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WO1993015047A1 - Derives d'aminoacides utilises comme antagonistes de facteur d'activation plaquettaire (paf) - Google Patents

Derives d'aminoacides utilises comme antagonistes de facteur d'activation plaquettaire (paf) Download PDF

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Publication number
WO1993015047A1
WO1993015047A1 PCT/GB1993/000167 GB9300167W WO9315047A1 WO 1993015047 A1 WO1993015047 A1 WO 1993015047A1 GB 9300167 W GB9300167 W GB 9300167W WO 9315047 A1 WO9315047 A1 WO 9315047A1
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alkyl
group
methyl
ethyl ester
compound
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PCT/GB1993/000167
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English (en)
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Stephen Arthur Bowles
Andrew Miller
Mark Whittaker
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British Bio-Technology Limited
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Publication of WO1993015047A1 publication Critical patent/WO1993015047A1/fr

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    • 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
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    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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    • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07C311/39—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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    • C07C311/40—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C311/43—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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Definitions

  • This invention relates primarily to novel substituted amino acid derivatives which possess pharmaceutical activity as antagonists of PAF.
  • Platelet activating factor is a bioactive phospholipid which has been identified as l-0-hexadecyl/octadecyl-2-acetyl-j/z-glyceryl-3-phosphoryl choline. PAF is released directly from cell membranes and mediates a range of potent and specific effects on target cells resulting in a variety of physiological responses which include hypotension, thrombocytopenia, bronchoconstriction, circulatory shock, and increased vascular permeability (oedema/erythema).
  • PAF antagonists include compounds which are structurally related to the PAF molecule such as glycerol derivatives (EP-A-0238202), and heterocyclic compounds such as 5- oxy derivatives of tetrahydrofuran (US-4, 888,337) and 2,5-diaryl tetrahydrofurans (EP-A-0144804).
  • the compounds of WO 91/17157 differ from the 5-oxy derivatives of tetrahydofuran described in US-4, 888,337 and from the 2,5-diaryl tetrahydrofurans such as L-659,989, in that they feature an appended heterocycle with an unsubstituted sp 2 nitrogen atom.
  • PAF antagonists in addition to those of WO 91/17157, for which the presence of a heterocyclic sp 2 nitrogen atom appears to be an important requirement for activity (Whittaker, M., Curr. Opin. Thera. Patents 2(5), 583- 623 (1992)).
  • the presence of a heterocyclic group possessing an unsubstituted sp 2 nitrogen atom is not a strict requirement for PAF antagonist activity.
  • the compounds of the present invention differ from the other PAF antagonists refered to above in that they are amino acid derivatives.
  • A represents:
  • X represents a 5- or 6-membered aromatic or heterocyclic ring, which may optionally be fused to a benzene ring or to a further 5- or 6-membered aromatic or heterocyclic ring and wherein any of the rings may be optionally substituted with one or more substituents;
  • substituents of the rings of the group X are -CN, -N02, halogen, -C1-C4 perfluoroalkyl, hydroxyl, carbonyl, thiocarbonyl, carboxyl, -CONH2, a group -D wherein D is as defined below, -R 1 1 , -OR 1 1 , -SR 11 , -SOR 11 , -SO2R 11 , -NHR 11 , -NRiiR 11 , CO2R 11 or -CONHR 11 wherein R 11 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl or -C4-C8 cycloalkenyl each of which is optionally substituted with one or more substituents selected from halogen, hydroxyl, amino, carboxyl, -C1-C4 perfluoroalkyl, -
  • n is an integer from 0 to 3
  • each of R5, R6 and R is independently hydrogen, -C1 -C6 alkyl, -OC ⁇ -C ⁇ 5 alkyl, -SC1 -C6 alkyl, -N(C ⁇ -C6 alkyl)2, -C2-C6 alkenyl, -C2-C6 alkynyl, -OCH2Ph, halogen, -CN, -CF3, -CO2H, -CO2C1-C6 alkyl, -CONH2, -CONHC1 -C6 alkyl, -CON(C ⁇ -C6 alkyl)2, -CHO, -CH2OH, -NH2, -NHCOC1-C6 alkyl, -SOC1-C6 alkyl, or -SO2C1-C6 alkyl; or
  • J represents a divalent alkanediyl, alkenediyl or alkynediyl group from 1 to 8 carbon atoms which may be a straight or branched-chain, wherein the said group is either unsubstituted or substituted by one or more substituents selected from hydroxy, -OC1-C6 alkyl, -SC1-C6 alkyl, halogen, -CF3, and -CN;
  • q is 0 or 1
  • V represents a phenylene, furandiyl, tetrahydrofurandiyl, thiophenediyl, tetrahydothiophenediyl, thiazolediyl or tetrahydothiazolediyl group, wherein the said group is either unsubstituted or substituted by one or more substituents selected from hydroxy, -OC1-C6 alkyl, -SC1-C6 alkyl, halogen, -CF3, and -CN;
  • n 0 or 1
  • R2 represents hydrogen, -Ci -C alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -COC1-C6 alkyl, -CO2C1-C6 alkyl, -C ⁇ 2(Cl-C6 alkyl)phenyl, -(C1-C6 alkyl)C02C ⁇ -C6 alkyl, -(C1 -C6 alkyl)phenyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl or a group -D wherein D is as defined above;
  • each of R3 and R4 may independenly represent hydrogen, halogen, -C ⁇ -C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -(C1-C6 alkyl)C02C ⁇ C6 alkyl, -(C1-C6 alkyl)SC ⁇ -C6 alkyl, -(C1-C6 alkyl)OC ⁇ -C6 alkyl, -(C1-C6 alkyl)N(C ⁇ -C6 alkyl)2, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, -(C1-C6 alkyl)C3-C8 cycloalkyl, -(C1-C6 alkyl)C4-C8 cycloalkenyl,
  • R 8 is hydrogen, -C ⁇ -Ci8 alkyl, -C2-C18 alkenyl, -C2-CI8 alkynyl, -(C ⁇ -C6 alkyl)OC ⁇ -C6 alkyl, -(C1-C6 alkyl)SC ⁇ -C6 alkyl, -(C ⁇ -C6 aIkyl)0(C ⁇ -C6 alkyl)OC ⁇ -C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl or pyridyl, (any of which may optionally be substituted with one or more substituents selected from halogen, hydroxyl, nitro, nitrile or carboxyl), -C1-C4 perfluoroalkyl, a group -D as defined above or a -(C ⁇ -C6 alkyl)OD group wherein D is as defined above;
  • each of R9 and R 1 ** is independently hydrogen, -C ⁇ -C ⁇ 8 alkyl, -C2-C18 alkenyl, -C2-C18 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl or pyridyl (any of which may optionally be substituted with one or more substituents selected from halogen, hydroxyl, nitro, nitrile or carboxyl) or a group -D as defined above;
  • E is a 5- or 6-membered heterocyclic ring containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, which may optionally be fused to a benzene ring, and the ring may be optionally substituted with one or more substituents selected from -C ⁇ -C6 alkyl, -OC ⁇ -C6 alkoxy, halogen, -CF3 and -CN; or
  • U is -N ⁇ 2 or -NH2 and J is a group -CHR- wherein R is as defined above;
  • V is not a 1,4-phenylene group
  • halogen or its abbreviation "halo" means fluoro, chloro, bromo or iodo.
  • Cx-Cg alkyl refers to straight chain or branched chain hydrocarbon groups having from one to six carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, neopentyl and hexyl.
  • C ⁇ -C alkyl refers to straight chain or branched chain hydrocarbon groups having from one to eight carbon atoms. Illustrative of such alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, pentyl, neopentyl, hexyl, heptyl and octyl.
  • C ⁇ -C ⁇ 8 alkyl refers to straight chain or branched chain hydrocarbon groups having from one to eighteen carbon atoms. Illustrative of such alkyl- groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl, hexyl, decyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, and octadecyl. From one to six carbon atoms may be preferred.
  • C2 ⁇ alkenyl refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl.
  • C2-C8 alkenyl refers to straight chain or branched chain hydrocarbon groups having from two to eight carbon atoms and having in addition one double bond, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2- methyl-2-propenyl, 3-pentenyl, 5-hexenyl, 6-heptenyI and 7-octenyl.
  • C2-C ⁇ 8 alkenyl refers to straight chain or branched chain hydrocarbon groups having from two to eighteen carbon atoms and having in addition one or more double bonds, of either E or Z stereochemistry where applicable. This term would include for example, vinyl, 1-propenyl, 1- and 2-butenyl, 2-methyl-2-propenyl, geranyl, and farnesyl. From two to six carbon atoms may be preferred.
  • C2-C6 alkynyl refers to straight chain or branched chain hydrocarbon groups having from two to six carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1- propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl.
  • C2-C ⁇ 8 alkynyl refers to straight chain or branched chain hydrocarbon groups having from two to eighteen carbon atoms and having in addition one triple bond. This term would include for example, ethynyl, 1-propynyl, 1- and 2-butynyl, 2-methyl-2-propynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 10- undecynyl, 4-ethyl-l-octyn-3-yl, 7-dodecynyl, 9-dodecynyl, 10-dodecynyl, 3- methyl-l-dodecyn-3-yl, 2-tridecynyl, 11-tridecynyl, 3-tetradecynyl, 7- hexynyl, 2-
  • C1-C4 perfluoroalkyl refers to straight chain or branched chain groups having from one to four carbon atoms and substituted by more than one fluorine atom. This term would include for example, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoro-n- propyl, sexafluoro-i-propyl, septafluoro-n-propyl, septafluoro-i-propyl, 4,4,4- trifluoro-n-butyl, nonafluoro-n-butyl, nonafluoro-sec-butyl and nonafluoro-i- butyl.
  • OC ⁇ -C6 alkyl refers to straight chain or branched chain alkoxy groups having from one to six carbon atoms. Illustrative of such alkoxy groups are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, neopentoxy and hexoxy.
  • SC ⁇ -C6 alkyl refers to straight chain or branched chain alkylthio groups having from one to six carbon atoms. Illustrative of such alkyl groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, neopentylthio and hexylthio.
  • C3-C8 cycloalkyl refers to an alicyclic group having from 3 to 8 carbon atoms. Illustrative of such cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • C4-C8 cycloalkenyl refers to an alicyclic group having from 4 to 8 carbon atoms and having in addition one or more double bonds. Illustrative of such cycloalkenyl groups are cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.
  • the term “5- or 6-membered heterocyclic ring” refers to such rings having from 5 to 6 atoms in the ring wherein the heteroatom(s) may be one or more nitrogen, oxygen or sulphur atoms.
  • nitrogen-containing heterocyclic ring refers to an aromatic or alicyclic ring comprising one or more nitrogen atoms and optionally one or more other heteroatoms.
  • Illustrative of such rings are pyrrolidine, piperidine, hexamethyleneimine, heptamethylenimine, morpholine and piperazine.
  • side chain of a naturally occurring amino acid includes the side chains of alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glycine, histidine, 5-hydroxylysine, 4-hydroxyproline, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine, ⁇ -aminoadipic acid, ⁇ -amino-n-butyric acid, 3,4- dihydroxyphenylalanine, homoserine, ⁇ -methylserine, omithine, pipecolic acid, and thyroxine.
  • diastereoisomers each of which consists of two enantiomers, with the appropriate R or S stereochemistry at each chiral center.
  • the invention is understood to include all such diastereoisomers, their optically active enantiomers and mixtures thereof.
  • pharmaceutically or veterinarily acceptable acid addition salt refers to a salt prepared by contacting a compound of formula (I) with an acid whose anion is generally considered suitable for human or animal consumption.
  • Examples of pharmaceutically and/or veterinarily acceptable acid addition salts include the hydrochloride, sulphate, phosphate, acetate, propionate, lactate, maleate, succinate and tartrate salts.
  • the linkage -(JqVm)- is considered to function as a spacer element, separating the the amino acid subunit from the group A.
  • the nature or identity of the linkeage -(JqVm)- is therefore not thought to be particularly critical and any of the wide range of -(JqVm)- groupings specified above may be used with retention of PAF antagonist activity.
  • the substituent groups R2, and B since the presence of the subunit (i) appears to be crucial for retention of PAF antagonist activity, there may be considerable variation of the substituent groups R2, and B without loss of such activity. Any of the the wide range of substituents R2 and B defined above may be used with retention of PAF antagonist activity.
  • the group A also appears to be important for activity. There may be considerable variation of the nature of group A without loss of activity. Any of the wide range of heterocycles and/or functional groups that contain heteroatoms defined above for A may be used with retention of PAF antagonist activity.
  • Preferred compounds include those in which, independently or in any compatible combination:
  • A represents a group -Q-X in which X represents a pyridyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, indolyl, quinolinyl, triazolyl, phenyl, furanyl, thiazolyl, thiadiazolyl or a oxadiazolyl group, all these groups being optionally substituted as defined for general formula I (typical examples of X are 3-nitropyrid-4-yl, 3-N-acetylpyrid-4-yl, benzo[b]thien-2-yl, benzimidazol-2-yl, benzoxazol-2-yl, benzthiazol-2-yl, 5-chlorobenzoxazol-2-yl, indol-3-yl, 2-methylquinolin-4-yl, 4- methyl-5-(2-thienyl)-l,2,4-triazol-3-yl, 4-methyl-5
  • J represents a -C1-C8 alkanediyl (for example methylene, propylene or pentylene) group;
  • V represents a phenylene group, particularly a 1,3- or a 1,4- phenylene group optionally substituted by halogen (for example fluorine) atom or a -OC ⁇ -C6 alkyl (for example ethoxy) group, or a thiophenediyl (for example a 2,5-thiophenediyI) group;
  • halogen for example fluorine
  • a -OC ⁇ -C6 alkyl for example ethoxy
  • thiophenediyl for example a 2,5-thiophenediyI
  • R2 represents a hydrogen atom, a -C ⁇ -C6 alkyl (for example methyl) group, a group -D or, together with R3 and the atoms to which they are attached, forms a 5 to 8 membered nitrogen-containing heterocyclic (for example morpholino) ring;
  • R3 represents a hydrogen atom, a -C ⁇ -C6 alkyl group, a -(C ⁇ -C6 alkyl)C02C ⁇ -C6 alkyl (for example -CH2CO2E1) group, the side chain of a naiinaiiy incurring ammo acid (for example the side chain of leucine or isoleucine), a group -D or R3, together with R2 and the atoms to which they are attached, forms a 5 to 8 membered nitrogen-containing heterocyclic ring (for example a mo ⁇ holino ring) or together with R4 and the carbon atom to which they are attached forms a C3-C8 cycloalkyl (for example cyclohexyl) ring;
  • R4 represents a hydrogen atom, a group -D or together with R3 and the carbon atom to which they are attached forms a C3-C8 cycloalkyl (for example cyclohexyl) ring;
  • n an integer of 0, 1 or 3;
  • R5 represents a hydrogen atom
  • R6 represents a hydrogen atom
  • R? represents a hydrogen atom
  • R 8 represents hydrogen atom, a -C ⁇ -C ⁇ alkyl (for example methyl, ethyl or undecyl) group, a -C2-C s alkenyl (for example allyl) group or a -(C1-C6 alkyl)OCl-C6 alkyl (for example 2-methoxyethyl) group;
  • E represents a tetrahydrofuranyl (for example 2-tetrahydrofuranyl) group, an indolyl (for example 3-indolyl) group or a tetrazolyl group;
  • Particularly preferred compounds include:
  • N-4-Azidomethylphenylsulphonyl-L-leucine ethyl ester 2. N-Methyl-N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester,
  • a process for preparing a compound of general formula I as defined above comprising: a) treating a compound represented by general formula II
  • R2, R3, 4 ? J $ q_ v, m, Y and B are as defined in general formula I, and L is a leaving group such as chloro, bromo, iodo, methanesulphonyloxy, p- toluenesulphonyloxy or trifluoromethanesulphonyloxy; or
  • R2, R3, R4 S and g are as defined in general formula I with a suitable base, followed by a compound of general formula V:
  • A, V, m and Y are as defined in general formula I and L is a leaving group as defined above; or
  • P is a group -NHCHRR 1 or -NRR with a suitable base, followed by a compound of general formula VII:
  • L is a leaving group as defined above
  • steps (a) to (c) optionally after any one of steps (a) to (c), converting, in one or a plurality of steps, a compound of general formula I into another compound of general formula I.
  • step (a) can, for preference, be conducted in an aprotic solvent (e.g. tetrahydrofuran, N,N-dimethylformamide or acetonitrile) to yield compounds of general formula I.
  • aprotic solvent e.g. tetrahydrofuran, N,N-dimethylformamide or acetonitrile
  • Suitable bases include sodium hydride, potassium hydride, sodium bis(trimethylsilyl)amide or potassium hydroxide, hi the case where an unsymmetrically substituted starting reagent is used the reactions can yield an isomeric mixture, which is separated by chromatography to yield compounds of general formula I.
  • step (b) can, for preference, be conducted in an aprotic solvent (e.g. tetrahydrofuran, N,N-dimethylformamide or acetonitrile) to yield compounds of general formula I.
  • aprotic solvent e.g. tetrahydrofuran, N,N-dimethylformamide or acetonitrile
  • Suitable bases include sodium hydride, potassium hydride or sodium bis(trimethylsilyl)amide when Y is a -CH2- group and triethylamine when Q is other than a -CH2- group.
  • step (c) can, for preference, be conducted in an aprotic solvent (e.g. tetrahydrofuran, N,N-dimethylformamide or acetonitrile) to yield compounds of general formula I.
  • aprotic solvent e.g. tetrahydrofuran, N,N-dimethylformamide or acetonitrile
  • a suitable base is triethylamine.
  • step (d) compounds of general formula I wherein B is a -CO2R 8 group can be converted to compounds of general formula I in which B is a -CO2H group by acid or base catalysed hydrolysis in a protic solvent.
  • Suitable acids for use in the hydrolysis include sulphuric and hydrochloric acids whilst base hydrolysis can be catalysed with sodium or potassium hydroxide.
  • B represents a -CO2R 8 group in which R 8 is a benzyl group
  • the conversion of B from an ester to an acid can also be effected by hydrogenation in a suitable solvent, for example, a lower alcohol such as ethanol using a noble metal catalyst such as palladium or platinum.
  • a suitable solvent for example, a lower alcohol such as ethanol using a noble metal catalyst such as palladium or platinum.
  • compounds of general formula I in which B is a -CO2R 8 group can be converted to compounds of general formula I in which B represents a -CH2OH group by reduction using any suitable method although lithium aluminium hydride or diisobutyl aluminium hydride in an aprotic solvent such as diethyl ether or toluene have proved to be particularly appropriate.
  • a suitable base e.g. sodium hydride, potassium hydride, sodium bis(trimethylsilyl)amide, or potassium hydroxide
  • R is as defined in general formula I and L is a leaving group as defined above.
  • compounds of general formula I wherein A is Q-X and Q is an -NR- group maybe prepared by treating a compound of general formula I wherein A is a -NRR 1 group wherein Rl is as defined in general formula I and R is a hydrogen atom, with a suitable base (e.g. sodium hydride, potassium hydride, sodium bis(trimethylsilyl)amide, or potassium hydroxide), followed by a compound of general formula IX
  • a suitable base e.g. sodium hydride, potassium hydride, sodium bis(trimethylsilyl)amide, or potassium hydroxide
  • step (d) compounds of general formula I wherein A is a group -NRR 1 wherein R and R 1 are hydrogen, maybe prepared by reduction of a compound of general formula I wherein A is a group -N3.
  • Appropriate reduction methods are hydrogenation over a noble metal catalyst such as palladium or platinum in a solvent such as a lower alcohol or treatment with triphenylphosphine in wet tetrahydrofuran.
  • Derivatives of general formulae II, III, IV, V, VI, VII, VIII and IX are generally available or may be prepared by a number of methods known to those skilled in the art.
  • the appropriate solvents employed in the above reactions are solvents wherein the reactants are soluble but do not react with the reactants.
  • the preferred solvents vary from reaction to reaction and are readily ascertained by one of ordinary skill in the art.
  • Angiotensin II is a bioactive octapeptide which is formed from angiotensin I by the action of angiotensin converting-enzyme.
  • Angiotensin II is a powerful vasopressor agent which has been implicated as a causative agent of high blood pressure in various mammalian species, such as the rat, dog and man.
  • Angiotensin II elevates blood pressure via binding to specific angiotensin II receptors on cell membranes.
  • the compounds of the invention by virtue of their ability to antagonise the actions of angiotensin ⁇ , should be of value in the treatment of elevated blood pressure and congestive heart failure, glaucoma and intraocular hypertension, cognitive dysfunction, psoriasis and any other conditions in which angiotensin Et is implicated.
  • angiotensin II antagonists include compounds which are structurally related to the angiotensin II peptide, but the experimental and clinical applications of these compounds have been limited by partial agonist activity (M.A. Ondetti and D.W. Cushman, Annual Reports in Medicinal Chemistry, 1978, 13, 82-91). Recently, several non-peptide compounds have been described as angiotensin II antagonists. Illustrative of such compounds are heterocyclic substituted biphenyl derivatives (DJ. Carini et al., J. Med. Chem., 1991, 34, 2525-2547; P.R. Bovy et al., Med. Chem. Res., 1991, 1, 86-94) and heterocyclic substituted benzofurans (EP-A- 434,249).
  • the compounds that are expected to be active as angiotensin II antagonists form a subset of the compounds of general formula I. It is considered that the main structural features of compounds of general formula I that are -particularly significant in providing their angiotensin ⁇ antagonist activity, are the A group and the B group.
  • the B group is preferably a carboxylic acid or any one of the groups claimed above for B that may serve as an acidic isostere (for example tetrazolyl).
  • group A should possess at least one -C1-C6 alkyl group, which is important for providing a lipophilic interaction with the angiotensin II receptor. It is understood that other substituents of the group A from the wide range specified above may enhance angiotensin II activity.
  • linkage -(JqVm)Y- and the substituents R2, R3, and R4 therefore is not thought to be particularly critical and any of the wide range of linkages -(JqVm)Y- and substituents R2, R3, and R4 specified above may be used with retention of angiotensin II antagonist activity.
  • a preferred grouping for -(JqVm)- is a 1,4- substituted -CH2C6H4- group for angiotensin II antagonist activity.
  • This invention also relates to methods of treatment for patients (or animals including mammalian animals raised in the dairy, meat, or fur trades, or as pets) suffering from disorders or diseases which can be attributed to PAF or to angiotensin II as previously described. More specifically, the invention relates to a method of treatment involving the administration of PAF antagonists of general formula I as the active ingredient and also to a method of treatment involving the administration of angiotensin II antagonists of general formula I as the active ingredient. In addition to the treatment of warm blooded animals such as mice, rats, horses, cattle, pigs, sheep, dogs, cats, etc., the compounds of the invention are effective in the treatment of humans.
  • a compound of general formula I for use in human or veterinary medicine particularly in the management of diseases mediated by PAF or by angiotensin II.
  • the compounds of general formula I can be used among other things to reduce inflammation and pain, to correct respiratory, cardiovascular, and intravascular alterations or disorders, and to regulate the activation or coagulation of platelets, to correct hypotension during shock, the pathogenesis of immune complex deposition and smooth muscle contractions.
  • the compounds of general formula I can be used in the treatment of conditions such as hypertension, congestive heart failure, glaucoma and intraocular hypertension, cognitive dysfunction and psoriasis although they also have potential in the treatment of other conditions.
  • a compound of general formula I in the preparation of an agent for the treatment or prophylaxis of PAF-mediated diseases, and/or the treatment of inflammatory disorders such as rheumatoid arthritis, osteoarthritis and eye inflammation, cardiovascular disorder, thrombocytopenia, asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immune regulation, gastric ulceration, transplant rejection, psoriasis, allergic dermatitis, urticaria, multiple sclerosis, cerebral, myocardial and renal ischemia and any other condition in which PAF is implicated.
  • inflammatory disorders such as rheumatoid arthritis, osteoarthritis and eye inflammation, cardiovascular disorder, thrombocytopenia, asthma, endotoxin shock, adult respiratory distress syndrome, glomerulonephritis, immune regulation, gastric ulceration, transplant rejection, psoriasis, allergic dermatitis, urticaria, multiple sclerosis, cerebral, myocardial and renal ischemia and
  • a compound of general formula I in the preparation of an agent for the treatment or prophylaxis of diseases and conditions mediated by angiotensin ⁇ . This includes the preparation of an agent for the treatment of the conditions mentioned above, particularly elevated blood pressure.
  • Compounds of general formula I may be administered orally, topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • a pharmaceutical or veterinary formulation comprising a compound of general formula I and a pharmaceutically and/or veterinarily acceptable carrier.
  • One or more compounds of general formula I may be present in association with one or more non-toxic pharmaceutically and/or veterinarily acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients.
  • the pharmaceutical compositions containing compounds of general formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and abso ⁇ tion in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally- occuring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example nepta ⁇ ecaetnyieneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p- hydroxybenzoate, one or more colouring agents, one or more flavouring agents, and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives for example ethyl, or n-propyl p- hydroxybenzoate
  • colouring agents for example ethyl, or n-propyl p- hydroxybenzoate
  • flavouring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.
  • Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono-or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of general formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Cream or ointment formulations that may be used for the drug are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics such as the British Pharmacopoeia.
  • compounds of general formula I may be made up into a solution or suspension in a suitable sterile aqueous or non- aqueous vehicle.
  • Additives for instance buffers, preservatives including bactericidal and fungicidal agents, such as phenyl mercuric acetate or nitrate, benzalkonium chloride or chlorohexidine, and thickening agents such as hypromellose may also be included.
  • Compounds of general formula I may be administered parenterally in a sterile medium.
  • the drag depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle.
  • adjuvants such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • Compounds of general formula I may be used for the treatment of the respiratory tract by nasal or buccal administration of, for example, aerosols or sprays which can disperse the pharmacological active ingredient in the form of a powder or in the form of drops of a solution or suspension.
  • Pharmaceutical compositions with powder-dispersing properties usually contain, in addition to the active ingredient, a liquid propellant with a boiling point below room temperature and, if desired, adjuncts, such as liquid or solid non-ionic or anionic surfactants and/or diluents.
  • Pharmaceutical compositions in which the pharmacological active ingredient is in solution contain, in addition to this, a suitable propellant, and furthermore, if necessary, an additional solvent and/or a stabiliser.
  • compressed air can also be used, it being possible for this to be produced as required by means of a suitable compression and expansion device.
  • Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day).
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day (about 1.0 mg to about 3.5 g per patient per day).
  • the dosage employed for the topical administration will, of course, depend on the size of the area being treated. For the eyes each dose will be typically in the range from 10 to 100 mg of the drug.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drag combination and the severity of the particular disease undergoing therapy.
  • Triphenylphosphine (101.80 g, 0.388 mol) was added to a solution of N-methyl- N-4-azidomethylphenylsulphonyl-L-leucine ethyl ester (71.5 g, 0.194 mol) in a mixture of THF and water (4:1, 200 ml), and the reaction mixture stirred overnight at ambient temperature. The THF was removed under reduced pressure, and the product extracted with ethyl acetate, dried, filtered and concentrated to an orange oil.
  • reaction mixture was stirred for 60 h, then washed with water, dried, filtered and the solvent removed under reduced pressure to leave a brown oil.
  • This was purified by chromatography (gradient elution 33% ethyl acetate in hexane to 100% ethyl acetate) to furnish N-methyl-N-4-(N'-3- nitropyrid-4-yl)aminomethylphenylsulphonyl-L-leucine ethyl ester (10.9 g, 62%) as a yellow amo ⁇ hous solid.
  • N-4-(N'-3,4-Dimethoxyphenyl)aminomethylphenylsulphonyl-L-leucine ethyl ester was prepared by the procedure of Example 4 employing 3,4- dimethoxyaniline in lieu of 3-mercapto-4-methyl-5-(2-thienyl)-l,2,4-triazole.
  • N-4-Bromomethylphenylsulphonyl-L-leucine ethyl ester (2.0 g, 5.1 mmol) was dissolved in dry THF (30 ml) under argon and cooled to 0°C.
  • Sodium hydride (60% dispersion in oil: 200 mg, 5.1 mmol) was added followed by methyl iodide (0.64 ml, 10.2 mmol) after a period of 5 mins.
  • the reaction mixture was allowed to warm to room temperature and was stirred overnight.
  • the reaction mixture was quenched with saturated aqueous ammonium chloride (30 ml) and extracted with ethyl acetate (2 x 50 ml).
  • N-Methyl-N-4-(benzoxazol-2-yl)thiomethylphenylsulphonyl-L-leucine ethyl ester was prepared by the procedure of Example 4 employing 2- mercaptobenzoxazole in lieu of 3-mercapto-4-methyI-5-(2-thienyl)-l,2,4- triazole and N-methyl-N-4-bromomethyl-phenylsulphonyl-L-leucine ethyl ester in lieu of N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester.
  • N-Methyl-N-4-(N'-3 ,4-dimethoxyphenyl)aminomethylphenylsulphonyl-3 -amino- propionic acid ethyl ester was prepared by the methods of Example 1 Step (b) and Example 6 employing ⁇ -alanine ethyl ester hydrochloride as starting material and 3,4-dimethoxyaniline in the final step.
  • N-Methyl-N-4-(N , -3,4-dimethoxyphenyl)aminomethylphenylsulphonyl-3-amino- propionic acid ethyl ester (1.0 g, 2.3 mmol) was treated with acetic anhydride (432 ⁇ l, 4.6 mmol) in the presence of 4-dimethylaminopyridine (10 mg) and pyridine (196 ⁇ l, 2.4 mmol) in dry DCM (60 ml) at 0°C. The mixture was allowed to warm up to room temperature and was stirred for 2 h. The products were treated with saturated aqueous ammonium chloride, extracted into ethyl acetate and evaporated under reduced pressure to yield an oil.
  • N-4-Bromomethylphenylsulphonyl-L-leucinyl methyl ether was prepared following the procedure of Example 1 Step (b) utilising L-leucinyl methyl ether in lieu of L-leucine ethyl ester.
  • N-4-(Benzthiazol-2-yl)thiomethylphenylsulphonyl-L-leucinyl methyl ether was prepared by the procedure of Example 2 employing 2-mercaptobenzthiazole in lieu of 3-mercapto-4-methyl-5-(2-thienyl)-l,2,4-triazole and N-4-bromo- methylphenylsulphonyl-L-leucinyl methyl ether in lieu of N-4-bromo- methylphenylsulphonyl-L-leucine ethyl ester.
  • Straw yellow oil (16% yield after chromatography (1:3 ethyl acetate/hexane)):
  • L-Leucinyl ethyl ether was prepared by the procedure of Example 9 Step (a) employing ethyl iodide in lieu of methyl iodide.
  • N-4-Bromomethylphenylsulphonyl-L-leucinyl ethyl ether was prepared by the procedure of Example 9 Step (b) employing L-leucinyl ethyl ether in lieu of L- leucinyl methyl ether.
  • N-4-Azidomethylphenylsulphonyl-L-leucinyl ethyl ether was prepared by the procedure of Example 1 Step (c) employing N-4-bromomethylphenylsulphonyl- L-leucinyl ethyl ether as starting material.
  • N-Methyl-N-4-azidomethyIphenylsulphonyl-L-leucinyl ethyl ether was prepared by the procedure of Example 2 employing N-4-azidomethylphenylsulphonyl-L- leucinyl ethyl ether as starting material.
  • N-Methyl-N-4-aminomethylphenylsulphonyl-L-leucinyl ethyl ether was prepared by the procedure of Example 3 Step (a) employing N-methyl-N-4- azidomethylphenylsulphonyl-L-leucinyl ethyl ether as starting material.
  • N-Methyl-N-4-(N'-3-nitropyrid-4-yl)aminomethyIphenylsuIphonyl-L-leucinyl ethyl ether was prepared by the procedure of Example 3 Step (b) employing N- methyl-N-4-aminomethylphenylsulphonyl-L-leucinyl ethyl ether as starting material. Yellow crystalline solid (63% yield): m.p. 129-130°C
  • N-4-(Benzoxazol-2-yl)thiomethylphenylsulphonyl-L-leucinyl ethyl ether was prepared by the procedure of Example 4 employing 2-mercaptobenzoxazole in lieu of 3-mercapto-4-methyl-5-(2-thienyl)-l,2,4-triazole and N-4- bromomethylphenylsulphonyl-L-leucinyl ethyl ether in lieu of N-4- bromomethylphenylsulphonyl-L-leucine ethyl ester.
  • N-Methyl-N-4-(benzoxazol-2-yl)thiomethylphenylsulphonyl-L-leucinyl ethyl ether was prepared by the procedure of Example 4 employing 2- mercaptobenzoxazole in lieu of 3-mercapto-4-methyl-5-(2-thienyl)-l,2,4- triazole and N-methyl-N-4-bromomethylphenylsulphonyl-L-leucinyl ethyl ether in lieu of N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester. Colourless oil (25% yield after chromatography (1:1 ethyl acetate/hexane)):
  • Examples 15-17 were prepared by the procedure of Example 4 employing the appropriate thiol or amine in lieu of 3-mercapto-4-methyl-5- (2-thienyl)- 1 ,2,4-triazole and N-methyl-N-4-bromomethylphenylsulphonyl-L- leucinyl ethyl ether in lieu of N-4-bromomethylphenylsuIphonyl-L-leucine ethyl ester.
  • N-4-(Benzoxazol-2-yl)thiomethylphenylsulphonyl-L-leucinyl methoxyethyl ether was prepared by the procedure of Example 9 employing 2-bromoethyl methyl ether in lieu of methyl iodide and 2-mercaptobenzoxazole in the last step.
  • N-Methyl-N-4-bromomethylphenylcarbonyl-L-leucinyl ethyl ether was prepared by the procedure of Example 1 Step (b) and Example 6 Step (a) employing 4- bromomethylbenzoyl chloride and leucine ethyl ether as starting materials. N- Methyl-N-4-bromomethylphenylcarbonyl-L-leucinyl ethyl ether was used without purification directly in the next step.
  • N-Methyl-N-4-(benzoxazol-2-yl)thiomethylphenylcarbonyl-L-leucinyl ethyl ether was prepared by the procedure of Example 4 employing 2- mercaptobenzoxazole in lieu of 3-mercapto-4-methyl-5-(2-thienyl)-l,2,4- triazole and N-methyl-N-4-bromomethylphenylcarbonyl-L-leucinyl ethyl ether in lieu of N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester.
  • Example 20 ⁇ c 172.50, 164.20, 151.90, 148.60, 141.80, 137.07, 136.73, 136.64, 129.03, 128.81, 127.81, 127.15, 124.30, 124.00, 118.45, 109.67, 70.93, 70.55, 66.70, 66.23, 56.15, 50.42, 38.28, 37.10, 36.18, 32.37, 26.65, 25.07, 24.29, 23.37, 23.06, 22.19, 15.21, 15.08.
  • Example 20 Example 20
  • N-Benzyl-N-4-bromomethylphenylsulphonyl-2-phenylethylamine was prepared by the procedure of Example 1 Step (b) employing N-benzylethylamine in lieu of L-leucine ethyl ester hydrochloride.
  • N-Benzyl-N-4-(benzoxazol-2-yl)tMomemylphenylsuIphonyl-2-phenylethylamine was prepared by the procedure of Example 4 employing 2-mercaptobenzoxazoIe in lieu of 3-mercapto-4-methyl-5-(2-thienyl)-l,2,4-triazole and N-benzyl-N-4- bromomethylphenylsulphonyl-2-phenylethylamine in lieu of N-4-bromo- methylphenylsulphonyl-L-leucine ethyl ester.
  • N-Methyl-N-4-(benzoxazol-2-yl)thiomethylphenylsulphonyl-l,2-diphenylethyl- amine was prepared by the procedure of Example 4 employing 2- mercaptobenzoxazole in lieu of 3-mercapto-4-methyl-5-(2-thienyl)-l,2,4- triazole and N-methyl-N-4-bromomethylphenylsulphonyl-l ,2-diphenylethyl- amine in lieu of N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester.
  • N-Methyl-N-4-(5-chlorobenzoxazol-2-yl)thiomethylphenylsulphonyl-l,2- diphenylethylamine was prepared by the procedure of Example 4 employing 2- mercapto-5-chlorobenzoxazole in lieu of 3-mercapto-4-methyl-5-(2-thienyl)- 1,2,4-triazole and N-methyl-N-4-bromomethylphenylsulphonyl-l ,2- diphenylethylamine in lieu of N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester.
  • Example 1(a) Utilizing the procedure described in Example 1(a) employing N-methyl-N-4- methylphenylcarbonylcyclohexylamine in lieu of p-toluenesulphonyl chloride and tetrachloromethane as solvent yielded crude N-methyl-N-4- bromomethylphenylcarbonylcyclohexylamine (67%) as an orange waxy solid.
  • N-Methyl-N-4-(benzoxazol-2-yl)thiomethylphenylsulphonylcyclohexylamine was prepared by the procedure described in Example 23 employing p-tosyl chloride in lieu of p-toluyl chloride as starting material.
  • Examples 26-29 were prepared by the procedure of Example 4 coupling N-4-bromomethylphenylsulphonyl-L-leucine ethyl ester with the appropriate thiol or amine derivative.
  • Examples 32-35 were prepared by the procedure of Example 31 coupling N-methyl-N-4-aminomethylphenylsulphonyl-L-leucine ethyl ester with the appropriate carboxylic acid chloride or activated ester.
  • N-Methyl-N-4-(N'-acetyl)aminomethylphenylsulphonyl-L-leucine ethyl ester was prepared by the method of Example 8 employing N-methyl-N-4- aminomethylphenylsulphonyl-L-leucine ethyl ester as starting material. Colourless oil (57% yield after chromatography (ethyl acetate)):
  • Triethylamine (1.12 ml, 8.07 mmol) was added dropwise to a stirred mixture of N-memyl-N-4-aminomethylphenylsulphonyl-L-leucine ethyl ester hydrochloride (2.50 g, 6.46 mmol) and 2-(tert-butoxycarbonyIoxyimino)-2-phenylacetonitrile (1.91 g, 7.75 mmol) in dioxane (15 ml) and water (15 ml) at room temperature. The dioxane was removed under reduced pressure and dichloromethane added to the residue. The mixture was washed with IN hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine.
  • Example 38-57 were prepared by the procedure of Example 1 Step (b) involving the condensation of the appropriate sulphonyl chloride derivative or carbonyl chloride derivative with the appropriate amine derivative.
  • Example 58 and 59 were prepared by the procedure of Example 1 Step (b) involving the condensation of the appropriate sulphonyl chloride derivative or carbonyl chloride derivative with N-methyl-N-4- aminomethylphenylsulphonyl-L-leucine ethyl ester hydrochloride.
  • N-4-(N'-2-Indolol-3-ylethyl)aminomethylphenylsulphonyl-L-leucinyl ethyl ether was prepared by the procedure of Example 4 employing 2-indolol-3- ylethylamine in lieu of 3-mercapto-4-methyl-5-(2-thienyl)-l,2,4-triazole and N- 4-bromomethylphenylsulphonyl-L-leucinyl ethyl ether in lieu of N-4- bromomethylphenylsulphonyl-L-leucine ethyl ester.
  • N-Methyl-N-4-(2-methyl-4-quinolinoxy)methylphenylsulphonylcyclohexylamine and N-Methyl-N-4-(lH-2-methyl-4-quinone)methylphenylsulphonylcyclohexyl- amine were prepared by the procedure of Example 4 employing 2-methyl-4- quinolinol in lieu of 3-mercapto-4-methyl-5-(2-thienyl)-l,2,4-triazole and N- methyI-N-4-bromomethylphenylsulphonylcyclohexylamine in lieu of N-4- bromomethylphenylsulphonyl-L-leucine ethyl ester.
  • the reaction gave a mixture of two regioisomers which were separated by column chromatography (5% methanol in DCM).
  • N-Methyl-N-4-(2-methyl-4-quinolinoxy)methylphenylsulphonyl-L-leucine ethyl ester and N-Methy l-N-4-( 1 H-2-methyl-4-quinone)methylphenylsulphonyl-L- leucine ethyl ester were prepared by the procedure of Example 30 employing 2- methyl-4-quinolinol in lieu of 2-mercaptobenzoxazole and N-4- bromomethylphenylsulphonyl-L-leucine ethyl ester in lieu of N-methyl-N-6- bromo-n-hexanoyl-L-leucine ethyl ester.
  • the reaction gave a mixture of two regioisomers which were separated by column chromatography (5% methanol in DCM).
  • N-benzyloxycarbonyl-L-leucine p-nitrophenyl ester (4.0 g, 10 mmol) in dry DCM (100 ml) was treated with tetrahydrofurfurylamine (4.3 ml, 42 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was washed with IN hydrochloric acid, aqueous sodium hydrogen carbonate, water and brine, dried, filtered and evaporated. Column chromatography (1:2 hexane/ethyl acetate) gave N-benzyloxycarbonyl-L-leucine tetrahydrofurfurylamide (2.2 g, 60%) as a pale yellow oil.
  • N-Memyl-N-4-(N'-acetyl-N'-memyI)aminophenylsulphonylcyclohexylamine was prepared by the method of Example 2 employing N-methyl-N-4-(N'-acetyI)- aminophenylsulphonylcyclohexylamine in lieu of N-4-azidomethylphenyl- sulphonyl-L-leucine ethyl ester.
  • N-4-(N'-Acetyl)aminophenylsulphonyl-L-leucinyl acetate was prepared by the procedure of Example 8 employing N-4-(N'-acetyl)aminophenylsulphonyl-L- leucine as starting material.
  • Triethylamine (11 ml) was added to a stirred mixture of L-leucine ethyl ester hydrochloride (11.0 g, 59 mmol) in dry THF (200 ml) at room temperature. After 10 min. 5-(4-bromomethylphenyl)-l,2,3-thiadiazole (5.0 g, 20 mmol) was added and the mixture stirred at room temperature for 3 days. Saturated aqueous ammonium chloride was added and the mixture extracted with ethyl acetate. The combined organic extracts were washed with aqueous citric acid and brine, dried, filtered and concentrated.
  • N-4-(l,2,3-Thiam ⁇ ol-5-yl)phenylmethyl-L-phenyIalanine ethyl ester was prepared by the method of Example 68 employing L-phenylalanine ethyl ester hydrochloride in lieu of L-leucine ethyl ester hydrochloride.
  • N-methyl-N-4-(N -3-nitropyrid-4-yl)aminomethylphenyl- sulphonyl-L-leucine ethyl ester (10.9 g, 0.023 mol) in ethanol (40 ml) was hydrogenated at 100 p.s.i. overnight in the presence of 10% palladium on charcoal (1.0 g).
  • the catalyst was removed by filtration through GF/F filter paper, and the filtrate evaporated under reduced pressure to give N-methyl-N-4- (N'-3-aminopyrid-4-yl)aminomethylphenylsulphonyl-L-leucine ethyl ester (8.90 g, 87%) as a brown foam.
  • N-t-Butyloxycarbonyl-L-leucine ethyl ester was obtained commercially.
  • N-4-(2-Methyl-4-quinolinoxy)methylphenylsulphonyl-L-leucine ethyl ester and N-4-(lH-2-methyl-4-quinone)methylphenylsulphonyl-L-leucine ethyl ester were prepared by the procedure of Example 4 employing 2-methyl-4-quinolinol in lieu of 3-mercapto-4-methyl-5-(2-thienyl)-l,2,4-triazole. The reaction gave a mixture of two regioisomers which were separated by column chromatography (5% methanol in DCM).
  • the platelet rich pellets were resuspended in a minimum volume of buffer (150 mM NaCl, 10 mM Tris, 2 mM EDTA, pH 7.5) and layered onto Ficoll-Paque gradients, 9 ml platelet concentrate to 2 ml Ficoll, and centrifuged at 1,900 m for 15 minutes in a SORVALL RT6000 centrifuge. This step removes the residual red blood cells and other nonspecific material such as lymphocytes from the preparation. The platelets which form a band between the plasma and the Ficoll were removed, resuspended in the above buffer and centrifuged at 3,000 ⁇ m for 10 minutes in a SORVALL RT6000 centrifuge.
  • buffer 150 mM NaCl, 10 mM Tris, 2 mM EDTA, pH 7.5
  • the pelleted platelets were resuspended in buffer (10 mM Tris, 5mM MgCl2, 2 mM EDTA, pH 7.0), snap freezed in liquid N2 and allowed to thaw slowly at room temperature in order to lyse the platelets. The latter step was repeated at least 3 times to ensure proper lysis.
  • the lysed platelets were centrifuged at 3,000 ⁇ m for 10 minutes in a SORVALL RT6000 centrifuge and resuspended in buffer. The latter step was repeated twice in order to remove any cytoplasmic proteins which may hydrolyse the platelet activating factor (PAF) receptor.
  • the prepared platelet membranes may be stored at -70°C. After thawing the prepared membranes were centrifuged in a SORVALL RT6000 at 3,000 ⁇ m for 10 minutes and resuspended in assay buffer.
  • the assay was conducted by preparing a series of Tris-buffered solutions of the selected antagonist of predetermined concentrations. Each of these solutions contained [ 3 H]-PAF (0.5 nM; l-0-[3H]octadecyl-2-acetyl-.m-glycero-3- phosphoryl choline with a specific activity of 132 Ci/mmol), unlabelled PAF (1000 nM), a known amount of the test antagonist, and a sufficient amount of Tris-buffer solution (lOmM Tris, 5mM MgCl2, pH 7.0, 0.25% BSA) to make the final volume 1ml.
  • Tris-buffer solution lOmM Tris, 5mM MgCl2, pH 7.0, 0.25% BSA
  • Table 1 lists results from this assay for inhibition of [ 3 H]-PAF receptor binding for illustrative examples of the compounds of this invention.
  • the activity of the compounds of general formula I is also demonstrated in vivo by their ability to reverse the hypotension caused by an infusion of PAF in rats.
  • Male Sprague-Dawley rats 300-350 g were anaesthetised with a mixture of sodium pentobarbitone, 22.5 mg/kg and thiopental 62.5 mg/kg. Through a midline incision in the neck, the trachea was cannulated and the animals breathed spontaneously. A carotid artery was cannulated for the measurement of blood pressure and this signal was used to trigger a rate meter to measure heart rate. Both jugular veins were cannulated: one for the infusion of PAF and the other for the bolus administration of test compounds.

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Abstract

Composés de la formule générale (I), dans lesquels: A représente: a) un groupe -Q-X dans lequel Q représente un groupe -O-, -S-, ou -NR- (R étant défini ci-dessous) ou une liaison; et X représente un noyau hetérocyclique ou aromatique à 5 ou 6 éléments; b) un groupe -CN, -NO2, -N3 -NRR1, -OR, -C(=O)NHCHRR1, -C(=O)NRR1, -NRC(=O)R1, -NRC(=O)OR1, -S(=O)¿2?NHCHRR?1¿, -S(=O)¿2NRR?1, -COR, -CO¿2?R, -SO2R, -SOR, -COX, -SO2X, X étant tel que défini ci-dessus, ou un atome d'halogène; J représente un groupe bivalent alcanediyle, alcènediyle, ou alkynediyl contenant entre 1 et 8 atomes de carbone; q vaut 0 ou 1; V représente un groupe phénylène, furandiyle, tétrahydrofurandiyle, thiophenediyle, tétrahydrothiophenediyle, thiazolediyle, ou tétrahydrothiazolediyle; m vaut 0 ou 1; Y représente une liaison, un groupe -CH2-, -C(=O)-, C(=S)-, -S(=O)2- ou -P(=O)(OC1-C6 alkyle)-; R?2¿ représente hydrogène, -C¿1?-C6 alkyle, -C2-C6 alcényle, -C2-C6 alcynyle, -COC1-C6 alkyle, -CO2C1-C6 alkyle, -CO2(C1-C6 alkyle)phényle, -(C1-C6 alkyle)CO2C1-C6 alkyle, -(C1-C6 alkyle)phényle, -C3-C8 cycloalkyle, -C4-C8 cycloalcényle ou un groupe -D, D étant tel que défini ci-dessus; ou R?2 et R3¿ ainsi que les atomes auxquels ils sont rattachés constituent un hétérocycle azoté contenant entre 5 et 8 éléments; R3 et R4 peuvent chacun représenter indépendamment hydrogène, halogène, -C¿1?-C6 alkyle, -C2-C6 alcényle, -C2-C6 alcynyle, -(C1-C6 alkyle)CO2C1-C6 alkyle, -(C1-C6 alkyle)SC1-C6 alkyle, -(C1-C6 alkyle)OC1-C6 alkyle, -(C1-C6 alkyle)N(C1-C6 alkyle)2, -C3-C8 cycloalkyle, -C4-C8 cycloalcényle, -(C1-C6 alkyle)C3-C8 cycloalkyle, -(C1-C6 alkyle)C4-C8 cycloalcényle, -(C1-C6 alkyle)OC3-C8 cycloalkyle, -(C1-C6 alkyle)OC4-C8 cycloalcényle, -(C1-C6 alkyle)SC3-C8 cycloalkyle ou -(C1-C6 alkyle)SC4-C8 cycloalcényle, une chaîne latérale d'un aminoacide naturel, un groupe -D tel que défini ci-dessus, ou un groupe -(C1-C6 alkyle)OD, D étant tel que défini ci-dessus; ou R?3 et R4¿, ainsi que l'atome de carbone auquel ils sont rattachés constituent un cycle C¿3?-C8 cycloalkyle; B représente: a) un groupe ZR?8¿, dans lequel Z représente une liaison, -C(=O)-, -C(=O)O-, -CH¿2?O-, -CH2OC(=O)-, -C(=S)-, -C(=S)O-, -CH2S-, -CH2OC(=O)NH-, -C(=O)NHSO2- ou -SO2NHC(=O)-; b) un groupe -CH2NR?9R10¿ ou un groupe -CONR9R10; c) un groupe E, E représentant un hétérocycle à 5 ou 6 éléments; d) un groupe -CH¿2?E, -C(=O)NHE ou -C(=O)NHCH2E, E étant tel que défini ci-dessus; Ces composés, ainsi que leurs hydrates et leurs sels d'addition d'acide acceptables d'un point de vue pharmaceutique et vétérinaire, sont des antagonistes du facteur d'activation plaquettaire (PAF), et conviennent ainsi au traitement et à la guérison de différentes maladies et affections induites par le PAF.
PCT/GB1993/000167 1992-01-28 1993-01-27 Derives d'aminoacides utilises comme antagonistes de facteur d'activation plaquettaire (paf) WO1993015047A1 (fr)

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US5756548A (en) * 1995-04-03 1998-05-26 Centaur Pharmaceuticals, Inc. Acetamidobenzamide compounds for neurodegenerative disorders
US5824696A (en) * 1993-09-01 1998-10-20 Smithkline Beecham Corporation Medicaments
US5955506A (en) * 1996-04-03 1999-09-21 Centaur Pharmaceuticals, Inc. Benzamides for neurodegenerative disorder treatment
US6518434B2 (en) 2000-02-07 2003-02-11 Astrazeneca Ab Coupling process
US6706712B2 (en) 2000-12-20 2004-03-16 Bristol-Myers Squibb Pharma Company Cyclic derivatives as modulators of chemokine receptor activity
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US7932392B2 (en) 2002-03-26 2011-04-26 Boehringer Ingelheim Pharmaceuticals, Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions, and uses thereof
US7037936B2 (en) 2002-06-17 2006-05-02 Signal Pharmaceuticals, Llc. Compounds useful for the treatment of cancer, compositions thereof and methods therewith
US7259277B2 (en) 2003-07-25 2007-08-21 Wyeth Advanced route for the synthesis of cPLA2 inhibitors
US8741897B2 (en) 2003-09-24 2014-06-03 Boehringer Ingelheim Pharmaceuticals Inc. Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
US7291744B2 (en) 2003-11-13 2007-11-06 Bristol-Myers Squibb Company N-ureidoalkyl-amino compounds as modulators of chemokine receptor activity
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US8658637B2 (en) 2006-12-06 2014-02-25 Boehringer Ingelheim International Gmbh Glucocorticoid mimetics, methods of making them, pharmaceutical compositions and uses thereof
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