IE911913A1 - Benzoic acid derivatives for treating leukotriene-related¹diseases - Google Patents
Benzoic acid derivatives for treating leukotriene-related¹diseasesInfo
- Publication number
- IE911913A1 IE911913A1 IE191391A IE191391A IE911913A1 IE 911913 A1 IE911913 A1 IE 911913A1 IE 191391 A IE191391 A IE 191391A IE 191391 A IE191391 A IE 191391A IE 911913 A1 IE911913 A1 IE 911913A1
- Authority
- IE
- Ireland
- Prior art keywords
- compound
- aliphatic
- aryl
- alkyl
- pharmaceutically acceptable
- Prior art date
Links
- 150000001558 benzoic acid derivatives Chemical class 0.000 title description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims description 78
- 125000001931 aliphatic group Chemical group 0.000 claims description 45
- 239000000203 mixture Substances 0.000 claims description 39
- 238000000034 method Methods 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- NRGGMCIBEHEAIL-UHFFFAOYSA-N 2-ethylpyridine Chemical compound CCC1=CC=CC=N1 NRGGMCIBEHEAIL-UHFFFAOYSA-N 0.000 claims description 16
- 201000010099 disease Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 150000002617 leukotrienes Chemical class 0.000 claims description 14
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 150000003254 radicals Chemical class 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 239000008024 pharmaceutical diluent Substances 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 4
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 3
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 101100295741 Gallus gallus COR4 gene Proteins 0.000 claims description 2
- 150000001768 cations Chemical class 0.000 claims description 2
- 238000007911 parenteral administration Methods 0.000 claims description 2
- 238000011200 topical administration Methods 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 2
- 208000019693 Lung disease Diseases 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 abstract description 3
- 239000003199 leukotriene receptor blocking agent Substances 0.000 abstract description 2
- HHNWFGQLXGBCES-UHFFFAOYSA-N 2-(3-phenylpyridin-2-yl)ethanol Chemical class OCCC1=NC=CC=C1C1=CC=CC=C1 HHNWFGQLXGBCES-UHFFFAOYSA-N 0.000 abstract 1
- 125000003118 aryl group Chemical group 0.000 description 136
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 93
- 238000006243 chemical reaction Methods 0.000 description 42
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 38
- 238000005481 NMR spectroscopy Methods 0.000 description 38
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
- 210000004027 cell Anatomy 0.000 description 29
- 239000002904 solvent Substances 0.000 description 29
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- -1 LTB4 Chemical class 0.000 description 26
- VNYSSYRCGWBHLG-AMOLWHMGSA-N leukotriene B4 Chemical compound CCCCC\C=C/C[C@@H](O)\C=C\C=C\C=C/[C@@H](O)CCCC(O)=O VNYSSYRCGWBHLG-AMOLWHMGSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 20
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
- 239000000377 silicon dioxide Substances 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 239000000243 solution Substances 0.000 description 18
- 239000012267 brine Substances 0.000 description 17
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 17
- 125000004938 5-pyridyl group Chemical group N1=CC=CC(=C1)* 0.000 description 16
- 150000001336 alkenes Chemical class 0.000 description 16
- 238000003818 flash chromatography Methods 0.000 description 16
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 125000001743 benzylic group Chemical group 0.000 description 15
- 239000007832 Na2SO4 Substances 0.000 description 14
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 229910052938 sodium sulfate Inorganic materials 0.000 description 14
- 235000011152 sodium sulphate Nutrition 0.000 description 14
- 239000012300 argon atmosphere Substances 0.000 description 13
- 239000003921 oil Substances 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 11
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 238000007792 addition Methods 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- SMBQBQBNOXIFSF-UHFFFAOYSA-N dilithium Chemical class [Li][Li] SMBQBQBNOXIFSF-UHFFFAOYSA-N 0.000 description 9
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 8
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
- 239000005557 antagonist Substances 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- 125000004076 pyridyl group Chemical group 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 150000001408 amides Chemical group 0.000 description 6
- 230000027455 binding Effects 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- YFHXZQPUBCBNIP-UHFFFAOYSA-N fura-2 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=3OC(=CC=3C=2)C=2OC(=CN=2)C(O)=O)N(CC(O)=O)CC(O)=O)=C1 YFHXZQPUBCBNIP-UHFFFAOYSA-N 0.000 description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 6
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- 125000000746 allylic group Chemical group 0.000 description 5
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- 238000002474 experimental method Methods 0.000 description 5
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- 239000007858 starting material Substances 0.000 description 5
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- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 5
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- 230000015572 biosynthetic process Effects 0.000 description 4
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 4
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- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 4
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- 229920006395 saturated elastomer Polymers 0.000 description 4
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- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- 238000011282 treatment Methods 0.000 description 3
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- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 229960003910 promethazine Drugs 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 230000016160 smooth muscle contraction Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical group 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- AQWOIRBQLOOZGX-UHFFFAOYSA-N triazolo[1,5-a]pyridine Chemical compound C1=CC=CC2=CN=NN21 AQWOIRBQLOOZGX-UHFFFAOYSA-N 0.000 description 1
- OVCXRBARSPBVMC-UHFFFAOYSA-N triazolopyridine Chemical compound C=1N2C(C(C)C)=NN=C2C=CC=1C=1OC=NC=1C1=CC=C(F)C=C1 OVCXRBARSPBVMC-UHFFFAOYSA-N 0.000 description 1
- LENLQGBLVGGAMF-UHFFFAOYSA-N tributyl([1,2,4]triazolo[1,5-a]pyridin-6-yl)stannane Chemical compound C1=C([Sn](CCCC)(CCCC)CCCC)C=CC2=NC=NN21 LENLQGBLVGGAMF-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 230000025033 vasoconstriction Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
This invention relates to certain substituted phenyl-(2-hydroxy)ethylpyridine compounds and their ketone and alkyl analogs which are useful as leukotriene antagonists.
Description
Benzoic Acid Derivatives For Treating Leukotriene-related Diseases Scope of the Invention This invention relates to certain substituted pyridyl-(25 hydroxyethyl)benzoic acid derivatives and their ketone analogs which are useful for treating diseases associated with leukotrienes. These compounds are particularly useful in treating diseases attributable to the hydroxyleukotrienes, especially LTB4 and LTB4-agonist active substances.
Background of the Invention The family of bioactive lipids known as the leukotrienes exert pharmacological effects on respiratory, cardiovascular and gastrointestinal systems. The leukotrienes are generally divided into two sub-classes, the peptidoleukotrienes (leukotrienes C4, D4 and E4) and the hydroxyleukotrienes (leukotriene B4). This invention is primarily concerned with the hydroxyleukotrienes (LTB) but is not limited to this specific group of leukotrienes.
The peptidoleukotrienes are implicated with the biological response associated with the Slow Reacting Substance of 0 Anaphylaxis (SRS-A). This response has been expressed in vivo as prolonged bronchoconstriction, in cardiovascular effects such as coronary artery vasoconstriction and numerous other biological responses. The pharmacology of the peptidoleukotrienes include • smooth muscle contractions, myocardial depression, increased vascular permeability and enhanced mucous production.
By comparison, LTB4 exerts its biological effects through stimulation of leukocyte and lymphocyte functions. It stimulates chemotaxis, chemokinesis and aggregation of polymorphonuclear leukocytes (PMNs). 0 Leukotriene B4 (LTB4) was first described by Borgeat and Samuelsson in 1979, and later shown by Corey and co-workers to be 5(S),12(R)-dihydroxy-(Z,E,E,Z)-6,8,10,14-eicosatetraenoic acid.
It is a product of the arachidonic acid cascade that results from the enzymatic hydrolysis of LTA4. It has been found to be produced by mast cells, polymorphonuclear leukocytes, monocytes and macrophages. LTB4 has been shown to be a potent stimulus in vivo for PMN leukocytes, causing increased chemotactic and chemokinetic migration, adherence, aggregation, degranulation, superoxide production and cytotoxicity. The effects of LTB4 are mediated through distinct receptor sites on the leukocyte cell surface which exhibit a high degree of stereospecificity. Pharmacological studies on human 0 blood PMN leukocytes indicate the presence of two classes of LTB4specific receptors that are separate from receptors specific for the peptide chemotactic factors. Each of the sets of receptors appear to be coupled to a separate set of PMN leukocyte functions. Calcium mobilization is involved in both mechanisms.
LTB4 has been established as an inflammatory mediator in vivo It has also been associated with airway hyperresponsiveness in the dog as well as being found in increased levels in lung lavages from humans with severe pulmonary dysfunction. In addition, as with the other leukotrienes, LTB4 has been implicated in inflammatory bowel 0 disease, rheumatoid arthritis, gout, and psoriasis. They are critically involved in mediating many types of cardiovascular, pulmonary, dermatological, renal, allergic, and inflammatory diseases including asthma, adult respiratory distress syndrome, cystic fibrosis, psoriasis, and inflammatory bowel disease.
By antagonizing the effects of LTB4, or other pharmacologically active mediators at the end organ, for example airway smooth muscle, the compounds and pharmaceutical compositions of the instant invention are valuable in the treatment of diseases in subjects, including human or animals, in which leukotrienes are a key factor. 0 SUMMARY OF THE INVENTION The compounds of this invention are represented by formula (I) or a pharmaceutically acceptable salt or N-oxide thereof where T is CO or CH(OH) R is Ci to C20-aliphatic, unsubstituted or substituted phenyl Ci to C{0-aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is Ci to C20-aliphatic-O-, or R is unsubstituted or substituted phenyl Ci to CiQ-aliphatic-Ο- where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo; Rl is -(Ci to C5 aliphatic)R3>-(Ci to C5 aliphatic)CHO, -(Ci to C5 aliphatic)CH2OR7, R3, -CH2OH or -CHO; 0 R2 and R3 are independently -COR4 where R4 is -OH, a pharmaceutically acceptable ester-forming group -OR5, or -OX where X is a pharmaceutically acceptable cation, or R4 is -N(R6)2 where R6 is H, or an aliphatic group of 1 to 10 carbon atoms or a cycloalkyl(CH2)n- group of 4 to 10 carbons where n is 0-3 or both R6 groups form a ring having 4 to 6 carbons, or R2 is an amine, amide or sulfonamide; and R7 is hydrogen, Cl to C6-alkyl, or Cj to C6-acyl, In another aspect, this invention covers pharmaceutical compositions containing the instant compounds and a 0 pharmaceutically acceptable excipient.
Treatment of diseases related to or caused by leukotrienes, particularly LTB4, or related pharmacologically active mediators at the end organ, are within the scope of this invention. This treatment can be effected by administering one or more of the compounds of formula I alone or in combination with a pharmaceutically acceptable excipient in an amount sufficient to prevent disease or treat it once it has occurred.
In yet another aspect, this invention relates to a method for making the compounds of this invention. This aspect of the invention 0 is illustrated in the reaction schemes given below and in the examples set forth in this specification.
DETAILED DESCRIPTION OF THE INVENTION The following definitions are used in describing this invention and setting out what the inventors believe to be their invention herein.
Aliphatic" is intended to include saturated and unsaturated radicals. This includes normal and branched chains, saturated or mono or poly unsaturated chains where both double and triple bonds may be present in any combination. The phrase lower alkyl means an alkyl group of 1 to 6 carbon atoms in any isomeric form, but particularly the normal or linear form. Lower alkoxy means the group lower alkyl-O-. Halo means fluoro, chloro, bromo or iodo. Acyl means the radical having a terminal carbonyl carbon.
When reference is made to a substituted phenyl ring, it is meant that the ring can be substituted with one or more of the named substituents as may be compatible with chemical synthesis. Multiple substituents may be the same or different, such as where there are three chloro groups, or a combination of chloro and alkyl groups and further where this latter combination may have different alkyl radicals in the chloro/alkyl substituent pattern.
The phrase a pharmaceutically acceptable ester-forming group in R.2 and R3 covers all esters which can be made from the acid function(s) which may be present in these compounds. The resultant esters will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the mono- or diesters will retain the biological activity of the parent compound and will not have an untoward or deleterious effect in their application and use in treating diseases. Such esters are, for example, those formed with one of the following radicals representing R5: Cl to ClO alkyl, phenyl-ClC6 alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, aminoalkyl, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl. Aryl includes phenyl and naththyl, or heteroaromatic radicals like furyl, thienyl, imidazolyl, triazolyl or tetrazolyl. The most preferred ester-forming radicals are those where R5 is alkyl, particularly alkyl of 1 to 10 carbons, [ie CH3-(CH2)rr where n is 0-9], or phenyl-(CH2)n_ where n is 0-4.
When R2 is referred to as being an amine, that includes the 0 radical -NH2 and mono- or dialkylate derivatives of this -NH2 radical.
Preferred alkylated amines are the mono- or disubstituted amines having 1 to 6 carbons. When R2 is referred to as being an amide, that includes all acylate derivatives of the NH2 radical. The preferred amides are those having 1 to 6 carbons.
Where there is an acid group, amides may be formed. The most preferred amides are those where -Rfi is hydrogen or alkyl of 1 to 6 carbon atoms. Particularly preferred is the diethylamide.
The hydroxyl group of the 2-hydroxyethylene linking group may be esterified. Lower alkyl acids of 1 to 6 carbon atoms may be used to form such esters using standard reaction conditions. This hydroxyl group also may be converted to an ether if so desired.
Again, such reactions are well known in the synthetic chemical arts.
Pharmaceutically acceptable salts of the instant compounds are 5 also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.
Pharmaceutically acceptable salts are prepared in a standard manner. The parent compound in a suitable solvent is reacted with an excess of an organic or inorganic acid, in the case of acid addition salts of a basic moiety, or an excess of organic or inorganic base in the case where R4 is OH. Representative acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, maleic acid, succinic acid or methanesulfonic acid. Cationic salts are readily prepared from alkali metal bases such as sodium, potassium, calcium, magnesium, zinc, copper or the like and ammonia. Organic bases include the mono or disubstituted amines, ethylene diamine, 0 piperazine, amino acids, caffeine, tromethamine, other tris compounds and the like.
Oxides of the pyridyl ring nitrogen may be prepared by means known in the art and as illustrated herein. These are to be considered part of the invention.
If by some combination of substituents, a chiral center is created or another form of an isomeric center is created in a compound of this invention, all forms of such isomer(s) are intended to be covered herein. Compounds with a chiral center may be administered as a racemic mixture or the racemates may be separated 0 and the individual enantiomer used alone.
As leukotriene antagonists, these compounds can be used in treating a variety of diseases associated with or attributing their origin or affect to leukotrienes, particularly LTB4. Thus it is expected that these compounds can be used to treat allergic diseases of a pulmonary and non-pulmonary nature. For example these compounds will be useful in antigen-induced anaphylaxis. They are useful in treating asthma and allergic rhinitis. Ocular diseases such as uveitis, and allergic conjunctivitis can also be treated with these compounds.
The preferred compounds of this invention are those where R is alkoxy, particularly alkoxy of 8 to 15 carbon atoms or substituted or unsubstituted phenyl Cj to Cio-aliphatic-O-; Rj is -(Ci to C5 aliphatic)R3 or -(Cj to C5 aliphatic)CH2OR7, and R2 is -COOH or N(A)(B) where A is H, or alkyl of 1 to 6 carbons and B is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons or -SO2Rs where Rs is -CF3, Ci to alkyl or phenyl. The more preferred compounds of this invention are those where R is alkoxy of 8 to 15 carbon atoms or alkoxy-substituted phenyl-Ci to Cs-alkoxy; Ri is COR4, -CH2CH2COR3 or -CH=CH-C0R3, and R2 is -COOH or -NHSO2Rs, particularly where R2 is at the meta position and Rs is -CF3.
The most preferred compounds are set out in Figure II.
T R Ri -R2 ho^N* H2iCio-0- **HOOC-CH=CH- m-COOH II H3C-O-Ph-(CH2)8-O- II II H2iCio-0- HOOCCH2CH2- II It H2iCio-0- **HOOCCH=CH- //-COOH The methylene carbon is substituted on the pyridyl ring. Trans configuration. 0 Synthesis These compounds may be made by the starting materials, intermediates and reagents and the synthetic steps set out in the following reaction flow charts. These charts trace the path used to make these compounds and are based on the detailed chemistry set out in the Examples recited below. These flow charts are intended to act as a road map to guide one from known starting materials to the desired products. These specific starting materials, intermediates and reagents are only given to illustrate the general case and are not intended to limit the chemistry illustrated thereby. Reagents, 0 intermediates, temperatures, solvents, reaction times, work-up procedures all may be varied to accommodate differences and Ί optimize the particular conditions for making a particular compound. Such variations will be apparent to a chemist or will not require more than minimal experimentation to optimize conditions and reagents for a particular step.
These reaction schemes first illustrate how to make certain portions of the R group which are not commercially available, then illustrate a means to assemble the whole compound using the materials from Reaction Scheme 1 or commercially available Rforming groups. 0 The preparation of certain embodiments of R are given in Scheme 1. (b) Pd l(Ph)3P]2 Cl2 H2, Pd-C t-Bu(Ph)2SiCl -► (CH2)nOSi(Ph)2-t-BuPh2 Bu4NF -► h3co // (CH2)n+2-OTs (f) In those instances where an ω-yn-l-ol is not commercially available, it can be prepared from a corresponding 3-yn-l-ol by treating the alcohol with a strong base. An alkali metal amide may be used. The alcohol is then protected in order to add the desired phenyl group at the terminal triple bond. A silyl ether was formed in this instance; it illustrates the general case. A halo-substituted-phenyl 0 adduct is used to add the phenyl group at the triple bond. The silyl group is removed and the resulting alcohol converted to the tosylate. •Ε 911913 or another group which is sufficiently reactive so as to provide ready formation of an ether later in the synthesis of these compound.
Scheme 1(b) illustrates another method for making certain alkoxy-substitutedphenylalkoxy R groups.
Scheme 1(b) CHO (Ph)3P=CH(CH2)3CO2- COH py r.
CH3O LiAlH4 series of steps and reagents may be used to make other co-(unsubstituted)phenylaliphatic or co-(substituted)phenylaliphatic groups denoted by R. The starting material, the benzaldehydes, are commercially available or can be readily made by known methods.
To make the acid, first an alkylsilazide is added to an inert solvent under an inert atmosphere. Then the phosphonium salt is added. This addition can be done at room temperature or thereabouts. After a brief period of mixing, this mixture is usually a suspension, the benzaldehyde is added slowly at about room temperature. A slight molar excess of the phosphonium salt is employed. After an additional brief period of stirring at about room temperature, the reaction is quenched with water. The solution is acidified and the acid (a) extracted with a suitable organic solvent. Further standard separatory and purification procedures may be employed as desired.
The alcohol is made by reducing the acid using a reducing agent Lithium aluminum hydride or similar reducing agents may be employed and conditions may be varied as needed to effect the reduction.
IE 911914 The tosylate is prepared in an inert solvent employing p-toluenesulfonylchloride and a base such as pyridine. Suitable conditions include carrying out the reaction at room temperature or thereabouts for a period of 1 to 5 hours. Other suitable leaving groups similar in function to the tosylate may be prepared and will be useful as a means for adding this R moiety to the pyridyl ring.
Compounds of formula I can then be synthesized by the sequence of steps outlined in the following schemes.
Scheme 2 HO HO N 1. LDA 2. m-iodobenzaldehyde 3. Pd(OAc)2 / dppf / CO MeOH/DMSO/TEA First 2,6-lutidine-a2,3-diol is oxidized to the 3-hydroxy-6methyl-2-pyridine carboxaldehyde. This aldehyde is then treated 0 with a 1-halosubstituted group which adds to the 3-hydroxy group to form an ether. This reaction is effected by base, for example a carbonate such as K2CO2. Hydrazine hydrate is then used to form an aminohydrazone. This reaction is carried out at an elevated temperature. The reaction mixture is then cooled and treated with a base before recovering the aminohydrazone. This hydrazone is then converted to a triazolo[ 1,5-a]pyridine(2a) by means of N1O2 or another oxidizing agent such as KFe(CN)6- If nickel peroxide is used, the reaction can be effected at room temperature or thereabouts, though it may require an extended reaction time. For the nickel peroxide ίο process, an inert atmosphere is preferred, as are dry conditions.
Other oxidizing agents may require elevated temperatures.
The 2-hydroxyethyl product is then made by first preparing in situ a reagent capable of extracting a proton from the triazolopyridine compound after which the triazolo compound is added followed by a halobenzaldehyde. A useful base is lithium diisopropylamide. It is preferable to prepare it at reduced temperatures, i.e. -40 to 0°C or thereabouts. After the triazolopyridine and benzaldehyde are added, the reaction is allowed to run its course at room temperature or 0 thereabouts. A carbonylation reaction is then carried out to introduce a carboxyl group into the phenyl ring. This is effected by Pd(OAc)2 and gaseous carbon monoxide in an appropriate solvent, preferably at an elevated temperature, i.e. 50-100°C. This gives the carbomethoxysubstituted phenyl compound (2b).
Treating the resulting triazolo compound with Br2 destroys the triazole ring and brominates the resulting 2-position carbon on the pyridine ring to afford the 2-(cc,a-dibromomethyl)pyridyl adduct.
This reaction is best carried out at reduced temperature, i.e. about 0°C and is complete in about an hour or so. Silver nitrate oxidation gives aldehyde (2c). A Wittig reaction is then earned out to form the carbomethoxyethylene group at position 2 on the pyridyl ring. This compound can be treated with a base to hydrolyze the esters, which is then acidified if the free acid (2d) is desired.
Alternatively, the ethylene group at position 2 can be saturated by catalytic hydrogenation, then saponified using a base, which gives the salt, or thereafter acidifying the soluton to obtain the free acid (see Scheme 3 below). The acid can be converted to a pharmaceutically acceptable salt or esterified by known means.
Amides can be made from the acids using known procedures. 0 Analogs of the compounds in Scheme 2 where Ri is an alkanoic acid can be made by simply hydrogenating the unsaturated bonds in that chain. Such process is illustrated in Scheme 3.
CO2Me 2. LiOH Scheme 3 1. Ho H21C10O HO2C CO2H IE 911913 1 Reducing the double bond is effected by catalytic mean using a heavy metal catalyst and hydrogen gas. Mild conditions will suffice. The illustrated esters can be hydrolyzed with base and further converted to other forms of formula I from there or transesterification can be used to convert to another ester.
Compounds where Ri contains a terminal -OH group, or an ester thereof, can be prepared by the series of steps given in Scheme 4.
Scheme 4 1. Br2 2. AgNOr 1. Pd(OAc)2 / dppf / CO MeOH 2. LiOH 3. H+ iC-iqO 3. (C6H5)3PCHCO2Me H0 4. DIBAL Starting material is derived from Scheme 2, then carried through that set of steps, except that the R2 carbomethoxy function is not introduced until after the Ri alcohol has been prepared. Also, separately and apart from the steps in Scheme 2, the Ri carbomethoxy group can be reduced to the alcohol using a reducing 0 agent such as diisobutylaluminum hydride (DIBAL) or a similar reducing agent. Catalytic hydrogenation can be used to saturate the ethylene group at position 2 on the pyridyl ring. A base can be used to saponify the ester to obtain the acid salt, or that salt can be acidified if the free acid is desired.
Each of the products containing an hydroxyl group in Schemes 2-4 can be oxidized to the corresponding ketone, that is where T is CH2C(O)-, by means of a mild oxidizing agent.
Formulations 0 Pharmaceutical compositions of the present invention comprise a pharmaceutical carrier or diluent and an amount of a compound of the formula (I) or a pharmaceutically acceptable salt, such as an alkal 2 metal salt thereof, sufficient to produce the inhibition of the effects of leukotrienes.
When the pharmaceutical composition is employed in the form of a solution or suspension, examples of appropriate pharmaceutical carriers or diluents include: for aqueous systems, water; for nonaqueous systems, ethanol, glycerin, propylene glycol, corn oil, cottonseed oil, peanut oil, sesame oil, liquid parafins and mixtures thereof with water; for solid systems, lactose, kaolin and mannitol; and for aerosol systems, dichlorodifluoromethane, chlorotrifluoroethane and compressed carbon dioxide. Also, in addition to the pharmaceutical carrier or diluent, the instant compositions may include other ingredients such as stabilizers, antioxidants, preservatives, lubricants, suspending agents, viscosity modifiers and the like, provided that the additional ingredients do not have a detrimental effect on the therapeutic action of the instant compositions.
The nature of the composition and the pharmaceutical carrier or diluent will, of course, depend upon the intended route of administration, for example parenterally, topically, orally or by 0 inhalation.
In general, particularly for the prophylactic treatment of asthma, the compositions will be in a form suitable for administration by inhalation. Thus the compositions will comprise a suspension or solution of the active ingredient in water for administration by means of a conventional nebulizer. Alternatively the compositions will comprise a suspension or solution of the active ingredient in a conventional liquified propellant or compressed gas to be administered from a pressurized aerosol container. The compositions may also comprise the solid active ingredient diluted with a solid 0 diluent for administration from a powder inhalation device. In the above compositions, the amount of carrier or diluent will vary but preferably will be the major proportion of a suspension or solution of the active ingredient. When the diluent is a solid it may be present in lesser, equal or greater amounts than the solid active ingredient.
For parenteral administration the pharmaceutical composition will be in the form of a sterile injectable liquid such as an ampule or an aqueous or nonaqueous liquid suspension. 3 For topical administration the pharmaceutical composition will be in the form of a cream, ointment, liniment, lotion, pastes, and drops suitable for administration to the eye, ear, or nose.
For oral administration the pharmaceutical composition will be 5 in the form of a tablet, capsule, powder, pellet, atroche, lozenge, syrup, liquid, or emulsion.
Usually a compound of formula I is administered to a subject in a composition comprising a nontoxic amount sufficient to produce an inhibition of the symptoms of a disease in which leukotrienes are a 0 factor. When employed in this manner, the dosage of the composition is selected from the range of from 50 mg to 1000 mg of active ingredient for each administration. For convenience, equal doses will be administered 1 to 5 times daily with the daily dosage regimen being selected from about 50 mg to about 5000 mg.
The pharmaceutical preparations thus described are made following the conventional techniques of the pharmaceutical chemist as appropriate to the desired end product.
Included within the scope of this disclosure is the method of treating a disease mediated by LTB4 which comprises administering 0 to a subject a therapeutically effective amount of a compound of formula I, preferably in the form of a pharmaceutical composition.
For example, inhibiting the symptoms of an allergic response resulting from a mediator release by administration of an effective amount of a compound of formula I is included within the scope of this disclosure.
The administration may be carried out in dosage units at suitable intervals or in single doses as needed. Usually this method will be practiced when relief of symptoms is specifically required. However, the method is also usefully carried out as continuous or prophylactic treatment. It is within the skill of the art to determine by routine 0 experimentation the effective dosage to be administered from the dose range set forth above, taking into consideration such factors as the degree of severity of the condition or disease being treated, and so forth.
Pharmaceutical compositions and their method of use also include the combination of a compound of formula I with Hi blockers where the combination contains sufficient amounts of both compounds to treat antigen-induced respiratory anaphylaxis or similar allergic reaction. Representative Hi blockers useful here include cromolyn sodium, compounds from the ethanolamines 4 (diphenhydramine), ethylenediamines (pyrilamine), the alkylamines (chlorpheniramine), the piperazines (chlorcyclizine), and the phenothiazines (promethazine). Hi blockers such as 2-[4-(5-bromo-3methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid-3-yl)methyl]-45 pyrimidone are particularly useful in this aspect of the invention. Bioassavs The specificity of the antagonist activity of a number of the compounds of this invention is demonstrated by relatively low levels of antagonism toward agonists such as potassium chloride, carbachol, 0 histamine and PGF2The receptor binding affinity of the compounds used in the method of this invention is measured by the ability of the compounds to bind to [3H]-LTB4 binding sites on human U937 cell membranes.
The LTB4 antagonists activity of the compounds used in the method of this invention is measured by their ability to antagonize in a dose dependent manner the LTB4 elicited calcium transient measured with fura-2, the fluorescent calcium probe. The methods employed were as follows.
U937 Cell Culture Conditions 0 U937 cells were obtained from Dr. John Bomalaski (Medical College of PA) and Dr. John Lee (SK&F, Dept. of Immunology) and grown in RPMI-1640 medium supplemented with 10% (v/v) heat inactivated fetal calf serum, in a humidified environment of 5% CO2, 95% air at 37°C. Cells were grown both in T-flasks and in Spinner culture. For differentiation of the U937 cells with DMSO to monocytelike cells, the cells were seeded at a concentration of 1 x 105 cells/ml in the above medium with 1.3% DMSO and the incubation continued for 4 days. The cells were generally at a density of 0.75-1.25 x 106 cells/ml and were harvested by centrifugation at 800 x g for 10 min. 0 Preparation of U937 Cell Membrane Enriched Fraction Harvested U937 cells were washed with 50 mM Tris-HCl, pH 7.4 at 25°C containing 1 mM EDTA (buffer A). Cells were resuspended in buffer A at a concentration of 5 x 107 cells/ml and disrupted by nitrogen cavitation with a Parr bomb at 750 psi for 10 min at 0°C.
The broken cell preparation was centrifuged at 1,000 x g for 10 min. The supernatant was centrifuged at 50,000 x g for 30 min. The pellet was washed twice with buffer A. The pellet was resuspended at about 3 mg membrane protein/ml with 50mM Tris-HCl, pH 7.4 at 25 C and aliquots were rapidly frozen and stored at -70°C.
Binding of i^HI-LTBa to U397 Membrane Receptors [3H]-LTB4 binding assays were performed at 25°C, in 50 mM Tris-HCl (pH 7.5) buffer containing 10 mM CaCl2, 10 mM MgCl2, [3H]LTB4, U937 cell membrane protein (standard conditions) in the presence (or absence of varying concentrations of LTB4, or SK&F compounds. Each experimental point represents the means of triplicate determinations. Total and non-specific binding of [3H]-LTB4 were determined in the absence or presence of 2 μΜ of unlabeled LTB4, respectively. Specific binding was calculated as the difference between total and non-specific binding. The radioligand competition experiments were performed, under standard conditions, using approximately 0.2 nM [3H]-LTB4, 20-40 pg of U937 cell membrane protein, increasing concentrations of LTB4 (0.1 nM to 10 nM) or other competing ligands (0.1 pM to 30 pM) in a reaction volume of 0.2 ml and incubated for 30 minutes at 25°C. The unbound radioligand and competing drugs were separated from the membrane bound ligand by a vacuum filtration technique. The membrance bound radioactivity on the filters was determined by liquid scintillation spectrometry.
Saturation binding experiments for U937 cells were performed, 0 under standard conditions, using approximately 15-50 pg of U937 membrane protein and increasing concentrations of [3H]-LTB4 (0.022.0 mM) in a reaction volume of 0.2 ml and incubation at 22°C, for 30 minutes. LTB4 (2 pM) was included in a separate set of incubation tubes to determine non-specific binding. The data from the saturation binding experiments was subjected to computer assisted non-linear least square curve fitting analysis and further analyzed by the method of Scatchard.
Uptake of Fura-2 by Differentiated U937 Cells Harvested cells were resuspended at 2 x 10^ cells/ml in Krebs 0 Ringer Hensilet buffer containing 0.1% BSA (RIA grade), 1.1 mM MgSO4, 1.0 mM CaCl2 and 5 mM HEPES (pH 7.4, buffer B). The diacetomethoxy ester of fura-2 (fura-2/AM) was added to a final concentration of 2 pM and cells incubated in the dark for 30 minutes at 37°C. The cells were centrifuged at 800 x g for 10 minutes and resuspended at 2 x 10^ cells/ml in fresh buffer B and incubated at 37°C for 20 minutes to allow for complete hydrolysis of entrapped ester. The cells were centrifuged at 800 x g for 10 minutes and resuspended in cold fresh buffer B at 5 x 106 cells/ml. Cells were maintained on ice in the dark until used for fluorescent measurements.
Fluorescent Measurements-Calcium Mobilization The fluorescence of fura-2 containing U937 cells was measured with a fluorometer designed by the Johnson Foundation Biomedical Instrumentation Group. Fluorometer is equipped with temperature control and a magnetic stirrer under the cuvette holder. The wave lengths are set at 339 nm for excitation and 499 nm for emission. All experiments were performed at 37°C with constant mixing. 0 U937 cells were diluted with fresh buffer to a concentration of 1 x 106 cells/ml and maintained in the dark on ice. Aliquots (2 ml) of the cell suspension were put into 4 ml cuvettes and the temperature brought up to 37°C, (maintained in 37°C, water bath for 10 min). Cuvettes were transferred to the fluorometer and fluorescence measured for about one minute before addition of stimulants or antagonists and followed for about 2 minutes post stimulus. Agonists and antagonists were added as 2 μΐ aliquots.
Antagonists were added first to the cells in the fluorometer in order to detect potential agonist activity. Then after about one 0 minute 10 nM LTB4 (a near maximal effective concentration) was added and the maximal Ca2+ mobilization [Ca2+]i was calculated using the following formula: [Ca2+]i = 224· F-Fzwtn Fmax-F F was the maximum relative fluorescence measurement of the sample Fmax was determined by lysing the cells with 10 μΐ of 10% Triton X100 (final concentration 0.02%). After F/ζιαχ was determined 67 μΐ of 100 mM EDTA solution (pH 10) was added to totally chelate the Ca2 + 0 and quench the fura-2 signal and obtain the Fmin. The [Ca2+]i level for 10 nM LTB4 in the absence of an antagonist was 100% and basal [Ca2+]i was 0%. The IC50 concentration is the concentration of antagonist which blocks 50% of the 10 nM LTB4 induced lCa2+)i mobilization. The EC50 for LTB4 induced increase in [Ca2+]i mobilization was the concentration for half maximal increase. The Ki for calcium mobilization was determined using the formula: 7 Kl [LTB4] [EC50] With the experiments described, the LTB4 concentration was 10 nM and the EC50 was 2 nM.
Results for compounds tested by these methods are given in Figure III.
Figure III Binding. IC50, (Ki). uM Ca-Mobilization U-937 PMN U-937 PMN Structure Membrane Whole Cell Whole cell , pM. % Agonist % Agonist Ex 1 1.6(0.55) 0.77 0.60 3.8 0 0 Ex 2 2.1(0.72) 0.74 - 3.4 0 0 Ex 3 2.3(0.81) 1.6 - 2.9 0 20 Ex 4 8.8(3.1) 1.2 - 4.0 0 0 Examples 0 The following set of examples are given to illustrate how to make and use the compounds of this invention. They are not intended to circumscribe or otherwise limit the scope of this invention. Reference is made to the claims for defining what is reserved to the inventors by this document.
Example A 8-(4-Me thoxy ph envDoc tan-1-(4-toluenesulfonate) A(l) 7-Qctvn-l-ol. 0 35% KH in mineral oil (27g, 240mmol) under an argon atmosphere was washed with hexane and treated dropwise with 1,3diaminopropane. The mixture was stirred at room temperature until it became homogeneous. The flask was cooled to 0°C and 3-octyn-l-ol (lOg, 79mmol, Lancaster Synthesis) was slowly added. The reaction was then stirred at room temperature for 18 hours. The reaction was quenched with H2O (50mL) and the product was extracted into ether.
The organic layer was washed with 10% HC1 (3X15mL) and brine and dried (MgSO4). Evaporation gave the title product which was used without further purification: ^H NMR (90MHz, CDCI3) δ 3.65 (t. J=5IIz, 0 2H, OCH2), 2.23 (m, 2H, CH2), 2.0 (m, 1H, acetylenic), 1.7-1.2 (m, 8H, (CH2)4); IR (neat) umax 3350, 2930, 2125 cm'L •Ε 911913 8 Α(2) 7-Octyn-l-r-butyldiphenylsilyl ether. 7-Octyn-l-ol (3.8g, 30mmol) was dissolved in dimethylformamide (lOmL) and treated with i-butylchlorodiphenylsilane 5 (10.2mL, 33mmol) and imidazole (3.65g, 45mmol) at 0°C. The reaction was stirred at 0°C for 10 minutes and at room temperature for 3 hours. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue purified by flash column chromatography (silica, hexanes) to give a yellow oil: NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.63 (t, 2H, OCH2), 2.23 (m, 2H, CH2), 1.97 (t, 1H, acetylenic), 1.6-1.3 (m, 8H, (CH2)4), 1.05 (s, 9H, z-butyl); IR~(film)umax 3321, 2940, 2125 cm'l.
A(3) 8-(4-MethoxyphenyI)-7-octyn-l-i-butyldiphenylsilyl ether To a flame-dried flask under an argon atmosphere was added 4-iodoanisole (5.34g, 22mmol) in triethylamine (50mL) followed by the addition of 7-octyn-l-t-butyIdiphenyIsily 1 ether.(9.84g, 27mmol), 0 (Ph3P)2PdCl2 (350mg, 0.44mmol), and Cul (200mg, 0.88mmol). The resulting mixture was heated at 50°C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered and the solvent evaporated. The residue was partitioned between ethyl acetate and H2O and the organic layer was collected and washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 1% ethyl acetate in hexanes) to give an oil: NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.7 (t, 2H, OCH2), 2.4 (t, 2H, CH2), 1.7-1.3 (m, 8H, (CH2)4), 1.05 (s, 9H, 0 r-butyl).
A(4) 8-(4-MethoxyphenyUoctan-l-t-butyldiphenylsilyl ether.
To 8-(4-methoxyphenyl)-7-octyn-1 -t-butyldiphenylsilyl ether (2.2g, 4.6mmol) in ethanol (lOmL) and ethyl acetate (lOmL) was added 5% Pd/C (lOOmg). The mixture was subjected to 75 psi of H2 for 4 hours. The reaction was filtered through Celite and the solvent evaporated to give an oil: NMR (250MHz, CDCI3) 5 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), IE θΉ9"'3 9 3.6 (t, 2H, OCH2), 2.5 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6), 1.0 (s, 9H, /-butyl).
A(5) 8-(4-Methoxyphenyl)octan-l-ol, 8-(4-Methoxyphenyl)octan-l-t-butyldiphenylsilyl ether (2.2g, 4.6mmol) in tetrahydrofuran (20mL) was cooled to 0°C and treated with tetrabutylammonium fluoride (14mL, 14mmol, 1M in tetrahydrofuran). The cooling bath was removed and the reaction was stirred at room temperature for 24 hours. The reaction was 0 diluted with ethyl acetate and was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 0-20% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CDCI3) δ 7.15 (d, 2H, aryl), 6.86 (d, 2H, aryl), 3.85 (s, 3H, OCH3), 3.68 (t, 2H, OCH2), 2.62 (t, 2H, benzylic), 1.75-1.3 (m, 12H, (CH2)6).
A (6) 8-(4-Met hoxyphenv Doc tan-1 -(4-toluenesulfonate). 6-(4-Methoxyphenyl)octan-l-ol (5.9g, 25mmol) was dissolved in dry CH2C12 (lOOmL) under an argon atmosphere and cooled to 0°C. 0 To this was added pyridine (2.5mL, 30mmol) and 4-toluenesulfonyl chloride (5.4g, 28mmol). The reaction was stirred at 0°C for 20 minutes and at room temperature for 24 hours. The reaction solution was washed with H2O and brine and dried (Na2SC>4). The solvent was evaporated and the residue purified by flash column chromatography (silica, 0-10% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CDCI3) δ 7.79 (d, 2H, aryl), 7.35 (d, 2H, aryl), 7.09 (d, 2H, aryl), 6.82 (d, 2H, aryl), 4.04 (s, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.55 (t, 2H, benzylic), 2.46 (s, 3H, CH3), 1.75-1.15 (m, 12H, (CH2)6). 0 Example B 6-(4-Methoxyphenvl)hexan-l- (4-toluenesulfonate) B(l) 5-Hexyn-1 - /-butyldiphenylsilyl ether -Hexyn-l-ol (3g, 30mmol, Aldrich) was dissolved in dimethylformamide (lOmL) and treated with /-butylchlorodiphenylsilane (10.2mL, 33mmol) and imidazole (3.65g, 45mmol) at 0°C. The reaction was stirred at 0°C for 10 minutes and at room temperature for 3 hours. Water was added and the product was extracted into ethyl acetate. The ethyl acetate extract was washed /e9K9f3 with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue purified by flash column chromatography (silica, hexanes) to give a yellow oil: ΪΗ NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 3.65 (t, 2H, OCH2), 2.2 (m, 2H, CH2), 1.9 (t, 1H, acetylenic), 1.7 (m, 4H, CH2-CH2), 1.05 (s, 9H, /-butyl).
B(2) 6-(4-Methoxyphenyl)-5-hexvn-l-/-butyldiphenylsilyl ether.
To a flame-dried flask under an argon atmosphere was added 4-iodoanisole (5.34g, 22mmol) in triethylamine (50mL) followed by the addition of 5-hexyn-l-/-butyldiphenylsilyl ether (8.83g, 27mmol), (Ph3P)2PdCl2 (350mg, 0.44mmol), and Cul (200mg, O.88mmol). The resulting mixture was heated at 50°C for 4 hours. Upon cooling to room temperature the reaction mixture was filtered and the solvent evaporated. The residue was partitioned between ethyl acetate and H2O and the organic layer was collected and washed with brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 1% ethyl acetate in hexanes) to give an oil: NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.35 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 0 3.7 (t, 2H, OCH2), 2.4 (t, 2H, CH2), 1.7 (m, 4H, CH2-CH2), 1.05 (s, 9H, /-butyl).
B(3) 6-(4-Methoxvphenyl)hexan-l-t-butyldiphenylsilvl ether.
To 6-(4-methoxyphenyl)-5-hexyn-l -/-butyldiphenylsilyl ether (2.0g, 4.6mmol) in ethanol (lOmL) and ethyl acetate (lOmL) was added 5% Pd/C (lOOmg). The mixture was subjected to 75 psi of H2 for 4 hours. The reaction was filtered through Celite and the solvent evaporated to give an oil: lH NMR (250MHz, CDCI3) δ 7.7 (d, 4H, aryl), 7.4 (m, 6H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 0 3.6 (t, 2H, OCH2), 2.5 (t, 2H, benzylic), 1.55 (m, 4H, CH2-CH2), 1.3 (m, 4H, CH2-CH2), 1.0 (s, 9H, /-butyl).
B(4) 6-(4-Methoxyphenyl)hexan-l -ol. 6-(4-Methoxyphenyl)hexan-1 -/-butyldiphenylsilyl ether (2.0g, 4.6mmol) in tetrahydrofuran (20mL) was cooled to 0°C and treated with tetrabutylammonium fluoride (14mL, 14mmol, 1M in tetrahydrofuran). The cooling bath was removed and the reaction was stirred at room temperature for 24 hours. The reaction was diluted with ethyl acetate and was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue was purified by flash column chromatography (silica, 0-20% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CDCI3) δ 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 3.8 (s, 3H, OCH3), 3.65 (t, 2H, 0CH2), 2.55 (t, 2H, benzylic), 1.6 (m, 4H, CH2-CH2), 1.4 (m, 4H, CH2-CH2).
B(5) 6-(4-Methoxyphenvl)hexan-l-(4-toluenesulfonate). 6-(4- Methoxyphenyl)hexan-l-ol (5.36g, 25mmol) was dissolved in dry CH2CI2 (lOOmL) under an argon atmosphere and 0 cooled to 0°C. To this was added pyridine (2.5mL, 30mmol) and 4toluenesulfonyl chloride (5.4g, 28mmol). The reaction was stirred at 0°C for 20 minutes and at room temperature for 24 hours. The reaction solution was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue purified by flash column chromatography (silica, 0-10% ethyl acetate in hexanes) to give a white solid: lH NMR (250MHz, CDCI3) δ 1.6-1.3 (m, 8H, (CH2)4), 2.4 (s, 3H, CH3), 2.5 (t, 2H, benzylic), 3.8 (s, 3H, OCH3), 4.0 (t, 2H, OCH2), 6.80 (d, 2H, aryl), 7.0 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.8 (d, 2H, aryl). 0 Example C E-6-(4-methoxyphenyI)-l-(4-toluenesulfonate)-5-hexene C( 1) E-4-Methoxvphenyl-5-hexenoic acid.
To a freshly prepared solution of lithium hexamethyldisilazide (64mmol) in tetrahydrofuran (30mL), under an argon atmosphere, was added a suspension of (4- carboxybutyl)triphenylphosphonium bromide (17.6g, 30mmol) in tetrahydrofuran (45mL) at room temperature. The reaction was stirred for 15 minutes during which time the orange-red color of the ylide developed. A solution of 0 4-anisaldehyde (4.5g, 30mmol) in tetrahydrofuran (30mL) was added dropwise and stirring was continued for an additional 20 minutes.
The reaction was quenched with H2O (50mL) and diluted with ether (30mL). The aqueous layer was acidified to pH 1.0 with 3N HC1 and the product was extracted into ethyl acetate (3X50mL). The combined organic layers were dried (MgSO4) and the product was purified by flash column chromatography (silica, 1% methanol in CH2CI2) to yield the E-olefin as a solid: ^H NMR (200MHz, CDCI3) δ 7.3 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.3 (d, 1H, olefin), 6.0 (m, 1H, olefin), 3.8 (s, 3IT, OCH3), 2.3 (m, 4H, allylic CH2 and CH2CO2), 1.8 (q, 2H, CH2).
C(2) E-4-Methoxyphenvl-5-hexen-l -ol.
E-4-Methoxyphenyl-5-hexenoic acid (l.lg, 5.0mmol) in dry ether (lOmL) was slowly added to a suspension of L1AIH4 (240mg, 6.0mmol) in ether (lOmL) under an argon atmosphere. The reaction mixture was refluxed for 45 minutes. Upon cooling to room temperature the reaction was quenched with H2O (lOmL) followed by 6N H2SO4 (7mL). Ethyl acetate (20mL) was added and the organic layer was separated and dried (MgSO4); evaporation gave a white 0 crystalline solid: mp. 65-66°C; lH NMR (200MHz, CDCI3) δ 7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.3 (d, 1H, olefin), 6.1 (m, 1H, olefin), 3.8 (s, 3H, OCH3), 3.6 (t, 2H, OCH2), 2.2 (q, 2H, allylic), 1.5 (m, 4H, CH2- CH2); Anal. Calcd. for C^HjgC^: C, 75.65; H, 8.80, found: C, 75.45; H, 8.95; MS (CI): 207 (M+H).
C(3) E-6-(4-methoxyphenyl)-l -(4-toluenesulfonate)-5-hexene.
E-4-Methoxyphenyl-5-hexen-l-ol (1.6g, 7.0mmol) was dissolved in dry CH2CI2 (50mL) under an argon atmosphere and treated with 4-toluenesulfonyl chloride (7.0g, 36mmol) and pyridine 0 (3mL). The reaction solution was stirred at room temperature for 3.5 hours. Water (40mL) was added to the reaction and the organic layer was separated and dried (MgSO4). The product was purified by flash column chromatography (silica, 10% ethyl acetate in hexane) to give an oil: !H NMR (200MHz, CDCI3) δ 7.8 (d, 2H, aryl), 7.3 (d, 2H, aryl), 7.2 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.2 (d, 1H, olefin), 6.0 (m, 1H, olefin), 4.1 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.4 (s, 3H, CH3), 2.1 (q, 2H, allylic ), 1.6 (m, 4H, CH2- CH2); MS (CI): 361 (M+H).
Example 1 0 2-(E-2-Carboxyethenyl)-3-decyloxv-6-12-(3-carboxy phenyl )-2hydroxylethylpvridine. dilithium salt 1(a) 3-Hydroxy-6-methyl-2-pvridine carboxaldehyde. 2,6-Lutidine-a2,3-diol (l.Og, 7.18mmol, Aldrich) was suspended 3 5 in dry CH2C12 (40mL) and treated with MnO2 (6.1g, 70mmol). The reaction was stirred at room temperature for 6 hours. The reaction mixture was filtered through a pad of Celite and the solvent was removed i_n vacuo. The aldehyde was used directly in the next step without further purification: 'll NMR (250MHz, CDCI3): δ 10.65 (s, 1H, ie OH), 10.30 (s, 1H, CHO), 7.30 (dd, 2H, 4-pyridyl, 5-pyridyl), 2.55 (s, 3H, CH3). 1(b) 3-Decyloxy-6-methyl-2-pvridine carboxaldehyde. 3-Hydroxy-6-methyl-2-pyridine carboxaldehyde obtained above was dissolved in dry dimethylformamide (lOmL) and treated with 1-iododecane (2.1mL, 8.62mmol) and anhydrous K2CO3 (3.0g, 21.7mmol) under an argon atmosphere. The reaction was heated at 90°C for 1 hour with vigorous stirring. Upon cooling to room 0 temperature the reaction mixture was poured into ethyl acetate (lOOmL); the ethyl acetate solution was washed with H2O (3X20mL) and brine and dried (MgSOz}.). The solvent was removed under reduced pressure and the crude product was used directly in the next step without further purification: lH NMR (250MHz, CDC13): δ 10.40 (s, 1H, CHO), 7.30 (dd, 2H, 4-pyridyl, 5-pyridyl), 4.07 (t, 2H. OCH?), 2.6 (s, 3H, CH3), 1.85-0.90 (m, 19H, aliphatic). 1(c) 3-Decyloxy-6-methyl-2-pyridine aminohvdrazone 3-decyloxy-6-methyl-2-pyridine carboxaldehyde (2.15g, 0 7.8mmol) was heated with hydrazine hydrate for 1 hour at 95°C.
Upon cooling to room temperature 25% NaOH was added and the mixture was extracted with ethyl acetate. The organic extract was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated to give an amorphous solid: ^H NMR (250MHz, CDCI3) δ 8.75 (broad singlet, 2H, NH2), 7.55 (s, 1H, CH-N), 7.10 (d, 1H, 5pyridyl), 6.95 (d, 1H, 4-pyridyl), 3.95 (t, 2H, OCH2), 2.55 (s, 3H, CH3), 1.80-0.90 (m, 19H, aliphatic). 1(d) 4-Decyloxv-7-methyl -1.2,3-triazolol 1,5-alpyridine. 0 To a flame-dried flask under an argon atmosphere was added 3 decyloxy-6-methyl-2-pyridine aminohydrazone (2.12g, 7.2mmol) in dry benzene (30mL). To the resulting solution was added N1O2 (790mg, 8.7mmol). The resulting mixture was stirred at room temperature for 72 hours and then filtered through Celite. The solvent was evaporated and the residue purified by flash column chromatography (silica, 10-15% ethyl acetate in hexanes) to give a white solid: !h NMR (250MHz, CDC13): δ 8.2 (s, 1H, CH-N), 6.68 (d. 111. 6-pyridyl), 6.4 (d, 1H, 5-pyridyl), 4.1 (t, 2H, OCH2), 2.8 (s, 3H. CH3), 1.90-0.90 (m, 19H, aliphatic); Anal. Calcd. for C17H27N3; C, 70.55; H, 9.40; N, 14.52, found: C, 70.60; H, 9.14; N, 14.47. 1(e) 1 -(3-lodophenyl)-2-(4-decyloxy-1.2.3-triazolon ,5-alpyridin-75 vDethan-1 -ol.
To a flame dried flask under an argon atmosphere was added diisopropylamine (500mg, 4.9mmol) in dry ether (lOmL). The resulting solution was cooled to -40°C (CH3CN/dry ice bath) and 2.5M n-BuLi (1.97mL, 4.9 mmol) was added. The mixture was stirred at 1 0 40°C for 10 minutes followed by the dropwise addition of 4-decyloxy7-methyl-l,2,3-triazolo[l,5- a]pyridine (1.3g, 4.4mmol) in dry ether (40mL) via addition funnel. The resulting red-brick colored mixture was stirred at - 40°C for 6 hours. 3-Iodobenzaldehyde (1.15g, 4.9mmol) in ether (30mL) was added in one portion. A color change from deep-red to yellow was observed. The mixture was allowed to warm to room temperature over a 2 hour period and then stirred at room temperature for 12 hours. The resulting reaction mixture was partitioned between ethyl acetate and H2O and the organic extract was washed with H2O, brine, and dried (Na2SO4). The solvent was 0 evaporated and the residue purified by flash column chromatography (silica, 10-30% ethyl acetate in hexanes) to give the alcohol as a white solid. A second component was isolated and identified as the 3-substituted triazolopyridine: NMR (250MHz, CDCI3): δ 8.2 (s, 1H, CH-N), 7.80 (s, 1H, aryl), 7.59 (d, 1H, aryl), 7.35 (d, 1H, aryl), 7.07 (t, 1H, aryl), 6.65 (d, 1H, 6-pyridyI), 6.4 (d, 1H, 5-pyridyl), 5.36 (m, 1H, CH-O), 4.11 (t, 2H, OCH2), 3.64 (dd, 1H, Py-CH), 3.45 (dd, 1H, Py-CH'), 3.25 (d, 1H, OH), 1.88-0.88 (m, 19H, aliphatic).
Iff) 1 -(3-Carboxymethylphenyl)-2-(4-decyloxy-l .2.3-triazolo3 0 11.5-alpyridine-7-yl)ethan-l-ol.
To a solution of l-(3-iodophenyl)-2-(4-decyloxy-l,2,3triazolo[l,5-a]pyridine-7-yl)ethan-l-ol (500mg, 0.96mmol) in dimethylsulfoxide (lOmL) was added methanol (4mL), triethylamine (0.3mL, 2.1mmol), Pd(OAc)2 (6.4mg, 0.029mmol), and bis diphenylphosphinopropane (11.9mg, 0.029mmol). Carbon monoxide was bubbled into the mixture for 4 minutes. The mixture was then heated at 85°C under positive carbon monoxide pressure for 6 hours. The mixture was cooled to room temperature and partitioned between ethyl acetate and H2O. The organic layer was washed with HoO, brine. and dried (Na2SO4). The solvent was evaporated and the residue purified by flash column chromatography (silica, 5-20% ethyl acetate in hexanes) to give a white solid: NMR (250MHz, CDCI3): δ 8.2 (s, 1H, CH-N), 8.1 (s, 1H, aryl), 7.95 (d, 1H, aryl), 7.63 (d, 1H, aryl), 7.4 (t, 1H, aryl), 6.65 (d, 1H, 6-pyridyl), 6.4 (d, 1H, 5-pyridyl), 5.45 (m, 1H, CH-O), 4.11 (t, 2H, OCH2), 3.9 (s, 3H, CO2CH3), 3.70 (dd, 1H, Py-CH), 3.45 (dd, 1H, Py-CH'), 3.25 (d, 1H, OH), 1.90-0.88 (m, 19H, aliphatic); Anal. Calcd. for C26H35N3O4: C, 68.85; H, 7.78; N, 9.26, found: C, 68.81; H, 7.73; N, 9.31. 1(g) 3-Decyloxy-2-(a.q-dibromomethvP-6-F2-(3-carboxymethylphenyP-2-hydroxylethylpyridine. -(3-Carboxy methylphen yl )-2-(4-dec y lox y-1,2,3-triazolo[l,5-a]pyridine-7-yl)ethan-l-ol (130mg, 0.28mmol) was dissolved in CH2C12 (3mL) and cooled to 0°C. To this was slowly added a solution of Br2 (46mg, 0.28mmol) in CH2C12 (3mL); gas evolution was observed and the reaction mixture was stirred at 0°C for 1 hour. The CH2C12 solution was washed with NaHCO3, H2O, and brine and dried (Na2SO4). The solvent was evaporated to give a yellow oil: lH NMR 0 (250MHz, CDCI3): δ 8.1 (s, 1H, aryl), 7.92 (d, 1H, aryl), 7.63 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.09 (d, 1H, 3-pyridyl), 7.07 (s, 1H, CHBr2), 7.0 (d, 1H, 4-pyridyl), 6.08 (d, 1H, OH), 5.25 (m, 1H, CH- O), 4.05 (t, 2H, OCH2), 3.9 (s, 3H, CO2CH3), 3.15 (m, 2H, Py-CH2), 1.90-0.88 (m, 19H, aliphatic). 1(h) 3-Decyloxv-6-12-(3-carboxy me thy 1 pheny P-2-hydroxyleth y 1-2pyridine carboxaldehyde.
To a solution of 3-decyloxy-2-(a,a-dibromomethyl)-6-[2-(3carboxymethylphenyl)-2-hydroxy]ethylpyridine (150mg, 0.26mmol) 0 in ethanol (3mL) was added AgNO3 (90mg, 0.56mmol) in H2O (ImL).
The resulting mixture was heated at reflux for 1 hour. The mixture was cooled to room temperature and concentrated HC1 (ImL) was added and the precipitated silver salt was removed by filtration. The filtrate was evaporated and the residue treated with saturated NaHCO3- The product was extracted into ethyl acetate and was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue purified by flash column chromatography (silica, 10-30% ethyl acetate in hexanes) to give a yellow oil: lH NMR (250MHz, CDCI3): δ 10.4 (s, 1H, CHO), 8.1 (s, 1H, aryl), 7.92 (d, 1H, aryl), 7.63 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.33 (d, 1H, 3pyridyl), 7.25 (d, 1H, 4-pyridyl), 5.25 (m, 1H, CH-O), 5.0 (d, 1H, OH), 4.1 (t, 2H, OCH2), 3.9 (s, 3H, CO2CH3), 3.15 (m, 2H, Py-CH2), 1.90- 0.88 (m, 19H, aliphatic); MS (CI): 277 (M+H). l(i) 2-(E-2-Carboxymethylethenyl)-3-decyloxy-6-f2-(3-carboxymethylphenyl)-2-hydroxvl ethyl pyridine. 3-Decyl oxy-6- [2-(3-carboxy methylphenyl)-2-hydroxy ]ethy 1-210 pyridine carboxaldehyde (40mg, 0.09mmol) was dissolved in dry benzene (2mL) under an argon atmosphere. To this was added methyl (triphenylphosphoranylidene)acetate (60mg, 0.18mmol) and the resulting mixture was heated at 45°C for 1 hour. Upon cooling to room temperature the reaction was diluted with ethyl acetate and was washed with H2O and brine and dried (Na2SO4). The solvent was evaporated and the residue purified by flash column chromatography (silica, 15-20% ethyl acetate in hexanes) to give a yellow oil: lH NMR (250MHz, CDCI3): δ 8.1 (s, 1H, aryl), 8.1 (d, J=16Hz, 1H, olefin), 7.9 (d, 1H, aryl), 7.65 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.15 (d, 1H, -pyridyl), 7.03 (d, 1H, 4-pyridyl), 6.95 (d, J=16Hz, 1H, olefin), 5.65 (d, 1H, OH), 5.2 (m, 1H, CH-O), 4.05 (t, 2H, OCH2), 3.9 (s, 3H, CO2CH3), 3.8 (s, 3H, CO2CH3), 3.10 (m, 2H, Py-CH2), 1.90-0.88 (m, 19H, aliphatic); MS (CI): 498 (M+H). l(i) 2-(E-2-Carboxyethenvl)-3-decv lox v-6-[2-(3-carboxvphenvl )-2hvdroxylethylpyridine. dilithium salt. 2-(E-2-Carboxymethylethenyl)-3-decyIoxy-6-[2-(3carboxymethylphenyl)-2-hydroxy]ethylpyridine (22mg, 0.04mmol) was dissolved in tetrahydrofuran, H2O, and methanol (0.50mL each) 0 and treated with LiOH monohydrate (5mg, 0.2mmol). The reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was dissolved in H2O and purified by Reversed Phased MPLC (RP-18 silica, 10-40% MeOH in H2O). The desired fractions were lyophilized to give a colorless amorphous solid: iH NMR (250MHz, CD3OD): δ 8.01 (s, 1H, aryl), 7.80 (d,lH, aryl), 7.76 (d, J=16Hz, 1H, olefin), 7.36 (d, 1H, aryl), 7.30 (t, 1H, aryl), 7.24 (d, 1H, 5- pyridyl), 7.07 (d,J=16Hz, 1H, olefin), 7.01 (d, 1H, 4-pyridyl), 5.11 (t, 1H, CH-O), 4.0 (t, 2H, OCH2), 3.1 (m, 2H, Py-CIb), 1.83- 0.89 (m, 19H, aliphatic); FAB-MS: 474.3 (M-H, monolithium salt), 468 (ΜΗ, free acid).
Example 2 2-(2-Carboxv ethyl )-3-decyloxy-6-ί 2-(3-carboxy phenyl )-2hydroxylethvlpyridine, dilithium salt 2(a) 2-(2-Carboxymethylethv I )-3-decyloxv-6-[2-(3-carboxy me thylp hen v l )-2-hydroxv1ethy 1 pyridine.
To 2-(E-2-carboxymethylethenyl)-3-decyloxy-6-[2-(3carboxymethylphenyl)-2-hydroxy]ethylpyridine (13mg, 0.02mmol) in ethanol (3mL) was added 5% Pd/C (2mg). The mixture was subjected to 5 psi of H2 for 1 hour. The mixture was filtered through Celite and the solvent was evaporated to give an oil: lH NMR (250MHz, CDC13): δ 8.08 (s, 1H, aryl), 7.9 (d, 1H, aryl), 7.6 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.05 (d, 1H, 5-pyridyl), 6.87 (d, 1H, 4- pyridyl), 6.0 (broad singlet, 1H, OH), 5.15 (m, 1H, CH-O), 4.01 (t, 2H, 0CH2), 3.9 (s, 3H, CO2CH3), 3.8 (s, 3H, CO2CH3), 3.2 (t, 2H, CH2), 3.05 (m, 2H, CH2), 2.8 (t, 2H, CH2), 1.83-0.88 (m, 19H, aliphatic). 2(b) 2-(2-Carboxyethv 1)-3-decyloxv-6-i2-(3-carboxy phenyl )-2hydroxylethvlpyridine, dilithium salt. 2-(2-Carboxymethylethyl)-3-decyIoxy-6-[2-(3carboxymethylphenyl)-2-hydroxy]ethyIpyridine (lOmg, 0.015mmol) was dissolved in tetrahydrofuran, H2O, and MeOH (0.5mL each) and treated with LiOH monohydrate (2mg, O.lOmmol). The reaction was stirred at room temperature for 24 hours. The solvent was evaporated and the residue was dissolved in H2O, filtered through a nylon filter and purified by Reversed Phased MPLC (RP-18 silica, 103 0 40% methanol in H2O). The desired fractions were lyophilized to give a colorless amorphous solid: ^H NMR (250MHz, CD3OD): δ 8.0 (s, 1H, aryl), 7.8 (d, 1H, aryl), 7.32 (d, 1H, aryl), 7.25 (t, 1H, aryl), 7.1 (d, 1H, - pyridyl), 6.9 (d, 1H, 4-pyridyl), 5.1 (t, 1H, CH-O), 4.0 (t, 2H, OCH2), 3.1 (t, 2H, CH2), 3.05 (m, 2H, CH2), 2.5 (t, 2H, CH2), 1.8-0.90 (m, 19H, aliphatic); FAB-MS: 484 (M+H).
Example 3 2-(E-3-Hydroxypropenyl)-3-decy I oxv-6-[2-(3-carboxvphenyl )-2hydroxylethvlpyridine, lithium salt. 3(a) 3-Decyloxy-2-(a.g-dibromomethyl)-6-r2-(3-iodophenyl)-2hydroxylethy I pyridine.
This compound was prepared from l-(3-iodophenyl)-2-(4decyloxy-1,2,3-triazolo[l,5-a]pyridin-7-yl)ethan-l -ol [Example 1(d)] according to the procedure described for 3-decyloxy-2-(a,a1 0 dibromomethyl)-6-[2-(3-carboxymethylphenyl)-2hydroxy]ethylpyridine [Example 1(f)]. 3(b) 3-Decyloxv-6-[2-(3-iodophenvl )-2-hydroxy]ethy I-2-pyridine carboxaldehvde.
This compound was prepared from 3-decyloxy-2-(a,adi bromo me thy 1)-6- [2-(3-iodophenyl )-2-hydroxy] ethyl pyridine according to the procedure described in Example 1(g). It was obtained as a white solid. lH NMR (250MHz, CDCI3): δ 10.4 (s, 1H, CHO), 7.8 (s, 1H, aryl), 0 7.6 (d, 1H, aryl), 7.4 (m, 2H, 3d pyridyl, aryl), 7.3 (d, 1H, 4-pyridyl), 7.1 (t, 1H, aryl), 5.1 (m, 1H, CH-O), 4.95 (d, 1H, OH), 4.1 (t, 2H, OCH?), 3.1 (m, 2H, Pyd CH2), 1.80-0.90 (m, 19H, aliphatic). 3(c) 2-(E-2-Carboxymethylethenyl)-3-decyloxy-6-[2-(3-iodophenyl)2 5 2-hydroxy]ethylpyridine.
The captioned compound was prepared from 3-decyloxy-6-[2(3-iodophenyl )-2-hydroxy]ethyl-2-pyridine carboxaldehyde [Example 3(b)] according to the procedure described for in Example 1(h): lH NMR (250MHz, CDCI3): δ 8.1 (d, J=15.9Hz, 1H, olefin), 7.8 (s, 0 1H, aryl), 7.6 (d, 1H, aryl), 7.4 (d, 1H, aryl), 7.2 (d, IH, 5- pyridyl), 7.05 (m, 2H, 4-pyridyl, aryl), 6.95 (d, J=15.9Hz, 1H, olefin), 5.6 (d, 1H, OH), 5.1 (m, 1H, CH-O), 4.05 (t, 2H, OCH2), 3.8 (s, 3H, CO2CH3), 3.05 (m, 2H, Py-CH2), 1.85-0.90 (m, 19H, aliphatic). 3(d) 2-(E-3-Hydroxypropeny 1)-3-decyl ox v-6-[2-(3-iodophenyl)-2hydroxylethylpyridine. 2-( E-2-Carboxymethylethenyl)-3-decyloxy-6-( 2-(3iodophenyl)-2-hydroxy]ethylpyridine (340mg, 0.60mmol) was dissolved in dry CH2C12 (6mL) under an argon atmosphere and cooled IE 911913 29 to 0°C. DIBAL (1.5mL, 1.5mmol, 1M in CH2CI2) was added dropwise and the reaction was maintained at 0°C for 20 minutes. The reaction was quenched with methanol (lOmL) and the solvent was evaporated. The residue was partitioned between ethyl acetate and H2O and the organic layer was washed with H2O and brine and dried (Na2SO4).
The solvent was evaporated and the residue purified by flash column chromatography (silica, 10-30% ethyl acetate in hexanes) to give a yellow oil. lH NMR (250MHz, CDCI3): δ 7.8 (s, 1H, aryl), 7.6 (d, 1H, aryl), 7.4 1 0 (d, 1H, aryl), 7.10 (m, 5H, olefinic, 4-pyridyl, 3-pyridyl, aryl), 6.4 (broad singlet, 1H, OH), 5.05 (m, 1H, CH-O), 4.4 (d, 2H, allylic), 3.95 (t, 2H, OCH2), 3.0 (m, 2H, Py-CH2), 1.90-0.90 (m, 19H, aliphatic). 3(e) 2-(E-3-Hvdroxypropenyl)-3-decvloxy-6-[2-(3-carboxy met hyl1 5 phenyl)-2-hydroxvlethyl pyridine.
This compound was prepared from -2-(E-3-hydroxypropenyl)-3decyloxy-6-[2-(3-iodophenyl)-2-hydroxy]ethylpyridine according to the procedure described in Example 1(e). lH NMR (250MHz, CDCI3): δ 8.15 (s, 1H, aryl), 7.9 (d, 1H, aryl), 0 7.65 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.10 (m, 4H, olefinic, 3-pyridyl, 4pyridyl), 6.4 (broad singlet, 1H, OH), 5.2 (m, 1H, CH-O), 4.4 (d, 2H, allylic), 4.0 (t, 2H, OCH2), 4.9 (s, 3H, CO2CH3), 3.1 (m, 2H, Py-CH2), 1.90-0.90 (m, 19H, aliphatic). 3(f) 2-(E-3-Hydroxypropenyl)-3-decvloxy-6-f2-(3-carboxyphenyl)2-hydroxvlethylpyridine. lithium salt.
This salt was prepared from 2-(E-3-hydroxypropenyl)-3decy loxy-6- [2-(3-carboxy methylphenyl)-2-hydroxy ]ethy lpyridine [Example 3(e)] according to the procedure described for 2-(E-23 0 car box ye thenyl )-3-decy loxy-6- [2-(3-carboxy pheny 1)-2hydroxy]ethylpyridine, dilithium salt [Example l(i)].
H NMR (250MHz, CD3OD): δ 8.0 (s, 1H, aryl), 7.8 (d, 1H, aryl), 7.4 (d, 1H, aryl), 7.3 (t, 1H, aryl), 7.2 (d, 1H, 3-pyridyl), 6.9 (m, 3H, olefinic, 4-pyridyl), 5.1 (m, 1H, CH-O), 4.3 (d, 2H, allylic), 4.0 (t, 2H, OCH2), 3.1 (m, 2H, Py-CH2), 1.85-0.85 (m, 19H, aliphatic); FAB-MS: (-ve), 460.3 (M-Li).
Example 4 2-(E-2-Carboxvethen vl )-3- i 6-(4-meth oxy phenyl) hexyl oxy 1-6- Γ2-(3carboxyphenyl)-2-hydroxylethylpyridine, dilithium salt 2-(E-2-Carboxyethenyl)-3-[6-(4-methoxyphenyl) hexyl oxy ]-65 [2-(3-carboxyphenyl)-2-hydroxy]ethylpyridine, dilithium salt was prepared according to the procedure described for 2-(E-2carboxyetheny 1)-3-decyl oxy-6- [2-(3-carboxy phenyl )-2hydroxy]ethylpyridine, dilithium salt recited in Example 1, but substituting 6-(4-methoxyphenyl)hexan-l -(4-toluenesulfonate) [Example B(5)] for 1-iododecane. 4(a) 3-[6-(4-Methoxvphenyl)hexyloxy 1-6-methyl-2-pyridine carboxaldehvde: !h NMR (250MHz, CDCI3): δ 10.4 (s, 1H, CHO), 7.3 (s, 2H, 4-pyridyl, 5-pyridyl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 4.1 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.6 (s, 3H, CH3), 2.6 (t, 2H, benzylic), 1.81.35 (m, 8H, aliphatic); Anal. Calcd. for C2oH25N03 · 1/8 H2O: C, 72.87; H, 7.72; N, 4.25, found: C, 72.75; H, 7.65; N, 4.10; MS (CI): 328 (M+H).
Following the procedures in Examples 1(b) et seq, but 0 substituting the appropriate adducts here for those recited in Example 1, the following compounds were made: 4(b) 3-i6-(4-Methoxyphenyl)hexyloxyl-6-methyl-2-pyridine aminohvdrazone: ^H NMR (250MHz, CDCI3): δ 8.2 (s, 1H, CH-N), 7.15 (d, 2H, aryl), 7.1 (d, 1H, 5-pyridyl), 7.0 (d, 1H, 4-pyridyl), 6.8 (d, 2H, aryl), 5.7 (broad singlet, 2H, NH2), 3.95 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.6 (s, 3H, CH3), 2.6 (t, 2H, benzylic), 1.8-1.35 (m, 8H, aliphatic). 4(c) 4-i6-(4-Methoxyphenyl)hexyloxvl-7-methyl-l .2.3-triazolo-f 1.53 0 alpyridine: lH NMR (250MHz, CDCI3): δ 8.2 (s, 1H, CH-N), 7.1 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.65 (d, 1H, 6-pyridyl), 6.4 (d, 1H, 5-pyridyl), 4.1 (t, 2H, OCH2), 3.8 (s, 3H, OCH3), 2.8 (s, 3H, CH3), 2.63 (t, 2H, benzylic), 1.90-1.35 (m, 8H, aliphatic). 4(d) 1 -(3 - lodophenv 1)-2-14-16-(4-me thoxy phenyl) hex v lox v 1-1.2,3triazolof 1,5-alpyridin-7-yl1ethan-l -ol: ^H NMR (250MHz, CDCI3): δ 8.2 (s, 1H, CH-N), 7.8 (s, 1H, aryl), 7.6 (d, 1H, aryl), 7.37 (d, 1H, aryl), 7.06 (t, 1H, aryl), 7.05 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.65 (d, 1H, 6pyridyl), 6.4 (d, 1H, 5-pyridyl), 5.4 (m, 1H, CH-O), 4.1 (t, 211, OCHo), 3.8 •Ε911913 (s, 3Η, OCH3), 3.7 (dd, 1H, Py-CH), 3.5 (dd, 1H, Py-CH'), 3.2 (d, 1H, OH), 2.63 (t, 2H, benzylic), 1.90-1.35 (m, 8H, aliphatic); MS (CI): 572 (M+H). 4(e) 1 -(3-Carboxymethv lphenvl )-2-f4-16-(4-methoxypheny 1)5 hexyloxvl-1.2,3-tri azoloi 1.5-a1pyridin-7-yl1ethan-l -ol: 1H NMR (250MHz, CDCI3): δ 8.2 (s, 1H, CH-N), 8.11 (s, 1H, aryl ), 7.95 (d, 1H, aryl), 7.6 (d, 1H, aryl), 7,4 (t, 1H, aryl), 7.1 (d, 2H, aryl), 6.8 (d, 2H, aryl), 6.6 (d, 1H, 6-pyridyl), 6.3 (d, 1H, 5- pyridyl), 5.5 (m, 1H, CH-O), 4.1 (t, 2H, OCH2), 3.9 (s, 3H, CO2CH3), 3.8 (s, 3H, OCH3), 3.7 (dd, 1H, Py10 CH), 3.5 (dd, 1H, Py- CH'), 3.2 (d, 1H, OH), 2.55 (t, 2H, benzylic), 1.901.40 (m, 8H, aliphatic); MS (CI): 504 (M+H). 4(f) 3-f6-(4-Methoxyphenyl)hexyloxyl-2-(a,g-dibromomethvl)-6-f2(3-carboxymethvlphenyl)-2-hydroxylethyl pyridine: NMR (250MHz, CDCI3): δ 8.15 (s, 1H, aryl), 7.9 (d, 1H, aryl), 7.65 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.1 (m, 4H, 3-pyridyl, 4-pyridyl, aryl), 6.8 (d, 2H, aryl), 5.3 (m, 1H, CH-O), 4.1 (t, 2H, OCH2), 3.95 (s, 3H, CO2CH3), 3.9 (s, 1H, CHBr2), 3.8 (s, 3H, OCH3), 3.15 (m, 2H, Py-CH2), 2.55 (t, 2H, benzylic), 1.85-1.40 (m, 8H, aliphatic). 4(g) 3-f6-(4-Methoxypheny l)hexvloxyl-6-f2-(3-carboxymethylphenyl)-2-hydroxy1ethyl-2-pyridine carboxaldehyde: 1H NMR (250MHz, CDCI3): δ 10.4 (s, 1H, CHO), 8.1 (s, 1H, aryl), 7.9 (d, 1H, aryl), 7.65 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.35 (d, 1H, 3-pyridyl), 7.25 (d, 1H, 4-pyridyl), 7.1 (d, 2H, aryl), 6.8 (d, 2H, aryl), 5.4 (m, 1H, CH-O), 5.0 (d, 1H, OH), 44.1 (t, 2H, OCH2), 3.95 (s, 3H, CO2CH3), 3.8 (s, 3H, OCH3), 3.2 (m, 2H, Py-CH2), 2.5 (t, 2H, benzylic), 1.90-1.40 (m, 8H, aliphatic); MS (CI): 492 (M+H). 0 4(h) 2-(E-2-Carboxymethylethenyl)-3-i6-(4-methoxyphenyl)hexyloxv 1-6-12-(3-carboxy methyl phenyl)-2-hydroxylethvl pyridine: lH NMR (250MHz, CDCI3): δ 8.07 (s, 1H, aryl), 8.05 (d, J=16Hz, 1H, olefin), 7.9 (d, 1H, aryl), 7.65 (d, 1H, aryl), 7.4 (t, 1H, aryl), 7.1 (m, 4H, 4-pyridyl, 5-pyridyl, aryl), 6.95 (d, J=16Hz, 1H, olefin), 6.8 (d, 2H, aryl), 5.7 (d, 1H, OH), 5.2 (m, 1H, CH-O), 4.05 (t, 2H, OCH?), 3.9 (s, 3H, CO2CH3), 3.8 (s, 3H, OCH3), 3.75 (s, 3H, CO2CH3), 3.15 (m, 2H, Py-CH2), 2.55 (t, 2H, benzylic), 1.90-1.40 (m, 8H, aliphatic); Anal. Calcd. for: C32H37NO7 · 9/8 H?O: C, 67.68; H, 6.97; N, 2.47, found: C, 67.45; H, 6.63; N, 2.34; MS (CI): 548 (M+H). 4(i) 2-(E-2-Carboxyethenyl)-3-r6-(4-methoxyphenyl)hexyloxyl-6-r2(3-carboxyphenyl)-2-hydroxy1ethylpyridine, dilithium salt: lH NMR (250MHz, CD3OD): δ 8.05 (s, 1H, aryl), 7.8 (d, 1H, aryl), 7.75 (d, J=16Hz, 1H, olefin), 7.35 (d, 1H, aryl), 7.25 (t, 1H, aryl), 7.2 (d, J=16Hz, 1H, olefin), 7.0 (m, 4H, 4-pyridyl, 5- pyridyl, aryl), 6.75 (d, 2H, aryl), 5.15 (t, 1H, CH-O), 4.0 (t, 2H, OCH2), 3.7 (s, 3H, OCH3), 3.1 (m, 2H, Py-CH2), 2.5 (t, 2H, benzylic), 1.80-1.35 (m, 8H, aliphatic); FAB-MS: (+ve), 532.2 (M+H); (-ve), 524.4 (M-Li). 0 Example 5 Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
Inhalant Formulation A compound of formula I, 1 to 10 mg/ml, is dissolved in isotonic saline and aerosolized from a nebulizer operating at an air flow adjusted to deliver the desired amount of drug per use. 0 Tablets Ineredients Per Tablet Per 10,000 Tablets Active ingredient (Cpd of Form. I) 40 mg 400 g Corn Starch 20 mg 200 g Alginic acid 20 mg 200 g Sodium alginate 20 mg 200 g Magnesium stearate 1..-3, mg 13 g 101.3 mg 1013 g Procedure for making tablets: Step 1 Blend ingredients No. 1, No. 2, No. 3 and No. 4 in a suitable mixer/blender.
Step 2 Add sufficient water portion wise to the blend from Step 1 3 5 with careful mixing after each addition. Such additions of water and mixing until the mass is of a consistency to permit its conversion to wet granules.
Step 3 The wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
Step 4 The wet granules are then dried in an oven at 410°F 5 (60°C) until dry.
Step 5 The dry granules are lubricated with ingredient No. 5.
Step 6 The lubricated granules are compressed on a suitable tablet press.
Suppositories: Ingredients Per Sudd. Per 1000 Supp. 1. Formula I compound 40.0 mg 40 g Active ingredient 2. Polyethylene Glycol 1350.0 mg 1,350 g 1000 3. polyethylene glycol 450.0 ms 450 2 4000 1840.0 mg 1,840 g Procedure: 0 Step 1. Melt ingredient No. 2 and No. 3 together and stir until uniform.
Step 2. Dissolve ingredient No. 1 in the molten mass from Step 1 and stir until uniform.
Step 3. Pour the molten mass from Step 2 into suppository moulds 2 5 and chill.
Step 4. Remove the suppositories from moulds and wrap.
Claims (24)
1.What is claimed is: 1. A compound of the formula or a pharmaceutically acceptable salt or oxide thereof where T is CO or CH(OH); R is Cj to C20-aliphatic, substituted or unsubstituted phenyl Ci to Cio-aliphatic where substituted phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo, or R is Ci to C20-aliphatic-O-, or R is unsubstltuted or substituted phenyl Cj to Cio-aliphatic-O- where phenyl has one or more radicals selected from the group consisting of lower alkoxy, lower alkyl, trihalomethyl, and halo; Rl is -(Ci to C5 aliphatic)R3, -(Cl to C5 aliphatic)CHO ? -(Cl to C5 aliphatic)CH2OR7, -R3, -CH2OH or -CHO; R2 and R3 are independently -COR4 where R4 is -OH, a pharmaceutically acceptable ester-forming group -OR5, or -OX where X is a pharmaceutically acceptable cation, or R4 is -N(R6)2 where R6 is H, or an aliphatic group of 1 to 10 carbon atoms, cycloalkyl-(CH2)ngroup of 4 to 10 carbons where n is 0-3 or both R6 groups form a ring having 4 to 6 carbons, or R2 is N(A)(B) where A is H, or alkyl of 1 to 6 carbons and B is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons or -SO2R8 where R8 is -CF3, Cl to C6 alkyl or phenyl; and R7 is hydrogen, Cl to C6-alkyl, or Cl to C6-acyl.
2. A compound of claim 1 where T is CH(OH).
3. A compound of claim 2 where R is Cl to C20 aliphatic-O-, Rl is -(Ci to C5 aliphatic)R3.
4. A compound of claim 3 where R is -C8 to Cl5-alkyl-Ο-, Rl is -CH=CHCOR5 where the double bond substituents are in the trans configuration and R2 is -COOH or -NHSO2R8·
5. A compound of claim 4 which is 2-(E-2-carboxyethenyl)3-decyloxy-6-[2-(3-carboxyphenyl)-2-hydroxy]ethylpyridine or a pharmaceutically acceptable salt thereof.
6. A compound of claim 2 where R is Cg to Cl5-alkyl-O-, Rl is -(Cl to C5 aliphatic)CH2OR7 and R2 is -COOH or -NHSO2R8 substituted at the meta position.
7. A compound of claim 6 which is 2-(E-3-hydroxypropenyl)-3-decyloxy-6-[2-(3-carboxy pheny 1)-2hydroxy]ethylpyridine or a pharmaceutically acceptable salt thereof.
8. A compound of claim 2 where R is substituted or unsubstituted phenyl Cj to Cjo aliphatic, Rl is -(Ci to C5 aliphatic)R3, and R2 is -COOH or -NHSO2R8 substituted at the meta or para position.
9. A compound of claim 8 where R is a lower alkoxysubstituted phenyl Cl to C8-alkyl-O- group.
10. A compound of claim 9 which is 2-(E-2-carboxyethenyl)3-[6-(4-methoxyphenyl)hexyloxy]-6-[2-(3-carboxy pheny 1)-2hydroxyjethylpyridine or a pharmaceutically acceptable salt thereof.
11. A compound of claim 2 where Rl is -(Ci to C5-alkyl)COR4.
12. A compound of claim 11 which is 2-(2-Carboxyethyl)-3decyloxy-6-[2-(3-carboxyphenyl)-2-hydroxy]ethylpyridine or a pharmaceutically acceptable salt thereof.
13. A compound of claim 2 where R2 is at the para position.
14. A compound of claim 1 where T is CO.
15. A compound of claim 14 where R is Cl to C20 aliphatic-O-, Rl is -(Ci to C5 aliphatic)R3 or -(Cl to C5 aliphatic)CH2OR7 and R2 is COOH or -NHSO2R8 substituted at the meta or para position.
16. A compound of claim 15 where R is -C8 to Ci5-alkyl-O-, Rl is -CH=CHCOR4.where the double bond substituents are in either the the cis or trans configuration and R2 is -COOH.
17. A compound of claim 14 where R is substituted or unsubstituted phenyl Ci to C10 -aliphatic-O-, Rl is -(Ci to C5 aliphatic)R3 or -(Cl to C5 aliphatic)CH2OR7 and R2 is -COOH or NHSO2R8 substituted at the meta or para position.
18. A compound of claim 18 where R is Cl to C20 aliphatic-O-, Rl is -(Ci to C5 aliphatic)R3.
19. A compound of claim 19 where R is -C8 to Ci5-alkyl-O-, Rl is -CH=CHCOR5 where the double bond substituents are in the trans configuration and R2 is -COOH or -NHSO2R8·
20. A pharmaceutical composition comprising a pharmaceutical carrier or diluent and a compound of claim 1.
21. A pharmaceutical composition according to claim 18 in a form suitable for administration by inhalation, parenteral administration, or oral administration or topical administration.
22. A composition according to claim 19 where T is CH(OH).
23. A composition according to claim 19 where T is CO
24. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 in the manufacture of a medicament for preventing or treating a pulmonary disease in which leukotrienes are a factor . 26. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in claim 1 in the manufacture of a medicament for preventing or treating a nonpulmonary disease in which leukotrienes are a factor. 27. A process for preparing a compound of formula (I) as defined in claim 1, substantially as described herein by way of example. 28. A compound whenever prepared by a process according to claim 27.
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IE191291A IE911912A1 (en) | 1990-06-07 | 1991-06-05 | Pyridyl-benzoic acid derivatives for treating¹leukotriene-related diseases |
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CA (1) | CA2083958A1 (en) |
FI (1) | FI925544A0 (en) |
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MA22926A1 (en) * | 1992-06-30 | 1994-04-01 | Smithkline Beecham Corp | PROCESS FOR THE PREPARATION OF NEW COMPOUNDS. |
EP0675718A1 (en) * | 1992-12-23 | 1995-10-11 | Smithkline Beecham Corporation | Substituted pyridyl compounds useful as leukotriene antagonists |
WO1995028386A1 (en) * | 1994-04-13 | 1995-10-26 | F. Hoffmann-La Roche Ag | Substituted pyridine leukotriene b4 antagonists |
WO2002076226A1 (en) * | 2001-03-27 | 2002-10-03 | Meiji Seika Kaisha, Ltd. | Process for producing puffed snack and production apparatus therefor |
WO2005019434A2 (en) | 2003-08-26 | 2005-03-03 | The Regents Of The University Of Colorado, A Body Corporate | Serine protease inhibitors for treatment of bacterial infections |
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1991
- 1991-05-15 WO PCT/US1991/003399 patent/WO1991018880A1/en not_active Application Discontinuation
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AU7901791A (en) | 1991-12-31 |
MA22196A1 (en) | 1992-04-01 |
WO1991018880A1 (en) | 1991-12-12 |
HU9203866D0 (en) | 1993-03-29 |
HUT64748A (en) | 1994-02-28 |
CN1058016A (en) | 1992-01-22 |
FI925544A (en) | 1992-12-07 |
IL98388A0 (en) | 1992-07-15 |
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CA2083958A1 (en) | 1991-12-08 |
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