NZ619685B2 - [1,2,4]thiadiazine 1,1-dioxide compounds for lowering serum uric acid - Google Patents
[1,2,4]thiadiazine 1,1-dioxide compounds for lowering serum uric acid Download PDFInfo
- Publication number
- NZ619685B2 NZ619685B2 NZ619685A NZ61968512A NZ619685B2 NZ 619685 B2 NZ619685 B2 NZ 619685B2 NZ 619685 A NZ619685 A NZ 619685A NZ 61968512 A NZ61968512 A NZ 61968512A NZ 619685 B2 NZ619685 B2 NZ 619685B2
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- New Zealand
- Prior art keywords
- mmol
- dihydro
- dioxo
- fluoro
- benzo
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- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
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- 125000000524 functional group Chemical group 0.000 description 1
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- 239000007897 gelcap Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960004275 glycolic acid Drugs 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-M heptanoate Chemical class CCCCCCC([O-])=O MNWFXJYAOYHMED-UHFFFAOYSA-M 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002757 inflammatory Effects 0.000 description 1
- 230000002452 interceptive Effects 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 239000003456 ion exchange resin Substances 0.000 description 1
- 229920003303 ion-exchange polymer Polymers 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- KQNPFQTWMSNSAP-UHFFFAOYSA-M isobutyrate Chemical class CC(C)C([O-])=O KQNPFQTWMSNSAP-UHFFFAOYSA-M 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000003893 lactate salts Chemical class 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 230000001665 lethal Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 239000006194 liquid suspension Substances 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 150000002690 malonic acid derivatives Chemical class 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- PWHULOQIROXLJO-UHFFFAOYSA-N manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 239000011572 manganese Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 125000005341 metaphosphate group Chemical group 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 1
- HKLDTKMTZPXEAZ-DTWKUNHWSA-N methyl (1R,4S)-4-[(2-methylpropan-2-yl)oxycarbonylamino]cyclopent-2-ene-1-carboxylate Chemical compound COC(=O)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C=C1 HKLDTKMTZPXEAZ-DTWKUNHWSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 239000007932 molded tablet Substances 0.000 description 1
- YNAVUWVOSKDBBP-UHFFFAOYSA-N morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 1
- 229940113083 morpholine Drugs 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 230000037125 natural defense Effects 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 239000002687 nonaqueous vehicle Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- KREXGRSOTUKPLX-UHFFFAOYSA-N octadecanoic acid;zinc Chemical compound [Zn].CCCCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O KREXGRSOTUKPLX-UHFFFAOYSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000002997 ophthalmic solution Substances 0.000 description 1
- 230000003287 optical Effects 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 150000003891 oxalate salts Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- HXNFUBHNUDHIGC-UHFFFAOYSA-N oxoallopurinol Chemical compound O=C1NC(=O)N=C2NNC=C21 HXNFUBHNUDHIGC-UHFFFAOYSA-N 0.000 description 1
- 239000006174 pH buffer Substances 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-L phosphate Chemical class OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 125000005498 phthalate group Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000223 polyglycerol Chemical class 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- KCXFHTAICRTXLI-UHFFFAOYSA-M propane-1-sulfonate Chemical class CCCS([O-])(=O)=O KCXFHTAICRTXLI-UHFFFAOYSA-M 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical class CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- UORVCLMRJXCDCP-UHFFFAOYSA-M propynoate Chemical class [O-]C(=O)C#C UORVCLMRJXCDCP-UHFFFAOYSA-M 0.000 description 1
- 230000004144 purine metabolism Effects 0.000 description 1
- 230000001698 pyrogenic Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 229960001886 rilonacept Drugs 0.000 description 1
- 108010046141 rilonacept Proteins 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical class OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- CXMXRPHRNRROMY-UHFFFAOYSA-L sebacate(2-) Chemical class [O-]C(=O)CCCCCCCCC([O-])=O CXMXRPHRNRROMY-UHFFFAOYSA-L 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 230000003248 secreting Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- RHLFTMGPBSLHRS-UHFFFAOYSA-M sodium;2-phenylbutanoate Chemical class [Na+].CCC(C([O-])=O)C1=CC=CC=C1 RHLFTMGPBSLHRS-UHFFFAOYSA-M 0.000 description 1
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 1
- GYBMSOFSBPZKCX-UHFFFAOYSA-N sodium;ethanol;ethanolate Chemical compound [Na+].CCO.CC[O-] GYBMSOFSBPZKCX-UHFFFAOYSA-N 0.000 description 1
- 239000007905 soft elastic gelatin capsule Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 125000003003 spiro group Chemical group 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- TYFQFVWCELRYAO-UHFFFAOYSA-L suberate(2-) Chemical class [O-]C(=O)CCCCCCC([O-])=O TYFQFVWCELRYAO-UHFFFAOYSA-L 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003871 sulfonates Chemical class 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000002600 sunflower oil Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002195 synergetic Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 238000004450 types of analysis Methods 0.000 description 1
- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 239000008136 water-miscible vehicle Substances 0.000 description 1
- GDJZZWYLFXAGFH-UHFFFAOYSA-M xylenesulfonate group Chemical group C1(C(C=CC=C1)C)(C)S(=O)(=O)[O-] GDJZZWYLFXAGFH-UHFFFAOYSA-M 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- AEMOLEFTQBMNLQ-QIUUJYRFSA-N β-D-glucuronic acid Chemical compound O[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-QIUUJYRFSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/04—Drugs for disorders of the urinary system for urolithiasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
Abstract
Disclosed herein are [1,2,4]thiadiazine 1,1-dioxide compounds for example N-{3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-azatricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1-benzo[1,2,4]thiadiazin-7-ylmethyl}-methane sulfonamide and pharmaceutically acceptable salts thereof and their use in the manufacture of medicaments for treatment of hyperuricemia and gout. their use in the manufacture of medicaments for treatment of hyperuricemia and gout.
Description
WO 20121170536
[1,2,4]THIADIAZINE l,l-DIOXIDE COMPOUNDS FOR LOWERING
SERUM URIC ACID
FIELD OF THE INVENTION
The invention provides [1,2,4 ]thiadiazine 1, I-dioxide compounds and
pharmaceutical compositions containing such compounds, useful for lowering serum
uric acid and treating or preventing diseases such as hyperuricemia, gout,
inflammation disease, urinary urolithiasis, reperfusion disease, renal dysfunction,
tumor lysis syndrome, hypertension and cardiovascular disease.
BACKGROUND OF THE INVENTION
An abnormal increase in blood uric acid level, i.e., hyperuricemia, is a
disorder that has close relation to gout, renal dysfunction, urolithiasis, etc. (Diagnosis
and Treatment, 220-224, 244-248 (2002)). It is known that, in organ transplantation
(Ren. Fail., 361-7 (2002)) or chemotherapy for cancer (Am. 1. Health Syst. Pharm.,
2213-22 (2003)), serum uric acid levels increase significantly, thereby causing renal
dysfunction, or in the case of chemotherapy, serum uric acid levels increase
of cellular destruction (tumor lysis syndrome).
significantly due to the rapid amount
Hyperuricemia is a condition or disorder that precedes gout, resulting
from increased production or decreased excretion of uric acid, or from a combination
of the two processes. In an individual with hyperuricemia, plasma and extracellular
fluids are supersaturated with urate, and crystal deposition in tissue is likely to occur,
resulting in the clinical manifestations of gout. When crystals form in the joints it
causes recurring attacks of joint inflammation. Chronic gout can also lead to deposits
of hard lumps of uric acid in and around the joints and may cause joint destruction
and decreased kidney function.
An agent for treating hyperuricemia may be roughly classified into an
or an uric acid synthesis inhibitor. The uricosuric agent may be
uricosuric agent
ineffective for cases whose renal function has lowered, and therefore allopurinol, an
uric acid synthesis inhibitor, is suitably used for patients having a lowered renal
function.
Xanthine oxidase is an enzyme that controls the biosynthesis of uric acid, and
use of a xanthine oxidase inhibitor to inhibit this enzyme is an effective treatment of
hyperuricemia and various diseases caused thereby, as an uric acid synthesis inhibitor.
Allopurinol is the only xanthine oxidase inhibitor that has been put into practical use at
present for clinical treatment, though it is known to induce undesirable side effects.
SUMMARY OF THE INVENTION
The present invention describes [1,2,4]thiadiazine 1,1-dioxide compounds and
pharmaceutically acceptable salts thereof, which are useful in lowering serum uric acid in
a patient comprising administering to the patient a therapeutically effective amount of a
[1,2,4]thiadiazine 1,1-dioxide compound.
In a general aspect, the invention relates to the use of a compound of Formula
wherein
Ring B is
A is
II(a)
, or
II(b)
(9131610_1):JJP
11 12
Z is –(CR R ) –,
13 14
Y is –(CR R ) –,
n is 1 or 2,
m is 2 or 3,
R is H, –NH , or –(CH ) –NH–S(O) CH , wherein q is 0 or 1,
2 2 q 2 3
2 15 15
R is C -C alkyl, C -C cycloalkyl, aryl, or –(CH )–R , wherein R is
1 6 3 6 2
16 18
16 17 18 19 20
wherein R , R , R , R and R are independently H, C -C alkyl, hydroxy, or
halo,
3 4 5 6 7 8 9 10 11 12 13 14
R , R, R , R, R , R , R , R , R , R , R , and R are independently H or
C - alkyl,
wherein each alkyl, cycloalkyl, or aryl are optionally substituted by one or more
alkyl, hydroxyl, or halo substituents,
or a pharmaceutically acceptable salt, hydrate, solvate, tautomer or stereoisomer
thereof for preparing a medicament fort he treatment or prevention ofh yperuricemia or
gout.
A further aspect of the invention provides f or use of a compound or pharmaceutically
acceptable salt thereof selected from
N-{3-[(1R,2S,7R,8S)(4-Fluoro-benzyl)hydroxyoxoaza-
2,7 6
tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin
ylmethyl}-methanesulfonamide,
N-{3-[(1R,2S,7R,8S)(4-Fluoro-benzyl)hydroxyoxoaza-
2,7 6
tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin
yl}-methanesulfonamide,
(1R,2S,7R,8S)(1,1-Dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazinyl)(4-
fluoro-benzyl)hydroxyaza-tricyclo[6.2.1.0 ]undecenone,
(4aR,7aS)-N-{3-[1-(4-Fluoro-benzyl)hydroxyoxo-2,4a,5,6,7,7a-hexahydro-
1H-[1]pyrindinyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazinyl}-
methanesulfonamide,
(10812590_1):KZA
N-[3-(1R,2S,7R,8S)Cyclopentylhydroxyoxoaza-
2,7 6
tricyclo[6.2.1.0 ]undecenyl)-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin
yl]-methanesulfonamide,
(1R,2S,7R,8S)(7-Amino-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazinyl)-
3-(4-fluoro-benzyl)hydroxyaza-tricyclo[6.2.1.0 ]undecenone,
N-{3-[(1S,2R,7S,8R)(4-Fluoro-benzyl)hydroxyoxoaza-
2,7 6
tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin
yl}-methanesulfonamide,
(1R,2S,7R,8S)-N-{3-[3-(4-Fluoro-benzyl)hydroxyoxoaza-
2,7 6
tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -thieno[2,3-
e][1,2,4]thiadiazinylmethyl}-methanesulfonamide,
N-{3-[(2S,7R)(4-Fluoro-benzyl)hydroxyoxoaza-
2,7 6
tricyclo[6.2.2.0 ]dodecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin
yl}-methanesulfonamide,
N-{3-[(1S,2S,7R,8R)(4-Fluoro-benzyl)hydroxyoxoaza-
2,7 6
tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin
yl}-methanesulfonamide, and
N-{3-[(1R,2R,7S,8S)(4-Fluoro-benzyl)hydroxyoxoaza-
2,7 6
tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin
yl}-methanesulfonamide,
for preparing a medicament for the treatment or prevention hof yp eruricemia or
gout.
In one embodiment, the invention relates to the use of compounds of Formula I
as set out in the first aspect above wherein Ring B is
.
(10812590_1):KZA
In one embodiment, the invention relates to the use of compounds of Formula I
as set out in the first aspect above wherein q is 1 and Ring B is
In one embodiment, the invention relates to the use of compounds of Formula I
as set out in the first aspect above wherein R is H.
In one embodiment, the invention relates to a method of using compounds of
2 15 15
Formula I wherein R is –(CH )–R and R is selected from
(10812590_1):KZA
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,and F
In one embodiment, the invention relates to a method of using
compounds of Formula I wherein q is O.
In one embodiment, the invention relates to a method of using
compounds of Formula I wherein n is 1.
In one embodiment, the invention relates to a method of using
compounds of Formula I wherein q is 0 and n is 1.
In one embodiment, the invention relates to a method of using
3 4 5 6 7 8 9 10 11 12 13 14
compounds of Formula I wheren R , R , R , R , R , R , R ,R ,R ,R ,R ,and R
areH.
In one embodiment, the invention relates to a method of using
compounds of Formula I wherein R 16, R 17, R 18, R 19, and R 20 are independently H,
methyl, or halo.
In one embodiment, the invention relates to a method of using
compounds of Formula I wherein R 16, R 17, R 18, R 19, and R 20 are independently H or
halo.
In one embodiment, the invention relates to a method of using
compounds of Formula I wherein R 18 is fluro and R 16, R 17, R 19, and R 20 are H.
In one embodiment, the invention relates to a method of using
compounds of Formula I wherein
q is 0 and n is 1,
3 4 5 6 7 8 9 10 11 12 13 14
R , R , R , R , R , R , R ,R ,R ,R ,R ,and Rare H, and
16 17 18 19 20
R , R , R , R , and R are independently H or halo.
In another embodiment, the invention relates to compounds selected
from
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N- {3-[ (lR,2S,7 R,SS)( 4-Fluoro-benzy 1)hydroxyoxoaza
tricyc1o[6.2.1.02.7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[1,2,4]thiadiazin-7 -ylmethyl} -methane sulfonamide,
N- {3-[ (lR,2S,7 R,SS)( 4-Fluoro-benzy 1)hydroxyoxoaza
tricyc1o[6.2.1.02.7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[1,2,4]thiadiazin-7 -yl} -methanesulfonamide,
(lR,2S,7 R,SS)(1, 1-Dioxo-1 ,4-dihydro-l"A -benzo[l ,2,4]thiadiazinyl)
(4-fluoro-benzyl)hydroxyaza-tricyc1o[ 6.2.1.02.7]undecenone,
(4aR,7aS)-N-{ 3-[1-( 4-Fluoro-benzyl)hydroxyoxo-2,4a,5,6,7 ,7a
hexahydro-1H-[1]pyrindinyl]-1, 1-dioxo-1 ,4-dihydro-lA -benzo[l ,2,4]thiadiazin
yl} -methanesulfonamide,
N-[3-(lR,2S,7R,SS)Cyc1opentylhydroxyoxoaza
tricyc1o[6.2.1.02.7]undecenyl)-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[ 1 ,2,4 ]thiadiazin-7 -yl]-methane sulfonamide,
(lR,2S,7 R,SS)(7 -Amino-1, 1-dioxo-1,4-dihydro-l"A -benzo[l ,2,4]thiadiazin-
3-y 1)( 4-fluoro-benzyl)hydroxyaza-tricyc1o[ 6.2.1.02.7]undecenone,
N- {3-[ (lS,2R,7 S,SR)( 4-Fluoro-benzy 1)hydroxyoxoaza
tricyc1o[6.2.1.02.7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[1,2,4]thiadiazin-7 -yl} -methanesulfonamide,
(lR,2S, 7 R,SS)-N- {3-[3-( 4-Fluoro-benzy 1)hydroxyoxoaza
tricyc1o[6.2.1.02.7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6 -thieno[2,3-
e] [1,2,4]thiadiazin-7 -ylmethyl }-methanesulfonamide,
N- {3-[ (2S,7 R)( 4-Fluoro-benzyl)hydroxyoxoaza
tricyc1o[6.2.2.02.7]dodecenyl]-1, 1-dioxo-1 ,4-dihydro-lA -benzo[l ,2,4]thiadiazinY 1 } -methanesulfonamide,
N- {3-[ (lS,2S, 7 R,SR)( 4-Fluoro-benzy 1)hydroxyoxoaza
tricyc1o[6.2.1.02.7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[1,2,4]thiadiazinyl}-methanesulfonamide, and
N- {3-[ (lR,2R, 7 S,SS)( 4-Fluoro-benzy 1)hydroxyoxoaza
tricyc1o[6.2.1.02.7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[1,2,4]thiadiazin-7 -yl} -methanesulfonamide,
or pharmaceutically acceptable salt thereof.
WO 20121170536
In one aspect, the invention encompasses a method for treating or
preventing hyperuricemia, gout, inflammation disease, urinary urolithiasis, a
reperfusion disease, renal dysfunction, tumor lysis syndrome, hypertension, or
cardiovascular disease, in a patient in need thereof, comprising administering to the
patient a therapeutically effective amount of a compound of Formula I and a
pharmaceutically acceptable excipient, carrier, or vehicle.
In another aspect, the invention encompasses a method for lowering
serum uric acid in a patient in need thereof, comprising administering to the patient a
therapeutically effective amount of a compound of Formula I and a pharmaceutically
acceptable excipient, carrier, or vehicle.
In another aspect, the invention encompasses a method for treating or
preventing a disease associated with an abnormality of plasma uric acid level selected
from hyperuricemic nephropathy and acute uric acid nephropathy.
In another aspect, the invention encompasses a method for treating or
preventing hyperuricemia, gout, inflammation disease, urinary urolithiasis, a
reperfusion disease, renal dysfunction, tumor lysis syndrome, hypertension, or
cardiovascular disease in a patient in need thereof, comprising administering to the
patient a therapeutically effective amount of a compound of Formula I and an
additional therapeutic agent.
DETAILED DESCRIPTION OF THE INVENTION
Where the following terms are used in this specification, they are used as
defined below:
The terms "comprising," "having" and "including" are used herein in
their open, non-limiting sense.
The term "Me" means methyl, "Et" means ethyl, and "Ac" means acetyl.
The term" alkyl", as used herein, unless otherwise indicated, includes 1-6
saturated monovalent hydrocarbon radicals having straight or branched moieties.
The term "cycloalkyl", as used herein, unless otherwise indicated refers to
a non-aromatic, saturated or partially saturated, monocyclic or fused, spiro or unfused
bicyclic or tricyclic hydrocarbon referred to herein containing a total of from 3 to 10
carbon atoms, preferably 5-8 ring carbon atoms. Exemplary cycloalkyls include
monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl,
WO 20121170536
cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Illustrative examples of
cycloalkyl are derived from, but not limited to, the following:
<J,D,Q,Q,O, O,,eb,
CO, CO, 0,0,0, CO,
tb,and IQ.
The term "aryl", as used herein, unless otherwise indicated, includes an
organic radical derived from an aromatic hydrocarbon by removal of one hydrogen,
and has from 6-14 carbon atoms in its ring system, such as phenyl or naphthyl.
The term "preventing" refers to the ability of a compound or composition
of the invention to prevent a disease identified herein in patients diagnosed as having
the disease or who are at risk of developing such disease. The term also encompasses
of the disease in patients who are already suffering
preventing further progression
from or have symptoms of such disease.
The term "patient" or "subject" means an animal (e.g., cow, horse,
sheep, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit, guinea pig, etc.) or a
mammal, including chimeric and transgenic animals and mammals. In the treatment
or prevention of, e.g., gout or hyperuricemia, the term "patient" or "subject"
preferably means a monkey, chimpanzee or a human, most preferably a human.
The term a "therapeutically effective amount" refers to an amount of the
compound of the invention sufficient to provide a benefit in the treatment or
prevention of, e.g., gout or hyperuricemia, to delay or minimize symptoms associated
with preventing gout or hyperuricemia, or to cure or ameliorate the disease or
infection or cause thereof. In particular, a therapeutically effective amount means an
amount sufficient to provide a therapeutic benefit in vivo. Used in connection with an
amount of a compound of the invention, the term preferably encompasses a non-toxic
amount that improves overall therapy, reduces or avoids symptoms or causes of
disease, or enhances the therapeutic efficacy of or synergies with another therapeutic
agent.
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The term "gout" refers to a group of disorders including inflammatory
arthritis, deposition of urate crystals in joints, deposition of urate crystals in renal
parenchyma, urolithiasis, and nephrolithiasis.
The term "in combination" refers to the use of more than one
prophylactic and/or therapeutic agents simultaneously or sequentially and in a manner
that their respective effects are additive or synergistic.
The term "treating" refers to:
(i) preventing a disease, disorder, or condition from occurring in an
animal that may be predisposed to the disease, disorder and/or condition, but has
not yet been diagnosed as having it;
(ii) inhibiting the disease, disorder, or condition, i.e., arresting its
development; and
(iii) relieving the disease, disorder, or condition, i.e., causing regression of
the disease, disorder, and/or condition.
The terms "R" and "S" indicate the specific stereochemical configuration
of a substituent at an asymmetric carbon atom in a chemical structure as drawn.
The term "rac" indicates that a compound is a racemate, which is defined
as an equimolar mixture of a pair of enantiomers. A "rac" compound does not exhibit
optical activity. The chemical name or formula of a racemate is distinguished from
those of the enantiomers by the prefix (±)- or rac- (or racem-) or by the symbols RS
and SR.
The terms "endo" and "exo" are descriptors of the relative orientation of
substituents attached to non-bridgehead atoms in a bicyclo[x.y.z]alkane (x:::: y > z > 0).
The terms "syn" and "anti" are descriptors of the relative orientation of
substituents attached to bridgehead atoms in a bicyclo[x.y.z]alkane (x:::: y > z> 0).
ant~. syn
[CHdz_1
~[~H2:-1
[CH 1_---,--- exo
2 y l
endo
The term "exo" is given to a substituent (e.g., Br attached to C-2 in the
example below) that is oriented towards the highest numbered bridge (z bridge, e.g.,
WO 20121170536
C-7 in example below); if the substituent is oriented away from the highest numbered
bridge it is given the description "endo".
The term "syn" is given to a substituent attached to the highest numbered
bridge (z bridge, e.g., F attached to C-7 in the example below) and is oriented towards
the lowest numbered bridge (x bridge, e.g., C-2 and C-3 in example below); if the
substituent is oriented away from the lowest numbered bridge it is given the
description "anti."
2-exo-bromo-7 -syn-fluoro-bicyclo[2.2.1]heptane
~Br
6 1 2
2-endo-bromoanti-fluoro-bicyclo[2.2.1]heptane
~-""'2
The terms "cis" and "trans" are descriptors which show the relationship
between two ligands attached to separate atoms that are connected by a double bond
or are contained in a ring. The two ligands are said to be located cis to each other if
they lie on the same side of a plane. If they are on opposite sides, their relative
position is described as trans. The appropriate reference plane of a double bond is
perpendicular to that of the relevant a-bonds and passes through the double bond. For
a ring it is the mean plane of the ring(s).
The compounds utilized in the methods of the invention may exhibit the
phenomenon of tautomerism. While Formula I cannot expressly depict all possible
tautomeric forms, it is to be understood that Formula I is intended to represent any
tautomeric form of the depicted compound and is not to be limited merely to a
specific compound form depicted by the formula drawings.
Some of the compounds may exist as single stereoisomers (i.e.,
essentially free of other stereoisomers), racemates, and/or mixtures of enantiomers
and/or diastereomers. All such single stereoisomers, racemates and mixtures thereof
are intended to be within the scope of the present invention. Preferably, the
compounds that are optically active are used in optically pure form.
WO 20121170536
As generally understood by those skilled in the art, an optically pure
compound having one chiral center (i.e., one asymmetric carbon atom) is one that
consists essentially of one of the two possible enantiomers (i.e., is enantiomerically
pure), and an optically pure compound having more than one chiral center is one that
is both diastereomerically pure and enantiomerically pure. Preferably, the compounds
utilized in the methods of the present invention are used in a form that is at least 90%
free of other enantiomers or diastereomers of the compounds, that is, a form that
contains at least 90% of a single isomer (80% enantiomeric excess ("e.e.") or
diastereomeric excess ("d.e.")), more preferably at least 95% (90% e.e. or d.e.), even
more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99%
(98% e.e. or d.e.).
Additionally, Formula I is intended to cover solvated as well as
unsolvated forms of the identified structures. For example, Formula I includes
compounds of the indicated structure in both hydrated and non-hydrated forms. Other
examples of solvates include the structures in combination with isopropanol, ethanol,
methanol, DMSO, ethyl acetate, pentyl acetate, acetic acid, or ethanolamine.
In addition to compounds of Formula I, the invention includes
pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and
pharmaceutically acceptable salts of such compounds and metabolites.
"A pharmaceutically acceptable prodrug" is a compound that may be
converted under physiological conditions or by solvolysis to the specified compound
or to a pharmaceutically acceptable salt of such compound prior to exhibiting its
pharmacological effect(s). Typically, the prodrug is formulated with the objective(s)
of improved chemical stability, improved patient acceptance and compliance,
improved bioavailability, prolonged duration of action, improved organ selectivity,
improved formulation (e.g., increased hydrosolubility), and/or decreased side effects
(e.g., toxicity). The prodrug can be readily prepared from the compounds of Formula I
using methods known in the art, such as those described by Burger's Medicinal
Chemistry and Drug Chemistry, 1, 172-178,949-982 (1995). See also Bertolini et aI.,
1. Med. Chem., 40, 2011-2016 (1997); Shan, et aI., 1. Pharm. Sci., 86 (7), 765-767;
Bagshawe, Drug Dev. Res., 34, 220-230 (1995); Bodor, Advances in Drug Res., 13,
224-331 (1984); Bundgaard, Design of Prodrugs (Elsevier Press 1985); Larsen,
Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-
WO 20121170536
Larsen et aI., eds., Harwood Academic Publishers, 1991); Dear et aI., 1. Chromatogr.
B, 748, 281-293 (2000); Spraul et aI., 1. Pharmaceutical & Biomedical Analysis, 10,
601-605 (1992); and Prox et aI., Xenobiol., 3,103-112 (1992).
"A pharmaceutically active metabolite" is intended to mean a
pharmacologically active product produced through metabolism in the body of a
specified compound or salt thereof. After entry into the body, most drugs are
substrates for chemical reactions that may change their physical properties and
biologic effects. These metabolic conversions, which usually affect the polarity of the
Formula I compounds, alter the way in which drugs are distributed in and excreted
from the body. However, in some cases, metabolism of a drug is required for
therapeutic effect. For example, anticancer drugs of the anti-metabolite class must be
converted to their active forms after they have been transported into a cancer cell.
Since most drugs undergo metabolic transformation of some kind, the
biochemical reactions that playa role in drug metabolism may be numerous and
diverse. The main site of drug metabolism is the liver, although other tissues may also
participate.
A feature characteristic of many of these transformations is that the
metabolic products, or "metabolites," are more polar than the parent drugs, although a
polar drug does sometime yield a less polar product. Substances with high lipid/water
partition coefficients, which pass easily across membranes, also diffuse back readily
from tubular urine through the renal tubular cells into the plasma. Thus, such
substances tend to have a low renal clearance and a long persistence in the body. If a
drug is metabolized to a more polar compound, one with a lower partition coefficient,
its tubular reabsorption will be greatly reduced. Moreover, the specific secretory
mechanisms for anions and cations in the proximal renal tubules and in the
parenchymal liver cells operate upon highly polar substances.
As a specific example, phenacetin (acetophenetidin) and acetanilide are
both mild analgesic and antipyretic agents, but are transformed within the body to a
more polar and more effective metabolite, p-hydroxyacetanilid (acetaminophen),
which is widely used today. When a dose of acetanilide is given to a person, the
successive metabolites peak and decay in the plasma sequentially. During the first
hour, acetanilide is the principal plasma component. In the second hour, as the
acetanilide level falls, the metabolite acetaminophen concentration reaches a peak.
WO 20121170536
Finally, after a few hours, the principal plasma component is a further metabolite that
is inert and can be excreted from the body. Thus, the plasma concentrations of one or
more metabolites, as well as the drug itself, can be pharmacologically important.
"A pharmaceutically acceptable salt" is intended to mean a salt that
retains the biological effectiveness of the free acids and bases of the specified
compound and that is not biologically or otherwise undesirable. A compound utilized
in the methods of the invention may possess a sufficiently acidic, a sufficiently basic,
or both functional groups, and accordingly react with any of a number of inorganic or
organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable
salt. Exemplary pharmaceutically acceptable salts include those salts prepared by
reaction of the compounds of the present invention with a mineral or organic acid or
an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites,
bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates,
metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates,
decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates,
propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates,
butyne-l ,4-dioates, hexyne-l ,6-dioates, benzoates, chlorobenzoates, methylbenzoates,
dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,
xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates,
lactates, y-hydroxybutyrates, glycolates, tartrates, methane-sulfonates,
propanesulfonates, naphthalene-I-sulfonates, naphthalenesulfonates, and
mandelates.
If the compound is a base, the desired pharmaceutically acceptable salt
may be prepared by any suitable method available in the art, for example, treatment of
the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such
as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid,
pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as
glucuronic acid or galacturonic acid, an a-hydroxy acid, such as citric acid or tartaric
acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as
benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or
ethanesulfonic acid, or the like.
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If the compound is an acid, the desired pharmaceutically acceptable salt
may be prepared by any suitable method, for example, treatment of the free acid with
an inorganic or organic base, such as an amine (primary, secondary or tertiary), an
alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative
examples of suitable salts include organic salts derived from amino acids, such as
glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic
amines, such as piperidine, morpho line and piperazine, and inorganic salts derived
from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,
aluminum and lithium.
In the case of agents that are solids, it is understood by those skilled in
the art that the compounds and salts may exist in different crystal, co-crystal, or
polymorphic forms, all of which are intended to be within the scope of the present
invention and specified formulas.
METHODS OF TREATMENT AND PREVENTION OF HYPERURICEMIA, ETC.
The present invention provides methods for lowering serum uric acid
and treating or preventing hyperuricemia, gout, inflammation disease, urinary
urolithiasis, a reperfusion disease, renal dysfunction, tumor lysis syndrome,
hypertension, or cardiovascular disease in a patient in need thereof, comprising
administering to the patient a therapeutically effective amount of a compound of
Formula I and a pharmaceutically acceptable excipient, carrier, or vehicle.
The magnitude of a prophylactic or therapeutic dose of a Formula I
compound of the invention or a pharmaceutically acceptable salt, solvate, or hydrate,
thereof in the acute or chronic treatment or prevention of elevated uric acid levels will
vary. The dose, and in some cases the dose frequency, will also vary according to the
disease or condition to be treated, the age, body weight, and response of the individual
patient. Suitable dosing regimens can be readily selected by those skilled in the art
with due consideration of such factors.
Doses
Toxicity and efficacy of the compounds utilized in the methods of the
invention can be determined by standard pharmaceutical procedures in cell cultures or
experimental animals, e.g., for determining the LD50 (the dose lethal to 50% of the
population) and the ED 50 (the dose therapeutically effective in 50% of the
WO 20121170536
population). The dose ratio between toxic and therapeutic effects is the therapeutic
index and it can be expressed as the ratio LD50/ED50.
The data obtained from the cell culture assays and animal studies can be
used in formulating a range of dosage of the compounds for use in humans. The
dosage of such compounds lies preferably within a range of circulating concentrations
that include the ED 50 with little or no toxicity. The dosage may vary within this range
depending upon the dosage form employed and the route of administration utilized.
For any compound used in the method of the invention, the therapeutically effective
dose can be estimated initially from cell culture assays. A dose may be formulated in
animal models to achieve a circulating plasma concentration range that includes the
EC50 (i. e., the concentration of the test compound that provokes a response half way
between the baseline and maximum response) as determined in cell culture;
alternatively, the dose of the Formula I compound may be formulated in animal
models to achieve a circulating plasma concentration range of the compound that
corresponds to the concentration required to achieve a fixed magnitude of response.
Such information can be used to more accurately determine useful doses in humans.
Levels in plasma may be measured, for example, by high performance liquid
chromatography.
The protocols and compositions utilized in the methods of the invention
are preferably tested in vitro, and then in vivo, for the desired therapeutic or
prophylactic activity, prior to use in humans. For example, in vitro assays which can
be used to determine whether administration of a specific therapeutic protocol is
indicated, include in vitro cell culture assays in which cells that are responsive to the
effects of the Formula I compounds are exposed to the ligand and the magnitude of
response is measured by an appropriate technique. The assessment of the Formula I
compound is then evaluated with respect to the Formula I compound potency, and the
degree of conversion of the Formula I compound prodrug, in instances where the
compound to be tested is a prodrug. Compounds for use in methods of the invention
can be tested in suitable animal model systems prior to testing in humans, including
but not limited to in rats, mice, chicken, cows, monkeys, chimpanzees, rabbits,
hamsters, etc. The compounds can then be used in the appropriate clinical trials.
Suitable dosing regimens can be readily selected by those skilled in the
art with due consideration of such factors. In one embodiment, the dose administered
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depends upon the specific compound to be used, and the weight and condition of the
patient. Also, the dose may differ for various particular Formula I compounds;
suitable doses can be predicted on the basis of the aforementioned in vitro
measurements and on the basis of animal studies, such that smaller doses will be
suitable for those Formula I compounds that show effectiveness at lower
concentrations than other Formula I compounds when measured in the systems
described or referenced herein. In general, the dose per day is in the range of from
about 0.001 to 100 mg/kg, preferably about 1 to 25 mg/kg, more preferably about 5 to
mg/kg.
Additionally, the recommended daily dose can be administered in cycles
as single agents or in combination with other therapeutic agents. In one embodiment,
the daily dose is administered in a single dose or in equally divided doses. In a related
embodiment, the recommended daily dose can be administered one time per week,
two times per week, three times per week, four times per week or five times per week.
In one embodiment, the compounds utilized in the methods of the
invention are administered to provide systemic distribution of the compound within
the patient. In a related embodiment, the compounds of the invention are administered
to produce a systemic effect in the body.
In another embodiment the compounds utilized in the methods of the
invention are administered via oral, mucosal (including sublingual or buccal),
parenteral (including subcutaneous, intramuscular, bolus injection, intraarterial, or
intravenous), transdermal, or topical administration. In a specific embodiment the
compounds of the invention are administered via mucosal (including sublingual or
buccal), parenteral (including subcutaneous, intramuscular, bolus injection,
intraarterial, or intravenous), transdermal, or topical administration. In a further
specific embodiment, the compounds of the invention are administered via oral
administration. In a further specific embodiment, the compounds of the invention are
not administered via oral administration.
Combination Therapy
Specific methods of the invention further comprise the administration of
an additional therapeutic agent (i.e., a therapeutic agent other than a compound of the
invention). In certain embodiments of the present invention, the compounds of the
invention can be used in combination with at least one other therapeutic agent.
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Therapeutic agents include, but are not limited to co1chicines, anti-inflammatory
agents, intraarticular glucocorticoids, IL-Ib antagonists (e.g., rilonacept, canakumab),
inhibitors of uric acid production like the xanthine oxidase inhibitors or prodrugs of
such inhibitors like febuxostat, oxypurinol, allopurinol, agents that degrade uric acid
like pegloticase and other uricases, and uricosuric agents like probenecid and
sulfinpyrazone. The compounds of the invention and the other therapeutics agent can
act additively or, more preferably, synergistically. In one embodiment, a composition
comprising a compound of the invention is administered concurrently with the
administration of another therapeutic agent, which can be part of the same
composition or in a different composition from that comprising the compounds of the
invention. In another embodiment, a compound of the invention is administered prior
to or subsequent to administration of another therapeutic agent. In a separate
embodiment, a compound of the invention is administered to a patient who has not
previously undergone or is not currently undergoing treatment with another
therapeutic agent.
In one embodiment, the methods of the invention comprise the
administration of one or more compounds of the invention without an additional
therapeutic agent.
PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS
Pharmaceutical compositions and single unit dosage forms comprising a
compound utilized in the methods of the invention, or a pharmaceutically acceptable
salt, or hydrate thereof, are also encompassed by the invention. Individual dosage
forms of the invention may be suitable for oral, mucosal (including sublingual or
buccal), parenteral (including subcutaneous, intramuscular, bolus injection,
intraarterial, or intravenous), transdermal, or topical administration. Pharmaceutical
compositions and dosage forms of the invention typically also comprise one or more
pharmaceutically acceptable excipients. Sterile dosage forms are also contemplated.
In an alternative embodiment, pharmaceutical composition encompassed
by this embodiment includes a compound of the invention, or a pharmaceutically
acceptable salt, or hydrate thereof, and at least one additional therapeutic agent.
Examples of additional therapeutic agents include, but are not limited to, those listed
above.
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The composition, shape, and type of dosage forms of the invention will
typically vary depending on their use. For example, a dosage form used in the acute
treatment of a disease or a related disease may contain larger amounts of one or more
of the active ingredients it comprises than a dosage form used in the chronic treatment
of the same disease. Similarly, a parenteral dosage form may contain smaller amounts
of one or more of the active ingredients it comprises than an oral dosage form used to
treat the same disease or disorder. These and other ways in which specific dosage
forms encompassed by this invention will vary from one another will be readily
apparent to those skilled in the art. See, e.g., Remington's Pharmaceutical Sciences,
18th ed., Mack Publishing, Easton PA (1990). Examples of dosage forms include, but
are not limited to: tablets; caplets; capsules, such as soft elastic gelatin capsules;
cachets; troches; lozenges; dispersions; ointments; cataplasms (poultices); pastes;
powders; dressings; creams; plasters; solutions; patches; gels; liquid dosage forms
suitable for oral or mucosal administration to a patient, including suspensions (e.g.,
aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or a water-in-oil
liquid emulsions), solutions, and elixirs; liquid dosage forms suitable for parenteral
administration to a patient; and sterile solids (e.g., crystalline or amorphous solids)
that can be reconstituted to provide liquid dosage forms suitable for parenteral
administration to a patient.
Typical pharmaceutical compositions and dosage forms comprise one or
more carriers, excipients or diluents. Suitable excipients are well known to those
skilled in the art of pharmacy, and non-limiting examples of suitable excipients are
provided herein. Whether a particular excipient is suitable for incorporation into a
pharmaceutical composition or dosage form depends on a variety of factors well
known in the art including, but not limited to, the way in which the dosage form will
be administered to a patient. For example, oral dosage forms such as tablets may
contain excipients not suited for use in parenteral dosage forms. The suitability of a
particular excipient may also depend on the specific active ingredients in the dosage
form.
This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since water can
facilitate the degradation of some compounds. For example, the addition of water
(e.g., 5%) is widely accepted in the pharmaceutical arts as a means of simulating
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long-term storage in order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Carstensen, Drug Stability: Principles &
Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80. In effect, water and
heat accelerate the decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or humidity are
commonly encountered during manufacture, handling, packaging, storage, shipment,
and use of formulations.
Anhydrous pharmaceutical compositions and dosage forms of the
invention can be prepared using anhydrous or low moisture containing ingredients
and low moisture or low humidity conditions.
An anhydrous pharmaceutical composition should be prepared and
stored such that its anhydrous nature is maintained. Accordingly, anhydrous
compositions are preferably packaged using materials known to prevent exposure to
water such that they can be included in suitable formulary kits. Examples of suitable
packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose
containers (e.g., vials), blister packs, and strip packs.
The invention further encompasses pharmaceutical compositions and
dosage forms that comprise one or more compounds that reduce the rate by which an
active ingredient will decompose. Such compounds, which are referred to herein as
"stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH
buffers, or salt buffers.
Like the amounts and types of excipients, the amounts and specific types
of active ingredients in a dosage form may differ depending on factors such as, but
not limited to, the route by which it is to be administered to patients. However, typical
dosage forms of the invention comprise compounds of the invention, or a
pharmaceutically acceptable salt or hydrate thereof comprise 0.1 mg to 1500 mg per
unit to provide doses of about 0.01 to 200 mg/kg per day.
Oral Dosage Forms
Pharmaceutical compositions utilized in the methods of the invention
that are suitable for oral administration can be presented as discrete dosage forms,
such as, but are not limited to, tablets (e.g., chewable tablets), caplets, capsules, and
liquids (e.g., flavored syrups). Such dosage forms contain predetermined amounts of
active ingredients, and may be prepared by methods of pharmacy well known to those
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skilled in the art. See generally, Remington's Pharmaceutical Sciences, 18th ed.,
Mack Publishing, Easton PA (1990).
Typical oral dosage forms of the invention are prepared by combining
the active ingredient(s) in an intimate admixture with at least one excipient according
to conventional pharmaceutical compounding techniques. Excipients can take a wide
variety of forms depending on the form of preparation desired for administration. For
example, excipients suitable for use in oral liquid dosage forms include, but are not
limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring
agents. Examples of excipients suitable for use in solid oral dosage forms (e.g.,
powders, tablets, capsules, and caplets) include, but are not limited to, starches,
sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders,
and disintegrating agents.
Because of their ease of administration, tablets and capsules represent
the most advantageous oral dosage unit forms, in which case solid excipients are
employed. If desired, tablets can be coated by standard aqueous or nonaqueous
techniques. Such dosage forms can be prepared by any of the methods of pharmacy.
In general, pharmaceutical compositions and dosage forms are prepared by uniformly
and intimately admixing the active ingredients with liquid carriers, finely divided
solid carriers, or both, and then shaping the product into the desired presentation if
necessary.
For example, a tablet can be prepared by compression or molding.
Compressed tablets can be prepared by compressing in a suitable machine the active
ingredients in a free-flowing form such as powder or granules, optionally mixed with
an excipient. Molded tablets can be made by molding in a suitable machine a mixture
of the powdered compound moistened with an inert liquid diluent.
Examples of excipients that can be used in oral dosage forms of the
invention include, but are not limited to, binders, fillers, disintegrants, and lubricants.
Binders suitable for use in pharmaceutical compositions and dosage forms include,
but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and
synthetic gums such as acacia, sodium alginate, alginic acid, other alginates,
powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose,
cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl
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cellulose, (e.g., Nos. 220S, 2906, 2910), microcrystalline cellulose, and mixtures
thereof.
Examples of fillers suitable for use in the pharmaceutical compositions
and dosage forms disclosed herein include, but are not limited to, talc, calcium
carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose,
dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and
mixtures thereof. The binder or filler in pharmaceutical compositions of the invention
is typically present in from about 50 to about 99 weight percent of the pharmaceutical
composition or dosage form.
Suitable forms of microcrystalline cellulose include, but are not limited
to, the materials sold as AVICEL-PH-101, AVICEL-PH-I03 AVICEL RC-5S1,
AVICEL-PH-105 (available from FMC Corporation, American Viscose Division,
Avicel Sales, Marcus Hook, PA), and mixtures thereof. A specific binder is a mixture
of microcrystalline cellulose and sodium carboxymethyl cellulose sold as AVICEL
RC-5Sl. Suitable anhydrous or low moisture excipients or additives include
AVICEL-PH-I03TM and Starch 1500 LM.
Disintegrants are used in the compositions of the invention to provide
tablets that disintegrate when exposed to an aqueous environment. Tablets that
contain too much disintegrant may disintegrate in storage, while those that contain too
little may not disintegrate at a desired rate or under the desired conditions. Thus, a
sufficient amount of disintegrant that is neither too much nor too little to detrimentally
alter the release of the active ingredients should be used to form solid oral dosage
forms of the invention. The amount of disintegrant used varies based upon the type of
formulation, and is readily discernible to those of ordinary skill in the art. Typical
pharmaceutical compositions comprise from about 0.5 to about 15 weight percent of
disintegrant, specifically from about 1 to about 5 weight percent of disintegrant.
Disintegrants that can be used in pharmaceutical compositions and
dosage forms of the invention include, but are not limited to, agar-agar, alginic acid,
calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized
starch, other starches, clays, other algins, other celluloses, gums, and mixtures thereof.
Lubricants that can be used in pharmaceutical compositions and dosage
of the invention include, but are not limited to, calcium stearate, magnesium
forms
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stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene
glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable
oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and
soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel (AEROSIL 200,
manufactured by W.R. Grace Co. of Baltimore, MD), a coagulated aerosol of
synthetic silica (marketed by Degussa Co. of Plano, TX), CAB-O-SIL (a pyrogenic
silicon dioxide product sold by Cabot Co. of Boston, MA), and mixtures thereof. If
used at all, lubricants are typically used in an amount of less than about 1 weight
percent of the pharmaceutical compositions or dosage forms into which they are
incorporated.
Delayed Release Dosage Forms
Active ingredients utilized in the methods of the invention can be
administered by controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are not limited to, those
described in U.S. Patent Nos.: 3,845,770; 3,916,899; 3,536,809; 3,598,123; and
4,008,719,5,674,533,5,059,595,5,591,767, 5,120,548, 5,073,543, 5,639,476,
,354,556, and 5,733,566, each of which is incorporated herein by reference. Such
dosage forms can be used to provide slow or controlled-release of one or more active
ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices,
gels, permeable membranes, osmotic systems, multilayer coatings, microparticles,
liposomes, microspheres, or a combination thereof to provide the desired release
profile in varying proportions. Suitable controlled-release formulations known to
those of ordinary skill in the art, including those described herein, can be readily
selected for use with the active ingredients of the invention. The invention thus
encompasses single unit dosage forms suitable for oral administration such as, but not
limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled
release.
All controlled-release pharmaceutical products have a common goal of
improving drug therapy over that achieved by their non-controlled counterparts.
Ideally, the use of an optimally designed controlled-release preparation in medical
treatment is characterized by a minimum of drug substance being employed to cure or
control the condition in a minimum amount of time. Advantages of controlled-release
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formulations include extended activity of the drug, reduced dosage frequency, and
increased patient compliance. In addition, controlled-release formulations can be used
to affect the time of onset of action or other characteristics, such as blood levels of the
drug, and can thus affect the occurrence of side (e.g., adverse) effects.
Most controlled-release formulations are designed to initially release an
amount of drug (active ingredient) that promptly produces the desired therapeutic
effect, and gradually and continually release other amounts of drug to maintain this
level of therapeutic or prophylactic effect over an extended period of time. In order to
maintain this constant level of drug in the body, the drug must be released from the
dosage form at a rate that will replace the amount of drug being metabolized and
excreted from the body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH, temperature, enzymes, water,
or other physiological conditions or compounds.
Parenteral Dosage Forms
Parenteral dosage forms can be administered to patients by various
routes including, but not limited to, subcutaneous, intravenous (including bolus
injection), intramuscular, and intraarterial. Because their administration typically
bypasses patients' natural defenses against contaminants, parenteral dosage forms are
preferably sterile or capable of being sterilized prior to administration to a patient.
Examples of parenteral dosage forms include, but are not limited to, solutions ready
for injection, dry and/or lyophylized products ready to be dissolved or suspended in a
pharmaceutically acceptable vehicle for injection (reconstitutable powders),
suspensions ready for injection, and emulsions.
Suitable vehicles that can be used to provide parenteral dosage forms of
the invention are well known to those skilled in the art. Examples include, but are not
limited to: Water for Injection USP; aqueous vehicles such as, but not limited to,
Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and
Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles
such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene
glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil,
peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
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Compounds that increase the solubility of one or more of the active
ingredients disclosed herein can also be incorporated into the parenteral dosage forms
of the invention.
Transdermal Dosage Forms
Transdermal dosage forms include "reservoir type" or "matrix type"
patches, which can be applied to the skin and worn for a specific period of time to
permit the penetration of a desired amount of active ingredients.
Suitable excipients (e.g., carriers and diluents) and other materials that
can be used to provide trans dermal and topical dosage forms encompassed by this
invention are well known to those skilled in the pharmaceutical arts, and depend on
the particular tissue to which a given pharmaceutical composition or dosage form will
be applied. With that fact in mind, typical excipients include, but are not limited to,
water, acetone, ethanol, ethylene glycol, propylene glycol, butane-I,3-diol, isopropyl
myristate, isopropyl palmitate, mineral oil, and mixtures thereof.
Depending on the specific tissue to be treated, additional components
may be used prior to, in conjunction with, or subsequent to treatment with active
ingredients of the invention. For example, penetration enhancers can be used to assist
in delivering the active ingredients to the tissue. Suitable penetration enhancers
include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and
tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide;
dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone;
Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble
sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
The pH of a pharmaceutical composition or dosage form, or of the tissue
to which the pharmaceutical composition or dosage form is applied, may also be
adjusted to improve delivery of one or more active ingredients. Similarly, the polarity
of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
Compounds such as stearates can also be added to pharmaceutical compositions or
dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or
more active ingredients so as to improve delivery. In this regard, stearates can serve as
a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a
delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or
WO 20121170536
solvates of the active ingredients can be used to further adjust the properties of the
resulting composition.
Topical Dosage Forms
Topical dosage forms of the invention include, but are not limited to,
creams, lotions, ointments, gels, solutions, emulsions, suspensions, or other forms
known to one of skill in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th
eds., Mack Publishing, Easton PA (1990); and Introduction to Pharmaceutical
Dosage Forms, 4th ed., Lea & Febiger, Philadelphia (1985).
Suitable excipients (e.g., carriers and diluents) and other materials that
can be used to provide trans dermal and topical dosage forms encompassed by this
invention are well known to those skilled in the pharmaceutical arts, and depend on
the particular tissue to which a given pharmaceutical composition or dosage form will
be applied. With that fact in mind, typical excipients include, but are not limited to,
water, acetone, ethanol, ethylene glycol, propylene glycol, butane-l,3-diol, isopropyl
myristate, isopropyl palmitate, mineral oil, and mixtures thereof.
Depending on the specific tissue to be treated, additional components
may be used prior to, in conjunction with, or subsequent to treatment with active
ingredients of the invention. For example, penetration enhancers can be used to assist
in delivering the active ingredients to the tissue. Suitable penetration enhancers
include, but are not limited to: acetone; various alcohols such as ethanol, oleyl, and
tetrahydrofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dimethyl acetamide;
dimethyl formamide; polyethylene glycol; pyrrolidones such as polyvinylpyrrolidone;
Kollidon grades (Povidone, Polyvidone); urea; and various water-soluble or insoluble
sugar esters such as Tween 80 (polysorbate 80) and Span 60 (sorbitan monostearate).
Mucosal Dosage Forms
Mucosal dosage forms of the invention include, but are not limited to,
ophthalmic solutions and sprays, or other forms known to one of skill in the art. See,
e.g., Remington's Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton P A
(1990); and Introduction to Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,
Philadelphia (1985).
In addition to the formulations described previously, a compound
utilized in the methods of the invention can also be formulated as a depot preparation.
Such long acting formulations can be administered by implantation (for example
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subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example,
the compounds can be formulated with suitable polymeric or hydrophobic materials
(for example, as an emulsion in an acceptable oil) or ion exchange resins, or as
sparingly soluble derivatives, for example, as a sparingly soluble salt.
Alternatively, other pharmaceutical delivery systems can be employed.
Liposomes, emulsions, self-emulsifying (SEDDS), and self micro-emulsifying
systems (SMEDDS) are well known examples of delivery vehicles that can be used to
deliver compositions of the invention. Such systems can also contain fatty acids, bile
salts and mixtures of mono-, di- and triglycerides to ameliorate potential food effects.
Other functional lipid excipients include esters of glycerol, PEG-esters, propylene
glycol esters and polyglycerol esters. Certain organic solvents such as
dimethylsulfoxide can also be employed, although usually at the cost of greater
toxicity. A compound of the invention can also be delivered in a controlled release
system. In one embodiment, a pump can be used (Sefton, CRC Crit. Ref Biomed Eng. ,
1987,14,201; Buchwald et al., Surgery, 1980,88,507; Saudek et al., N. Engl. 1.
Med., 1989,321,574). In another embodiment, polymeric materials can be used (see
Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres.,
Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Design and
Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas,
1. Macromol. Sci. Rev. Macromol. Chem., 1983,23,61; see also Levy et al., Science,
1985,228, 190; During et al., Ann. Neurol., 1989,25,351; Howard et al., 1.
Neurosurg., 71, 105 (1989). In yet another embodiment, a controlled-release system
can be placed in proximity of the target of the compounds of the invention thus
requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical
Applications of Controlled Release, supra, vol. 2, pp. 115 (1984)). Other controlled
release systems can be used (see, e.g., Langer, Science, 1990,249,1527).
Suitable excipients (e.g., carriers and diluents) and other materials that
can be used to provide mucosal dosage forms encompassed by this invention are well
known to those skilled in the pharmaceutical arts, and depend on the particular site or
method which a given pharmaceutical composition or dosage form will be
administered. With that fact in mind, typical excipients include, but are not limited to,
water, ethanol, ethylene glycol, propylene glycol, butane-1 ,3-diol, isopropyl
myristate, isopropyl palmitate, mineral oil, and mixtures thereof, which are non-toxic
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and pharmaceutically acceptable. Examples of such additional ingredients are well
known in the art. See, e.g., Remington's Pharmaceutical Sciences, 18th eds., Mack
Publishing, Easton PA (1990).
The pH of a pharmaceutical composition or dosage form, or of the tissue
to which the pharmaceutical composition or dosage form is applied, can also be
adjusted to improve delivery of one or more active ingredients. Similarly, the polarity
of a solvent carrier, its ionic strength, or tonicity can be adjusted to improve delivery.
Compounds such as stearates can also be added to pharmaceutical compositions or
dosage forms to advantageously alter the hydrophilicity or lipophilicity of one or
more active ingredients so as to improve delivery. In this regard, stearates can serve as
a lipid vehicle for the formulation, as an emulsifying agent or surfactant, and as a
delivery-enhancing or penetration-enhancing agent. Different salts, hydrates or
solvates of the active ingredients can be used to further adjust the properties of the
resulting composition.
Kits
The invention provides a pharmaceutical pack or kit comprising one or
more containers comprising a compound of the invention useful for lowering serum
uric acid and the treatment or prevention of, e.g., gout or hyperuricemia. In other
embodiments, the invention provides a pharmaceutical pack or kit comprising one or
more containers comprising a compound of the invention useful for lowering serum
uric acid and the treatment or prevention of gout or hyperuricemia and one or more
containers comprising an additional therapeutic agent.
The invention also provides a pharmaceutical pack or kit comprising one
or more containers comprising one or more of the ingredients of the pharmaceutical
compositions of the invention. Optionally associated with such container(s) can be a
notice in the form prescribed by a governmental agency regulating the manufacture,
use or sale of pharmaceuticals or biological products, which notice reflects approval
by the agency of manufacture, use or sale for human administration.
The inventive agents may be prepared using the reaction routes and
synthetic schemes as described below, employing the general techniques known in the
art using starting materials that are readily available. The synthesis of non
exemplified compounds according to the invention may be successfully performed by
modifications apparent to those skilled in the art, e.g., by appropriately protecting
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interfering groups, by changing to other suitable reagents known in the art, or by
making routine modifications of reaction conditions. Alternatively, other reactions
disclosed herein or generally known in the art will be recognized as having
applicability for preparing other compounds of the invention.
Preparation of Compounds
In the synthetic schemes described below, unless otherwise indicated all
temperatures are set forth in degrees Celsius and all parts and percentages are by
weight. Reagents were purchased from commercial suppliers such as Aldrich
Chemical Company or Alfa Aesar. and were used without further purification unless
otherwise indicated. All solvents were purchased from commercial suppliers such as
Aldrich, EMD Chemicals or Fisher and used as received. The reactions set forth
below were done generally under a positive pressure of argon or nitrogen at an
ambient temperature (unless otherwise stated) in anhydrous solvents, and the reaction
flasks were fitted with rubber septa for the introduction of substrates and reagents via
syringe. Glassware was oven dried and/or heat dried.
The reactions were assayed by TLC and/or analyzed by LC-MS or
HPLC and terminated as judged by the consumption of starting material. Analytical
thin layer chromatography (TLC) was performed on glass-plates precoated with silica
gel 60 F 0.25 mm plates (EMD Chemicals), and visualized with UV light (254 nm)
and/or iodine on silica gel and/or heating with TLC stains such as ethanolic
phosphomolybdic acid, ninhydrin solution, potassium permanganate solution or ceric
sulfate solution. Preparative thin layer chromatography (prepTLC) was performed on
glass-plates precoated with silica gel 60 F 54 0.5 mm plates (20 x 20 cm, from
Thomson Instrument Company) and visualized with UV light (254 nm).
Work-ups were typically done by doubling the reaction volume with the
reaction solvent or extraction solvent and then washing with the indicated aqueous
solutions using 25% by volume of the extraction volume unless otherwise indicated.
Product solutions were dried over anhydrous sodium sulfate and/or magnesium sulfate
prior to filtration and evaporation of the solvents under reduced pressure on a rotary
evaporator and noted as solvents removed in vacuo. Column chromatography was
completed under positive pressure using Merck silica gel 60, 230-400 mesh or 50-200
mesh neutral alumina, Teledyne Isco flash-chromatography using prepacked RediSep
silica gel columns, or Analogix flash column chromatography using prepacked
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SuperFlash silica gel columns. Hydrogenolysis was done at the pressure indicated in
the examples or at ambient pressure.
IH-NMR spectra and 13C-NMR were recorded on a Varian Mercury-
VX400 instrument operating at 400 MHz. NMR spectra were obtained as CDCb
solutions (reported in ppm), using chloroform as the reference standard (7.27 ppm for
the proton and 77.00 ppm for carbon), CD 0D (3.4 and 4.8 ppm for the protons and
49.3 ppm for carbon), DMSO-d (2.49 ppm for proton), or internally tetramethylsilane
(0.00 ppm) when appropriate. Other NMR solvents were used as needed. When peak
multiplicities are reported, the following abbreviations are used: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), br (broadened), bs (broad singlet), dd
(doublet of doublets), dt (doublet of triplets). Coupling constants, when given, are
reported in Hertz (Hz).
Infrared (IR) spectra were recorded on an ATR FT-IR Spectrometer as
neat oils or solids, and when given are reported in wavenumbers (cm- ). Mass spectra
reported are (+)-ES or APCI ( +) LC/MS conducted by the Analytical Chemistry
Department of Anadys Pharmaceuticals, Inc. Elemental analyses were conducted by
the Atlantic Microlab, Inc. in Norcross, GA. Melting points (mp) were determined on
an open capillary apparatus, and are uncorrected.
Enantiomeric excess (ee) values were determined by HPLC-analysis
using the Chiralpak (Chiral Technologies Inc.) columns AS-RH, 2.1 x 150 mm, 5
micron, "A = 312 nm or AS-RH, 4.6 x 250 mm, 5 micron, "A = 310 nm. AS-RH, 2.1 x
150 mm, 5 micron: Binary gradient HPLC separation. Solvent A: 0.1% Formic Acid
in Water, Solvent B: 0.1 % Formic Acid in Acetonitrile. Injected 10 ilL of sample
dissolved in 50% methanol- 50% water [0.1 mg/mL].
Time (min) %B Flow (mL/min)
0.0 55 0.3
.0 95 0.3
.5 95 0.3
6.0 55 0.3
12.0 55 0.3
AS-RH, 4.6 x 250 mm, 5 micron: Binary gradient HPLC separation. Solvent A: 0.05
% TFA in Water, Solvent B: 0.05 % TFA in Acetonitrile. Injected 3-5 III of sample
dissolved in acetonitrile [1 mg/mL].
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Time (min) %B Flow (mL/min)
0.0 50 0.8
8.0 95 0.8
.0 0.8
1l.0 50 0.8
13.0 50 0.8
The described synthetic pathways and experimental procedures utilize
many common chemical abbreviations, 2,2-DMP (2,2-dimethoxypropane), Ac
(acetyl), ACN (acetonitrile), Bn (benzyl), BnOH (benzyl alcohol), Boc (tert
butoxycarbonyl), Boc 0 (di-tert-butyl dicarbonate), Bz (benzoyl), CSA
(camphorsulfonic acid), CSI (chlorosulfonyl isocyanate), DBU (1,8-
diazabicyc1o[5,4,0]undec-7 -ene), DCC (N,N' -dicyc1ohexylcarbodiimide), DCE (1,2-
dichloroethane), DCM (dichloromethane), DEAD (diethylazodicarboxylate), DIBAL
(diisobutylaluminum hydride), DIEA (diisopropylethylamine), DMA (N,N
dimethylacetamide), DMAP (4-(N,N-dimethylamino )pyridine), DMF (N,N
dimethylfonnamide), DMSO (dimethyl sulfoxide), EDC (1-(3-dimethylaminopropyl)-
3-ethylcarbodiimide hydrochloride), Et (ethyl), EtOAc ( ethyl acetate), EtOH
(ethanol), HATU (O-(7-azabenzotriazolyl)-1, 1,3,3-tetramethyluronium
hexafluorophosphate), HBTU (O-benzotriazolyl-N,N,N',N'-tetramethyluronium
hexafluorophosphate), HF (hydrogen fluoride), HOAc (acetic acid), HOBT (1-
hydroxybenzotriazole hydrate), HPLC (high pressure liquid chromatography), IPA
(isopropyl alcohol), KHMDS (potassium bis(trimethylsilyl)amide), KN(TMSh
(potassium bis(trimethylsilyl)amide), KOtBu (potassium tert-butoxide), LDA (lithium
diisopropylamine), MCPBA (3-chloroperbenzoic acid), Me (methyl), MeCN
(acetonitrile), MeOH (methanol), NaCNBH3 (sodium cyanoborohydride), NaH
(sodium hydride), NaN(TMSh (sodium bis(trimethylsilyl)amide), NaOAc (sodium
acetate), NaOEt (sodium ethoxide), NEt3 (triethylamine), NMM (N
methylmorpholine), Phe (phenylalanine), PPTS (pyridinium p-toluenesulfonate), PS
(polymer supported), Py (pyridine), pyBOP (benzotriazol
yloxy)tripyrrolidinophosphonium hexafluorophosphate), TEA (triethylamine), TF A
(trifluoroacetic acid), TFAA (trifluoroacetic anhydride), THF (tetrahydrofuran), TLC
(thin layer chromatography), Tol (toluoyl), Val (valine), and the like.
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Scheme 1 provides a specific procedure that was used to prepare the
compound of Example 1, an N-methylene methanesulfonamide [1,2,4]thiadiazine 1,1-
dioxide derivative.
Scheme 1
CuCN
120 DC
conc. HCI
MeOH
O,,/p o~ ",,0
= OH ~/s~~/s,
MsCI
- ~ N~
Pyridine
rrlX
'lAF
The N-substituted cyclic B-amino acid ester intermediate shown was
coupled to (7-iodo-l, I-dioxo-l,4-dihydro-lA,6-benzo[I,2,4]thiadiazinyl)-acetic acid
(prepared as described in W0200715000lAl) in the presence of 0-(7-
azabenzotriazol-l-yl)-I,I,3,3-tetramethyluronium hexafluorophosphate (HATU) and
N-methylmorpholine to afford the amide intermediate which was cyclized in the
presence of triethylamine to afford the desired cyclic intermediate. Displacement of
the iodo moiety with copper (I) cyanide gave the desired nitrile intermediate.
Reduction of the nitrile under standard hydrogenation conditions yielded the desired
benzyl amine derivative which was then treated with methanesulfonyl chloride to
afford the desired [1,2,4 ]thiadiazine 1, I-dioxide compound.
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Example 1: N- {3-[(lR,2S,7 R,8S)( 4-Fluoro-benzyl)hydroxyoxo-
3-aza-tricyc1o[6.2.l.02.7]undecenyl]-1, l-dioxo-l,4-dihydro-l"A _
benzo[1,2,4]thiadiazinylmethyll-methanesulfonamide
0" //0 q,..,O
S S ....
OH N" ~N" \
dX~--V H
a) (lR,2S,7 R,8S)( 4-Fluoro-benzyl)hydroxy(7 -iodo-l, l-dioxo-
1 ,4-dihydro-l "A -benzo[ 1 ,2,4 ]thiadiazinyl)aza -tricyc1o[ 6.2.l.02.7]undecen
0,/0
= OH ~~SyYl
- ~ N~
(7 -Iodo-l, I-dioxo-l,4-dihydro-l "A -benzo[I,2,4 ]thiadiazinyl)-acetic
as described in US patent application US 2008/0031852; 2.51 g, 6.86
acid (prepared
mmol), (IS,2R,3S,4R)(4-fluoro-benzylamino)-bicyc1o[2.2.1]heptanecarboxylic
acid ethyl ester (For the preparation of B-amino acid intermediates see Examples 2f-l
described below) (2 g, 6.86 mmol) and O-(7-azabenzotriazol-l-yl)-N,N,N,N
tetramethyluronium hexafluorophosphate (2.74 g, 7.2 mmol) were combined and
dissolved in anhydrous N,N-dimethylformamide (18 mL). N-Methylmorpholine (3
mL, 27.44 mmol) was added and the mixture was stirred at 25°C for 2 h.
Triethylamine (3.82 mL, 27.44 mmol) was added and the mixture stirred at 60°C for
16 h. Upon cooling, the mixture was slowly added to a 1.0 M aqueous hydrochloric
acid solution (200 mL) while stirring. The product precipitated immediately. Stirring
was continued for 5 min. The solid was collected by vacuum filtration, rinsed with
water (2 x 60 mL) and dried in vacuo for 16 h to afford the desired product,
(IS,2R,3S,4R)( 4-fluoro-benzyl)hydroxy(7 -iodo-l, I-dioxo-l,4-dihydro-l"A _
benzo[I,2,4]thiadiazinyl)aza-tricyc1o[6.2.1.02.7]undecenone (1.94 g, 3.27
WO 20121170536
mmol, 48%), as a white, brittle foam. IH NMR (400 MHz, DMSO-d ) 8: 1.20 - 1.23
(lH, m), 1.38 - 1.61 (5H, m), 2.50 - 2.53 (lH, m), 2.62 (lH, d, J = 3.2 Hz), 2.98 (lH,
d, J = 9.3 Hz), 3.52 (lH, d, J = 9.4 Hz), 4.40 (lH, d, J = 15.7 Hz), 4.95 (lH, d, J =
14.9 Hz), 7.12 - 7.16 (2H, m), 7.30 - 7.34 (3H, m), 7.97 (lH, dd, h = 8.6 Hz, h = 1.4
Hz), 8.07 (lH, d, J = 1.7 Hz).
b) (lR,2S,7 R,8S) [3-(4-Fluoro-benzyl)hydroxyoxoaza-
tricyc1o[6.2.l.02.7]undecenyl]-1, l-dioxo-l ,4-dihydro-l ",6_
benzo[ 1 ,2,4 ]thiadiazine-7 -carbonitrile
OH N~S~N
cdX~)J
(lR,2S,7 R,8S)( 4-Fluoro-benzyl)hydroxy(7 -iodo-l, l-dioxo-l,4-
dihydro-l ", -benzo[ 1 ,2,4 ]thiadiazinyl)aza -tricyc1o[ 6.2.1. 02.7]undecenone
(0.5 g, 0.84 mmol) and copper(I) cyanide (0.151 g, 1.7 mmol) were suspended in
anhydrous N,N-dimethylformamide (4 mL). The mixture was stirred at 120°C, under
nitrogen for 24 h. Upon cooling, the mixture was diluted with ethyl acetate (20 mL)
and washed with saturated aqueous ammonium chloride solution (3 x 15 mL). The
organic phase was passed through a short plug of Celite followed by a short plug of
silica gel (Merck silica gel 60, 40-63 11m), eluting with ethyl acetate. The filtrate was
concentrated in vacuo to afford a yellow solid. Purification by flash column
chromatography (Teledyne Isco RediSep column; 25-100% ethyl acetate in hexanes)
followed by concentration in vacuo afforded the desired product, (lR,2S,7R,8S)[3-
(4-fluoro-benzyl)hydroxyoxoaza-tricyc1o[ 6.2.1.02.7]undecenyl]-1, 1-
dioxo-1,4-dihydro-IA -benzo[1,2,4]thiadiazinecarbonitrile (0.398 g, 0.808 mmol,
96%), as a white, brittle foam. IH NMR (400 MHz, DMSO-d ) 8: 1.15 - 1.15 (lH,
m), 1.34 - 1.61 (5H, m), 2.48 - 2.48 (lH, m), 2.60 (lH, d, J = 3.3 Hz), 2.90 (lH, d, J =
9.4 Hz), 3.48 (lH, d, J = 9.4 Hz), 4.38 (lH, d, J = 15.6 Hz), 4.96 (lH, d, J = 15.4 Hz),
7.11 - 7.16 (2H, m), 7.31 (2H, dd, h = 8.6 Hz, h = 5.4 Hz), 7.60 (lH, d, J = 8.6 Hz),
8.02 (lH, dd, h = 8.6 Hz, h = 2.5 Hz), 8.37 (lH, s). LC-MS (ESI) calculated for
C25H21FN404S 492.13, found 493.1 [M+H+].
WO 20121170536
c) (IR,2S,7 R,8S)-S-(7 -Aminomethyl-l, I-dioxo-l,4-dihydro-lA, _
benzo[I,2,4]thiadiazinyl)(4-fluoro-benzyl)hydroxyaza
tricyc1o[6.2.1.02.7]undec-S-enone hydrochloride
O~/o
I:l OH ~ ... ~NH2· Hel
cdX~~
llAF
(IR,2S, 7 R,8S)[3-( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyc1o[6.2.1.02.7]undec-S-en-S-yl]-I, I-dioxo-l ,4-dihydro-l ')..,6_
benzo[I,2,4]thiadiazinecarbonitrile (0.38 g, 0.77 mmol) was dissolved in methanol
(required gentle heating via heat gun). Concentrated aqueous hydrochloric acid
solution (S mL) was added followed by 10% palladium on carbon (-ISO mg). The
mixture was degassed and backfilled with hydrogen gas via balloon. The mixture
stirred at 2S °C for 3 h. The mixture was passed through a plug of Celite, eluting with
additional methanol (200 mL). The filtrate was concentrated in vacuo to afford the
desired product, (IR,2S, 7 R,8S)-S-(7 -aminomethy 1-1, I-dioxo-l ,4-dihydro-l ').., _
benzo[I,2,4]thiadiazinyl)(4-fluoro-benzyl)hydroxyaza
tricyc1o[6.2.1.02.7]undec-S-enone hydrochloride (-0.77 mmol), as a pale yellow
solid. The solid was used directly in the next step without further purification or
characterization. LC-MS (ESI) calculated for C25H25FN404S 496.16, found 497.3
[M+H+].
d) N- {3-[(IR,2S,7 R,8S)( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyc1o[6.2.1.02.7]undec-S-en-S-yl]-I, I-dioxo-l ,4-dihydro-l ')..,6_
benzo[I,2,4]thiadiazin-7 -ylmethyl} -methane sulfonamide
0" //0 q,..,O
S s ....
= OH ~ ... ~~ ... \
- '-':: N~
llAF
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(lR,2S,7 R,8S)(7 -Aminomethyl-1, 1-dioxo-1 ,4-dihydro-lA,
benzo[1,2,4]thiadiazinyl)(4-fluoro-benzyl)hydroxyaza
tricyclo[6.2.1.02.7]undecenone hydrochloride (crude from previous step, - 0.77
mmol) was dissolved in methylene chloride (10 mL). Triethylamine (2 mL) and
pyridine (2 mL) were added. Methane sulfonyl chloride (2 mL) was added and the
mixture stirred at 25°C for 20 min. Water (50 mL) was added and the mixture stirred
for 5 min. The solution was diluted with ethyl acetate (200 mL) and washed with 1.0
M aqueous hydrochloric acid solution (3 x 300 mL), saturated aqueous ammonium
chloride solution (2 x 200 mL) and saturated aqueous brine solution (200 mL). The
organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to
afford a clear oil. Purification by flash column chromatography (Teledyne Isco
RediSep column; 25-100% ethyl acetate in hexanes) followed by concentration in
vacuo afforded the desired product, N-{3-[(lR,2S,7R,8S)(4-fluoro-benzyl)
hydroxyoxoaza-tricyclo[6.2.1.02.7]undecenyl]-1, 1-dioxo-1,4-dihydro-lA, _
benzo[1,2,4]thiadiazinylmethyl}-methanesulfonamide (0.139 g, 0.238 mmol, 31 %)
as a white, brittle foam. IH NMR (400 MHz, DMSO-d ) 8: 1.19 - 1.25 (lH, m), 1.40
- 1.64 (5H, m), 2.50 - 2.54 (lH, m), 2.64 (lH, d, J = 2.5 Hz), 2.92 (3H, s), 3.04 (lH,
d, J = 8.8 Hz), 3.53 (lH, d, J = 9.5 Hz), 4.25 (2H, d, J = 6.2 Hz), 4.42 (lH, d, J = 15.8
Hz), 4.97 (lH, d, J = 14.7 Hz), 7.12 - 7.17 (2H, m), 7.33 (2H, dd, h = 7.7 Hz, h = 5.4
Hz), 7.52 (lH, d, J = 8.7 Hz), 7.63 - 7.70 (2H, m), 7.81 (lH, s). LC-MS (ESI)
calculated for C26H27FN406S2 574.14, found 575.3 [M+H+].
Scheme 2 provides a general procedure that can be used to prepare
saturated 5,6-dihydro-1H-pyridinone compounds of Examples 2, 3, 5, 6, 7, 9, 10
and 11.
Scheme 2
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n = 1,2
R = an aliphatic or lDCC'DMF
aromatic leaving group
The saturated cyclic N-substituted-B-amino acid ester intermediates can
be obtained as described by one of the methods in Schemes 2a-e which can be
condensed with a carboxylic acid intermediate using standard peptide coupling
conditions used for the formation of amide bonds, such as DCC, to yield the shown
amide. This intermediate can be cyclized with or without isolation in the presence of
a base (e.g., triethylamine) to give the desired saturated 5,6-dihydro-lH-pyridinone
compounds.
Scheme 2a
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W-C(O)-RW
Pd-C, H2 (1 atm)
NaCNBH , NaOAc
EtOAc, 25°C
4A mol. sieves
MeOH, 25 OC
Commercially available saturated cyclic meso-anhydrides can be
desymmetrized with the help of enzymes or chiral reagents, such as cinchona
alkaloids (e.g., quinine or quinidine) as described in the literature to provide optically
1. Org. Chern., 65, 6984-
active saturated cyclic dicarboxylic acid monoesters. See
6991 (2000); Synthesis, 11,1719-1730 (2001), and references cited therein. These
intermediates can be further elaborated into protected optically active saturated cyclic
B-amino acid esters (e.g., Cbz-protected) via a rearrangement reaction, such as the
Curtius rearrangement (shown) or a Hofmann degradation. Hydrogenation of the
protected saturated cyclic B-amino acid esters under standard conditions can be used
to remove the protecting group and furnish the optically active saturated cyclic B
amino acid esters, which can be isolated (and used) as either the free bases or their
corresponding salts. The optically active saturated cyclic B-amino acid esters (or their
salts) can then be treated with aldehydes or ketones, where R and R are
independently C}-C5 alkyl, C -C cycloalkyl, -C}-C5 alkylene(C -C cycloalkyl), -C}
3 8 3 8
C5 alkylene(aryl), -C}-C5 alkylene(heterocyclyl), aryl, or heterocyclyl, or R can
combine with R to form a 3- to 8-membered ring, in the presence of a reducing agent
(such as sodium cyanoborohydride) to afford the desired optically active saturated
cyclic N-substituted-B-amino acid ester intermediates. Alternatively, the reaction
sequence described above can be performed without enzymes or chiral reagents
leading to the corresponding achiral intermediates and products.
Scheme 2b provides a general procedure that can be used to prepare
cyclic N-substituted-B-amino acid ester intermediates from unsaturated anhydrides.
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Scheme 2b
RX-CHO
RX-C(O)-RW
1. H 2, 5% Pd/C, EtOAc NaCNBH , NaOAc
2. HCI-dioxane
4A mol. sieves
Et 0
MeOH, 25 OC
Commercially available unsaturated cyclic meso-anhydrides can be
desymmetrized as described above in Scheme 2b to provide optically active
unsaturated cyclic dicarboxylic acid monoesters. These intermediates can be further
elaborated into protected optically active unsaturated cyclic B-amino acid esters (e.g.,
CBz-protected) via a rearrangement reaction, such as the Curtius rearrangement
(shown) or a Hofmann degradation. The CBz protecting group can then be removed
and the olefin reduced via catalytic hydrogenation, thus leading to the optically active
unsaturated cyclic B-amino acid ester intermediates, which can be isolated (and used)
as either the salts or their corresponding free bases.
Scheme 2c provides an alternate general procedure that can be used to
prepare saturated cyclic N-substituted-B-amino acid ester intermediates.
Scheme 2c
aq. HCI
RX-CHO
RX-C(O)-RW
NaCNBH , NaOAc
4A mol. sieves
MeOH, 25°C
Bicyclic olefins, such as norbornene, can be reacted with chlorosulfonyl
isocyanate to yield the B-lactams shown. These intermediates can be hydrolyzed in
WO 20121170536
the presence of a strong acid (such as hydrochloric acid) to afford the saturated cyclic
B-amino acids (or their salts), which can then be further elaborated into the
corresponding esters using standard conditions. The saturated cyclic B-amino acid
esters can then be treated with aldehydes or ketones in the presence of a reducing
agent, such as sodium cyanoborohydride, to afford the desired saturated cyclic N
substituted-B-amino acid ester intermediates.
Scheme 2d provides a general scheme describing a method that can be
used to resolve the di-exo enantiomers by diastereomeric crystallization.
Scheme 2d
(15)CSA
EtOAc
rac-di-exo
rac-di-exo
R = Me, Et
RX-CHO
RX-C(O)-RW
NaCNBH , NaOAc
ORa 3
= NH2 4A mol. sieves
ltl"L
MeOH,25 "C
The racemic di-exo-B-amino acid ester derivatives obtained from
norbornene as described above, can be resolved by forming diastereomeric salts with
an optically pure acid, such as (lS)-(+)-lO-camphorsulfonic acid. The (lR,2R,3S,4S)
B-amino acid ester derivatives form a crystalline salt with (lS)-( + )
camphorsulfonic acid that can be selectively isolated by filtration from an appropriate
solvent (e.g., ethyl acetate) and treated with a base, such as sodium carbonate, to
afford the free enantiomerically pure cyclic (lR,2R,3S,4S)-B-amino acid esters. The
optically pure cyclic (lR,2R,3S,4S)-B-amino acid esters (or their salts) can then be
treated with aldehydes or ketones in the presence of a reducing agent, such as sodium
cyanoborohydride, to afford the desired optically pure saturated cyclic N-substituted
(lR,2R,3S,4S)-B-amino acid ester intermediates.
Scheme 2e provides an alternative procedure that can be used to prepare
enantiomerically pure saturated cyclic N-substituted-B-amino acid ester intermediates.
Scheme 2e
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K C0 , EtOAc
then
RX-CHO or
(1 S)CSA
RX-C(O)-RW
CCd:
crf:.Eto,s~
EtOAc, EtOH
7 NH
NaCNBH , AcOH
3 H '
rac-di-exo R2
50-75°C
EtOH,25 'C
The B-lactam (prepared as described in Scheme 2c) can be opened and
resolved by forming diastereomeric salts with an optically pure acid, such as (lS)-( +)-
1O-camphorsulfonic acid (as described in scheme 2d) in the presence of an alcohol
(e.g., ethanol) to directly afford the diastereomerically pure (lR,2R,3S,4S)-B-amino
acid ester as a salt with (lS)-( + )-1O-camphorsulfonic acid. Treatment with a base,
such as potassium carbonate, followed by reductive alkylation with aldehydes or
ketones in the presence of a reducing agent, such as sodium cyanoborohydride,
affords the desired enantiomerically pure saturated cyclic N-substituted
(lR,2R,3S,4S)-B-amino acid ester intermediates.
Example 2: N-{ 3-[(1R,2S,7 R,8S)( 4-Fluoro-benzyl)hydroxyoxo-
3-aza-tricyclo[6.2.1.02,7]undec-S-en-S-yl]-1, 1-dioxo-1,4-dihydro-1"A _
benzo[ 1 ,2,4 Hhiadiazin-7 -yl} -methanesulfonamide
0l\./..O H
"S" N
OH HN .... V's""""" ~~
~ ~ ~ 0 0
- ~ N ~
llAF
a) (lS,2S,3R,4R)(Methoxycarbonyl)bicyclo[2.2.1]hept-S-ene
carboxylic acid
~OCH3
The title compound was prepared as described in 1. Org. Chern. 2000,
65, 6984-6991. cis-S-Norbornene-endo-2,3-dicarboxylic anhydride (S g, 30.4S mmol)
was suspended in a 1:1 mixture of toluene and carbon tetrachloride (610 mL). The
mixture was stirred for 10 min. Quinine (10.87 g, 33.S mmol) was added and the
WO 20121170536
flask was degassed and backfilled with nitrogen. The solution was cooled to -55°C.
While stirring, methanol (3.7 mL, 91.35 mmol) was added. The mixture was stirred
at -55°C for 16 h. Upon warming to 25°C, the mixture was concentrated in vacuo to a
foam. The foam was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M
aqueous hydrochloric acid solution (400 mL). The layers were separated and the
organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2 x
200 mL), aqueous saturated brine solution (100 mL) and dried over magnesium
sulfate, filtered, and concentrated in vacuo to afford the desired product,
(IS,2S,3R,4R)(methoxycarbonyl)bicyclo[2.2.1]heptenecarboxylic acid (5.95
g, 30.3 mmol, 99% yield) as a clear oil. IH NMR (400 MHz, DMSO-d6) 8: 1.31 (IH,
d, J = 8.5 Hz), 1.98 (IH, d, J = 8.6 Hz), 2.51 (2H, d, J = 1.6 Hz), 2.95 (2H, bs), 3.52
(3H, s), 6.17 - 6.21 (2H, m), 12.16 (IH, s).
b) Methyl (IR,2R,3S,4S)
{[(benzyloxy)carbonyl]amino} bicyclo[2.2.1]heptenecarboxylate
~OCH3
~N-CbZ
(IS,2S,3R,4R)(Methoxycarbonyl)bicyclo[2.2.1]heptene
carboxylic acid (5.9 g, 30 mmol) was dissolved in anhydrous tetrahydrofuran (133
mL). The flask was degassed and backfilled with nitrogen and the mixture was
O°C. Triethylamine (12.64 mL, 90 mmol) was added followed by the
cooled to
dropwise addition of ethyl chloroformate (5.72 mL, 60 mmol) with vigorous stirring.
Immediate precipitation was observed. The mixture was stirred at O°C for 1 h.
Sodium azide (5.86 g, 90 mmol) was dissolved in water (40 mL) and added to the
O°C. The mixture was stirred at O°C for 5 min. The ice bath was
reaction mixture at
removed. The mixture was warmed to 25°C and continued to stir for 2 h. The
mixture was poured into water (300 mL) and the product extracted into ethyl acetate
(300 mL). The organic layer was further washed with V2 saturated aqueous sodium
(2 x 100 mL), aqueous saturated brine solution (100 mL), dried
bicarbonate solution
over magnesium sulfate, filtered, and concentrated in vacuo to afford a light brown
oil. The oil was dissolved in anhydrous benzene (66 mL) and refluxed while stirring
under nitrogen for 2 h. Upon cooling to 25°C the solution was concentrated in vacuo
to afford a light brown oil. The oil was dissolved in dichloromethane (40 mL) and
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benzyl alcohol (3041 mL, 33 mmol) was added followed by triethylamine (8044 mL,
60 mmol). The mixture was refluxed under nitrogen for 16 h. Upon cooling to 25°C
the solution was concentrated in vacuo to afford a thick oil. Purification by flash
column chromatography (Merck silica gel 60, 40-63 11m, column 1: 3:1 hexanes/ethyl
acetate; column 2: 2:4: 1 dichloromethane/pentane/diethyl ether) afforded the desired
product, methyl (lR,2R,3S,4S){ [(benzyloxy)carbonyl] amino } bicyclo[2.2.l]hept
enecarboxylate (6.95 g, 23.09 mmol, 77% yield) as a pale yellow oil. IH NMR
(400 MHz, CDCh) 8: 1.59 (lH, d, J = 9.3 Hz), 1.96 (lH, d, J = 9.3 Hz), 2.66 (lH, d, J
= 7.9 Hz), 2.75 (lH, s), 2.96 (lH, s), 3.59 (3H, s), 4.01 (lH, t, J = 8.5 Hz), 5.09 (2H,
q, J = lOA Hz), 5046 (lH, d, J = 904 Hz), 6.17 - 6.22 (2H, m), 7.29 - 7.36 (5H, m).
LC-MS (ESI) calcd for C H N0 301.13, found 258.1 (100%), 302.2 [M+H+]
17 19 4
(70%),603.5 [2M+H+] (20%).
c) Methyl (1 S ,2R,3S ,4R)aminobicyclo [2. 2.1 ]heptanecarboxy late
hydrochloride
OCH3
crr:
~ NH2 - Hel
Methyl (lR,2R,3S,4S)
{[(benzyloxy)carbonyl]amino} bicyclo[2.2.1]heptenecarboxylate (1 g, 3.32
mmol) was dissolved in ethyl acetate (15 mL). 5% Palladium on carbon (120 mg)
was added. The flask was degassed and backfilled with hydrogen gas via balloon.
The mixture was stirred at 25°C for 16 h. The mixture was passed through a plug of
Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil
was dissolved in diethyl ether (10 mL) and added dropwise, with vigorous stirring, to
a mixture of 4.0 M hydrochloric acid solution in l,4-dioxane (1.8 mL) in diethyl ether
(18 mL). The desired product began to precipitate as a white solid. Additional
diethyl ether (10 mL) was added and the mixture was stirred for 10 min. The
precipitate was collected by vacuum filtration, washed with additional diethyl ether (2
x 8 mL). The solid was further dried in vacuo for 1 h. to afford the desired product,
methyl (lS,2R,3S,4R)aminobicyclo[2.2.1]heptanecarboxylate hydrochloride
(0.64 g, 3.11 mmol, 94% yield) as a white powder. IH NMR (400 MHz, DMSO-d6)
8: 1.17 -1.27 (3H, m), lAO -1.61 (2H, m), 1.91 (lH, d, J= 10.7 Hz), 2.36 (lH, d, J=
4.1 Hz), 2044 (lH, d, J = 3.1 Hz), 2.75 (lH, d, J = 7.8 Hz), 3.30 - 3.38 (lH, m), 3.61
WO 20121170536
(3H, s), 8.0S (3H, bs). LC-MS (ESI) ca1cd for C9H15N02 (free amine) 169.11, found
170.3 [M+H+] (100%), 339.3 [2M+H+] (SO%).
({f: 3
llAF
d) Methyl (lS,2R,3S,4R)[( 4-
Fluorobenzyl) amino ]bicyclo[2.2.1 ]heptanecarboxylate Methyl (lS,2R,3S,4R)
aminobicyclo[2.2.1]heptanecarboxylate hydrochloride (O.S g, 2.43 mmol) was
dissolved in methanol (12 mL). Sodium acetate (0.4 g, 4.86 mmol) was added
followed by 4A powdered molecular sieves (O.S g) and 4-fluoro-benzaldehyde (0.302
g, 2.43 mmol). Sodium cyanoborohydride (0.30S g, 4.86 mmol) was added and the
mixture was stirred at 2SoC for 16 h. The mixture was poured into a mixture of
aqueous saturated sodium bicarbonate solution (200 mL) and ethyl acetate (300 mL).
After shaking, both layers were passed through a plug of Celite. The organic phase
was further washed with aqueous saturated sodium bicarbonate solution (100 mL),
aqueous saturated brine solution (100 mL), dried over magnesium sulfate, filtered,
and concentrated in vacuo to afford the crude product, methyl (lS,2R,3S,4R)[(4-
fluorobenzyl)amino]bicyclo[2.2.1]heptanecarboxylate (0.663 g, 2.39 mmol, 98%
yield) as a clear oil. LC-MS (ESI) ca1cd for C16H20FN02 277.1S, found 278.2
[M+H+] (100%).
e) N- {3-[(lR,2S, 7 R,8S)( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyclo[6.2.1.02.7]undec-S-en-S-yl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[1,2,4]thiadiazin-7 -yl} -methanesulfonamide
0l\./..O H
"s~ N
OH HN .... V "'s"""'"
~ ~ ....., 0 0
- ~ N ~
llAF
Methyl (lS,2R,3S,4R)[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-
2-carboxylate (0.6 g, 2.16 mmol) was dissolved in anhydrous N,N-
WO 20121170536
dimethylfonnamide (20 mL). (7-Methanesulfonylamino-l, l-dioxo-l ,4-dihydro-l "A _
benzo[1,2,4]thiadiazinyl)-acetic acid (US 7,939,524 B2) (0.72 g, 2.16 mmol) was
added followed by N-methylmorpholine (0.5 mL, 4.54 mmol). The mixture was
stirred until everything dissolved, approximately 5 min. 1-(3-Dimethylaminopropyl)-
3-ethy1carbodiimide hydrochloride (0.435 g, 2.27 mmol) was added and the mixture
was stirred at 25°C for 45 min. Triethylamine (0.91 mL, 6.48 mmol) was added and
the mixture was stirred at 50°C for 16 h.
Upon cooling to 25°C, the solution was diluted with ethyl acetate (300
mL) and washed with 1.0 M aqueous hydrochloric acid solution (3 x 300 mL),
aqueous saturated brine solution (100 mL), dried over magnesium sulfate, filtered,
and concentrated in vacuo to afford a golden oil. Purification by flash column
chromatography (Merck silica gel 60, 40-63 11m, 0 to 0.75% methanol in
dichloromethane) afforded the product as white foam. The foam was dissolved in
methanol (10 mL) and the product was precipitated by the addition of 1.0 M aqueous
hydrochloric acid solution (20 mL) while stirring. The solid was collected by vacuum
filtration and further dried in vacuo to afford the desired product, N-{3-
[(lR,2S,7 R,8S)( 4-fluoro-benzyl)hydroxyoxoaza-tricyc1o[ 6.2.1.0 .7 ]undec-
-enyl]-1, l-dioxo-l,4-dihydro-l"A -benzo[1,2,4 ]thiadiazin-7 -yl}
methanesulfonamide (0.573 g, 1.02 mmol, 47% yield) as a white powder. IH NMR
(400 MHz, DMSO-d ) 8: 1.16 - 1.22 (2H, m), 1.37 - 1.65 (4H, m), 2.49 - 2.53 (lH,
m), 2.63 (lH, d, J = 2.3 Hz), 3.02 (lH, d, J = 8.5 Hz), 3.05 (3H, s), 3.52 (lH, d, J =
9.4 Hz), 4.41 (lH, d, J = 15.6 Hz), 4.95 (lH, d, J = 15.6 Hz), 7.14 (2H, t, J = 9.0 Hz),
7.32 (2H, dd, h = 8.1 Hz, h = 5.7 Hz), 7.50 (lH, dd, h = 9.5 Hz, h = 2.3 Hz), 7.55 -
7.57 (2H, m), 1O.l7 (lH, s). LC-MS (ESI) ca1cd for C25H25FN406S2 560.12, found
561.3 [M+H+] (100%). ee = 90% [HPLC-analysis: Chiralpak AS-RH 2.1 x 150
mm,5 micron at r.t., Solvent A - Solvent B (see table for gradient), 0.3 mL/min, 312
nm, tl = 4.3 min (major), t2 = 6.0 min].
Alternatively, N- {3-[(IS,2S, 7 R,8R)( 4-fluoro-benzyl)hydroxy
oxoaza-tricyc1o[6.2.1.02.7]undecenyl]-I, I-dioxo-l ,4-dihydro-l"A _
benzo[I,2,4]thiadiazinyl}-methanesulfonamide can be prepared as follows:
f) (rac-di-exo )Aza-tricyc1o[ 4.2.1.0 .5]nonanone
WO 20121170536
rac-di-exo
To a solution of bicyc1o[2.2.l]heptene (21.29 g, 223.8 mmol) in
diethyl ether (100 mL) at O°C was added a solution of chlorosulfonyl isocyanate (20.0
mL, 225.7 mmol) in diethyl ether (40 mL) dropwise over 10 min. The mixture was
allowed to slowly warm to 25°C for 12 h. The reaction mixture was cooled to O°C
and a solution of sodium sulfite (39.16 g, 301.4 mmol) in water (300 mL) was added
dropwise with stirring. The mixture was allowed to warm to 25°C. To this mixture
was added 10% aqueous potassium hydroxide solution until the pH reached 7-8. The
organic layer was separated and the aqueous layer was extracted with diethyl ether (2
x 100 mL). The combined organic layers were washed with aqueous saturated brine
solution (100 mL), dried over anhydrous magnesium sulfate, concentrated in vacuo,
and dried under high vacuum to afford the crude (rac-di -exo )aza-
tricyc1o[ 4.2.1.0 .5]nonanone (23.37 g, l70.4 mmol, 76% yield) as a white solid. IH
NMR (400 MHz, CDCh) 8: 1.02 - 1.11 (2H, m), 1.24 (lH, dt, h = 10.9 Hz, 12 = 1.6
Hz), 1.51 - 1.72 (3H, m), 2.37 - 2.37 (lH, m), 2.43-2.44 (lH, m), 2.99-3.00 (lH, m),
3.40 (lH, d, 1 = 3.4 Hz), 5.73 (lH, bs).
g) (rac-di-exo )Amino-bicyc1o[2.2.l]heptanecarboxylic acid
hydrochloride
rac-di-exo
To (rac-di -exo )aza-tricyc1o[ 4.2.l.0 .5]nonanone (23.37 g, 170.4
mmol) was added 12.0 M aqueous hydrochloric acid solution (150 mL). The mixture
was stirred at 25°C for 12 h. The solvent was evaporated in vacuo and the crude
compound was dried under high vacuum for 0.5 h. The crude compound was
triturated with acetone and filtered to afford (rac-di-exo )amino
bicyc1o[2.2.l]heptanecarboxylic acid hydrochloride (28.43 g, 148.3 mmol, 87%
yield) as a white solid. IH NMR (400 MHz, DMSO-d6) 8: 1.15 - 1.26 (3H, m), 1.42-
1.59 (2H, m), 1.87 (lH, d, 1 = 10.3 Hz), 2.33 (lH, d, 1 = 3.4 Hz), 2.45 (lH, d, 1 = 2.3
Hz), 2.67 (lH, d, 1 = 7.6 Hz), 3.23-3.26 (lH, m), 7.93 (3H, bs), 12.73 (lH, bs).
WO 20121170536
h) (rac-di-exo )Amino-bicyc1o[2.2.1]heptanecarboxylic acid ethyl
ester hydrochloride
rac-di-exo
To absolute ethanol (75 mL) at _10°C was added thionyl chloride (4.1
mL, 54.5 mmol) dropwise followed by (rac-di-exo )amino-bicyc1o[2.2.1]heptane
carboxylic acid hydrochloride (9.60 g, 50.1 mmol). The mixture was stirred at O°C
for 1 h, at 25°C for 4 h, and heated at reflux for 0.5 h. The solution was concentrated
in vacuo and dried under high vacuum to afford the crude (rac-di-exo )amino
bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester hydrochloride (11.01 g, 50.1
mmol, 100% yield) as an off-white solid. IH NMR (400 MHz, DMSO-d6) 8: 1.17-
1.27 (3H, m), 1.21 (3H, t, J = 7.0 Hz), 1.43-1.57 (2H, m), 1.91 (lH, d, J = 10.0 Hz),
2.36 (lH, d, J = 3.9 Hz), 2.42 (lH, d, J = 3.0 Hz), 2.72 (lH, d, J = 7.6 Hz), 3.28 (lH,
d, J = 8.3 Hz), 4.00-4.13 (2H, m), 8.06 (3H, bs).
i) (rac-di-exo )Amino-bicyc1o[2.2.1]heptanecarboxylic acid ethyl
ester
rac-di-exo
To (rac-di -exo )amino-bicyc1o[2.2.1]heptanecarboxylic acid ethyl
ester hydrochloride (11.01 g, 50.1 mmol) was added saturated aqueous sodium
bicarbonate solution (50 mL) and the mixture was stirred at 25°C for 0.5 h. The crude
product was extracted with ethyl acetate (3 x 100 mL). The solution was dried over
anhydrous magnesium sulfate, filtered, concentrated in vacuo and dried under high
vacuum for 2 h to afford the crude (rac-di-exo)amino-bicyc1o[2.2.1]heptane
carboxylic acid ethyl ester (8.17 g, 44.6 mmol, 89% yield) as a brown oil. IH NMR
(400 MHz, CDCb) 8: 1.10-1.26 (3H, m), 1.29 (3H, t, J = 7.0 Hz), 1.45-1.62 (2H, m),
1.86 (2H, bs), 1.95 (lH, dt, h = 10.3 Hz, h = 1.9 Hz), 2.09 (lH, d, J = 4.5 Hz), 2.49
(lH, d, J = 4.2 Hz), 2.56 (lH, d, J = 9.0 Hz), 3.24 (lH, d, J = 7.7 Hz), 4.09-4.21 (2H,
WO 20121170536
j) (lR,2S,3R,4S)Ethoxycarbonyl-bicyc1o[2.2.1]heptyl-ammonium
(1' S)-( + )-1O-camphorsulfonate
crfO~t03S~
f1 3
To a solution of (rac-di-exo )amino-bicyc1o[2.2.1]heptane
carboxylic acid ethyl ester (4.00 g, 21.8 mmol) in ethyl acetate (120 mL) was added
(lS)-( + )-1O-camphorsulfonic acid (2.57 g, 11.0 mmol). The mixture was stirred at
°C vigorously for 0.5 h. The solid (3.23 g, 7.77 mmol) was filtered and
recrystallized in ethyl acetate (360 mL) to afford (lR,2S,3R,4S)ethoxycarbonyl
bicyc1o[2.2.1]heptyl-ammonium (1' S)-( + )-1O-camphorsulfonate (2.76 g, 6.64
mmol, 30% yield) as a white solid. IH NMR (400 MHz, CDCb) 8: 0.84 (3H, s), 1.08
(3H, s), 1.30 (3H, t, 1 = 6.9 Hz), 1.32-1.43 (4H, m), 1.58-1.75 (3H, m), 1.89 (lH, d, 1
= 17.7 Hz), 1.95-2.07 (3H, m), 2.33 (lH, dt, h = 18.4 Hz, 12 = 3.9 Hz), 2.53 (lH, s),
2.58-2.65 (lH, m), 2.69 (lH, d, 1 = 2.9 Hz), 2.76-2.79 (2H, m), 3.26 (lH, d, 1 = 14.1
Hz), 3.60 (lH, d, 1 = 7.4 Hz), 4.14-4.27 (2H, m), 7.80 (3H, bs).
k) (lS,2R,3S,4R)Amino-bicyc1o[2.2.1]heptanecarboxylic acid ethyl
ester
ltill.lL
= NH2
To (lR,2S,3R,4S)Ethoxycarbonyl-bicyc1o[2.2.1 ]heptyl-ammonium
(1' S)-( + )-1O-camphorsulfonate (2.76 g, 6.64 mmol) was added ethyl acetate (28 mL)
and saturated aqueous sodium carbonate solution (28 mL) and the mixture was stirred
at 25°C for 0.5 h. The organic layer was separated and the aqueous layer was
extracted with ethyl acetate (2 x 50 mL). The solution was dried over anhydrous
magnesium sulfate, concentrated in vacuo and dried under high vacuum for 1 h to
afford (lS,2R,3S,4R)amino-bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester
(1.15 g, 6.28 mmol, 95% yield) as a colorless oil. IH NMR (400 MHz, CDCb) 8:
1.10-1.26 (3H, m), 1.29 (3H, t, 1 = 7.0 Hz), 1.45-1.62 (2H, m), 1.86 (2H, bs), 1.95
(lH, dt, h = 10.3 Hz, h = 1.9 Hz), 2.09 (lH, d, 1 = 4.5 Hz), 2.49 (lH, d, 1 = 4.2 Hz),
2.56 (lH, d, 1 = 9.0 Hz), 3.24 (lH, d, 1 = 7.7 Hz), 4.09-4.21 (2H, m).
WO 20121170536
In order to determine enantiomeric excess, (lS,2R,3S,4R)amino-
bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester was derivatized to the (S)
mandelate salt as follow: To a solution of (lS,2R,3S,4R)amino
bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester (34.2 mg, 0.187 mmol) in ethyl
acetate (1 mL) was added (S)-a-hydroxyphenylacetic acid (28.7 mg, 0.187 mmol) and
the mixture was stirred at 25°C for 0.5 h. The solid was filtered and dried under high
vacuum to afford (lR,2S,3R,4S)ethoxycarbonyl-bicyc1o[2.2.1]heptyl
ammonium (S)-a-hydroxyphenylacetate (11.4 mg, 0.034 mmol, 18% yield, 97% de)
as a white solid. IH NMR (400 MHz, CDCb) 8: 1.08-1.20 (3H, m), 1.28 (3H, t, J =
7.1 Hz), 1.50-1.59 (2H, m), 1.79 (lH, d, J = 10.9 Hz), 2.23 (lH, s), 2.46-2.48 (2H, m),
3.04 (lH, d, J = 7.8 Hz), 4.05-4.18 (2H, m), 4.89 (lH, s), 5.49 (3H, bs), 7.22-7.31
(3H, m), 7.43 (2H, d, J = 6.9 Hz).
1) (lS,2R,3S,4R)( 4-Fluorobenzylamino )-bicyc1o[2.2.1]heptane
carboxylic acid ethyl ester
lti"'L
llAF
To a solution of (lS,2R,3S,4R)amino-bicyc1o[2.2.1]heptane
carboxylic acid ethyl ester (1.15 g, 6.28 mmol) in ethanol (30 mL) was added 4-
fluorobenzaldehyde (0.68 mL, 6.31 mmol), glacial acetic acid (0.4 mL, 6.99 mmol),
and sodium cyanoborohydride (1.04 g, 15.7 mmol) at 25°C. After stirring for 3 h, the
mixture was diluted with ethyl acetate (50 mL) and quenched with saturated aqueous
sodium bicarbonate (50 mL) for 0.5 h. The mixture was filtered through Celite. The
organic layer was separated and the aqueous layer was extracted with ethyl acetate
(50 mLx2). When all solvent was removed, a solid was fonned. The solid was
filtered, washed with water, and dried under vacuum to afford (lS,2R,3S,4R)(4-
fluorobenzylamino)-bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester (1.74 g, 5.97
mmol, 95% yield) as a white solid. IH NMR (400 MHz, CDCb) 8: 1.05-1.16 (2H,
m), 1.21 (lH, dt, h = 8.0 Hz, h = 1.6 Hz), 1.27 (3H, t, J = 7.4 Hz), 1.45-1.61 (2H,
m), 1.94 (lH, dt, h = 10.1 Hz, h = 1.9 Hz), 2.28 (lH, d, J = 3.9 Hz), 2.43 (lH, d, J =
3.3 Hz), 2.60 (lH, dd, h = 8.8 Hz, h = 1.5 Hz), 2.94 (lH, d, J = 7.8 Hz), 3.66 (lH, d,
WO 20121170536
J = 13.2 Hz), 3.80 (lH, d, J = 13.5 Hz), 4.13 (2H, q, J = 7.0 Hz), 6.97 (2H, t, J = 8.5
Hz), 7.26 (2H, t, J = 7.1 Hz).
m) (lS,2R,3S,4R) {( 4-Fluorobenzyl)-[2-(7 -methanesulfonylamino-1, 1-
dioxo-1 ,4-dihydro- U -benzo[1,2,4 ]thiadiazinyl)-acetyl]-amino}
bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester
- OEt II 0
o s'/
- ):JH
:N I "~N
f1 I 'S-
~ N __ ~\\
F~ H 00
To a solution of (lS,2R,3S,4R)(4-fluorobenzylamino)-
bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester (100.6 mg, 0.345 mmol) in N,N
dimethylfonnamide (3.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-
dihydro-U -benzo[1,2,4]thiadiazinyl)-acetic acid (US 7,939,524 B2) (120.8 mg,
0.362 mmol), 4-dimethylaminopyridine (10.6 mg, 0.086 mmol), and 1-[3-
(dimethylamino)propyl]ethy1carbodiimide hydrochloride (70.9 mg, 0.362 mmol).
After stirring at 25°C for 12 h, the mixture was diluted with ethyl acetate and acidified
with 1.0 M aqueous hydrochloric acid solution to pH 1. The organic layer was
separated and the aqueous layer was extracted with ethyl acetate (2 x 20 mL). The
combined organic layer was dried over anhydrous magnesium sulfate, filtered,
concentrated in vacuo, and dried under high vacuum to afford the crude
(lS,2R,3S,4R){ (4-fluorobenzyl)-[2-(7 -methanesulfonylamino-1, 1-dioxo-1,4-
dihydro- U -benzo[1,2,4 ]thiadiazinyl)-acetyl]-amino} -bicyc1o[2.2.1]heptane
carboxylic acid ethyl ester as a faintly yellow oil. The crude product was used in the
next step without further purification. LC-MS (ESI) ca1cd for C27H31FN407S2
(M+H+) 607.17, found 607.2.
n) N- {3-[(lR,2S,7 R,8S)( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyc1o[6.2.1.02.7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[1,2,4]thiadiazin-7 -yl} -methanesulfonamide
WO 20121170536
O,p H
'd N
NI":V~ ~/~{'
= '" 0 0
- ~ N //
To a solution of (IS,2R,3S,4R){ (4-fluorobenzyl)-[2-(7-
methanesulfonylamino-l, I-dioxo-l,4-dihydro- U -benzo[1 ,2,4]thiadiazinyl)
acetyl]-amino }-bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester (209.3 mg, 0.345
mmol) in absolute ethanol (3 mL) was added a 21 wt. % solution of sodium ethoxide
in ethanol (0.51 mL, 1.37 mmol). After stirring at 60°C for 2 h, the mixture was
diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution
to pH 1. The organic layer was separated and the aqueous layer was extracted with
ethyl acetate (2 x 20 mL). The combined organic layer was dried over anhydrous
magnesium sulfate, filtered, and concentrated in vacuo. The crude mixture was
purified by flash column chromatography (Teledyne ISCO RediSep column, 0 to
100% ethyl acetate in hexanes) to afford N-{3-[(IR,2S,7R,8S)(4-fluoro-benzyl)
hydroxyoxoaza-tricyc1o[6.2.1.02,7]undecenyl]-I, I-dioxo-l,4-dihydro-lA, _
benzo[I,2,4]thiadiazinyl}-methanesulfonamide (131.5 mg, 0.235 mmol, 68%
yield) as an off-white solid. IH NMR (400 MHz, MeOH-d ) 8: 1.28 (2H, d, J = 11.0
Hz), 1.47 (IH, t, J = 10.8 Hz), 1.57-1.74 (3H, m), 2.56 (IH, d, J = 3.2 Hz), 2.75 (IH,
d, J = 2.3 Hz), 2.96 (IH, d, J = 9.2 Hz), 3.02 (3H, s), 3.58 (IH, d, J = 9.2 Hz), 4.42
(IH, d, J = 15.5 Hz), 5.03 (IH, d, J = 15.7 Hz), 7.04 (2H, t, J = 8.5 Hz), 7.31 (2H, dd,
h = 7.9 Hz, h = 5.5 Hz), 7.37 (IH, d, J = 8.8 Hz), 7.54 (IH, dd, h = 8.3 Hz, h = 2.3
Hz), 7.69 (IH, d, J = 2.3 Hz). LC-MS (ESI) ca1cd for CZ5HZ5FN406SZ (M+H+)
561.13, found 561.4. ee = 98.5% [HPLC-analysis: Chiralpak AS-RH 2.1 x 150 mm, 5
micron at r.t., Solvent A - Solvent B (see table above for gradient), 0.3 mLimin, 312
nm, tl = 7.58 min (major), t2 = 8.95 min].
Example 3: (lR,2S,7 R,8S)(l,1-Dioxo-l ,4-dihydro-lA, _
benzo[I,2,4]thiadiazinyl)(4-fluoro-benzyl)hydroxyaza
tricyc1o[6.2.1.02,7]undecenone
WO 20121170536
0" //0
= OH ~/s~
- --=::: N~
llAF
_a) N-(2-Sulfamoyl-phenyl)-malonamic acid ethyl ester
2-Amino-benzenesulfonamide (5 g, 29 mmol) was dissolved in N,N-
dimethylacetamide (25 mL) and diethyl ether (25 mL). Ethylchlorooxo
propionate (4.6 g, 30.45 mmol) was added into the above reaction solution. The
reaction mixture was stirred at 25°C for 3 h. The product started to precipitate and
was collected by vacuum filtration. The solid was dissolved in ethyl acetate (200 mL)
and extracted with water (200 mL). The aqueous layer was back-extracted with ethyl
acetate (200 mL). The combined organic layers were dried over sodium sulfate,
filtered, and concentrated in vacuo to afford the crude product, N-(2-sulfamoyl
phenyl)-malonamic acid ethyl ester, as a white solid, which was used in the next step
without further purification. IH NMR (400 MHz, DMSO-d6) 8: 1.23 (3H, t, J = 7.0
Hz), 3.61 (2H, s), 4.14 (2H, quartet, J = 7.0 Hz), 7.29 - 7.33 (lH, m), 7.53 (2H, bs),
7.56 - 7.60 (lH, m), 7.84 - 7.86 (lH, m), 7.97 - 7.99 (lH, m), 9.54 (lH, bs). LC-MS
(ESI) ca1cd for C H N 05S 286.06, found 287.1 [M+H+].
ll 14 2
b) (1, 1-Dioxo-1,4-dihydro-lA, -benzo[l ,2,4]thiadiazinyl)-acetic acid
0,/0
° N/~
HO~N~
Solid sodium hydroxide (3.48 g, 87 mmol) was dissolved in water to
make a saturated solution. The crude N-(2-sulfamoyl-phenyl)-malonamic acid ethyl
ester was added into the sodium hydroxide solution. The reaction mixture was heated
at 110 °C for 2.5 h, and then was cooled down to 25 DC. The reaction mixture was
acidified by slowly adding a 12.0 M aqueous hydrochloric acid solution (9.67 g, 116
WO 20121170536
mmol) while cooling in an ice- water bath. The product precipitated and was
collected by vacuum filtration. The solid was washed with cold water and dried under
high vacuum to afford the crude product, (1,1-dioxo-l,4-dihydro-lA,6-
benzo[1,2,4]thiadiazinyl)-acetic acid (5 g, 20.8 mmol, 71.7% over two steps), as a
white solid. IH NMR (400 MHz, DMSO-d ) 8: 3.58 (2H, s), 7.31 (lH, d, J = 8.0 Hz),
7.44 (lH, dd, h = 7.8 Hz, h = 7.8 Hz), 7.67 (lH, dd, h = 7.8 Hz, h = 7.8 Hz), 7.79
(lH, d, J = 7.9 Hz), 12.18 (lH, bs), l3.03 (lH, bs). LC-MS (ESI) calcd for
C H N 0 S 240.02, found 241.1 [M+H+].
8 2 4
c) (lS,2R,3S,4R)[[2-(1, 1-Dioxo-1,4-dihydro-lA, 6_
benzo[ 1 ,2,4 ]thiadiazinyl)-acetyl]-( 4-fluoro-benzyl)-amino ]-bicyc1o[2.2.1 ]heptane-
2-carboxylic acid ethyl ester
o 0 0
. OEt ,,//
- 0 ~.-s~
:N~N~
f1UH
.0 F
(1, 1-Dioxo-1,4-dihydro-lA, -benzo[l ,2,4]thiadiazinyl)-acetic acid
(0.2 g, 0.833 mmol) was dissolved in anhydrous N,N-dimethylformamide (8 mL).
(lS,2R,3S,4R)( 4-Fluoro-benzylamino )-bicyc1o[2.2.1 ]heptanecarboxylic acid
ethyl ester (prepared as described in Example 21, 0.244 g, 0.833 mmol) was added
followed by 1-(3-dimethylaminopropyl)ethylcarbodiimide hydrochloride (0.168 g,
0.875 mmol). Then N-methylmorpholine (0.177 g, 1.75 mmol) was added into the
above reaction mixture. The mixture was stirred at 25°C for 16 h. The solution was
poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer
was extracted with ethyl acetate (2 x 100 mL). The organic layer was dried over
sodium sulfate, filtered, and concentrated in vacuo to afford the crude product,
(lS,2R,3S,4R)[[2-(1, 1-dioxo-1 ,4-dihydro-lA, -benzo[l ,2,4]thiadiazinyl)-acetyl]
(4-fluoro-benzyl)-amino]-bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester, as an
orange oil, which was used in the next step without any further purification. LC-MS
(ESI) calcd for C26H28FN305S 513.58, found 514.4 [M+H+].
d) (lR,2S,7 R,8S)(1,1-Dioxo-1, 2-dihydro-lA,6-benzo[1,2,4]thiadiazin-
3-y 1)( 4-fluoro-benzyl)hydroxyaza-tricyc1o[ 6.2.1.02.7]undecenone
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0,/0
~ OH ~--~
rlX~~
llAF
The crude (lS,2R,3S,4R)[[2-(1, 1-dioxo-1,4-dihydro-IA
benzo[ 1 ,2,4 ]thiadiazinyl)-acetyl]-( 4-fluoro-benzyl)-amino ]-bicyc1o[2.2.1 ]heptane-
2-carboxylic acid ethyl ester was dissolved in ethanol (8 mL), and a 21 wt. % solution
of sodium ethoxide in ethanol (1.6 mL, 4.2 mmol) was added into the above solution.
The mixture was stirred at 60°C for 4 h and allowed to cool down to 25°C. The
mixture was poured into 0.5 M aqueous hydrochloric acid solution (100 mL). The
product started to precipitate and was collected by vacuum filtration. The precipitate
was purified by flash column chromatography (Teledyne Isco RediSep column; 100%
ethyl acetate) to afford the desired product, (lR,2S,7R,8S)(1,1-dioxo-1, 2-dihydro-
1A -benzo[ 1 ,2,4 ]thiadiazinyl)( 4-fluoro-benzyl)hydroxyaza
tricyc1o[6.2.1.02.7]undecenone (0.242 g, 0.517 mmol, 62.1 % over two steps), as
a white solid. IH NMR (400 MHz, DMSO-d6) 8: 1.16 - 1.22 (2H, m), 1.40 - 1.60
(4H, m), 2.51 (lH, bs), 2.64 (lH, d, J = 2.1 Hz), 3.03 (lH, d, J = 8.0 Hz), 3.54 (lH, d,
J = 9.3 Hz), 4.42 (lH, d, J = 15.6 Hz), 4.97 (lH, d, J = 15.7 Hz), 7.15 (2H, t, J = 8.8
h = 8.0 Hz, h = 5.9 Hz), 7.45 - 7.53 (2H, m), 7.67 - 7.71 (lH, m),
Hz), 7.33 (2H, dd,
7.85 (lH, d, J = 7.9 Hz). LC-MS (ESI) ca1cd for C24H22FN304S 467.13, found 468.2
[M+H+]. Anal. ca1cd for C24H22FN304S: C, 61.66; H, 4.74; N, 8.99; found C, 61.96;
H, 4.88; N, 8.99.
Scheme 3 provides a specific procedure that was used to prepare the 5,6-
dihydro-1H-pyridinone compound of Example 4.
Scheme 3
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DCC, DMF
0" //0
.... SX)NHS02Me
H OH N I
dX~ ~
IlAF
Example 4: (4aR,7aS)-N-{3-[1-(4-Fluoro-benzvl)hvdroxvoxo-
2,4a,5,6,7,7 a-hexahvdro-lH-[1]pvrindinvl]-1, l-dioxo-l ,4-dih dro- U _
benzo[ 1 ,2,4 Hhiadiazin-7 -vI} -methanesulfonamide
o 0 H
,,// /
OH N .... SX)N,S ....
-= I I (/'0
. ~ N ~
llAF
a) (lR,2S)Amino-cyc1opentanecarboxylic acid methyl ester
hydrochloride
NH "HCI
(lR,2S)Amino-cyc1opentanecarboxylic acid hydrochloride (96 mg,
0.58 mmol) was dissolved in a 1:1 mixture of benzene and methanol (6 mL). The
mixture was cooled to 0 0c. A 2.0 M solution of (trimethylsilyl)diazomethane in
hexanes (0.44 mL, 0.87 mmol) was added and the reaction was stirred at 25°C for 30
min. The mixture was concentrated and dried in vacuo. The crude product was
directly used in the next step.
b) (lR,2S)( 4-Fluoro-benzylamino )-cyc1opentanecarboxylic acid
methyl ester
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llAF
To a solution of (lR,2S)amino-cyclopentanecarboxylic acid methyl
ester hydrochloride (104 mg, 0.58 mmol) in tetrahydrofuran (6 mL) at 25°C was
added magnesium sulfate (200 mg), triethylamine (0.085 mL, 0.61 mmol), and 4-
fluorobenzaldehyde (0.13 mL, l.19 mmol) sequentially. The reaction was stirred at
°C for 16 h. The mixture was passed through a short pad of Celite and the filtrate
was concentrated and dried in vacuo. The residue was re-dissolved in methanol (10
mL) at 25°C. To this solution was added slowly sodium borohydride (45 mg, l.19
mmol). The mixture was stirred at 25°C for 1 h. It was then poured into a saturated
mL) and the mixture was extracted into
sodium bicarbonate aqueous solution (10
ethyl acetate (20 mL). The organic layer was dried over magnesium sulfate, filtered,
and concentrated in vacuo to afford a clear oil. Purification by flash column
chromatography (Merck silica gel 60, 40-63 11m; 0-15% ethyl acetate in hexanes)
afforded the desired product, (lR,2S)(4-fluoro-benzylamino)
cyclopentanecarboxylic acid methyl ester (116 mg, 0.46 mmol, 79%), as a clear oil.
IH NMR (400 MHz, CDCb) 8: l.55 - l.73 (2H, m), l.83 - l.93 (3H, m), l.99 - 2.08
(lH, m), 2.97 (lH, dd, h = 14.4 Hz, h = 8.0 Hz), 3.31 (lH, dd, h = 14.4 Hz, h = 7.2
Hz), 3.70 (3H, s), 3.77 (2H, dd, h = 19.6 Hz, h = 12.0 Hz), 4.67 (lH, s), 6.96 - 7.06
(2H, m), 7.26 - 7.35 (2H, m). LC-MS (ESI) ca1cd for C14HlSFN0225l.30, found
252.1 [M+H+].
c) (lR,2S) {( 4-Fluoro-benzyl)-[2-(7 -methanesulfonylamino-1, 1-dioxo-
1 ,4-dihydro- U -benzo[ 1 ,2,4 ]thiadiazinyl)-acetyl ]-amino } -cyclopentanecarboxylic
acid methyl ester
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(lR,2S)( 4-Fluoro-benzylamino )-cyc1opentanecarboxylic acid methyl
ester (106 mg, 0.42 mmol) and (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-U -
benzo[1,2,4]thiadiazinyl)-acetic acid (prepared as described in US 7,939,524 B2,
140 mg, 0.42 mmol) were dissolved in a 1: 1 mixture of dichloromethane and N,N' -
dimethylfonnamide (6 mL). A 1.0 M solution of N,N' -dicyc1ohexy1carbodiimide in
dichloromethane (0.46 mL, 0.46 mmol) was added. The reaction was stirred at 25°C
for 16 h. The mixture was concentrated in vacuo and purified by flash column
chromatography (Merck silica gel 60, 40-63 11m; 0-85% ethyl acetate in hexanes) to
afford the desired product, (lR,2S){(4-fluoro-benzyl)-[2-(7-
methanesulfonylamino-1, 1-dioxo-1,4-dihydro-U -benzo[l ,2,4]thiadiazinyl)
acetyl]-amino }-cyc1opentanecarboxylic acid methyl ester (127 mg, 0.22 mmol, 52%),
as a white solid. IH NMR (400 MHz, CDCb) 8: 1.80 - 2.22 (6H, m), 3.07 (3H, s),
3.24 (lH, dd, h = 18.8 Hz, h = 8.0 Hz), 3.32 (lH, dd, h = 15.6 Hz, h = 8.0 Hz), 3.69
(lH, s), 4.63 (2H, d, J = 4.8 Hz), 4.67 - 4.74 (lH, m), 4.82 - 4.89 (lH, m), 6.99 - 7.14
(5H, m), 7.51 - 7.64 (2H, m). LC-MS (ESI) ca1cd for C24H27FN407S2 566.62, found
567.1 [M+H+].
d) (4aR,7aS)-N-{ 3-[1-( 4-Fluoro-benzyl)hydroxyoxo-2,4a,5,6,7,7 a-
hexahydro-1H-[1]pyrindinyl]-1, 1-dioxo-1 ,4-dihydro- U -benzo[l ,2,4]thiadiazin
yl} -methanesulfonamide
o 0 H
~SyYN, /
&~JV ~o
llAF
(lR,2S){ (4-Fluoro-benzyl)-[2-(7 -methanesulfonylamino-1, 1-dioxo-
1 ,4-dihydro- U -benzo[ 1 ,2,4 ]thiadiazinyl)-acetyl ]-amino } -cyc1opentanecarboxylic
acid methyl ester (117 mg, 0.21 mmol) was dissolved in ethanol (10 mL). A 21 %
w/w solution of sodium ethoxide in ethanol (0.17 mL, 0.46 mmol) was added and the
mixture was stirred at 60°C for 4 h. The reaction was allowed to cool to 25°C and
quenched with 1.0 M aqueous hydrochloric acid solution (10 mL). The mixture was
extracted with ethyl acetate (3 x 20 mL). The organic layers were combined, dried
over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was
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purified by flash column chromatography (Merck silica gel 60, 40-63 11m; 0-5%
methanol in dichloromethane) to afford the desired product, (4aR,7aS)-N-{3-[1-(4-
fluoro-benzyl)hydroxyoxo-2,4a,5,6,7 ,7a-hexahydro-lH-[1]pyrindinyl]-1, 1-
dioxo-l,4-dihydro-U -benzo[1,2,4]thiadiazinyl}-methanesulfonamide (80 mg,
0.15 mmol, 71 %), as a white solid. IH NMR (400 MHz, DMSO-d ) 8: 1.46 - 1.61
(4H, m), 1.95 - 2.12 (2H, m), 3.07 (3H, s), 3.85 (lH, bs), 4.48 (lH, bs), 4.91 (lH, d, J
= 14.8 Hz), 7.16 (2H, t, J = 8.4 Hz), 7.40 (2H, bs), 7.50 - 7.61 (3H, m), 10.18 (lH, s).
LC-MS (ESI) ca1cd for C H FN 06S2 534.58, found 535.1 [M+H+]. e.e. = 98%
23 23 4
[HPLC-analysis: Chiralpak AS-RH 4.6 x 250 mm, 5 micron at 25°C, 0.7 mLimin,
310 nm, t1 = 14.89 min, t2 = 22.20 min (major)]. aD = - 40.76 (c = 0.92,
dichloromethane/methanol1 : 1). Anal. ca1cd for C23H23FN406S2 . 0.3 H 0. 0.3
EtOAc ·0.2 Et 0: C, 51.66; H, 4.86; N, 9.64, found C, 51.64; H, 4.90; N, 9.56.
Example 5: N-[3-(1R,2S,7R,8S)Cyc1opentylhydroxyoxoaza-
tricyc1o[6.2.1.02.7]undecenyl)-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[ 1 ,2,4 Hhiadiazin-7 -yl]-methane sulfonamide
o 0 H
~SyYN, /
cdX~~ ~o
R6 a
a) (lS,2R,3S,4R)Cyc1opentylamino-bicyc1o[2.2.1]heptane
carboxylic acid ethyl ester
Cyc1opentanone (0.12 mL, 1.38 mmol) was added to a solution of
(lS,2R,3S,4R)amino-bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester (prepared
as described in Example 2k, 230 mg, 1.26 mmol) in anhydrous methanol (10 mL) at
DC under a nitrogen atmosphere. After stirring for 10 min, glacial acetic acid (0.5
mL) and sodium cyanoborohydride (260 mg, 3.15 mmol) were added sequentially,
and the resulting mixture was stirred at 50 DC for 30 min. The reaction mixture was
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poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl
acetate. The combined organic layers were washed with saturated aqueous brine
solution, dried over sodium sulfate and filtered. The filtrate was concentrated in
vacuo to afford the desired product, (lS,2R,3S,4R)cyc1opentylamino
bicyc1o[2.2.l]heptanecarboxylic acid ethyl ester (237 mg, 0.94 mmol, 75%), as a
yellow oil. LC-MS (ESI) ca1cd for C15H25N02 251.19, found 252.0 [M+H+].
b) N- [3-(lR,2S, 7 R,8S)Cyc1opentylhydroxyoxoaza-
tricyc1o[6.2.1.02.7]undecenyl)-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[ 1 ,2,4 ]thiadiazin-7 -yl]-methane sulfonamide
o 0 H
~SyYN, /
cdX~~ ~o
R6 a
To a stirred solution of (lS,2R,3S,4R)cyc1opentylamino-
bicyc1o[2.2.1]heptanecarboxylic acid ethyl ester (150 mg, 0.60 mmol) and (7-
methanesulfonylamino-1, 1-dioxo-1,4-dihydro-l"A -benzo[1,2,4 ]thiadiazinyl)-acetic
acid (prepared as described in US 7,939,524 B2, 181 mg, 0.54 mmol) in anhydrous
N,N-dimethylformamide (5 mL) under a nitrogen atmosphere, N-methylmorpholine
(0.12 mL, 1.08 mmol) and 1-(3-dimethylaminopropyl)ethy1carbodiimide
hydrochloride (104 mg, 0.54 mmol) were added sequentially. The mixture was stirred
at 25 DC for 45 min, triethylamine (0.25 mL, 1.76 mmol) was added and the resulting
mixture was stirred at 50 DC for 60 h. The reaction mixture was allowed to cool to 25
DC, diluted with ethyl acetate, washed with 1.0 M aqueous hydrochloric acid solution
and saturated aqueous brine solution, dried over magnesium sulfate and filtered. The
filtrate was concentrated in vacuo and the residue was purified by prep-HPLC
[Column Luna 511 C18 (2) 100A AXIA 150 x 21.2 mm, 5 micron, 30%-95% in 7 min
@ 30 mUmin flow rate, 0.05% trifluoroacetic acid in acetonitrile/ 0.05%
trifluoroacetic acid in water] to afford the desired product, N-[3-(lR,2S,7 R,8S)
cyc1opentylhydroxyoxoaza-tricyc1o[ 6.2.1.0 .7 ]undecenyl)-1, 1-dioxo-
1,4-dihydro-l"A -benzo[1,2,4]thiadiazinyl]-methanesulfonamide (80 mg, 0.15
mmol, 26%), as a yellow solid. IH NMR (400 MHz, DMSO-d6) 8: 1.20 - 1.65 (8H,
m), 1.75 - 1.95 (6H, m), 2.42 (lH, s), 2.60 (lH, s), 2.99 (lH, d, J = 9.2 Hz), 3.05 (3H,
WO 20121170536
s), 3.60 (lH, d, J = 9.2 Hz), 3.93 (lH, m), 7.48 - 7.58 (3H, m), 10.17 (lH, s). LC-MS
(ES1) ca1cd for C23H2SN406S2 520.15, found 521.4 [M+H+].
Example 6: (lR,2S,7 R,8S)(7 -Amino-I, 1-dioxo-1 ,4-dihydro-lA, _
benzo[1,2,4]thiadiazinyl)(4-fluoro-benzyl)hydroxyaza
tricyc1o[6.2.1.02.7]undecenone
0" //0
= OH ~ ... Sl(YNH2
- "=:: N~
llAF
a) (lR,2S,7 R,8S)(7 -Azido-1, 1-dioxo-1 ,4-dihydro-lA, _
benzo[1,2,4]thiadiazinyl)(4-fluoro-benzyl)hydroxyaza
tricyc1o[6.2.1.02.7]undecenone
0" //0
~:X)N3
llAF
(lR,2S,7 R,8S)( 4-Fluoro-benzyl)hydroxy(7 -iodo-1, 1-dioxo-1,4-
dihydro-1 "A -benzo[ 1 ,2,4 ]thiadiazinyl)aza -tricyc1o[ 6.2.1. 02.7]undecenone
(prepared as described in Example la, 0.513 g, 0.864 mmol), sodium azide (1.12 g,
17.2 mmol), sodium ascorbate (0.086 g, 0.43 mmol), copper (I) iodide (0.16 g, 0.84
mmol), and trans-N,N'-dimethy1cyc1ohexane-1,2-diamine (0.20 mL, 1.27 mmol) were
dissolved in a 5:1 mixture of dimethyl sulfoxide and water (10 mL) at 25°C. The
reaction flask was degassed and backfilled with nitrogen (5 x). After stirring at 25 °C
for 14 h, the reaction mixture was partitioned between water (150 mL) and ethyl
acetate (2 x 150 mL). The organic layer was dried over sodium sulfate, filtered and
concentrated in vacuo. The residue was purified by flash column chromatography
(Teledyne 1sco RediSep column; 0 to 60% ethyl acetate in hexanes) to afford the
desired product, (lR,2S,7 R,8S)(7 -azido-1, 1-dioxo-1 ,4-dihydro-lA, _
benzo[1,2,4]thiadiazinyl)(4-fluoro-benzyl)hydroxyaza-
WO 20121170536
tricyc1o[6.2.1.02,7]undecenone (0.348 g, 0.684 mmol, 79%), as a dark brown
foam, which was used in the next step without any further purification.
b) (IR,2S,7 R,8S)(7 -Amino-I, l-dioxo-I,4-dihydro-lA, _
benzo[I,2,4]thiadiazinyl)(4-fluoro-benzyl)hydroxyaza
tricyc1o[6.2.1.02,7]undecenone
0" //0
= OH ~ ... Sl(YNH2
- "=:: N~
llAF
(IR,2S,7 R,8S)(7 -Azido-l, l-dioxo-I,4-dihydro-lA, _
benzo[I,2,4]thiadiazinyl)(4-fluoro-benzyl)hydroxyaza
tricyc1o[6.2.1.02,7]undecenone (0.348 g, 0.684 mmol) was dissolved in a 1:1
mixture of methanol and ethyl acetate (15 mL) at 25°C. Palladium on carbon (0.40 g,
%, "wet") was added, resulting in a black suspension. The reaction was maintained
under a hydrogen atmosphere (balloon) at 25°C for 6 h, and then was filtered through
Celite. The Celite was washed with ethyl acetate (2 x 30 mL) and the filtrate was
concentrated in vacuo. The residue was purified by flash column chromatography
50 to 100% ethyl acetate in hexanes) to afford the
(Teledyne Isco RediSep column;
desired product, (lR,2S, 7 R,8S)(7 -amino-1, 1-dioxo-1 ,4-dihydro-1 "A _
benzo[1,2,4]thiadiazinyl)(4-fluoro-benzyl)hydroxyaza
tricyc1o[6.2.1.02,7]undecenone (0.159 g, 0.330 mmol, 48%), as a pale yellow
solid. IH NMR (400 MHz, CDCb) 8: 1.08 - 1.19 (3H, m), 1.40 - 1.57 (3H, m), 2.99
(lH, d, J = 7.2 Hz), 3.31 (3H, s), 3.36 - 3.37 (lH, m), 3.50 (lH, d, J = 7.8 Hz), 4.39
(lH, d, J = 14.6 Hz), 4.93 (lH, d, J = 14.5 Hz), 6.86 - 6.91 (3H, m), 7.13 - 7.15 (2H,
m), 7.21 (lH, d, J = 8.8 Hz), 7.30 (2H, bs), 13.79 (lH, s). LC-MS (ESI) ca1cd for
C24H23FN404S 482.14, found 483.4 [M+H+].
Example 7: N-{ 3-[(1S.2R,7 S,8R)( 4-Fluoro-benzyl)hydroxyoxo-
3-aza-tricyc1o[6.2.1.02,7]undecenyl]-1, 1-dioxo-1,4-dihydro-1"A _
benzo[ 1.2,4 lthiadiazin-7 -yl} -methanesulfonamide
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O~ /,,0 H /
~ .... S'(YN6F~·o
~ ~ N~
ccCC
a) (lR,2R,3S,4S)(Methoxycarbonyl)bicyclo[2.2.1]heptene
carboxylic acid
~ HO OMe
=- OH
This compound was prepared as described in 1. Org. Chern. 2000,65,
6984-6991. cisNorbornene-exo-2,3-dicarboxylic anhydride (5 g, 30.45 mmol) was
suspended in a 1: 1 mixture of toluene and carbon tetrachloride (150 mL). The
mixture was stirred for 10 min. Quinidine (10.9 g, 33.5 mmol) was added and the
flask was degassed and backfilled with nitrogen. The solution was cooled to -55°C.
While stirring, methanol (3.7 mL, 91.35 mmol) was added. The mixture was stirred
at -55°C for 16 h. Upon warming to 25°C, the mixture was concentrated in vacuo to
a foam. The foam was dissolved in a mixture of ethyl acetate (400 mL) and 1.0 M
aqueous hydrochloric acid solution (400 mL). The layers were separated and the
organic layer was further washed with 1.0 M aqueous hydrochloric acid solution (2 x
100 mL), saturated aqueous brine solution (100 mL) and dried over magnesium
sulfate, filtered, and concentrated in vacuo to afford the desired product,
(lR,2R,3S,4S)(methoxycarbonyl)bicyclo[2.2.1]heptenecarboxylic acid (5.92
g, 30.2 mmol, 99%), as a clear oil. IH NMR (400 MHz, DMSO-d6) 8: 1.29 (lH, d, I
= 10.2 Hz), 1.96 (lH, d, 1= 8.6 Hz), 2.47 - 2.49 (2H, m), 2.93 - 2.94 (2H, m), 3.51
(3H, s), 6.15 - 6.20 (2H, m), 12.15 (lH, s).
b) Methyl (lS,2S,3R,4R)
{[(benzyloxy)carbonyl]amino} bicyclo[2.2.1]heptenecarboxylate
~OMe
~N-CbZ
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This intermediate was prepared as described in Synthesis 2001, 11, 1719-
1730. (lR,2R,3S,4S)(Methoxycarbonyl)bicyc1o[2.2.1]heptenecarboxylic
acid (5.9 g, 30 mmol) was dissolved in anhydrous tetrahydrofuran (133 mL). The
flask was degassed and backfilled with nitrogen and the mixture was cooled to 0 0c.
Triethylamine (12.64 mL, 90 mmol) was added followed by the dropwise addition of
ethyl chloroformate (5.72 mL, 60 mmol) with vigorous stirring. Immediate
precipitation was observed. The mixture was stirred at 0 °C for 1 h. Sodium azide
(5.86 g, 90 mmol) was dissolved in water (40 mL) and added to the reaction mixture
at 0 0c. The mixture was stirred at 0 °C for 5 min. The ice bath was removed. The
mixture was warmed to 25°C and continued to stir for 2 h. The mixture was poured
into water (300 mL) and the product extracted into ethyl acetate (350 mL). The
organic layer was further washed with half-saturated aqueous sodium bicarbonate
solution (2 x 100 mL), saturated aqueous brine solution (100 mL), dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford a light brown oil.
The oil was dissolved in anhydrous benzene (66 mL) and refluxed
while stirring under nitrogen for 2 h. Upon cooling to 25°C the solution was
concentrated in vacuo to afford a light yellow oil. The oil was dissolved in
dichloromethane (40 mL) and benzyl alcohol (3.41 mL, 33 mmol) was added
followed by triethylamine (8.44 mL, 60 mmol). The mixture was refluxed under
nitrogen for 16 h. Upon cooling to 25°C the solution was concentrated in vacuo to
afford a thick oil. Purification by flash column chromatography (Merck silica gel 60,
40-63 11m; 1 st column: 3: 1 hexanes/ethyl acetate; 2 column: 2:4: 1
dichloromethane/pentane/diethyl ether) afforded the desired product, methyl
(lS,2S,3R,4R){ [(benzyloxy)carbonyl] amino } bicyc1o[2.2.1]heptene
carboxylate (6.195 g, 20.58 mmol, 69%), as a faintly yellow oil. IH NMR (400 MHz,
CDCb) 8: 1.60 (lH, d, J = 9.4 Hz), 1.97 (lH, d, J = 9.3 Hz), 2.66 (lH, d, J = 7.5 Hz),
2.75 (lH, s), 2.96 (lH, s), 3.60 (3H, s), 4.02 (lH, t, J = 8.9 Hz), 5.09 (2H, q, J = 10.5
Hz), 5.47 (lH, d, J = 8.8 Hz), 6.18 - 6.23 (2H, m), 7.29 - 7.37 (5H, m). LC-MS (ESI)
calcd for C H N0 301.13, found 258.1 (100%),302.2 [M+H+] (70%),603.4
17 19 4
[2M+H+] (20%).
c) Methyl (lR,2S,3R,4S)aminobicyc1o[2.2.1]heptanecarboxylate
hydrochloride
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~OMe
4 o Hel
Methyl (lS,2S,3R,4R)
{[(benzyloxy)carbonyl]amino} bicyclo[2.2.1]heptenecarboxylate (1 g, 3.32
mmol) was dissolved in ethyl acetate (15 mL). 5% Palladium on carbon (120 mg)
was added. The flask was degassed and backfilled with hydrogen gas via balloon.
The mixture was stirred at 25°C for 16 h. The mixture was passed through a plug of
Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil
was dissolved in diethyl ether (10 mL) and added dropwise, with vigorous stirring, to
a mixture of 4.0 M hydrochloric acid solution in l,4-dioxane (1.8 mL, 7.2 mmol) in
diethyl ether (18 mL). The desired product began to precipitate as a white solid.
Additional diethyl ether (10 mL) was added and the mixture was stirred for 10 min.
The precipitate was collected by vacuum filtration and washed with additional diethyl
ether (2 x 8 mL). The solid was further dried in vacuo for 1 h to afford the desired
product, methyl (lR,2S,3R,4S)aminobicyclo[2.2.1]heptanecarboxylate
hydrochloride (0.554 g, 2.7 mmol, 81 %), as a white powder. IH NMR (400 MHz,
DMSO-d6) 8: 1.18 - 1.27 (3H, m), 1.37 - 1.61 (2H, m), 1.90 (lH, d, J = 11.0 Hz), 2.35
(lH, d, J = 3.8 Hz), 2.44 (lH, d, J = 3.1 Hz), 2.75 (lH, d, J = 8.7 Hz), 3.29 - 3.34 (lH,
m), 3.61 (3H, s), 8.03 (3H, bs). LC-MS (ESI) ca1cd for C9H15N02 (free amine)
169.11, found 170.3 [M+H+] (100%), 339.3 [2M+H+] (50%).
d) Methyl (lR,2S,3R,4S)[( 4-
fluorobenzyl) amino ]bicyclo[2.2.1 ]heptanecarboxy late
llAF
Methyl (lR,2S,3R,4S)aminobicyclo[2.2.1]heptanecarboxylate
hydrochloride (0.5 g, 2.43 mmol) was dissolved in methanol (12 mL). Sodium
acetate (0.4 g, 4.86 mmol) was added followed by 4A powdered molecular sieves (0.5
g) and 4-fluoro-benzaldehyde (0.302 g, 2.43 mmol). Sodium cyanoborohydride
(0.305 g, 4.86 mmol) was added and the mixture was stirred at 25°C for 3 h. The
WO 20121170536
mixture was poured into ethyl acetate (300 mL) and shaken with saturated aqueous
sodium bicarbonate solution (200 mL). Both layers were passed through a plug of
Celite. The organic layer was further washed with saturated aqueous sodium
bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product,
methyl (lR,2S,3R,4S) [(4-fluorobenzyl)amino ]bicyclo[2.2.l ]heptanecarboxylate
(0.675 g, 2.43 mmol, 99%), as a clear oil. LC-MS (ESI) ca1cd for C16H20FN02
277.15, found 278.2 [M+H+].
e) N- {3-[(lS,2R, 7 S,8R)( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyclo[6.2.1.02.7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[1,2,4]thiadiazin-7 -yl} -methanesulfonamide
O~ /P H /
.... SON ...
oH ~ I cl~o
::: ~ N ~
crt(
Methyl (lR,2S,3R,4S)[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-
2-carboxylate (0.6 g, 2.16 mmol) was dissolved in anhydrous N,N
dimethylformamide (20 mL). (7-Methanesulfonylamino-1, 1-dioxo-1 ,4-dihydro-1 ').., _
benzo[1,2,4]thiadiazinyl)-acetic acid (prepared as described in US 7,939,524 B2,
0.72 g, 2.16 mmol) was added followed by N-methylmorpholine (0.5 mL, 4.54
mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-
(3-Dimethylaminopropyl)ethy1carbodiimide hydrochloride (0.435 g, 2.27 mmol)
was added and the mixture was stirred at 25°C for 45 min. Triethylamine (0.91 mL,
6.48 mmol) was added and the mixture was stirred at 50°C for 16 h. Upon cooling to
°C, the solution was diluted with ethyl acetate (300 mL) and washed with 1.0 M
aqueous hydrochloric acid solution (3 x 300 mL), saturated aqueous brine solution
(100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford
a golden oil. Purification by flash column chromatography (Merck silica gel 60, 40-
63 11m, 0 to 0.75% methanol in dichloromethane) afforded the product as white foam.
The foam was dissolved in methanol (10 mL) and the product was precipitated by the
addition of 1.0 M aqueous hydrochloric acid solution (20 mL) while stirring. The
WO 20121170536
solid was collected by vacuum filtration and further dried in vacuo to afford the
desired product, N-{ 3-[(IS,2R,7 S,8R)( 4-fluoro-benzyl)hydroxyoxoaza
tricyc1o[6.2.1.02.7]undecenyl]-I, I-dioxo-l ,4-dihydro-l ')..,6_
benzo[I,2,4]thiadiazinyl}-methanesulfonamide (0.592 g, 1.06 mmol, 49%), as a
white powder. IH NMR (400 MHz, DMSO-d ) 8: 1.15 - 1.22 (2H, m), 1.39 - 1.61
(4H, m), 2.49 - 2.55 (IH, m), 2.62 - 2.63 (IH, m), 3.02 (IH, d, J = 9.8 Hz), 3.05 (3H,
s), 3.52 (IH, d, J = 9.3 Hz), 4.41 (IH, d, J = 15.5 Hz), 4.95 (IH, d, J = 15.5 Hz), 7.14
(2H, t, J = 8.7 Hz), 7.32 (2H, dd, h = 8.2 Hz, h = 5.7 Hz), 7.50 (IH, dd, h = 8.4 Hz,
h = 2.4 Hz), 7.55 - 7.57 (2H, m), 10.17 (IH, s). LC-MS (ESI) ca1cd for
C25H25FN406S2 560.12, found 561.3 [M+H+]. ee = 96% [HPLC-analysis: Chiralpak
AS-RH 2.1 x 150 mm, 5 micron at r.t., Solvent A - Solvent B (see table above for
gradient), 0.3 mLimin, 312 nm, tl = 4.3 min, t2 = 6.0 min (major)].
Scheme 4a provides a specific procedure that was used to prepare the 2-
amino( methanesulfony lamino-methyl)-thiophene-3 -sulfonic acid amide
intermediate.
Scheme 4a
iPrMgCI
CIC0 Et
Br--Q
S THF ooc
0-25°C
DIBAL
PMe3, DEAD
0 OC
THF, 25°C
1. CI
DCM, HOAc, H 0
o OC,1 h
1,4-Dioxane
OC
Pd on C
OC
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Scheme 4b provides a specific procedure that was used to prepare the
,6-dihydro-lH-pyridinone compound of Example 8.
Scheme 4b
1. CI~OEt, Et3N H OH 0
DCM, 25 ac
~OEt
2. NaOEt
EtOH, 60 ac
l\f~
llAF
1,4-Dioxane
i-PrNEt
110°C
1 ,4-Dioxane, 25°C
0=8-
OH N o .... n
: I I~
= -..-::::: N 8
llAF
Example 8: (lR,2S,7 R,8S)-N-{3-[3-( 4-Fluoro-benzyl)hydroxyoxo-
3-aza-tricyc1o[6.2.1.02,7]undecenyl]-1, I-dioxo-l,4-dihydro-l"A -thieno[2,3-
e] [1,2,4 lthiadiazin-7 -ylmethyl} -methanesulfonamide
O'/.:ON,S/
"S~ /. ,
I:l OH~'" I ~ O~ "0
rlX~ s
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a) 4-Bromo-thiophenecarboxylic acid ethyl ester
C0 Et
Br-Q
Isopropylmagnesium chloride (263 mL of a 2.0 M solution in
tetrahydrofuran, 0.527 mol) was added via cannula over 35 min to a solution of 3,4-
dibromo-thiophene (102 g, 0.421 mol) in tetrahydrofuran (600 mL) at 0 0c. The
mixture was allowed to warm to 25°C and was stirred at that temperature for 18 h.
Water (25 mL) was added, and the mixture was stirred at 25°C for 15 min, and then
was concentrated in vacuo to -200 mL volume. The concentrate was partitioned
between 1.0 M aqueous hydrochloric acid solution (400 mL) and ethyl acetate (2 x
350 mL). The combined organic layers were dried over sodium sulfate, filtered and
were concentrated in vacuo to afford the crude product, 4-bromo-thiophene
carboxylic acid ethyl ester (91.9 g, 0.391 mol, 93%), as a yellow/brown oil. IH NMR
(400 MHz, CDCb) 8: 1.40 (3H, t, J = 7.5 Hz), 4.36 (2H, q, J = 7.3 Hz), 7.31 (lH, d, J
= 3.9 Hz), 8.10 (lH, d, J = 3.0 Hz).
b) 4-Bromonitro-thiophenecarboxylic acid ethyl ester
C0 Et
Br16
4-Bromo-thiophenecarboxylic acid ethyl ester (97.6 g, 0.415 mol) was
added over 10 min via pipette to 18.0 M sulfuric acid (660 mL) at 0 0c. After stirring
min at 0 °c, fuming nitric acid (18 mL) dissolved in 18.0 M sulfuric acid (130 mL)
was added via addition funnel over 30 min. After the addition was completed, the
reaction mixture was stirred for 5 min at 0 °c, and then was poured onto ice (3.5 kg).
The resulting precipitate was collected by filtration and was washed sequentially with
water (300 mL), 10% aqueous sodium bicarbonate solution (400 mL) and water (300
mL). The brown/yellow solid thus obtained was dried in a vacuum oven overnight at
40°C to afford the crude product, 4-bromonitro-thiophenecarboxylic acid ethyl
ester (97.9 g, 0.350 mol, 84%). This material was further purified by flash column
chromatography (Merck silica gel 60, 40-63 11m; 25% hexanes in dichloromethane) in
g portions prior to use in the next step (recovery = 80-90%). IH NMR (400 MHz,
DMSO-d6) 8: 1.31 (3H, t, J = 7.0 Hz), 4.30 (4H, q, J = 7.0 Hz), 8.68 (lH, s).
WO 20121170536
c) 4-Benzylsulfanylnitro-thiophenecarboxylic acid ethyl ester
~ C02 Et
~S)Q
An aqueous solution of potassium carbonate (9.90 g, 71.6 mmol,
dissolved in 40 mL water) was added to a suspension of 4-bromonitro-thiophene
carboxylic acid ethyl ester (20.06 g, 71.6 mmol) in ethanol at 25°C. Benzyl
mercaptan (8.41 mL, 71.6 mmol) was added via pipette, and the dark red reaction
mixture was stirred at 25°C for 4 h and then was concentrated in vacuo to near-
dryness. The remaining orange-brown solid was triturated with water (200 mL) and
was collected by filtration. After washing with water (200 mL), the resulting solid
was air-dried overnight to afford the desired product, 4-benzylsulfanylnitro
thiophenecarboxylic acid ethyl ester (22.63 g, 70.0 mmol, 98%), as a yellow/brown
solid. IH NMR (400 MHz, CDCb) 8: 1.41 (3H, t, J = 7.1 Hz), 4.25 (2H, s), 4.39 (2H,
q, J = 7.0 Hz), 7.18 - 7.23 (5H, m), 8.07 (lH, s).
d) (4-Benzylsulfanylnitro-thiophenyl)-methanol
S\--{CH 0H
02 S
Diisobutylaluminum hydride (154 mL of a 1.0 M solution in
dichloromethane, 154 mmol) was added via cannula over 25 min to a solution of 4-
benzylsulfanylnitro-thiophenecarboxylic acid ethyl ester (22.63 g, 70.0 mmol)
at -50°C. The reaction mixture was stirred at -50 °C for 2 h, then was warmed to 0 °C
and was maintained at that temperature for 35 min. Water (200 mL) was added via
addition funnel over 15 min and the resulting suspension was warmed to 25°C
whereupon additional water (200 mL) and D/L-tartaric acid (20 g) were added. After
stirring vigorously at 25°C for 30 min, the reaction mixture was partitioned between
1.0 M aqueous hydrochloric acid solution (300 mL) and dichloromethane (2 x 400
mL). The combined organic layers were dried over sodium sulfate, filtered and were
concentrated in vacuo. Purification of the residue by flash column chromatography
(Merck silica gel 60, 40-63 11m; 10-50% ethyl acetate in hexanes) afforded the desired
product, (4-benzylsulfanylnitro-thiophenyl)-methanol (10.52 g, 37.4 mmol,
WO 20121170536
53%), as a dark brown oil. IH NMR (400 MHz, CDCh) 8: 4.21 (2H, s), 4.40 (2H, s),
7.09 - 7.12 (lH, m), 7.21 - 7.24 (4H, m), 7.39 (lH, s).
e) Boc-N-( 4-Benzylsulfanylnitro-thiophenylmethyl)-
methanesulfonamide
o O~sP
~s N' "-
)OBoe
02 S
Triethylamine (22.0 mL, 158 mmol), di-tert-butyl dicarbonate (27.5 g,
126 mmol), and 4-(N,N-dimethylamino)pyridine (1.28 g, 10.5 mmol) were added
sequentially to a solution of methanesulfonamide (10.0 g, 105 mmol) in
dichloromethane (300 mL) at 25°C. The mixture was stirred at 25 °C for 2 h, and then
was concentrated in vacuo to -40 mL volume. Ethyl acetate (350 mL) was added and
the mixture was washed with 1.0 M aqueous hydrochloric acid solution (300 mL).
The aqueous layer was extracted with ethyl acetate (250 mL) and the combined
organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo
to afford Boc-N-methanesulfonamide (17.1 g, 87.6 mmol, 83 %) as a white solid. IH
NMR (400 MHz, CDCh) 8: 1.53 (9H, s), 3.27 (3H, s).
Boc-N-methanesulfonamide (11.0 g, 56.3 mmol), trimethylphosphine
(56.1 mL of a 1.0 M solution in tetrahydrofuran, 56.1 mmol), and a 40 wt. % solution
of diethyl azodicarboxylate in toluene (25.6 mL, 56.0 mmol) were added sequentially
to a solution of (4-benzylsulfanylnitro-thiophenyl)-methanol (10.52 g, 37.4
mmol) in tetrahydrofuran (300 mL) at 25°C. The mixture was stirred for 3.5 h at 25
°C, and then was concentrated in vacuo. Purification of the residue by flash column
chromatography (Merck silica gel 60, 40-63 11m; 20% ethyl acetate in hexanes)
afforded the desired product, Boc-N-(4-benzylsulfanylnitro-thiophenylmethyl)
methanesulfonamide (9.79 g, 21.3 mmol, 57%), as a dark brown oil. IH NMR (400
MHz, CDCh) 8: 1.50 (9H, s), 3.29 (3H, s), 4.19 (2H, s), 4.68 (2H, s), 7.15 - 7.18 (2H,
m), 7.22 - 7.25 (3H, m), 7.40 (lH, s).
f) Boc(Methanesulfony lamino-methy 1)nitro-thiophene-3 -sulfonic
acid amide
WO 20121170536
o 0" /P
" -;,0 ,S"
HN ... S~N\
2 ~_~ Boc
02 S
Boc-N-(4-Benzylsulfanylnitro-thiophenylmethyl)-
methanesulfonamide (4.90 g, 10.7 mmol) was dissolved in dichloromethane (65 mL)
and the dark brown solution was cooled to 0 0c. A mixture of glacial acetic acid (15
mL) and water (20 mL) was then added slowly, producing a biphasic mixture.
Chlorine gas was bubbled through this mixture at 0 °C for 5 min using a pipette. The
resulting yellow biphasic mixture was stirred at 0 °C for an additional 35 min, then
was poured into a separatory funnel and the layers separated. The aqueous layer was
extracted with dichloromethane (1 x 50 mL) and the combined organic layers were
washed with water (1 x 50 mL), dried over sodium sulfate, filtered and concentrated
in vacuo to -25 mL volume. Heptane (80 mL) was then added to this solution via
addition funnel over 30 min. The resulting orange precipitate was collected by
filtration, washed with heptane (2 x 20 mL), and air-dried to afford Boc
(methanesulfonylamino-methyl)nitro-thiophenesulfonyl chloride (2.45 g, 5.63
mmol,53%).
Concentrated aqueous ammonium hydroxide solution (3 mL) was added
to a solution of Boc(methanesulfonylamino-methyl)nitro-thiophenesulfonyl
chloride (3.30 g, 7.59 mmol) in acetonitrile (90 mL) at 0 0c. The mixture was stirred
at 0 °C for 45 min, and then was partitioned between half-saturated aqueous sodium
bicarbonate solution (150 mL) and ethyl acetate (2 x 150 mL). The combined organic
layers were dried over sodium sulfate, filtered and were concentrated in vacuo.
Purification of the residue by flash column chromatography (Teledyne Isco RediSep
column; 20-90% ethyl acetate in hexanes) afforded the desired product, Boc
(methanesulfonylamino-methyl)nitro-thiophenesulfonic acid amide (2.64 g, 6.35
mmol, 84%), as a yellow solid. IH NMR (400 MHz, CDCb) 8: 1.54 (9H, s), 3.35 (3H,
s), 5.12 (2H, s), 5.81 (2H, bs), 7.61 (lH, s).
g) 4-(Methanesulfony lamino-methyl)nitro-thiophenesulfonic acid
amide
WO 20121170536
o O~/P
\~O ,S ..........
HN.-v~NH
2 ~_')
02 S
Hydrogen chloride (20 mL of a 4.0 M solution in l,4-dioxane) was
added to a solution of Boc(methanesulfonylamino-methyl)nitro-thiophene
sulfonic acid amide (0.600 g, 1.44 mmol) in l,4-dioxane (10 mL) at 25°C. The
mixture was stirred at 25 °C for 18 h, and then was partitioned between half-saturated
aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2 x 150 mL). The
combined organic layers were dried over sodium sulfate, filtered and were
concentrated in vacuo. Purification of the residue by flash column chromatography
(Teledyne Isco RediSep column; 60-100% ethyl acetate in hexanes) provided a
yellow oil. This material was triturated with dichloromethane to afford a yellow solid
that was collected by filtration to afford the desired product, 4-
(methanesulfonylamino-methyl)nitro-thiophenesulfonic acid amide (00400 g,
1.27 mmol, 88%). IH NMR (400 MHz, DMSO-d6) 8: 2.96 (3H, s), 3.31 (2H, s), 4.35
(lH, d, J = 504 Hz), 7.61 (lH, t, J = 6.2 Hz), 7.85 (lH, s), 7.87 (2H, bs).
h) 2-Amino( methanesulfony lamino-methyl )-thiophene-3 -sulfonic
acid amide
o O~/P
\\ -;-0 ,S ..........
HN.-S~NH
2 ~_')
H2N S
Palladium on carbon (10%, 0.150 g, dry) was added to a solution of 4-
(methanesulfonylamino-methyl)nitro-thiophenesulfonic acid amide (0.156 g,
00495 mmol) in tetrahydrofuran (12 mL) at 25°C. The flask was degassed and
backfilled with hydrogen gas via balloon and the mixture was stirred under a positive
pressure of hydrogen (2 balloons) for 17 h. The mixture was then filtered through
Celite and the Celite was washed with tetrahydrofuran (3 x 20 mL). The combined
filtrate and washings were concentrated in vacuo to afford the crude product, 2-
amino(methanesulfonylamino-methyl)-thiophenesulfonic acid amide, as a
yellow oil. This material was used in subsequent synthetic transformations without
additional purification.
WO 20121170536
i) (lR,2S,7 R,8S)( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyc1o[6.2.1.02,7]undecenecarboxylic acid ethyl ester
f:l OH 0
llAF
Triethylamine (4.22 mL, 30.3 mmol) and ethyl malonyl chloride (1.91
of (lS,2R,3S,4R)(4-
mL, 15.2 mmol) were added sequentially to a solution
fluorobenzylamino )-bicyc1o[2.2.1 ]heptanecarboxy lic acid ethyl ester (prepared as
described in Example 21, 4.21 g, 14.4 mmol) in dichloromethane at 25°C. The
mixture was stirred at 25 °C for 1 h, and then was partitioned between 1.0 M aqueous
(150 mL) and ethyl acetate (2 x 150 mL). The combined
hydrochloric acid solution
organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo
to afford a yellow/orange oil.
This material was dissolved in absolute ethanol (80 mL) at 25°C and a
21 wt. % solution of sodium ethoxide in ethanol (14.0 mL, 43.2 mmol) was added.
The mixture was heated to 60°C for 45 min, and then was allowed to cool to 25 0c.
The mixture was then concentrated in vacuo and the resulting orange/brown solid was
partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl
acetate (2 x 150 mL). The combined organic layers were dried over sodium sulfate,
filtered and were concentrated in vacuo. Purification of the residue by flash column
chromatography (Teledyne Isco RediSep column; 10-80% ethyl acetate in hexanes)
afforded the desired product, (lR,2S,7 R,8S)( 4-fluoro-benzyl)hydroxyoxo
aza-tricyc1o[6.2.1.02,7]undecenecarboxylic acid ethyl ester, as a pale yellow oil.
This material was used directly in the next synthetic step.
q) (lR,2S,7 R,8S)( 4-Fluoro-benzyl)hydroxyaza-
tricyc1o[6.2.1.02,7]undecenone
llAF
WO 20121170536
(lR,2S,7 R,8S)( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyc1o[6.2.1.02,7]undecenecarboxylic acid ethyl ester was suspended in a 111
mixture of l,4-dioxane and 1.0 M aqueous sulfuric acid solution (200 mL). The
mixture was heated to 110 °C for 40 min, and then was allowed to cool to 25°C. The
cooled mixture was poured into a separatory funnel and was extracted with ethyl
acetate (2 x 150 mL). The combined organic layers were dried over sodium sulfate,
filtered and were concentrated in vacuo to afford a white solid. This material was
triturated with hexanes and was collected by filtration, washed with hexanes (2 x 15
mL) and air-dried to afford the desired product, (lR,2S,7R,8S)(4-fluoro-benzyl)
hydroxyaza-tricyc1o[6.2.1.0 .7]undecenone (2.24 g, 7.80 mmol, 54% over
three steps), as a white solid. IH NMR (major tautomer, 400 MHz, CDCb) 8: 1.11 -
1.16 (lH, m), 1.20 - 1.39 (3H, m), 1.57 - 1.69 (2H, m), 2.53 (lH, d, J = 8.4 Hz), 2.63
(lH, bs), 2.73 (lH, bs), 3.39 (lH, d, J = 4.1 Hz), 3.51 (lH, d, J = 9.5 Hz), 4.29 (lH, d,
J = 14.9 Hz), 5.20 (lH, d, J = 14.9 Hz), 6.98 - 7.04 (2H, m), 7.19 - 7.24 (2H, m).
r) (lR,2S,7 R,8S)-N-{ 3-[3-( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyc1o[6.2.1.02,7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6 -thieno[2,3-
e] [1,2,4]thiadiazin-7 -ylmethyl }-methanesulfonamide
O'/.:ON,S/
"S~ /. ,
I:l OH~'" I ~ O~ "0
rlX~ s
N,N-Diisopropylethylamine (0.974 mL, 5.59 mL) and (bis-
methylsulfanyl-methylene)-methyl-sulfonium tetrafluoro borate salt (prepared as
described in , 0.466 g, 1.94 mmol) were added sequentially to a
solution of (lR,2S,7 R,8S)( 4-fluoro-benzyl)hydroxyaza
tricyc1o[6.2.1.02,7]undecenone (0.197 g, 0.686 mmol) in l,4-dioxane (50 mL) at
°C. The orange mixture was stirred at 25 °C for 2 h, and then was partitioned
between water (100 mL) and ethyl acetate (2 x 100 mL). The combined organic
layers were dried over sodium sulfate, filtered and were concentrated in vacuo to
afford an orange oil.
WO 20121170536
This material was dissolved in acetonitrile (8 mL) and was added to a
solution of crude 2-amino(methanesulfonylamino-methyl)-thiophenesulfonic
acid amide (described above; Example 8h, 0.495 mmol) in acetonitrile (4 mL) at 85
°C. The mixture was maintained at 85°C for 4 days, then was allowed to cool to 25
°C and was concentrated in vacuo. The residue was purified by prep-HPLC [Column
Thomson ODS-A 100A 511,150 x 21.2 mm, 30%-100% in 1l.5 min @ 22 mUmin
flow rate, 0.05% trifluoroacetic acid in acetonitrile/ 0.05% trifluoroacetic acid in
water] to afford the crude product. Purification of this material by flash column
chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes)
afforded the desired product, (IR,2S,7 R,8S)-N- {3-[3-( 4-fluoro-benzyl)hydroxy
oxoaza-tricyc1o[6.2.1.02.7]undecenyl]-I, I-dioxo-l ,4-dihydro-lA, -thieno[2,3-
e][I,2,4]thiadiazinylmethyl}-methanesulfonamide (0.060 g, 0.103 mmol, 21 %), as
an off-white solid. IH NMR (400 MHz, DMSO-d ) 8: 0.84 - 0.90 (IH, m), 1.08 - 1.60
(5H, m), 1.99 (IH, s), 2.61 (IH, bs), 2.96 (3H, s), 3.50 (IH, d, J = 9.4 Hz), 3.96 - 3.99
(IH, m), 4.24 (IH, d, J = 5.7 Hz), 4.38 (IH, d, J = 14.8 Hz), 4.93 (IH, d, J = 15.7 Hz),
7.11 - 7.16 (2H, m), 7.27 (IH, s), 7.29 - 7.33 (2H, m), 7.65 (IH, t, J = 5.9 Hz). LC
MS (ESI) calculated for C24H25FN406S3 580.09, found 581.1 [M+H+].
Example 9: N-{ 3-[(2S,7 R)( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyc1o[6.2.2.02.7]dodecenyl]-1. I-dioxo-l.4-dihydro-lA -benzo[1 ,2,4]thiadiazinY I} -methanesulfonamide
o 0 H
,,// /
OH N .... S:ryN ... ,
: I I 6/ "0
- '-'::: N .0
llAF
a) 4-0xa-tricyc1o[5.2.2.0 . ]undecane-3,5-dione
4-0xa-tricyc1o[5.2.2.0 . ]undecene-3,5-dione (4.00 g, 22.45 mmol)
was dissolved in ethyl acetate (100 mL). 10% Palladium on carbon (400 mg) was
added. The flask was degassed and backfilled with hydrogen gas via balloon. The
WO 20121170536
mixture was stirred at 25°C for 16 h. The mixture was passed through a plug of
Celite and the filtrate was concentrated in vacuo to afford a thick clear oil.
Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to
% ethyl acetate in hexanes) afforded the desired product, 4-oxa
tricyclo[5.2.2.0 • ]undecane-3,5-dione (2.92 g, 16.20 mmol, 72%), as a white powder.
IH NMR (400 MHz, DMSO-d6) 8: 1.55 - 1.64 (6H, m), 1.76 (2H, d, J = 9.2 Hz), 2.25
(2H, s), 3.11 (2H, s). LC-MS (ESI) calcd for C H 0 180.20, found 181.0 [M+H+].
lO 12 3
b) (2S,3R)-Bicyclo[2.2.2]octane-2,3-dicarboxylic acid monomethyl ester
~~~e
4-0xa-tricyclo[5.2.2.0 • ]undec-3,5-dione (0.90 g, 4.99 mmol) was
dissolved in toluene (50 mL) and carbon tetrachloride (50 mL). Quinine (1.78 g, 5.49
mmol) was added and the mixture was cooled to - 55°C. Methanol (0.61 mL, 14.97
mmol) was added dropwise to the above mixture. The reaction was stirred at - 55°C
for 18 h. The reaction was warmed to 25 DC and concentrated in vacuo. The crude
material was dissolved in ethyl acetate (50 mL) and washed with 1.0 M aqueous
hydrochloric acid solution (2 x 40 mL). The organic layer was further washed with
saturated aqueous brine solution (20 mL), dried over magnesium sulfate, filtered, and
concentrated in vacuo to afford a clear oil. Purification by flash column
chromatography (Teledyne Isco RediSep column; 0 to 50% ethyl acetate in hexanes)
afforded the desired product, (2S,3R)-bicyclo[2.2.2]octane-2,3-dicarboxylic acid
monomethyl ester (1.10 g, 5.18 mmol, 92%), as a clear oil. IH NMR (400 MHz,
DMSO-d6) 8: 1.31 (2H, dd, h = 20.0 Hz, J = 12.4 Hz), 1.52 - 1.54 (4H, m), 1.63
(lH, t, J = 10.4 Hz), 1.75 (lH, t, J = 9.6 Hz), 1.87 (2H, bs), 2.84 (2H, dd, h = 29.6
Hz, h = 10.8 Hz), 3.52 (3H, s), 12.01 (lH, s). LC-MS (ESI) calcd for C H 604
ll 1
212.24, found 213.1 [M+H+].
c) (2R,3S)Benzyloxycarbonylamino-bicyclo[2.2.2]octane
carboxylic acid methyl ester
~OMe
lJ+NHCbz
WO 20121170536
(2S,3R)-Bicyclo[2.2.2]octane-2,3-dicarboxylic acid monomethyl ester
(1.01 g, 4.76 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL). The flask
was degassed and backfilled with nitrogen and the mixture was cooled to 0 0c.
Triethylamine (1.99 mL, 14.28 mmol) was added followed by the dropwise addition
of ethyl chloroformate (0.91 mL, 9.52 mmol) with vigorous stirring. The mixture was
stirred at 0 °C for 1 h. Sodium azide (0.93 g, 14.28 mmol) was dissolved in water (5
mL) and added to the reaction mixture at 0 0c. The mixture was stirred at 0 °C for 5
min. The ice bath was removed. The mixture was warmed to 25°C and was stirred
for 2 h. The mixture was poured into water (50 mL) and the product extracted into
ethyl acetate (50 mL). The organic layer was further washed with half-saturated
aqueous sodium bicarbonate solution (2 x 20 mL), saturated aqueous brine solution
(20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a
clear oil. The oil was dissolved in anhydrous benzene (10 mL) and refluxed while
stirring under nitrogen for 2 h. Upon cooling to 25°C the solution was concentrated
in vacuo to afford a slightly yellow oil. The oil was dissolved in dichloromethane (10
mL) and benzyl alcohol (0.54 mL, 5.24 mmol) was added followed by triethylamine
(1.33 mL, 9.52 mmol). The mixture was refluxed under nitrogen for 16 h. Upon
cooling to 25°C the solution was concentrated in vacuo to afford a golden oil.
Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to
% ethyl acetate in hexanes) afforded the desired product, (2R,3S)
benzyloxycarbonylamino-bicyclo[2.2.2]octanecarboxylic acid methyl ester (0.58 g,
1.83 mmol, 38%), as a clear oil. IH NMR (400 MHz, CDCb) 8: 1.18 - 1.28 (2H, m),
1.42 - 1.50 (5H, m), 1.73 - 1.96 (3H, m), 2.88 (IH, d, h = 5.6 Hz), 3.27 (IH, s), 3.42
(3H, s), 4.00 - 4.04 (IH, m), 4.97 (2H, dd, h = 46.4 Hz, h = 12.8 Hz), 7.06 (IH, d, J
= 9.6 Hz), 7.24 - 7.34 (4H, m). LC-MS (ESI) calcd for ClsH23N04 317.38, found
317.9 [M+H+].
d) (2R,3S)Amino-bicyclo[2.2.2]octanecarboxylic acid methyl ester
hydrochloride
- OMe
= NH • Hel
f1 2
(2R,3S)Benzyloxycarbonylamino-bicyclo[2.2.2]octanecarboxylic
acid methyl ester (0.57 g, 1.79 mmol) was dissolved in ethyl acetate (20 mL). 10%
WO 20121170536
Palladium on carbon (60 mg) was added. The flask was degassed and backfilled with
hydrogen gas via balloon. The mixture was stirred at 25°C for 16 h. The mixture
was passed through a plug of Celite and the filtrate was concentrated in vacuo to
afford a thick clear oil. The oil was dissolved in diethyl ether (6 mL) and added
dropwise with vigorous stirring to a mixture of 4.0 M solution of hydrochloric acid in
l,4-dioxane (1.02 mL) and diethyl ether (10 mL). The desired product began to
precipitate as a white solid. The mixture was stirred for 20 min. The precipitate was
collected by vacuum filtration and washed with additional diethyl ether (5 mL). The
solid was further dried in vacuo for 1 h to afford the desired product, (2R,3S)
amino-bicyclo[2,2,2]octanecarboxylic acid methyl ester hydrochloride (0.33 g,
1.50 mmol, 84%), as a white powder. IH NMR (400 MHz, DMSO-d6) 8: 1.38 (2H,
dd, h = 21.2 Hz, h = 13.6 Hz), 1.55 - 1.63 (5H, m), 1.76 - 1.89 (3H, m), 3.02 (lH,
dd, h = 10.0 Hz, h = 2.4 Hz), 3.47 (lH, bs), 3.65 (3H, s), 7.97 (3H, s). LC-MS (ESI)
ca1cd for C H N0 (free amine) 183.25, found 184.2 [M+H+].
lO 17 2
e) (2R,3S)( 4-Fluoro-benzylamino )-bicyclo[2.2.2]octanecarboxylic
acid methyl ester
GroMe
(2R,3S)Amino-bicyclo[2,2,2]octanecarboxylic acid methyl ester
hydrochloride (0.34 g, 1.54 mmol) was dissolved in methanol (10 mL). Sodium
acetate (0.25 g, 3.08 mmol) was added followed by 4A powdered molecular sieves
(0.34 g) and 4-fluoro-benzaldehyde (0.16 mL, 1.54 mmol). Sodium
cyanoborohydride (0.19 g, 3.08 mmol) was added and the mixture was stirred at 25°C
for 16 h. The mixture was poured into a mixture of saturated aqueous sodium
bicarbonate solution (20 mL) and ethyl acetate (30 mL). After shaking, both layers
were passed through a plug of Celite. The organic layer was further washed with
saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine
solution (10 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to
afford the crude product, (2R,3S)( 4-fluoro-benzylamino )-bicyclo[2,2,2]octane
WO 20121170536
carboxylic acid methyl ester (0.32 g, l.ll mmol, 72%), as a clear oil. LC-MS (ESI)
ca1cd for C H FN0 29l.36, found 292.2 [M+H+].
17 22 2
f) N-{ 3-[(2S,7 R)( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyclo[6.2.2.02.7]dodecenyl]-1, 1-dioxo-1 ,4-dihydro-lA -benzo[l ,2,4]thiadiazinY I} -methanesulfonamide
o 0 H
,,// /
OH N .... S:vN ... S-...
: I I 0"0
- '-'::: N .0
llAF
(2R,3S)( 4-Fluoro-benzy lamino )-bicyclo[2,2,2]octanecarboxylic
acid methyl ester (93 mg, 0.32 mmol) was dissolved in anhydrous N,N-
dime thy lfonnamide (4 mL). (7-Methanesulfony lamino-1, 1-dioxo-1 ,4-dihydro-1 "A _
benzo[1,2,4]thiadiazinyl)-acetic acid (prepared as described in US 7,939,524 B2,
107 mg, 0.32 mmol) was added followed by N-methylmorpholine (74 ilL, 0.67
mmol). The mixture was stirred until everything dissolved, approximately 5 min. 1-
(3-Dimethylaminopropyl)ethy1carbodiimide hydrochloride (65 mg, 0.34 mmol)
was added and the mixture was stirred at 25°C for 16 h. The reaction was quenched
of saturated aqueous sodium bicarbonate solution (20 mL). The mixture
via addition
was extracted with ethyl acetate (3 x 30 mL). The combined organic layers were
washed with saturated aqueous brine solution (20 mL), dried over magnesium sulfate,
filtered, and concentrated in vacuo to afford a golden oil. The oil was dissolved in
(5 mL). A 21 wt. % solution of sodium ethoxide in ethanol (0.36 mL, 0.96
ethanol
mmol) was added. The reaction was refluxed for 16 h. The reaction was quenched
via the addition of l.0 M aqueous hydrochloric acid solution (10 mL). The mixture
was extracted with ethyl acetate (3 x 20 mL). The organic layer was further washed
mL), saturated aqueous brine
with saturated sodium bicarbonate solution (2 x
solution (20 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to
afford a clear oil. Purification by flash column chromatography (Teledyne Isco
RediSep column; 0 to 20% ethyl acetate in dichloromethane) afforded the desired
product, N- {3- [(2S, 7 R)( 4-fluoro-benzyl)hydroxyoxoaza
tricyclo[6.2.2.02.7]dodecenyl]-1, 1-dioxo-1 ,4-dihydro-lA -benzo[l ,2,4]thiadiazin-
WO 20121170536
7-yl}-methanesulfonamide (0.11 g, 0.19 mmol, 59%), as a white powder. IH NMR
(400 MHz, DMSO-d ) 8: l.39 (2H, d, J = 8.0 Hz), l.54 - l.59 (8H, m), l.9l (lH, s),
2.14 (lH, s), 3.06 (3H, s), 3.75 (lH, d, J = 1l.6 Hz), 4.28 (lH, d, J = 15.2 Hz), 5.03
(lH, d, J = 15.6 Hz), 7.13 - 7.17 (2H, m), 7.34 - 7.37 (2H, m), 7.50 - 7.60 (3H, m),
.18 (lH, s). LC-MS (ESI) ca1cd for C26H27FN406S2 574.64, found 575.1 [M+H+].
m.p.: 203.8 - 205.7 0c. ee = 94.4% [HPLC-analysis: Chiralpak AS-RH 4.6 x 250
mm,5 micron, 0.8 mL/min, 310 nm].
Example 10: N- {3-[(1S,2S,7 R,8R)( 4-Fluoro-benzyl)hydroxy
oxoaza-tricyc1o[6.2.1.02,7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-lA, _
benzo[ 1 ,2,4 Hhiadiazin-7 -yl} -methanesulfonamide
O~ /P H /
~ OH ~ ... S~N6/S~O
:: - ~ N~
crtc
llAF
_a) (lR,2S,3R,4S)(Methoxycarbonyl)bicyc1o[2.2.1]heptene
carboxylic acid
~ ~O OMe
:. _ OH
The starting material (a) was prepared as described in J. Org. Chern.
2000, 65,6984-699l. cisNorbornene-endo-2,3-dicarboxylic anhydride (4.104 g,
mmol) was suspended in a 1: 1 mixture of toluene and carbon tetrachloride (500
mL). The mixture was stirred for 20 min. Quinine (8.92 g, 27.5 mmol) was added
and the flask was degassed and backfilled with nitrogen. The solution was cooled to -
55°C. While stirring, methanol (3.04 mL, 75 mmol) was added. The mixture was
stirred at -55°C for 20 h. Upon warming to 25°C, the mixture was concentrated in
vacuo to a thick oil. The oil was dissolved in ethyl acetate (400 mL), washed with l.0
M aqueous hydrochloric acid solution (2 x 400 mL), saturated aqueous brine solution
(100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford
the desired product, (lR,2S,3R,4S)(methoxycarbonyl)bicyc1o[2.2.1]heptene
WO 20121170536
carboxylic acid (4.8 g, 24.5 mmol, 98%), as a clear waxy solid. IH NMR (400 MHz,
DMSO-d ) 8: l.26 (lH, d, J = 8.5 Hz), l.33 (lH, d, J = 8.8 Hz), 3.00 (lH, s), 3.03
(lH, s), 3.21 - 3.30 (2H, m), 3.45 (3H, s), 6.02 - 6.04 (lH, m), 6.14 - 6.16 (lH, m),
1l.86 (lH, s).
b) Methyl (lS,2R,3S,4R)
{[(benzyloxy)carbonyl]amino} bicyclo[2.2.l]heptenecarboxylate
~OMe
~N-CbZ
(lR,2S,3R,4S)(Methoxycarbonyl)bicyclo[2.2.l]heptene
carboxylic acid (4.61 g, 23.5 mmol) was dissolved in anhydrous tetrahydrofuran (40
mL). The flask was degassed and backfilled with nitrogen and the mixture was
0 0c. Triethylamine (9.9 mL, 70.5 mmol) was added followed by the
cooled to
dropwise addition of ethyl chlorofonnate (4.48 mL, 47 mmol) with vigorous stirring.
Immediate precipitation was observed. Additional tetrahydrofuran (60 mL) was
added. The mixture was stirred at 0 °C for 1 h. Sodium azide (4.58 g, 70.5 mmol)
(30 mL) and added to the reaction mixture at 0 0c. The
was dissolved in water
mixture was stirred at 0 °C for 5 min. The ice bath was removed. The mixture was
warmed to 25°C and was stirred for 2 h. The mixture was poured into water (300
mL) and the product extracted into ethyl acetate (300 mL). The organic layer was
further washed with half-saturated aqueous sodium bicarbonate solution (2 x 100
mL), saturated aqueous brine solution (100 mL), dried over magnesium sulfate,
filtered, and concentrated in vacuo to afford a clear oil. The oil was dissolved in
anhydrous benzene (50 mL) and refluxed while stirring under nitrogen for 2 h. Upon
cooling to 25°C the solution was concentrated in vacuo to afford a slightly yellow oil.
The oil was dissolved in dichloromethane (30 mL) and benzyl alcohol (2.68 mL, 25.9
mmol) was added followed by triethylamine (6.61 mL, 47 mmol). The mixture was
refluxed under nitrogen for 16 h. Upon cooling to 25°C the solution was
in vacuo to afford a golden oil. Purification by flash column
concentrated
chromatography (Merck silica gel 60, 40-63 11m, 15% ethyl acetate in hexanes)
afforded the desired product, methyl (lS,2R,3S,4R)
{[(benzyloxy)carbonyl] amino } bicyclo[2.2.1]heptenecarboxylate (5.51 g, 18.31
mmol, 78%), as a clear oil. IH NMR (400 MHz, CDCb) 8: l.38 (lH, d, J = 9.1 Hz),
WO 20121170536
1.50 (lH, d, J = 9.4 Hz), 3.10 (2H, s), 3.21 (lH, dd, h = 9.2 Hz, h = 2.3 Hz), 3.53
(3H, s), 4.62 (lH, dt, h = 9.4 Hz, h = 2.9 Hz), 5.07 (2H, q, J = 13.0 Hz), 5.29 (lH, d,
J = 8.6 Hz), 6.15 - 6.17 (lH, m), 6.37 - 6.38 (lH, m), 7.29 - 7.35 (5H, m). LC-MS
(ESI) ca1cd for C H N0 301.13, found 258.1 (100%), 302.2 [M+H+] (70%), 603.5
17 19 4
[2M+H+] (20%).
c) Methyl (lR,2R,3S,4S)aminobicyclo[2.2.1]heptanecarboxylate
hydrochloride
~OMe
QNH 0HCI
Methyl (lS,2R,3S,4R)
{[(benzyloxy)carbonyl]amino} bicyclo[2.2.1]heptenecarboxylate (5.5 g, 18.27
mmol) was dissolved in ethyl acetate (75 mL). 5% Palladium on carbon (650 mg)
was added. The flask was degassed and backfilled with hydrogen gas via balloon.
The mixture was stirred at 25°C for 16 h. The mixture was passed through a plug of
Celite and the filtrate was concentrated in vacuo to afford a thick clear oil. The oil
was dissolved in ethyl acetate (15 mL) and added dropwise, with vigorous stirring, to
a mixture of a 4.0 M solution of hydrochloric acid in l,4-dioxane (10 mL, 40 mmol)
in diethyl ether (90 mL). The desired product began to precipitate as a white solid.
The mixture was stirred for 20 min. The precipitate was collected by vacuum
filtration, and was washed with additional diethyl ether (15 mL). The solid was
(lR,2R,3S,4S)
further dried in vacuo for 1 h to afford the desired product, methyl
aminobicyclo[2.2.1]heptanecarboxylate hydrochloride (2.61 g, 12.69 mmol, 69%),
as a white powder. IH NMR (400 MHz, DMSO-d6) 8: 1.34 - 1.43 (4H, m), 1.54 (lH,
d, J = 9.5 Hz), 1.68 (lH, d, J = 11.4 Hz), 2.47 - 2.48 (2H, m), 3.03 (lH, dd, h = 11.0
Hz, h = 4.0 Hz), 3.49 - 3.53 (lH, m), 3.62 (3H, s), 8.07 (3H, bs). LC-MS (ESI) ca1cd
for C9H15N02 (free amine) 169.11, found 170.1 [M+H+] (100%),339.2 [2M+H+]
(50%).
d) Methyl (lR,2R,3S,4S)[(4-
fluorobenzyl) amino ]bicyclo[2.2.1 ]heptanecarboxy late
WO 20121170536
QOMe
Methyl (lR,2R,3S,4S)aminobicyclo[2.2.1]heptanecarboxylate
hydrochloride (1 g, 4.S6 mmol) was dissolved in methanol (23 mL). Sodium acetate
(0.755 g, 9.2 mmol) was added followed by 4A powdered molecular sieves (1 g) and
4-fluoro-benzaldehyde (0.571 g, 4.6 mmol). Sodium cyanoborohydride (0.578 g, 9.2
mmol) was added and the mixture was stirred at 25°C for 16 h. The mixture was
poured into a mixture of saturated aqueous sodium bicarbonate solution (200 mL) and
ethyl acetate (300 mL). After shaking, both layers were passed through a plug of
Celite. The organic layer was further washed with saturated aqueous sodium
bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product,
methyl (lR,2R,3S,4S) [(4-fluorobenzyl) amino ]bicyclo[2.2.l ]heptanecarboxylate
(1.172 g, 4.23 mmol, 92%), as a clear oil. LC-MS (ESI) ca1cd for C16H20FN02
277.15, found 27S.2 [M+H+].
e) N- {3- [(IS,2S, 7 R,SR)( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyclo[6.2.1.02.7]undecenyl]-I, I-dioxo-l ,4-dihydro-l ')..,6_
benzo[I,2,4]thiadiazin-7 -yl} -methanesulfonamide
O~ /P H /
~ OH ~ ... S~N6/S~O
:: - ~ N~
crtc
Methyl (IR,2R,3S,4S)[(4-fluorobenzyl)amino]bicyclo[2.2.1]heptane-
2-carboxylate (0.OS7 g, 0.3 mmol) was dissolved in anhydrous N,N
dimethylfonnamide (2.S mL). (7 -Methanesulfonylamino-l, I-dioxo-l ,4-dihydro-l"A _
benzo[I,2,4]thiadiazinyl)-acetic acid (prepared as described in US 7,939,524 B2,
0.1 g, 0.3 mmol) was added followed by N-methylmorpholine (0.07 mL, 0.63 mmol).
The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-
WO 20121170536
Dimethylaminopropyl)ethy1carbodiimide hydrochloride (0.061 g, 0.315 mmol) was
added and the mixture was stirred at 25°C for 4 h. Triethylamine (0.126 mL, 0.9
mmol) was added and the mixture was stirred at 50°C for 16 h. Upon cooling to 25
°c, the solution was diluted with ethyl acetate (25 mL) and washed with l.0 M
aqueous hydrochloric acid solution (2 x 25 mL), saturated aqueous brine solution (10
mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a
golden oil. The oil was dissolved in methanol (4 mL) and the product was
precipitated by the addition of l.0 M aqueous hydrochloric acid solution (4 mL) while
stirring. The solid was collected by vacuum filtration and further dried in vacuo to
afford the desired product, N-{3-[(lS,2S,7R,8R)(4-fluoro-benzyl)hydroxy
oxoaza-tricyc1o[6.2.l.02.7]undecenyl]-1, l-dioxo-l ,4-dihydro-lA, _
benzo[1,2,4]thiadiazinyl}-methanesulfonamide (0.0805 g, 0.144 mmol, 48%), as a
white powder. IH NMR (400 MHz, DMSO-d6) 8: l.23 - 1.48 (6H, m), 2.67 - 2.68
(2H, m), 3.06 (3H, s), 3.24 (lH, d, J = 15.0 Hz), 3.72 (lH, d, J = 1l.9 Hz), 4.07 (lH,
d, J = 15.6 Hz), 5.12 (lH, d, J = 15.7 Hz), 7.14 (2H, t, J = 8.4 Hz), 7.39 (2H, dd, h =
8.2 Hz, h = 5.8 Hz), 7.51 (lH, dd, h = 8.4 Hz, h = 2.3 Hz), 7.57 - 7.60 (2H, m),
.18 (lH, s). LC-MS (ESI) ca1cd for C25H25FN406S2 560.12, found 56l.3 [M+H+].
ee = 99% [HPLC-analysis: Chiralpak AS-RH 4.6 x 250 mm, 5 micron at r.t., Solvent
A - Solvent B (see table for gradient), 0.8 mLimin, 310 nm, tl = 7.58 min (major), t2
= 10.08 min].
Example 11: N- {3- [(1R,2R,7 S,8S)( 4-Fluoro-benzyl)hydroxy
oxoaza-tricyc1o[6.2.1.02.7]undecenyl]-1, I-dioxo-l ,4-dihydro-lA, _
benzo[ 1,2,4 lthiadiazin-7 -yl} -methanesulfonamide
O~ ~O H /
.... SON ...
oH ~ I c/~O
~ N ~
ctC(
a) (IS,2R,3S,4R)(Methoxycarbonyl)bicyc1o[2.2.1]heptene
carboxylic acid
WO 20121170536
H °OMe
The starting material (a) was prepared as described in 1. Org. Chern.
2000, 65, 6984-699l. cisNorbornene-endo-2,3-dicarboxylic anhydride (8.21 g, 50
mmol) was suspended in a 1: 1 mixture of toluene and carbon tetrachloride (250 mL).
The mixture was stirred for 10 min. Quinidine (17.84 g, 55 mmol) was added and the
flask was degassed and backfilled with nitrogen. The solution was cooled to -55°C.
While stirring, methanol (6.08 mL, 150 mmol) was added. The mixture was stirred at
-55°C for 18 h. Upon warming to 25°C, the mixture was concentrated in vacuo to a
thick oil. The oil was dissolved in a mixture of ethyl acetate (400 mL) and l.0 M
aqueous hydrochloric acid solution (300 mL). After shaking, the layers were
separated and the organic layer was further washed with 1.0 M aqueous hydrochloric
acid solution (2 x 100 mL), saturated aqueous brine solution (100 mL), dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford the desired product,
(lS,2R,3S,4R)(methoxycarbonyl)bicyclo[2.2.l]heptenecarboxylic acid (9.15
g, 46.6 mmol, 94%), as a clear oil. IH NMR (400 MHz, DMSO-d ) 8: l.26 (lH, d, I
= 8.4 Hz), l.33 (lH, d, 1= 8.4 Hz), 3.00 (lH, s), 3.03 (lH, s), 3.21 - 3.29 (2H, m),
3.45 (3H, s), 6.02 - 6.04 (lH, m), 6.14 - 6.16 (lH, m), 1l.86 (lH, s).
b) Methyl (lR,2S,3R,4S)
{[(benzyloxy)carbonyl]amino} bicyclo[2.2.l]heptenecarboxylate
~OMe
Ill.+ -
N Cbz
This intermediate was prepared as described in Synthesis 2001, 11, 1719-
1730. (lS,2R,3S,4R)(Methoxycarbonyl)bicyclo[2.2.1]heptenecarboxylic
acid (8.94 g, 45.57 mmol) was dissolved in anhydrous tetrahydrofuran (200 mL). The
flask was degassed and backfilled with nitrogen and the mixture was cooled to 0 0c.
Triethylamine (19.2 mL, 136.7 mmol) was added followed by the dropwise addition
of ethyl chloroformate (8.69 mL, 9l.l mmol) with vigorous stirring. Immediate
precipitation was observed. The mixture was stirred at 0 °C for 1 h. Sodium azide
(8.89 g, 136.7 mmol) was dissolved in water (60 mL) and added to the reaction
WO 20121170536
mixture at 0 °C. The mixture was stirred at 0 °C for 1 h. The ice bath was removed.
The mixture was warmed to 25°C and continued to stir for 2 h. The mixture was
poured into water (400 mL) and the product extracted into ethyl acetate (400 mL).
The organic layer was further washed with half-saturated aqueous sodium bicarbonate
solution (2 x 200 mL), saturated aqueous brine solution (2 x 200 mL), dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford a slightly brown oil.
The oil was dissolved in anhydrous benzene (100 mL) and refluxed while stirring
under nitrogen for 2 h. Upon cooling to 25°C the solution was concentrated in vacuo
to afford a slightly brown oil. The oil was dissolved in dichloromethane (60 mL) and
benzyl alcohol (5.19 mL, 50.13 mmol) was added followed by triethylamine (12.81
mL, 91.14 mmol). The mixture was refluxed under nitrogen for 16 h. Upon cooling
to 25°C the solution was concentrated in vacuo to afford a golden oil. Purification by
flash column chromatography (Merck silica gel 60, 40-63 11m, 10% ethyl acetate in
hexanes) afforded the desired product, methyl (lR,2S,3R,4S)
{[(benzyloxy)carbonyl]amino} bicyclo[2.2.1]heptenecarboxylate (10.1 g, 33.55
mmol, 74%), as a clear oil. IH NMR (400 MHz, CDCb) 8: 1.38 (lH, d, J = 8.7 Hz),
1.50 (lH, d, J = 8.4 Hz), 3.10 (2H, s), 3.21 (lH, d, J = 8.8 Hz), 3.53 (3H, s), 4.59 -
4.64 (lH, m), 5.07 (2H, q, J = 13.0 Hz), 5.29 (lH, d, J = 8.3 Hz), 6.15 - 6.17 (lH, m),
6.37 - 6.38 (lH, m), 7.27 - 7.36 (5H, m). LC-MS (ESI) calcd for C H N0 301.13,
17 19 4
found 258.1 (100%),302.2 [M+H+] (70%), 603.5 [2M+H+] (20%).
c) Methyl (1 S ,2S ,3R,4R)aminobicyclo [2. 2.1 ]heptanecarboxy late
hydrochloride
Methyl (lR,2S,3R,4S)
{[(benzyloxy)carbonyl]amino} bicyclo[2.2.1]heptenecarboxylate (10 g, 33.22
mmol) was dissolved in ethyl acetate (150 mL). 5% Palladium on carbon (1.5 mg)
was added. The flask was degassed and backfilled with hydrogen gas via balloon.
The mixture was stirred at 25°C for 2 h. The mixture was passed through a plug of
Celite and the filtrate was concentrated in vacuo to a volume of 50 mL. The solution
was added dropwise, with vigorous stirring, to a mixture of 4.0 M hydrochloric acid
solution in l,4-dioxane (20 mL) in diethyl ether (200 mL). The desired product began
WO 20121170536
to precipitate as a white solid. The mixture was stirred for 10 min. The precipitate
was collected by vacuum filtration, washed with additional diethyl ether (15 mL).
The solid was further dried in vacuo for 1 h to afford the desired product, methyl
(lS,2S,3R,4R)aminobicyclo[2.2.l]heptanecarboxylate hydrochloride (5.21 g,
.33 mmol, 76.3%), as a white powder. IH NMR (400 MHz, DMSO-d6) 8: 1.33 -
1.42 (4H, m), 1.54 (lH, d, J = 10.3 Hz), 1.69 (lH, d, J = 11.5 Hz), 2.46 - 2.48 (2H,
m), 3.03 (lH, dd, h = 10.8 Hz, h = 4.1 Hz), 3.46 - 3.55 (lH, m), 3.62 (3H, s), 8.09
(3H, bs). LC-MS (ESI) ca1cd for C9H15N02 (free amine) 169.11, found 170.1
[M+H+] (100%), 339.2 [2M+H+] (50%).
d) Methyl (lS,2S,3R,4R)[(4-
fluorobenzyl) amino ]bicyclo[2.2.1 ]heptanecarboxy late
({f:OMe
llAF
Methyl (lS,2S,3R,4R)aminobicyclo[2.2.1]heptanecarboxylate
hydrochloride (1 g, 4.86 mmol) was dissolved in methanol (23 mL). Sodium acetate
(0.755 g, 9.2 mmol) was added followed by 4A powdered molecular sieves (1 g) and
4-fluoro-benzaldehyde (0.571 g, 4.6 mmol). Sodium cyanoborohydride (0.578 g, 9.2
mmol) was added and the mixture was stirred at 25°C for 16 h. The mixture was
poured into a mixture of saturated aqueous sodium bicarbonate solution (200 mL) and
ethyl acetate (300 mL). After shaking, both layers were passed through a plug of
Celite. The organic layer was further washed with saturated aqueous sodium
bicarbonate solution (100 mL), saturated aqueous brine solution (100 mL), dried over
magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product,
methyl (lS,2S,3R,4R) [(4-fluorobenzyl)amino ]bicyclo[2.2.1 ]heptanecarboxylate
(1.11 g, 4.0 mmol, 87%), as a clear oil. LC-MS (ESI) ca1cd for C16H20FN02 277.15,
found 278.2 [M+H+].
e) N- {3-[(lR,2R,7 S,8S)( 4-Fluoro-benzyl)hydroxyoxoaza-
tricyclo[6.2.1.02.7]undecenyl]-1, 1-dioxo-1 ,4-dihydro-1 ')..,6_
benzo[1,2,4]thiadiazin-7 -yl} -methanesulfonamide
WO 20121170536
o~ ~O H /
.... SON .....
OH ~ I c!/~O
~ N ~
Methyl (lS,2S,3R,4R)[(4-fluorobenzyl)amino]bicyc1o[2.2.l]heptane-
2-carboxylate (0.087 g, 0.3 mmol) was dissolved in anhydrous N,N
dimethylformamide (2.8 mL). (7 -Methanesulfonylamino-l, l-dioxo-l ,4-dihydro-lA, _
benzo[1,2,4]thiadiazinyl)-acetic acid (prepared as described in US 7,939,524 B2,
0.1 g, 0.3 mmol) was added followed by N-methylmorpholine (0.07 mL, 0.63 mmol).
The mixture was stirred until everything dissolved, approximately 5 min. 1-(3-
Dimethylaminopropyl)ethy1carbodiimide hydrochloride (0.061 g, 0.315 mmol) was
added and the mixture was stirred at 25°C for 4 h. Triethylamine (0.126 mL, 0.9
mmol) was added and the mixture was stirred at 50°C for 16 h. Upon cooling to 25
°c, the solution was diluted with ethyl acetate (25 mL) and washed with l.0 M
aqueous hydrochloric acid solution (2 x 25 mL), saturated aqueous brine solution (10
mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a
golden oil. The oil was dissolved in methanol (4 mL) and the product was
precipitated by the addition of l.0 M aqueous hydrochloric acid solution (4 mL) while
stirring. The solid was collected by vacuum filtration and further dried in vacuo to
afford the desired product, N-{3-[(lR,2R,7S,8S)(4-fluoro-benzyl)hydroxy
oxoaza-tricyc1o[6.2.l.02.7]undecenyl]-1, l-dioxo-l ,4-dihydro-lA, _
benzo[1,2,4]thiadiazinyl}-methanesulfonamide (0.0781 g, 0.139 mmol, 46%), as a
white powder. IH NMR (400 MHz, DMSO-d6) 8: l.23 - 1.48 (6H, m), 2.67 - 2.68
(2H, m), 3.06 (3H, s), 3.24 (lH, d, J = 15.0 Hz), 3.72 (lH, d, J = 1l.9 Hz), 4.07 (lH,
d, J = 15.6 Hz), 5.12 (lH, d, J = 15.7 Hz), 7.14 (2H, t, J = 8.4 Hz), 7.39 (2H, dd, h =
8.2 Hz, h = 5.8 Hz), 7.51 (lH, dd, h = 8.4 Hz, h = 2.3 Hz), 7.57 - 7.60 (2H, m),
.18 (lH, s). LC-MS (ESI) ca1cd for C25H25FN406S2 560.12, found 56l.3 [M+H+].
ee = 99% [HPLC-analysis: Chiralpak AS-RH 4.6 x 250 mm, 5 micron at r.t., Solvent
A - Solvent B (see table for gradient), 0.8 mLimin, 310 nm, t1 = 7.58 min, t2 = 10.08
min (major)].
WO 20121170536
BIOLOGICAL TESTING
The ability of Formula I compounds to reduce serum uric acid levels in a
patient was demonstrated in a Phase I study of healthy subjects. Six patients were
administered a single 800 mg oral dose of N-{3-[(lR,2S,7R,8S)(4-Fluoro-benzyl)-
6-hydroxyoxoaza-tricyc1o[6.2.1.02.7]undecenyl]-1, 1-dioxo-1 ,4-dihydro
U -benzo[1,2,4]thiadiazinyl}-methanesulfonamide (the compound of Example 2)
while two patients received a matching placebo. Significant unexpected decreases
(24-40%) in uric acid from the baseline to the end of the trial were found in all
patients receiving the compound (see Table 1).
Table 1
Subject Agel
No. Gender
--------- --------- Screen Predose 4hr 24hr 48hr 144hr
1 381M 5.1 5.3 5.0 3.4 3.3 4.6
2 33/F 2.9 2.8 2.9 1.6 1.8 2.8
53/M 6.3 5.0 5.0 2.8 3.4 5.3
4 321M P 5.1 4.3 4.3 4.7 4.7 6.0
411F 4.9 4.8 4.9 2.4 2.3 4.3
6 28/F P 3.5 3.4 3.4 3.8 3.3 4.3
7 251M 6.2 6.2 6.2 4.6 4.5 5.8
8 351M 5.9 6.4 5.5 4.9 4.3 5.8
Uric Acid (mg/dL)
P = Placebo
Inhibition of Uric Acid Uptake
Uric Acid (UA) is the end product of purine metabolism in humans. It is
secreted into the urine and 90% of it is reabsorbed into the blood stream. Screening
lead compounds for the inhibition of URAT1 evaluates their potential to decrease UA
reabsorption thus decreasing UA blood levels which might be beneficial to certain
patient populations.
The EC50 values of the inhibition of uric acid uptake were measured.
Human Embryonic Kidney (HEK293) cells expressing URAT1 (HEK293 cells
transfected with vectors containing human URAT1 cDNA) and control cells
(HEK293 cells transfected with only vectors) were used. Prior to the experiments,
cells were cultured in 75-cm bottom flasks and subjected to passage every 3 or 4
days. The control cells and URAT1 expressing cells were seeded in Collagen I coated
24 well plates at a density of 1 to 4x 10 cellslwell, and incubated in a CO incubator
WO 20121170536
(37°C and 5% CO ) for 1 to 3 days to prepare cell monolayers for the determination
of the cellular transport activity (cleared volume).
The EC50 values of the inhibition of UA uptake into HEK293 cells
facilitated by URATI expressed in the cells range from -0.5 11M to 14.8 11M for the
compounds of Examples 1-11 tested. Under the same conditions, the EC50 of
benzbromarone, the positive control URATI inhibitor, is <0.1 11M.
Claims (19)
1. Use of a compound of Formula I 5 wherein Ring B is A is II(a) , or II(b) 10 , 11 12 Z is –(CR R ) –, 13 14 Y is –(CR R ) –, n is 1 or 2, m is 2 or 3, 15 R is H, –NH , or –(CH ) –NH–S(O) CH , wherein q is 0 or 1, 2 2 q 2 3 2 15 15 R is C -C alkyl, C -C cycloalkyl, aryl, or –(CH )–R , wherein R is 1 6 3 6 2 16 18 16 17 18 19 20 wherein R , R , R , R and R are independently H, C -C alkyl, hydroxy, or halo, (9131545_1):JJP 3 4 5 6 7 8 9 10 11 12 13 14 R , R, R , R, R , R , R , R , R , R , R , and R are independently H or C -C alkyl, wherein each alkyl, cycloalkyl, or aryl are optionally substituted by one or more alkyl, hydroxyl, or halo substituents, 5 or a pharmaceutically acceptable salt, hydrate, solvate, tautomer ors tereoisomer thereof, for preparing a medicament fort he treatment or prevention ofh yperuricemia or gout.
2. The use of claim 1 wherein Ring B is 10
3. The use of claim 1 wherein q is 1 and Ring B is
4. The use of claim 1 where A is II(a)
5. The use of claim 1 wherein R is H. 2 15 15 15
6. The use of claim 1 wherein R is –(CH )–R and R is selected from. (10812590_1):KZA F F F F F Cl F , F OH F , and F OH , , . , OH
7. The use of claim 1 wherein q is 0. 5
8. The use of claim 1 wherein n is 1.
9. The use of claim 1 wherein q is 0 and n is 1. 3 4 5 6 7 8 9 10 11 12 13
10. The use of claim 1 wherein R , R , R , R , R , R , R , R , R , R , R , and 10 R are H. 16 17 18 19 20
11. The use of claim 1 wherein R , R , R , R , and R are independently H, methyl, or halo. 16 17 18 19 20 15
12. The use of claim 1 wherein R , R , R , R , and R are independently H or halo. 18 16 17 19 20
13. The use of claim 1 wherein R is fluro and R , R , R , and R are H. 20
14. The use of claim 1 wherein q is 0 and n is 1, 3 4 5 6 7 8 9 10 11 12 13 14 R , R , R , R , R , R , R , R , R , R , R , and R are H, and 16 17 18 19 20 R , R , R , R , and R are independently H or halo. 25
15. The use of claim 1 wherein the patient is a human. (9131545_1):JJP
16. The use of claim 1 further comprising administering an additional therapeutic agent to the patient.
17. Use of a compound or pharmaceutically acceptable salt thereof selected from 5 N-{3-[(1R,2S,7R,8S)(4-Fluoro-benzyl)hydroxyoxoaza- 2,7 6 tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin ylmethyl}-methanesulfonamide, N-{3-[(1R,2S,7R,8S)(4-Fluoro-benzyl)hydroxyoxoaza- 2,7 6 tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin 10 yl}-methanesulfonamide, (1R,2S,7R,8S)(1,1-Dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazinyl)(4- fluoro-benzyl)hydroxyaza-tricyclo[6.2.1.0 ]undecenone, (4aR,7aS)-N-{3-[1-(4-Fluoro-benzyl)hydroxyoxo-2,4a,5,6,7,7a-hexahydro- 1H-[1]pyrindinyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazinyl}- 15 methanesulfonamide, N-[3-(1R,2S,7R,8S)Cyclopentylhydroxyoxoaza- 2,7 6 tricyclo[6.2.1.0 ]undecenyl)-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin yl]-methanesulfonamide, (1R,2S,7R,8S)(7-Amino-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazinyl)- 20 3-(4-fluoro-benzyl)hydroxyaza-tricyclo[6.2.1.0 ]undecenone, N-{3-[(1S,2R,7S,8R)(4-Fluoro-benzyl)hydroxyoxoaza- 2,7 6 tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin yl}-methanesulfonamide, (1R,2S,7R,8S)-N-{3-[3-(4-Fluoro-benzyl)hydroxyoxoaza- 2,7 6 25 tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -thieno[2,3- e][1,2,4]thiadiazinylmethyl}-methanesulfonamide, N-{3-[(2S,7R)(4-Fluoro-benzyl)hydroxyoxoaza- 2,7 6 tricyclo[6.2.2.0 ]dodecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin yl}-methanesulfonamide, (9131545_1):JJP N-{3-[(1S,2S,7R,8R)(4-Fluoro-benzyl)hydroxyoxoaza- 2,7 6 tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin yl}-methanesulfonamide, and N-{3-[(1R,2R,7S,8S)(4-Fluoro-benzyl)hydroxyoxoaza- 2,7 6 5 tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo-1,4-dihydro-1λ -benzo[1,2,4]thiadiazin yl}-methanesulfonamide, for preparing a medicament for the treatment or prevention of hyperuricemia or gout.
18. The use of claim 17 wherein said compound isN -{3-[(1R,2S,7R,8S) 10 (4-Fluoro-benzyl)hydroxyoxoaza-tricyclo[6.2.1.0 ]undecenyl]-1,1-dioxo- 1,4-dihydro-1λ -benzo[1,2,4]thiadiazinyl}-methanesulfonamide.
19. The use of any one of cl aims 1 to 18 wherein the medicament is for treating or preventing gout. Anadys Pharmaceuticals, Inc. 15 By the Attorneys for the Applicant SPRUSON & FERGUSON Per: (10812590_1):KZA
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161494288P | 2011-06-07 | 2011-06-07 | |
US61/494,288 | 2011-06-07 | ||
PCT/US2012/041106 WO2012170536A1 (en) | 2011-06-07 | 2012-06-06 | [1,2,4]thiadiazine 1,1-dioxide compounds for lowering serum uric acid |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ619685A NZ619685A (en) | 2016-01-29 |
NZ619685B2 true NZ619685B2 (en) | 2016-05-03 |
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