NaNO2 (8.2 g, 0.12 mol) in water (50 mL), maintaining the
reaction temperature at -50C. This slurry was then added dropwise over a period of Ih to the above mixture (thionyl chloride/water mixture), maintaining temperature between -5 and O0C. (Note: the diazotized mixture should be kept below -50C through out the addition). As the addition proceeded, a white solid precipitated. The reaction mixture was stirred for an additional hour below 0 0C. The precipitate was collected by filtration, washed with cold water and dried under vacuum to afford the title compound as light yellow solid (5.1 g, 27%). 1H NMR (300 MHz, DMSOd6) δ ppm 9.20 (s, 1 H), 8.48 (s, 2 H), 7.82 (bs, 1 H), 5.87 (bs, 1 H)
Claims
1. A compound of formula (I) :
(I) wherein:
Ring A is carbocyclyl or heterocyclyl; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R7;
R1 is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-όalkoxy, C1-6alkanoyl, Ci-6alkanoyloxy, TV-(C i-6alkyl)amino, N,/V-(C1-6alkyl)2amino, Ci-6alkanoylamino, 7V-(Ci-6alkyl)carbamoyl, /V,/V-(Ci-6alkyl)2carbamoyl, Ci-6alkylS(O)a wherein a is 0 to 2, Ci-6alkoxycarbonyl, /V-(Ci-6alkyl)sulphamoyl, iV,iV-(Ci-6alkyl)2sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl, heterocyclyl; wherein R1 may be optionally substituted on carbon by one or more R8; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from
R9; n is 0-5; wherein the values of R1 may be the same or different;
R2 is selected from Ci-6alkyl, C2-6alkenyl or C2-6alkynyl, carbocyclyl or heterocyclyl; wherein R2 may be optionally substituted on carbon by one or more R10; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R11;
R3 is selected from hydrogen, Ci-6alkyl, C2-6alkenyl or C2-6alkynyl; wherein R3 may be optionally substituted on carbon by one or more R12; wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R13;
R4 is absent or selected from hydrogen, Chalky I or carbocyclyl; wherein R4 may be optionally substituted on carbon by one or more R14;
X and Y are independently selected from CH, C or N;
Ring B is a 5-membered ring and is a single or double bond; Ring D is fused to Ring B of formula (I) and is a 5-7 membered ring; wherein if said ring contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R15;
R5 is a substituent on carbon or nitrogen and is independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy, Ci-6alkanoyl, 
TV-(C i-6alkyl)amino, 7V,iV-(Ci.6alkyl)2amino, Ci-6alkanoylamino, N-(Ci -6alkyl)carbamoyl, N,N-(Ci-6alkyl)2carbamoyl, Chalky IS(O)3 wherein a is 0 to 2, Ci-6alkoxycarbonyl, N-(Ci-6alkyl)sulphamoyl, N,N-(Ci-6alkyl)2Sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R5 may be optionally substituted on carbon by one or more R16; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R17; m is 0-5; wherein the values of R5 may be the same or different;
R6 is selected from hydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy, Ci-6alkanoyl, Ci-6alkanoyloxy, JV-(C i-6alkyl)amino, N,N-(Ci-6alkyl)2amino, Ci-6alkanoylamino, N-(Ci-6alkyl)carbamoyl, N,./V-(Ci-6alkyi)2carbamoyl, Ci-6alkylS(O)a wherein a is 0 to 2, Ci-6alkoxycarbonyl, N-(Ci-6alkyl)sulphamoyl, N,iV-(Ci.6alkyl)2sulphamoyl or Ci-6alkylsulphonylamino; wherein R may be optionally substituted on carbon by one or more R18;
R8, R14, R16 and R18 are independently selected from halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, Ci-6alkyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy, Ci-6alkanoyl, Ci-6alkanoyloxy, JV-(C i-6alkyl)amino, N,N-(Ci-6alkyl)2amino, Ci-6alkanoylamino, N-(Ci-6alkyi)carbamoyl, ΛζN-(Ci-6alkyl)2carbamoyl, C i-6alky IS(O)3 wherein a is 0 to 2, Ci-6alkoxycarbonyl, N-(Ci -6alkyl)sulphamoyl,
N, N-(C i-6alky I)2 sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R8, R14, R16 and R18 may be independently optionally substituted on carbon by one or more R20; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R21;
R10 and R12 are independently selected from halo, nitro, cyano, hydroxy, amino, carbamoyl, mercapto, sulphamoyl, C2-6alkenyl, C2-6alkynyl, Ci-6alkoxy, Ci-6alkanoyl, Ci-όalkanoyloxy, N-(Ci-6alkyl)amino, N,N-(Ci-6alkyl)2amino, Ci.6alkanoylamino, N-(Ci-6alkyl)carbamoyl, N,N-(Ci-6alkyl)2carbamoyl, Ci-6alkylS(O)a wherein a is 0 to 2, N-(Ci-6alkyl)sulphamoyl, N,N-(Ci.6alkyl)2sulphamoyl, Ci-6alkylsulphonylamino, carbocyclyl or heterocyclyl; wherein R10 and R12 may be independently optionally substituted on carbon by one or more R22; and wherein if said heterocyclyl contains an -NH- moiety that nitrogen may be optionally substituted by a group selected from R23;
R7, R9, R11, R13, R15, R17, R19, R21 and R23 are independently selected from C,-6alkyl, Ci-6alkanoyl, Ci-6alkylsulphonyl, Ci-6alkoxycarbonyl, carbamoyl, benzyl, benzyloxycarbonyl, benzoyl and phenylsulphonyl;
R20 and R22 are independently selected from halo, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, carboxy, carbamoyl, mercapto, sulphamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl, ethylsulphonyl, methoxycarbonyl, ethoxy carbonyl, N-methylsulphamoyl, N-ethylsulphamoyl, N,N-dimethylsulphamoyl, N,N-diethylsulphamoyl or N-methyl-N-ethylsulphamoyl; or a pharmaceutically acceptable salt thereof; with the proviso that said compound is not:
4-chloro-N-[2,2,2-trichloro- 1 -( 1 ,3-dimethyl- 1 ,4,5,6,7,8-hexahydrocyclohepta[6]pyrrol-2- yl)ethyl]benzenesulfonamide;
4-chloro-N-[2,2,2-trichloro- 1 -( 1 -methyl- 1 ,4,5,6,7,8-hexahydrocyclohepta[6]pyrrol-2- yl)ethyl]benzenesulfonamide;
4-chloro-iV-[2,2,2-trichloro-l-(l-methyl-4,5,6,7-tetrahydro-lH-indol-2- yl)ethyl]benzenesulfonamide;
4-methyl-N-[l-(3-methyl-lH-indol-2-yl)ethyl]benzenesulfonamide; N-[l-(lH-inden-2-yl)ethyl]-4-nitrobenzenesulfonamide; N-[I-(I H-inden-2-yl)ethyl]-4-methylbenzenesulfonamide;
N- [ 1 -(2,3 -dihydro- 1 H- inden-2-y l)-2-hydroxy ethyl] -5 -chlorothiophene-2-sulfonamide; or N-[(3-methyl-lH-indol-2-yl)(phenyl)methyl]pyridine-2-sulfonamide.
2. A compound of formula (I) according to claim 1 having formula (Ia) 
(Ia) wherein R3 is hydrogen and A, B, D, R1, R2, R4, R5, R6, m and n are as defined in claim 1, and pharmaceutically acceptable salts thereof.
3. A compound according to claim 1 or 2 wherein Ring A is phenyl or pyridinyl.
4. A compound of formula (I) according to claim 1 selected from 4-chloro-iV-[ 1 -( 1 -ethyl- 1 H-indol-2-yl)ethyl]benzenesulfonamide; 4-chloro-N- [ 1 -( 1 -ethy 1-3 -fluoro- 1 H-indol-2-y l)ethy 1] benzenesulfonam ide ; N-[l-(3-Bromo-l-ethyl-lH-indol-2-yl)ethyl]-4-chlorobenzenesulfon-amide; 4-Chloro-N-[ 1 -(3-cyano- 1 -ethyl- lH-indol-2-yl)ethyl]benzenesulfonamide; N-[l-(3-Ethylpyrazolo[l,5-α]pyridin-2-yl)ethyl]-4-methylbenzenesulfonamide; 4-Chloro-iV-[l-(7-ethyl-2,3-dihydropyrazolo[5,l-ό][l,3]oxazol-6- yl)ethyl]benzenesulfonamide;
4-Chloro-N-[ 1 -(3-ethyl-6,7-dihydro-5H-pyrazolo[5, 1 -b] [ 1 ,3]oxazin-2- yl)ethyl]benzenesulfonamide;
4-Chloro-N-[l-(3-ethyl-6,7-dihydro-5H-pyrazolo[5,l-6][l,3]oxazin-2- yl)ethyl]benzenesulfonamide;
4-Chloro-N- [ 1 -(3 -ethyl-5 ,6,7,8-tetrahydropyrazolo [5 , 1 -b] [ 1 ,3 ]oxazepin-2-y l)-2- phenylethyljbenzenesulfonamide;
4-Chloro-N-[l-(3-methoxy-6,7-dihydro-5H-pyrazolo[5,l-6][l,3]oxazin-2- yl)ethyl]benzenesulfonamide;
4-Chloro-Λ/-[l-(3-ethyl-4,5,6,7-tetrahydropyrazolo[l,5-α]pyridin-2- yl)ethyl]benzenesulfonamide;
4-Chloro-jV-[l-(3-ethyl-4,5,6,7-tetrahydropyrazolo[l,5-α]pyrimidin-2-yl)-2- pheny lethy 1] benzenesulfonamide ;
4-Chloro-iV-[l-(3-ethylpyrazolo[l,5-α]pyrimidin-2-yl)-2-phenylethyl] benzenesulfonamide; N-(I-(I -Ethyl-6-(trifluoromethy I)- 1 H-pyrrolo [3 ,2-c]pyridin-2-y l)ethyl)-4- fluorobenzenesulfonamide;
4-Cyano-N-( 1 -(I -ethyl-6-(trifluoromethyl)- 1 H-pyrrolo [3, 2-c]pyridin-2- yl)ethyl)benzenesulfonamide;
6-Cyano-N-( 1 -( 1 -ethyl-6-(trifluoromethyl)- 1 H-pyrrolo [3 ,2-c]pyridin-2-y l)ethy l)pyridine-3 - sulfonamide;
5-(N-( 1 -(I -Ethyl-6-(trifluoromethyl)- 1 H-pyrrolo [3, 2-c]pyridin-2- yl)ethyl)sulfamoyl)picolinamide; and pharmaceutically acceptable salts thereof.
5. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any of the preceding claims in association with a pharmaceutically-acceptable carrier, diluent or excipient.
6. A compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 - 4 for use as a medicament.
7. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1 - 4 in the manufacture of a medicament for use in the production of a Edg-1 antagonistic effect in a warm-blooded animal such as man.
8. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1- 4 in the manufacture of a medicament for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
9. The use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1- 4 in the manufacture of a medicament for use in the treatment of angiogenesis-related diseases including, but not limited to, non-solid tumors such as leukemia, multiple myeloma, hematologic malignancies or lymphoma, and also solid tumors and their metastases such as melanoma, non-small cell lung cancer, glioma, hepatocellular carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostrate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, esophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumors.
10. A method for producing an Edg-1 antagonistic effect in a warm-blooded animal, such as man, which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1- 4.
11. A method for producing an anti-cancer effect in a warm-blooded animal, such as man, which comprises administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-4.
12. A method of treating of angiogenesis-related diseases including non-solid tumors, solid tumors and their metastases, non-small cell lung cancer, glioma, hepatocellular (liver) carcinoma, glioblastoma, carcinoma of the thyroid, bile duct, bone, gastric, brain/CNS, head and neck, hepatic, stomach, prostrate, breast, renal, testicular, ovarian, skin, cervical, lung, muscle, neuronal, esophageal, bladder, lung, uterine, vulval, endometrial, kidney, colorectal, pancreatic, pleural/peritoneal membranes, salivary gland, and epidermoid tumors, in a warm-blooded animal in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1- 4.
13. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1- 4, in association with a pharmaceutically-acceptable carrier, diluent or excipient for use in the production of a Edg-1 antagonistic effect in a warm-blooded animal such as man.
14. A pharmaceutical composition which comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1- 4, in association with a pharmaceutically-acceptable carrier, diluent or excipient for use in the production of an anti-cancer effect in a warm-blooded animal such as man.
15. Processes for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 1 , wherein the variables are, unless otherwise specified, as defined in claim 1 , which processes comprise Process a) reacting compounds of formula (IV), (V) and (VI):
(IV)
(V)
R2-M-Z (VI) wherein:
M is a metal atom, for example Mg;
Z is a halo, for example Cl or Br and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt; or
Process b) reacting a compound of formula (II):
(H) with an amine of formula (III):
(III) wherein
L is a displaceable group, for example, halo e.g. chloro or bromo, and thereafter if necessary: i) converting a compound of the formula (I) into another compound of the formula (I); ii) removing any protecting groups; iii) forming a pharmaceutically acceptable salt.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86635306P | 2006-11-17 | 2006-11-17 | |
| US60/866,353 | 2006-11-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2008059238A1 true WO2008059238A1 (en) | 2008-05-22 |
Family
ID=38962039
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2007/004342 WO2008059238A1 (en) | 2006-11-17 | 2007-11-15 | Benzenesulfonamide compounds as edg-1 antagonists useful in the treatment of cancer |
Country Status (1)
| Country | Link |
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| WO (1) | WO2008059238A1 (en) |
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| CN105732470A (en) * | 2016-03-23 | 2016-07-06 | 暨南大学 | Efficient preparation method of 3-fluoro-indol-2-carbonyl compound |
| EP3241830A1 (en) | 2016-05-04 | 2017-11-08 | Bayer CropScience Aktiengesellschaft | Condensed bicyclic heterocyclic derivatives as pesticides |
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| US8026240B2 (en) | 2007-09-11 | 2011-09-27 | Abbott Laboratories | Octahydro-pyrrolo[3,4-b]pyrrole N-oxides |
| CN105732470A (en) * | 2016-03-23 | 2016-07-06 | 暨南大学 | Efficient preparation method of 3-fluoro-indol-2-carbonyl compound |
| EP3241830A1 (en) | 2016-05-04 | 2017-11-08 | Bayer CropScience Aktiengesellschaft | Condensed bicyclic heterocyclic derivatives as pesticides |
| WO2018015289A1 (en) | 2016-07-19 | 2018-01-25 | Bayer Cropscience Aktiengesellschaft | Condensed bicyclic heterocycle derivatives as pest control agents |
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