WO2001027096A1 - Aminomethyl-(hetero)aryl derivatives and their use as tryptase inhibitors - Google Patents

Aminomethyl-(hetero)aryl derivatives and their use as tryptase inhibitors Download PDF

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WO2001027096A1
WO2001027096A1 PCT/GB2000/003832 GB0003832W WO0127096A1 WO 2001027096 A1 WO2001027096 A1 WO 2001027096A1 GB 0003832 W GB0003832 W GB 0003832W WO 0127096 A1 WO0127096 A1 WO 0127096A1
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alkyl group
alkyl
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unsubstituted
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WO2001027096A9 (en
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Sarah Elizabeth Lively
Bohdan Waszkowycz
Martin James Harrison
Juha Andrew Clase
Neil Jason Naylor
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Tularik Limited
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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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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
    • C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings 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 of a carbon skeleton containing six-membered aromatic rings
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    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—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
    • C07C311/18—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 nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C311/30—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
    • 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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    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/62—Benzothiazoles
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions

  • the present invention relates to chemical compounds useful as pharmaceuticals. More particularly it relates to certain novel aminomethyl derivatives, to pharmaceutical compositions comprising aminomethyl derivatives, to the use of aminomethyl derivatives as tryptase inhibitors, to a process for preparing aminomethyl derivatives, and to intermediates useful m the preparation of aminomethyl derivatives.
  • Tryptase is an enzyme that belongs to a large class of enzymes known as the se ⁇ ne proteases. It is secreted by mast cells and has been found to be involved m a variety of biological processes, such as inflammation. It is believed to be a mediator m the development of such diseases as asthma, allergic rhinitis, inflammatory bowel disease, eczema, psoriasis, atopic dermatitis, urticaria, conjunctivitis and rheumatoid arthritis.
  • Inhibitors of the enzyme are therefore envisaged to be useful m the treatment of mast cell mediated diseases such as these (See, for example, Kyle C Elrod & Robert P Numerof, "Emerging therapeutic targets in asthma: the rationale for mast cell tryptase inhibition”, Emerging Therapeutic Targets (1999) 3(2), 203-212).
  • WO 9940073 discloses certain bifunctional compounds as tryptase inhibitors.
  • the exemplified compounds include certain bis- am omethylphenyl derivatives (i.e. compounds having an ammomethylphenyl group at each end of the molecule) .
  • the present invention provides a compound of general formula I
  • Ar represents an aromatic ring of formula
  • a 2 and A 3 are each selected independently from CH, 0, S, N and NH; provided that A 1 , A 2 and A 3 are selected so that they, together with the carbon atoms to which they are attached, form an aromatic ring;
  • R 1 represents a hydrogen atom, an ammo group or a group of formula NHX 1 (CH 2 ) b R 3 ;
  • R 2 represents a group of formula COR 4 or, when R 1 represents a group of formula NHX 1 (CH 2 ) b R 3 , a hydrogen atom;
  • X 1 represents a bond, CO, S0 2 , COO or CONH
  • a 0, 1 or 2;
  • b represents 0 or an integer of from 1 to 4;
  • R 3 represents an unsubstituted or substituted aromatic, heterocyclic, (1-lOC) alkyl, (2-10C) alkenyl, (2-10C) alkynyl or ( 3-10C) cycloalkyl group;
  • R 4 represents a group of formula COR 5 , a group of formula CF 2 R 6 or an unsubstituted or substituted heteroaromatic group of formula
  • R 5 represents a (1-6C) alkyl, fluoro ( 1-6C) alkyl or (3-
  • R 6 represents a fluorine atom, a (1-6C) alkyl, fluoro ( 1-6C) alkyl or (3-10C) cycloalkyl group, an unsubstituted or substituted aromatic or heterocyclic group, a group of formula COOR 10 or a group of formula CONR u R 12 ;
  • a 4 represents 0, NH or S
  • a 5 represents 0, NH or S
  • R 7 , R 8 , R 9 , R 10 , R :: and R 12 are each selected independently from a hydrogen atom, a (1-6C) alkyl group, a ( 3-6C) cycloalkyl group and an unsubstituted or substituted aromatic group; or respectively R 8 and R 9 or R 11 and R 12 together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; but excluding N-[4- (aminomethyl) benzyl] naphthalene-1-sulfona ide; or a pharmaceutically acceptable metabolically labile amide thereof; or a pharmaceutically acceptable salt of said compound of formula I or said metabolically labile amide thereof.
  • Compounds of formula I have been found to possess activity as tryptase inhibitors.
  • the term unsubstituted or substituted m relation to a group and without further qualification signifies that the group is unsubstituted or substituted by one or more (for example one, two or three) substituents, said substituent or substituents being selected from any atom and group (other than a group containing an ammomethylphenyl group) which, when present in the compound of formula I, do not prevent the compound of formula I from functioning as a tryptase inhibitor.
  • aromatic group as used herein includes a phenyl or naphthyl group, such as 1-naphthyl or 2-naphthyl.
  • heterocyclic group includes a heteroaromatic group and a non-aromatic heterocyclic group.
  • heteroaromatic group includes a 5- or 6-membered aromatic ring containing from one to four heteroatoms selected from 0, N and S, the remaining ring atoms being carbon, which ring may be fused with a benzene ring or a second 5- or 6- membered aromatic ring containing from one to four heteroatoms selected from 0, N and S, the remaining ring atoms being carbon.
  • heteroaromatic group examples include furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, lmidazolyl, benzimidazolyl, pyrrolyl, mdolyl, pyridyl and py ⁇ midyl .
  • An unsubstituted or substituted aromatic or heteroaromatic group may, for example, be unsubstituted or substituted by (1- 4C) alkylenenedioxy or by one, two or three substituents selected independently from a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a (3-7C) cycloalkyl (1-4C) alkyl group; a halo (1-4C) alkyl group; a group of formula (CH 2 ) C X 2 (CH 2 ) d X 3 R 13 in which c represents 0, 1 or 2, d represents 0, 1 or 2, X 2 represents 0, S, SO, S0 2 , NR 14 , CO, CONH, NHCO, OCONH, NHCOO, COO, 0C0, S0 2 NH or NHS0 2 , X 3 represents a bond,
  • R 13 may represent, for example, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1- 4C) alkyl group and a (l-4C)alkoxy group.
  • Examples of particular values are: for X 2 : 0, S0 2 , NH, NHCH 3 , CONH, NHCO, NHCOO or S0 2 NH; for X 3 : a bond or 0; for c: 0; for d: 0, 1 or 2; and for R i3 : methyl, isopropyl, cyclohexyl, m ⁇ an-1-yl, pyr ⁇ d-4- yl, naphth-1-yl, naphth-2-yl, phenyl, 2-fluorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3-methylphenyi, 4-methylphenyl or 4- ⁇ sopropylphenyl . for X 14 : 0; for w: 0 or 1 for x: 0 or 1 for R 38 : methyl or phenyl.
  • Examples of particular values for a substituent on a substituted aromatic group or a substituted heteroaromatic group are methylenedioxy, nitro, methyl, isopropyl, cyclohexylmethyl, ammo, methoxy, isopropoxy, phenoxy, benzyloxy, phenoxyethoxy, dimethylammo, acetylammo, phenylacetylammo, cyclohexylamido, cyclohexylmethylammocarbonyl, mdan-l-ylammocarbonyl, py ⁇ d- 4-ylammocarbonyl, naphth-1-ylam ⁇ do, naphth-2-ylam ⁇ do, benzamido, benzoylam o, 3-methylbenzylammocarbonyl, 4- methylbenzylammocarbonyl, 2-fluorobenzylammocarbonyl, 3- chlorobenzylamido, 4-chlorobenzylam ⁇
  • Examples of particular values for an unsubstituted or substituted aromatic group are phenyl, 2-naphthyl, 4- methylphenyl, 3, 5-d ⁇ methylphenyl, 2 , 4 , 6-tr ⁇ methylphenyl, 4- lsopropylphenyl, 3-methyl-4-n ⁇ trophenyl, 3-methyl-4- ammophenyl, 4- ⁇ sopropoxyphenyl, 3, -d ⁇ methoxyphenyl, 4- phenylphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4- (2- phenoxyethoxy) phenyl, 4- (N, N-dimethylammo) phenyl , 4- (N- acetylammo) phenyl, 4-methanesulphonylphenyl and 4- hydroxyphenyl .
  • Examples of particular values for an unsubstituted or substituted heteroaromatic group are th ⁇ en-2-yl, pyrrol-2-yl, 3-benzyloxycarbonylammo-6-methyl-pyr ⁇ d-2-one-l-yl, 3- acetylammo-6-methyl-pyr ⁇ d-2-one-l-yl and 3-benzyloxycarbonyl- ammo-6-cyclohexyImethyl-py ⁇ d-2-one-l-yl, th ⁇ azol-2-yl, benzoth ⁇ azol-2-yl, 6-benzylammocarbonylbenzoth ⁇ azol-2-yl, 5- phenyl-th ⁇ azol-2-yl, 6-phenylcarboxam ⁇ dobenzoth ⁇ azol-2-yl, 6- ( -methyl) benzylammocarbonylbenzotn ⁇ azol-2-yl, 6- cyclohexylmethylammocarbonylbenzoth ⁇ azol-2-yl, 6-
  • non-aromatic heterocyclic group includes a non- aromatic 5- or 6-membered ring containing from one to four heteroatoms selected from 0, N and S, the remaining ring atoms being carbon, which ring may be fused with a non-aromatic or aromatic carbocyclic ring or a second 5- or 6-membered aromatic or non-aromatic ring containing from one to four heteroatoms selected from 0, N and S, the remaining ring atoms being carbon.
  • non-aromatic heterocyclic group examples include pyrrolidmyl, such as pyrrol ⁇ dm-2-yI, pipe ⁇ dmyl, such as p ⁇ pe ⁇ dm-4-yl, piperaz yl, such as p ⁇ perazm-3-yl and 2,3- dihydrobenzofuranyl, such as 2 , 3-d ⁇ hydrobenzofuran-5-yl .
  • An unsubstituted or substituted non-aromatic heterocyclic group may, for example, be unsubstituted or substituted by one, two or three of: a (1-4C) alkyl group; oxo; a group of formula -X 6 - (CHR 18 ) g -X 7 - (CH 2 ) h -R 19 m which g represents 0, 1 or 2, h represents 0, 1 or 2, X 6 represents 0, S, SO, S0 2 , NR 20 , CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S0 2 NH or NHS0 2 , X 7 represents a bond, 0, S, SO, S0 2 , NR 21 , CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S0NH or NHS0 2 , R 18 and R 19 each independently represents a hydrogen atom, an (1-4C) alkyl group, a (2-4C) alkenyl group
  • Examples of particular values are: for X D : CO; for R 18 : hydrogen or methyl; for X 7 : a bond, NHCO or NHS0 2 ; for R 19 : methyl, cyclopentyl, cyclohexyl, th ⁇ en-2-yl, pyrrol-
  • Examples of particular values for a substituent on a substituted non-aromatic heterocyclic group are oxo, acetyl, 2- acetylammopropionyl, 2- (2-th ⁇ enyl) acetylammopropionyl, 2- cyclopentanoylammopropionyl, pyrrol-2-ylcarbonyl, 2- cyclohexylacetylammopropionyl, 2- (2- thienyl) carbonylammopropionyl, 2- (4- hydroxyphenyl ) acetylammopropionyl, 2-phenylsulfonylammo- propionyl, 2-benzylsulfonylammopropionyl, 2-naphthylmethyl and
  • 3-chiorobenzyl examples of particular values for an unsubstituted or substituted non-aromatic heterocyclic group are 2,3- dihydrobenzofuran-5-yl, l-acetylp ⁇ pe ⁇ dm-4-yl, l-(2- acetylammopropionyl) pyrrol ⁇ dm-2-yl, 1- (2- (2-th ⁇ enyl) - acetylammopropionyl) pyrrol ⁇ dm-2-yl, 1- (2- cyclopentanoylammopropionyl ) pyrrol ⁇ dm-2-yl, 1- (pyrrol-2-oyl) - pyrrol ⁇ dm-2-yl, 1- (2-cyclohexylacetylammo- propionyl) pyrrol ⁇ dm-2-yl, 1- (2- (2- thienyl) carbonylammopropionyl) pyrrol ⁇ dm-2-yl, 1- (2- (4- hydroxyphen
  • An unsubstituted or substituted non-aromatic heterocyclic group may be, for example, a group of formula
  • (1-lOC) alkyl signifies a straight chain or branched group. It includes (1-4C) alkyl. Examples of a (1- 10C) alkyl group include methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl .
  • An unsubstituted or substituted (1-lOC) alkyl group may be substituted by, for example, one or two substituents selected from a halogen atom and a (l-4C)alkoxy group.
  • substituent on a substituted (1-lOC) alkyl group is fluoro.
  • the term (2-10C) alkenyl signifies a straight chain or branched group. It includes (2-4C) alkenyl . Examples of a (2- 10C) alkenyl group include ethenyl .
  • An unsubstituted or substituted (2-10C) alkenyl group may be substituted by, for example, a phenyl group that is unsubstituted or substituted by a halogen atom, a (1-4C) alkyl group or a (l-4C)alkoxy group.
  • An example of a substituent on a substituted (2-10C) alkenyl group is phenyl.
  • (2-10C) alkynyl signifies a straight chain or branched group. It includes (2-4C) alkynyl . Examples of a (2- 10C) alkynyl group include ethynyl .
  • An unsubstituted or substituted (2-10C) alkynyl group may be substituted by, for example, a phenyl group that is unsubstituted or substituted by a halogen atom, a (1-4C) alkyl group or a (l-4C)alkoxy group.
  • An example of a substituent on a substituted (2-10C) alkynyl group is phenyl.
  • ( 3-10C) cycloalkyl signifies a saturated monocyclic or polycyclic carbocyclic group. It includes (3- 6C) cycloalkyl . Examples of values for a ( 3-10C) cycloalkyl group include cyclopropyl, cyclobutyl, cyclohexyl and adamantyl .
  • An unsubstituted or substituted (3-10C) cycloalkyl group may be substituted by, for example, one, two or three (1- 4C) alkyl groups.
  • An example of a substituent is methyl.
  • the term ( 1-4C) alkylenedioxy includes methylenedioxy and ethylenedioxy .
  • the group Ar is preferably unsubstituted.
  • one of A 2 and A 3 represents CH or N and the other represents CH.
  • a is preferably 0.
  • R 1 preferably represents a group of formula NHX 1 (CH 2 ) b R 3 • Accordingly, a preferred group of compounds of formula I is that of formula lb X 1 is preferably selected from CO, S0 2 or COO. b is preferably 0 or 1. Examples of particular values for R 3 when it represents an unsubstituted or substituted (1-lOC) alkyl group are (1- 4C) alkyl groups such as methyl, ethyl, propyl and t-butyl.
  • R 3 when it represents an unsubstituted or substituted (2-10C) alkenyl group are (2- 4C) alkenyl such as ethenyl, and styryl.
  • R 3 when it represents an unsubstituted or substituted (2-10C) alkynyl group are (2- 4C) alkynyl such as ethynyl .
  • R 3 when it represents an unsubstituted or substituted ( 3-10C) cycloalkyl group are cyclohexyl and adamantyl.
  • the aromatic group in an unsubstituted or substituted aromatic group represented by R 3 may be, for example, a phenyl, 1-naphthyl or 2-naphthyl group.
  • the heterocyclic group m an unsubstituted or substituted heterocylic group represented by R 3 may be, for example a heteroaromatic group selected from furyl, benzofuryl, thienyl, benzothienyl, pyrrolyl, mdolyl, pyridyl and pyrimidyl.
  • An unsubstituted or substituted aromatic or heteroaromatic group represented by R 3 may, for example, be unsubstituted or substituted by ( 1-4C) alkylenenedioxy or by one, two or three substituents selected independently from a halogen atom; a cyano group; a mtro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a (3-7C) cycloalkyl (1-4C) alkyl group; a halo ( 1-4C) alkyl group; a group of formula (CH 2 ) C X 2 (CH 2 ) d ⁇ 3 R 13 in which c represents 0, 1 or 2, d represents 0, 1 or 2, X 2 represents 0, S, SO, S0 2 , NR 14 , CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S0 2 NH or NHS0 2 , X
  • R 16 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a ( 3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (l-4C)alkoxy group
  • R 17 represents a hydrogen atom, a (1-4C) alkyl group or, together with R 16 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperid yl or morpholmo group.
  • R 3 when it represents an unsubstituted or substituted aromatic group examples include phenyl, 2- naphthyl, 4-methylphenyl, 3 , 5-d ⁇ methylphenyl, 2,4,6- t ⁇ methylphenyl, 4- ⁇ sopropylphenyl, 3-methyl-4-n ⁇ trophenyl, 3- methyl-4-ammophenyl, 4- ⁇ sopropoxyphenyl, 3, 4-d ⁇ methoxyphenyl, 4-phenylphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-(2- phenoxyethoxy) phenyl, 4- (N, N-dimethylammo) phenyl, 4-(N- acetylammo) phenyl , 4-methanesulphonylphenyl and 4- hydroxyphenyl .
  • R 3 represents an unsubstituted or substituted non- aromatic heterocyclic group, this may be, for example, a group of formula
  • R when it represents an unsubstituted or substituted heterocyclic group examples are 2,3- d ⁇ hydrobenzofuran-5-yl, l-acetylp ⁇ per ⁇ dm-4-yl , 1- (2- acetylammopropionyl) pyrrolidin-2-yl , 1- (2- (2-thienyl) - acetylammopropionyl )pyrrolidin-2-yl, 1- (2- cyclopentanoylammopyrrol ⁇ dm-2-yl, i- (pyrrol-2-oyl) pyrrolidm- 2-yl, 3-benzyloxycarbonylammo-6-methyl-py ⁇ d-2-one-l-yl , l-(2- cyclohexylacetylaminopropionyl) -pyrrol ⁇ dm-2-yl, l-(2-(2- thienyl) carbonylaminopropionyl) -pyrrol
  • R 2 preferably represents COR 4 .
  • the heteroaromatic group represented by R 4 may, for example, be unsubstituted or substituted by ( 1-4C) alkylenedioxy or by one or two substituents selected independently from a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo ( 1-4C) alkyl group; a group of formula (CH 2 ) kX 9 (CH 2 ) m R 25 in which k represents 0, 1 or 2, m represents 0, 1 or 2, X 9 represents 0, S, SO, S0 2 , NR 2b , CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S0 2 NH or NHS0 2 , R 25 represents a hydrogen atom, an (1-4C) alkyl group, a (2- 4C) alkenyl
  • R 2D may represent, for example, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1- 4C) alkyl group and a (l-4C)alkoxy group.
  • R 4 represents a heteroaromatic group
  • this group may, for example, be selected from groups of formula m which :
  • a 4 and A 5 are as defined above;
  • R 29 and R 3C are together ( 1-4C) alkylenedioxy or are each selected independently from a hydrogen atom; a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo ( 1-4C) alkyl group; a group of formula (CH 2 ) a X l ⁇ (CH 2 ) r R 33 m which q represents 0, 1 or 2, r represents 0, 1 or 2, X 11 represents 0, S, SO, S0 2 , NR 34 , CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S0 2 NH or NHS0 2 , R 33 represents a hydrogen atom, an (1-4C) alkyl group, a (2- 4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) al
  • An examples of a particular value for p is 0.
  • Examples of particular values for r are 0 or 1.
  • Examples of particular values for X 11 are CONH and NHCO. Examples of particular values for R 3j are methyl, phenyl and cyclohexyl .
  • An example of a particular value for R 34 is hydrogen.
  • An example of a particular value for s is 1.
  • An example of a particular value for t is 1.
  • An example of a particular value for X 12 is NHCO.
  • An example of a particular value for R 35 is phenyl.
  • An example of a particular value for R 36 is hydrogen.
  • An aromatic or heteroaromatic group represented by R 37 may be, for example, a thienyl, pyridyl, naphthyl or phenyl group.
  • R 37 may represent, for example, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1- 4C) alkyl group a (l-4C)alkoxy group.
  • R 37 examples of particular values for R 37 are cyclohexyl, mdan-1-yl, pyr ⁇ d-4-yl, naphth-1-yl, naphth-2-yl, 2- fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl and 4- ⁇ sopropylphenyl .
  • a 4 and A 5 each preferably represents S.
  • R 4 examples of particular values for R 4 are methoxycarbonyl, th ⁇ azol-2-yl, benzoth ⁇ azol-2-yl, 6- benzylammocarbonylbenzothiazolyl, 5-phenylth ⁇ azol-2-yl, 6- phenylcarboxam ⁇ dobenzoth ⁇ azol-2-yl, 6-benzylammocarbonyl- benzoth ⁇ azol-2-yl, 6- (4-methyl) benz lammocarbonylbenzothiazol- 2-yl, 6-cyclohexylmethylammo-carbonylbenzoth ⁇ azol-2-yl, 6- phenylammocarbonylbenzoth ⁇ azol-2-yl, 6- (3- methylbenzylammocarbonylbenzoth ⁇ azol-2-yl, 6- ndan-l- ylammocarbonyl-benzoth ⁇ azol-2-yl, 6- (2- fluoro) benzylammocarbonylbenzoth ⁇ azol
  • a particularly preferred group of compounds of formula Id is that of formula If
  • a particularly preferred group of compounds of formula Ie is that of formula Ig
  • R 29 represents a hydrogen atom and R 30 is a phenyl or naphthyl group that is unsubstituted or substituted by ( 1-4C) alkylenedioxy or by one or two substituents selected from a halogen atom; a cyano group; a nitro group; an (1- 4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo (1-4C) alkyl group; and a group of formula (CH 2 ) S X (CH 2 ) t R ,35 which s represents 0, 1 or 2, t represents 0, 1 or 2, X 12 represents 0, S, SO, S0 2 , NR ,36, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S0 2 NH or NHS0 2 , R 35 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkeny selected from
  • R 29 is a hydrogen atom.
  • R 30 examples of particular values for R 30 are phenyl, 2 naphthyl and 3, 4-ethylenedioxphenyl .
  • R 32 represents a hydrogen atom and R 31 is a hydrogen atom; a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo (1-4C) alkyl group; a group of formula
  • R 3 in which u represents 0, 1 or 2, v represents 0, 1 or 2, X 13 represents 0, S, SO, S0 2 , NR 38 , CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S0 2 NH or NHS0 2 , R 37 represents a hydrogen atom, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3-
  • R 38 represents a hydrogen atom, a (1-4C) alkyl group or, together with R 37 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidmyl or morpholino group.
  • Examples of particular values are: for X 13 : NHCO, CONH or S0 2 NH; for R 37 : cyclohexyl, mdan-2-yl, py ⁇ d-4-yl, naphth-1-yl, naphth-2-yl, phenyl, 2-fluorophenyi, 3-chloro ⁇ henyl, 4- chlorophenyl, 3-methylphenyl, 4-methylphenyl, 4- ⁇ so ⁇ ropylphenyl and th ⁇ en-2-yl; for u: 0; and for v: 0 or 1.
  • R 31 examples of particular values for R 31 are hydrogen, benzylaminocarbonyl , phenylcarboxamido, 2- thienylmethylammocarbonyl, phenylammocarbonyl, cyclohexylammocarbonyl, cyclohexylamido, cyclohexylmethylammocarbonyl, ⁇ ndan-2-ylammocarbonyl, pyrid- 4-ylammocarbonyl, naphth-i-ylamido, naphth-2-ylam ⁇ do, 3- methylbenzylammocarbonyl, 4-methylbenzylammocarbonyl, 2- fluorobenzyl-ammocarbonyl, 3-chlorobenzylam ⁇ do, 4- chlorobenzylamido, benzylamido, benzylsulfonylammo and 4- lsopropylbenzamido .
  • R 32 is a hydrogen atom.
  • R ⁇ preferably represents a hydrogen atom or a group of formula NHX 1 (CH 2 ) b R 3 m which R 3 represents a ( 1-lOC) alkyl, (3-10C) cycloalkyl, phenyl or naphthyl group.
  • R 1 in formula Ih are hydrogen, acetamido, cyclohexylmethylamido and benzamido.
  • the term pharmaceutically acceptable salt refers to an acid addition or base salt of a compound of formula I.
  • acid addition salts include salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid or sulfuric acid, and organic acids, such as acetic acid, trifluoroacetic acid, benzoic acid, oxalic acid, succinic acid, p-toluene sulfonic acid and methanesulfonic acid.
  • Base salts include ammonium, sodium and potassium salts.
  • pharmaceutically acceptable metabolically labile amide refers to an amide formed between a pharmaceutically acceptable carboxylic acid and the amino group in the aminomethyl group of a compound of formula I, which amide is hydrolysed m vivo to afford the aminomethyl compound of formula I and the carboxylic acid.
  • pharmaceutically acceptable carboxylic acids include acetic acid.
  • the present invention provides a process for the preparation of a compound of formula I, or a pharmaceutically acceptable metabolically labile ester thereof or a pharmaceutically acceptable salt of said compound of formula I or said pharmaceutically acceptable metabolically labile amide thereof, which comprises deprotecting a compound of formula
  • amme groups are well known, and is described, for example, m McOmie, Protecting Groups Organic Chemistry, Plenum Press, NY., 1973 and Greene and Wutts, Protecting Groups m Organic Synthesis, 2 nd Ed., John Wiley and Sons, NY., 1991.
  • am e protecting groups are acyl groups, for example t-butoxycarbonyl .
  • An acyl protecting group such as t-butoxycarbonyl is conveniently removed by reaction with an acid, for example an inorganic acid such as hydrochloric acid, or an organic acid such as t ⁇ fluoroacetic acid.
  • the reaction is conveniently performed at a temperature of from -10 to 100°C.
  • Convenient solvents include halogenated hydrocarbons, such as dichloromethane .
  • R b represents an alkoxy group, such as methoxy, or N- (1-4C) alkoxy-N- (1-4C) alkylammo, such as N-methoxy-N- methylammo with an unsubstituted or substituted compound of formula
  • M represents a metal residue, such as a lithium, magnesium, copper or zinc residue.
  • the reaction is conveniently performed at a temperature of -78 to -25°C.
  • Convenient solvents include ethers, such as tetrahydrofuran .
  • the compound of formula IV or V may be generated in situ from the corresponding compound of formula IV or V m which M represents a hydrogen atom by reaction with an appropriate organometallic reagent, for example an alkyl lithium such as n- butyl lithium.
  • the oxidation is conveniently effected using Dess-Martm reagent, 1, 1, 1-tr ⁇ acetoxy-l, 1-d ⁇ hydro-l, 2-benz ⁇ odoxol-3 ( IH) - one.
  • Other oxidizing agents include py ⁇ dmium chlorochromate, pyridmium dichromate, potassium permanganate and dimethylsulfoxide/oxalyl chloride .
  • Compounds of formula III m which R b represents N-(l- 4C) alkoxy-N- ( 1-4C) alkylammo may be prepared by reacting a corresponding compound of formula III m which R b represents alkoxy with an N- ( 1-4C) alkoxy-N- ( 1-4C) alkylamme, or a salt thereof such as a hydrochloride m the presence of an organometallic reagent, such as dimethylalummium chloride.
  • they may be prepared by reacting a compound of formula III m which R b represents a hydroxyl group with an N- (1-4 ) alkoxy-N- ( 1-4C) alkylamme, or a salt thereof, with a carbodnmide such as 1- ( 3-d ⁇ methylammopropyl ) -3- ethylcarbodnmide hydrochloride m the presence of a base, such as t ⁇ ethylamme .
  • a convenient solvent is dichloromethane .
  • the leaving atom or group represented by Z 1 may be, for example, a halogen atom, such as a chlorine atom.
  • a halogen atom such as a chlorine atom.
  • it may be generated in si tu, for example by reacting a compound of formula VII n which Z 1 represents hydroxyl with a coupling agent, for example a carbodiimide, such as 1- [3- (dimethylamino) -propyl] -3-ethylcarbod ⁇ m ⁇ de .
  • a coupling agent for example a carbodiimide, such as 1- [3- (dimethylamino) -propyl] -3-ethylcarbod ⁇ m ⁇ de .
  • the reaction is conveniently performed m the presence of a base, such as t ⁇ ethylamine, dnsopropylethylamine, pyridme or 4- dimethylaminopyridme .
  • Convenient solvents include amides, such as dimethylformamide and halogenated hydrocarbons, such as dichloromethane and chloroform.
  • the reaction is conveniently performed at a temperature in the range of from 0 to 150°C.
  • Compounds of formula III in which R 1 represents an ammo group and R b represents alkoxy are known or may be prepared from known compounds by methods known in the art. See, for example, Tetrahedron (1977), 33(20), 2715-7 and European patent applications, publication numbers EP 31794 and EP 580008.
  • Compounds of formula III in which R 1 represents an amino group may also be prepared by reducing a compound of formula
  • the reduction is conveniently performed by catalytic hydrogenation in the presence of a Group VIII metal catalyst, such as Raney nickel or palladium on charcoal.
  • Convenient solvents include esters, such as ethyl acetate. The reduction is conveniently performed at a temperature m the range of from 0 to 100°C and a pressure of from 1 to 35 x 10 5 Pa.
  • IX with a strong base, such as potassium bis (t ⁇ methylsilyl ) - amide, and a t ⁇ organosulfonylazide, such as trnsopropyl- benzenesulfonyl azide, followed by an acid, such as acetic acid.
  • a strong base such as potassium bis (t ⁇ methylsilyl ) - amide
  • a t ⁇ organosulfonylazide such as trnsopropyl- benzenesulfonyl azide
  • an acid such as acetic acid.
  • Suitable solvents include ethers, such as tetrahydrofuran .
  • each R c represents a (1-6C) alkyl group, such as ethyl, with a mercury (II) chloride, mercury oxide and an alcohol of formula HOR 4 .
  • the reaction is conveniently performed at a temperature the range of from 0 to 100°C.
  • the alcohol of formula HOR 4 may also serve as reaction solvent.
  • Compounds of formula X may be prepared by reacting a compound of formula
  • XII in the presence of a strong base, such as t-butyllithium.
  • a strong base such as t-butyllithium.
  • the reaction is conveniently performed at a temperature m the range of from -78 to -25°C.
  • Convenient solvents include ethers, such as tetrahydrofuran.
  • Compounds of formula XI may be prepared by reacting a compound of formula III which R represents N- ( 1-4C) alkoxy- N- ( 1-4C) alkylammo with a reducing agent, such as di sobutylalummium hydride.
  • Convenient solvents include tetrahydrofuran .
  • Many of the intermediates described herein, including the compounds of formula II, III (where R represents N-methoxy-N- methylamme), VIII and XI are believed to be novel and are provided as further aspects of the invention.
  • the compounds exemplified herein have all been tested by this method and found to possess tryptase inhibitor activity with a Ki of less than lOO ⁇ M.
  • the tests were performed in 0.1 M phosphate buffer (to pH 7.4) containing 0.5 mg/ml heparm at ambient temperature using purified human lung tryptase (supplied by Dr. Andrew Walls, Immunopharmacology Group, Southampton General Hospital, Southampton, UK) and the chromogenic tryptase substrate S-2366 (supplied by Quadratech, Epsom, Surrey, UK) .
  • Compounds were dissolved dimethylsulfoxide and tested at concentrations of from lnM- lOOmM in 96 well microplates.
  • Inhibitor activity was determined by measuring light absorption by p-nitroamlme (produced by the action of tryptase on the chromogenic substrate) at 405nm using a Dynatech MR 5000 reader (supplied by Dynex Ltd., Billmghurst , UK) . SAS software was then used to determine Km (Michaelis constant) and Ki values. S-2366 was calculated to give a Km of 216 ⁇ M. The selectivity of compounds for tryptase over other se ⁇ ne proteases may be determined by the same test method, but using the appropriate chromogenic serme protease substrate. As described here above, it is envisaged that a variety of mast cell mediate diseases may be treated by the compounds of the present invention through their action as tryptase inhibitors .
  • the present invention provides a method of inhibiting tryptase in a patient requiring such treatment, which comprises administering an effective amount of a compound of formula I, or a metabolically labile amide thereof, or a pharmaceutically acceptable salt of said compound of formula I or said metabolically labile ester thereof .
  • treatment includes prophylaxis, amelioration or elimination of a condition for which a patient is being treated.
  • the term patient includes a warm blooded animal, such as a human, pig, horse, sheep, cow, mouse, hamster, guinea pig dog or chicken, and a reptile.
  • the patient is a human.
  • the effective amount, or dose of compound administered to a patient will of course be determined by the particular circumstances surrounding the case, including the species, size, age, weight and sex of the patient, the compound to be administered, the route of administration and the particular condition being treated.
  • the compounds can be administered by a variety of routes, such as by oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes, or by inhalation. Alternatively, the compound may be administered by continuous infusion.
  • a typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention.
  • daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg.
  • the dose when administered by inhalation may be lower, for example m the range of from 0.01 to 2.0 mg for a patient weighing 70kg.
  • the present invention also provides the use of a compound 5 of formula I, or a metabolically labile amide thereof, or a pharmaceutically acceptable salt of said compound of formula I or said metabolically labile ester thereof for the manufacture of a medicament for use as a tryptase inhibitor.
  • tryptase inhibitor should have utility where mast cells have been induced to degranulate by whatever mechanism, including anaphylactic reactions due to exogenous substances, e.g.
  • the present invention accordingly provides the use of the compounds for the treatment of each of these conditions .
  • the compounds according to the invention may be administered with other pharmaceutically active agents, such as a bronchodilator, for example a ⁇ -agonist such as salbutamol or terbutalme; a methylxanthme, such as theophyllme; a corticosteroid such as beclomethasone dipropionate; a chromolyn, such as sodium chromoglycate; a leukot ⁇ ene antagonist such as zaf rlukast or montelukast; a 5-l ⁇ poxygenase inhibitor, such as zileuton; or a tachykm antagonist.
  • a bronchodilator for example a ⁇ -agonist such as salbutamol or terbutalme; a methylxanthme, such as theophyllme; a corticosteroid such as beclomethasone dipropionate; a chromol
  • the compounds of the present invention are preferably administered to patients in a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition, which comprises a compound of formula I, or a pharmaceutically acceptable metabolically labile amide thereof, or a pharmaceutically acceptable salt of said compound of formula I or said pharmaceutically acceptable metabolically labile amide thereof, and a pharmaceutically-acceptable carrier.
  • compositions may be prepared by methods known in the art using well-known and readily available ingredients.
  • the active ingredient is mixed with the carrier, diluted by the carrier, or enclosed within the carrier, and may be in the form of a capsule, sachet, paper, or other container.
  • the carrier acts as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient.
  • compositions can be the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile m ⁇ ectable solutions, and sterile packaged powders.
  • compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known the art.
  • compositions are preferably formulated m a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably about 25 mg to about 300 mg of the active ingredient.
  • unit dosage form refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, m association with a suitable pharmaceutical carrier, diluent, or excipient.
  • suitable pharmaceutical carrier diluent, or excipient.
  • Hard gelatin capsules are prepared using the following ingredients :
  • Tablets each containing 60 mg of active ingredient are made as follows :
  • BOC refers to t-butoxycarbonyl
  • DMAP 4-dimethylaminopyridine
  • DMF dimethylformamide
  • TBTU 2 ( lH-benzctr ⁇ azol-1-yl ) - 1 , 3, 3-tetramethyluron ⁇ um tetrafluoroborate
  • THF refers to tetrahydrofuran
  • TFA trifluoroacetic acid
  • DCM refers to dichloromethane
  • DIBAL-H refers to diisobutylene- aluminium hydride.
  • Dess-Martin reagent refers to 1, 1, 1-tr ⁇ acetoxy-l, 1-dihydro-l, 2-benz ⁇ odoxol-3 ( IH) -one .
  • reaction mixture was partitioned between ethyl acetate (50ml) and ammonium carbonate solution (50ml) and the organic layer dried (MgS0 4 ) . Purification on silica gel afforded the ketone (168mg; 37%).
  • Hplc Magneticellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid
  • LC/MS Magneticellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid
  • Hplc Magneticellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid
  • LC/MS Magneticellan C18 Gradient 2, water/acetonitrile/ trifluoroacetic acid
  • Hplc Magneticellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid
  • LC/MS Magneticellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid
  • reaction was further diluted with diethyl ether (10 ml) and water (5 ml) and the organic layer washed with 1M sodium bicarbonate solution (5 ml), water (2x5 ml) . dried (MgS0 ) and reduced m va cuo to afford the product (44 mg; 85%) as a pale yellow solid.
  • N- [4-BOC (aminomethyl) benzyl] - 1- (2-ammoprop ⁇ onyl) -2-pyrrol ⁇ dmam ⁇ de (87 mg; 0.22 mmol) was added and the reaction stirred for 18 hours.
  • the dimethylformamide was removed m va cuo and reaction mixture partitioned between ethyl acetate (40 ml) and saturated citric acid solution (40 ml) .
  • the organic layer was washed with 1M sodium bicarbonate solution (40 ml) and dried (MgS0 ) .
  • Hplc Magneticellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid
  • LC/MS Magneticellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid
  • Hplc Magneticellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid
  • LC/MS Magneticellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid
  • Hplc Magneticellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid
  • LC/MS Magneticellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid
  • Example 54 0 N- [ ⁇ - (6- (Cyclohexylmethylamido)benzothiazol-2-oyl-4- (aminomethyl) benzyl] benzamide trifluoroacetate salt.
  • Example 56 N- [a- ( (6- (3-Methylbenzyl) amido) benzothiazol-2-oyl) -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt.
  • Example 50 The following ten examples were prepared in an analogous manner to Example 50, using the indicated carboxylic acid to form an amide from 6-ammobenzoth ⁇ azole, and the indicated derivative of 4- (aminomethyl ) phenylglycme .
  • Benzothiazole-6-carboxylic acid 1.0 g, 5.6 mmol
  • l-(3- dimethylaminopropyl) -3-ethylcarbodnmide hydrochloride 1.2 g, 6.1 mmol
  • aniline 560 ⁇ L, 570 mg, 6.1 mmol
  • the mixture was stirred overnight before water (10 mL) and dichloromethane (20 mL) were added. The layers were separated and the aqueous phase was extracted with ethyl acetate (25 mL) .
  • N-phenyl benzothiazole-6-amide 214 mg, 0.84 mmol
  • dry THF 5 mL
  • n-butyllithium 2.07 M in hexane, 0.81 mL, 1.69 mmol
  • syringe a solution of N, O-Dimethyl [ 4 - ( N-t- butoxycarbonylaminomethyl) phenyl-acetyl] hydroxylamide (130 mg, 0.42 mmol) in dry THF (1.5 mL) was added by cannula.
  • Ar represents an aromatic ring of formula
  • a 2 and A 3 are each selected independently from CH, 0, S, N and NH; provided that A 1 , A 2 and A 3 are selected so that they, together with the carbon atoms to which they are attached, form an aromatic ring;
  • R 1 represents a hydrogen atom, an amino group or a group of formula NHX 1 (CH 2 ) b R 3 ;
  • X 1 represents a bond, CO, S0 2 , COO or CONH

Abstract

Compounds of general formula (I) in which Ar, a, R?1 and R2¿ and have any of the meanings given in the specification, are tryptase inhibitors useful in the treatment of inflammatory and other conditions, such as asthma.

Description

AMINOMETHYL -(HETERO)ARYL DERIVATIVES AND THEIR USE
AS TRYPTASE INHIBITORS
The present invention relates to chemical compounds useful as pharmaceuticals. More particularly it relates to certain novel aminomethyl derivatives, to pharmaceutical compositions comprising aminomethyl derivatives, to the use of aminomethyl derivatives as tryptase inhibitors, to a process for preparing aminomethyl derivatives, and to intermediates useful m the preparation of aminomethyl derivatives.
Tryptase is an enzyme that belongs to a large class of enzymes known as the seπne proteases. It is secreted by mast cells and has been found to be involved m a variety of biological processes, such as inflammation. It is believed to be a mediator m the development of such diseases as asthma, allergic rhinitis, inflammatory bowel disease, eczema, psoriasis, atopic dermatitis, urticaria, conjunctivitis and rheumatoid arthritis. Inhibitors of the enzyme are therefore envisaged to be useful m the treatment of mast cell mediated diseases such as these (See, for example, Kyle C Elrod & Robert P Numerof, "Emerging therapeutic targets in asthma: the rationale for mast cell tryptase inhibition", Emerging Therapeutic Targets (1999) 3(2), 203-212).
A variety of tryptase inhibitors are known m the art. International patent application publication number WO 9926925 discloses certain pyπmidmones having tryptase inhibitor activity. The exemplified compounds all possess a strongly basic amidine or guanidme group.
International patent application publication number WO 9532945 discloses certain bis-ammomethyl and guanidyl derivatives having tryptase inhibitor activity. The exemplified compounds include certain bis-ammomethylphenyl derivatives (i.e. compounds having an ammomethylphenyl group at each end of the molecule) .
International patent application publication number WO 9940073 discloses certain bifunctional compounds as tryptase inhibitors. The exemplified compounds include certain bis- am omethylphenyl derivatives (i.e. compounds having an ammomethylphenyl group at each end of the molecule) .
International Patent Application Publication Number WO 9720822 discloses N- [4- (aminomethyl) benzyl] naphthalene-1- sulfonamide as an intermediate.
Novel compounds possessing one aminomethyl group have now been found which are tryptase inhibitors.
According to one aspect, therefore, the present invention provides a compound of general formula I
Figure imgf000003_0001
I in which: -
Ar represents an aromatic ring of formula
Figure imgf000003_0002
which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1- 4C)alkyl group and a (l-4C)alkoxy group;
A1 represents 0, NH, S, CH or CH=CH; and A2 and A3 are each selected independently from CH, 0, S, N and NH; provided that A1, A2 and A3 are selected so that they, together with the carbon atoms to which they are attached, form an aromatic ring;
R1 represents a hydrogen atom, an ammo group or a group of formula NHX1 (CH2) bR3;
R2 represents a group of formula COR4 or, when R1 represents a group of formula NHX1 (CH2) bR3, a hydrogen atom;
X1 represents a bond, CO, S02, COO or CONH;
a represents 0, 1 or 2;
b represents 0 or an integer of from 1 to 4;
R3 represents an unsubstituted or substituted aromatic, heterocyclic, (1-lOC) alkyl, (2-10C) alkenyl, (2-10C) alkynyl or ( 3-10C) cycloalkyl group;
R4 represents a group of formula COR5, a group of formula CF2R6 or an unsubstituted or substituted heteroaromatic group of formula
Figure imgf000004_0001
R5 represents a (1-6C) alkyl, fluoro ( 1-6C) alkyl or (3-
10C) cycloalkyl group, an unsubstituted or substituted aromatic or heterocyclic group, a group of formula OR or a group of formula NR8R9; R6 represents a fluorine atom, a (1-6C) alkyl, fluoro ( 1-6C) alkyl or (3-10C) cycloalkyl group, an unsubstituted or substituted aromatic or heterocyclic group, a group of formula COOR10 or a group of formula CONRuR12;
A4 represents 0, NH or S;
A5 represents 0, NH or S; and
R7, R8, R9, R10, R:: and R12 are each selected independently from a hydrogen atom, a (1-6C) alkyl group, a ( 3-6C) cycloalkyl group and an unsubstituted or substituted aromatic group; or respectively R8 and R9 or R11 and R12 together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring; but excluding N-[4- (aminomethyl) benzyl] naphthalene-1-sulfona ide; or a pharmaceutically acceptable metabolically labile amide thereof; or a pharmaceutically acceptable salt of said compound of formula I or said metabolically labile amide thereof. Compounds of formula I have been found to possess activity as tryptase inhibitors.
As used herein, the term unsubstituted or substituted m relation to a group and without further qualification signifies that the group is unsubstituted or substituted by one or more (for example one, two or three) substituents, said substituent or substituents being selected from any atom and group (other than a group containing an ammomethylphenyl group) which, when present in the compound of formula I, do not prevent the compound of formula I from functioning as a tryptase inhibitor. The term aromatic group as used herein includes a phenyl or naphthyl group, such as 1-naphthyl or 2-naphthyl.
The term heterocyclic group includes a heteroaromatic group and a non-aromatic heterocyclic group. The term heteroaromatic group includes a 5- or 6-membered aromatic ring containing from one to four heteroatoms selected from 0, N and S, the remaining ring atoms being carbon, which ring may be fused with a benzene ring or a second 5- or 6- membered aromatic ring containing from one to four heteroatoms selected from 0, N and S, the remaining ring atoms being carbon. Examples of a heteroaromatic group are furyl, benzofuryl, thienyl, benzothienyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, lmidazolyl, benzimidazolyl, pyrrolyl, mdolyl, pyridyl and pyπmidyl .
An unsubstituted or substituted aromatic or heteroaromatic group may, for example, be unsubstituted or substituted by (1- 4C) alkylenenedioxy or by one, two or three substituents selected independently from a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a (3-7C) cycloalkyl (1-4C) alkyl group; a halo (1-4C) alkyl group; a group of formula (CH2) CX2 (CH2) dX3R13 in which c represents 0, 1 or 2, d represents 0, 1 or 2, X2 represents 0, S, SO, S02, NR14, CO, CONH, NHCO, OCONH, NHCOO, COO, 0C0, S02NH or NHS02, X3 represents a bond, 0, S, SO, S02, NR15, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R13 represents a hydrogen atom, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a ( 3-7C) cycloalkyl group, an danyl group, an aromatic or heteroaromatic group tnat is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a group of formula (CH2) X14 (CH2) R38 m which w represents 0, 1 or 2, x represents 0, 1 or 2, X14 represents 0, S, SO, S02, NH, CONH, NHCO, NHS02 or S02NH and RJ° represents a hydrogen atom, a (1-4C) alkyl group or a phenyl group that is unsubstituted or substituted by a halogen atom, a (1-4C) alkyl group or a (l-4C)alkoxy group, R14 and R15 each independently represents a hydrogen atom, a (1-4C) alkyl group or, together with R13 and the nitrogen atom to which they are attached, a pyrrolidmyl, pipeπdmyl or morpholmo group; and a phenyl or naphthyl group that is unsubstituted or substituted by ( 1-4C) alkylenenedioxy, or one or two substituents selected from a halogen atom, a cyano group, a nitro group, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a group of formula (CH2) eX4 (CH2) fR16 m which e represents 0, 1 or 2, f represents C, 1 or 2, X4 represents 0, S, SO, S02, NR17, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R16 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (l-4C)alkoxy group, R17 represents a hydrogen atom, a (1-4C) alkyl group or, together with R16 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidmyl or morpholmo group. An aromatic or heteroaromatic group represented by R13 may be, for example, a thienyl, pyπdyl, naphthyl or phenyl group.
R13 may represent, for example, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1- 4C) alkyl group and a (l-4C)alkoxy group. Examples of particular values are: for X2: 0, S02, NH, NHCH3, CONH, NHCO, NHCOO or S02NH; for X3: a bond or 0; for c: 0; for d: 0, 1 or 2; and for Ri3: methyl, isopropyl, cyclohexyl, mαan-1-yl, pyrιd-4- yl, naphth-1-yl, naphth-2-yl, phenyl, 2-fluorophenyl, 3- chlorophenyl, 4-chlorophenyl, 3-methylphenyi, 4-methylphenyl or 4-ιsopropylphenyl . for X14: 0; for w: 0 or 1 for x: 0 or 1 for R38 : methyl or phenyl.
Examples of particular values for a substituent on a substituted aromatic group or a substituted heteroaromatic group are methylenedioxy, nitro, methyl, isopropyl, cyclohexylmethyl, ammo, methoxy, isopropoxy, phenoxy, benzyloxy, phenoxyethoxy, dimethylammo, acetylammo, phenylacetylammo, cyclohexylamido, cyclohexylmethylammocarbonyl, mdan-l-ylammocarbonyl, pyπd- 4-ylammocarbonyl, naphth-1-ylamιdo, naphth-2-ylamιdo, benzamido, benzoylam o, 3-methylbenzylammocarbonyl, 4- methylbenzylammocarbonyl, 2-fluorobenzylammocarbonyl, 3- chlorobenzylamido, 4-chlorobenzylamιdo, benzylamido, benzylsulfonylammo, 4-ιsopropylbenzamιdo, benzyloxycarbonylammo, methanesulfonyl , hydroxy and phenyl. Examples of particular values for an unsubstituted or substituted aromatic group are phenyl, 2-naphthyl, 4- methylphenyl, 3, 5-dιmethylphenyl, 2 , 4 , 6-trιmethylphenyl, 4- lsopropylphenyl, 3-methyl-4-nιtrophenyl, 3-methyl-4- ammophenyl, 4-ιsopropoxyphenyl, 3, -dιmethoxyphenyl, 4- phenylphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4- (2- phenoxyethoxy) phenyl, 4- (N, N-dimethylammo) phenyl , 4- (N- acetylammo) phenyl, 4-methanesulphonylphenyl and 4- hydroxyphenyl . Examples of particular values for an unsubstituted or substituted heteroaromatic group are thιen-2-yl, pyrrol-2-yl, 3-benzyloxycarbonylammo-6-methyl-pyrιd-2-one-l-yl, 3- acetylammo-6-methyl-pyrιd-2-one-l-yl and 3-benzyloxycarbonyl- ammo-6-cyclohexyImethyl-pyπd-2-one-l-yl, thιazol-2-yl, benzothιazol-2-yl, 6-benzylammocarbonylbenzothιazol-2-yl, 5- phenyl-thιazol-2-yl, 6-phenylcarboxamιdobenzothιazol-2-yl, 6- ( -methyl) benzylammocarbonylbenzotnιazol-2-yl, 6- cyclohexylmethylammocarbonylbenzothιazol-2-yl, 6- phenylammocarbonylbenzothιazol-2-yl, 6- (3- methylbenzylammocarbonylbenzothιazol-2-yl, 6-mdan-l- ylammocarbonyl-benzothιazol-2-yl, 6- (2- fluoro) benzylammocarbonylbenzothιazol-2-yl, 6- (4- chloro) benzylcarbonylammobenzothιazol-2-yl, 6- ( 3- chloro) benzylcarbonylammobenzothιazol-2-yl, 6- cyclohexylcarbonylammobenzothιazol-2-yl, 6- (4- lsopropyl) phenylcarbonylammobenzothιazol-2-yl, 6-naphth-l- ylcarbonylammobenzothιazol-2-yl, 6-naphth-2- ylcarbonylammobenzothιazol-2-yl , 6- benzylsulfonylammobenzothιazol-2-yl, and 6-pyrιd-4- ylammocarbonylbenzothιazol-2-yl .
The term non-aromatic heterocyclic group includes a non- aromatic 5- or 6-membered ring containing from one to four heteroatoms selected from 0, N and S, the remaining ring atoms being carbon, which ring may be fused with a non-aromatic or aromatic carbocyclic ring or a second 5- or 6-membered aromatic or non-aromatic ring containing from one to four heteroatoms selected from 0, N and S, the remaining ring atoms being carbon. Examples of a non-aromatic heterocyclic group are pyrrolidmyl, such as pyrrolιdm-2-yI, pipeπdmyl, such as pιpeπdm-4-yl, piperaz yl, such as pιperazm-3-yl and 2,3- dihydrobenzofuranyl, such as 2 , 3-dιhydrobenzofuran-5-yl . An unsubstituted or substituted non-aromatic heterocyclic group may, for example, be unsubstituted or substituted by one, two or three of: a (1-4C) alkyl group; oxo; a group of formula -X6- (CHR18) g-X7- (CH2) h-R19 m which g represents 0, 1 or 2, h represents 0, 1 or 2, X6 represents 0, S, SO, S02, NR20, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, X7 represents a bond, 0, S, SO, S02, NR21, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S0NH or NHS02, R18 and R19 each independently represents a hydrogen atom, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a ( 3-7C) cycloalkyl group, a thienyl group, a pyrrolyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group, a hydroxy group and a (l-4C)alkoxy group, and R20 and R21 each independently represents a hydrogen atom, a (1-4C) alkyl group or, together with R19 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group; and a group R22 in which R22 is (3-7C) cycloalkyl (1-4C) alκyl or a phenyl, naphthyl, phenyl ( 1-4C) alkyl or naphthyl ( 1-4C) alkyl group that is unsubstituted or substituted on any phenyl or naphthyl moeity by ( 1-4C) alkylenedioxy or one or two substituents selected from a halogen atom, a cyano group, a nitro group, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2- 4C) alkynyl group, a halo ( 1-4C) alkyl group, a group of formula (CH2) iX8 (CH2) jR23 in which i represents 0, 1 or 2, j represents 0, 1 or 2, X8 represents 0, S, SO, S02, NR24, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R23 represents a hydrogen atom, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3- 7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (l-4C)alkoxy group, R24 represents a hydrogen atom, a (1-4C) alkyl group or, together with R23 and the nitrogen atom to which they are attached, a pyrrolidmyl, pipeπdmyl or morpholmo group.
Examples of particular values are: for XD: CO; for R18 : hydrogen or methyl; for X7: a bond, NHCO or NHS02; for R19: methyl, cyclopentyl, cyclohexyl, thιen-2-yl, pyrrol-
2-yl, phenyl or 4-hydroxyphenyl; for g: 0 or 1; for h: 0 or 1; and for R22 : 2-naphthylmethyl and 3-chlorobenzyl .
Examples of particular values for a substituent on a substituted non-aromatic heterocyclic group are oxo, acetyl, 2- acetylammopropionyl, 2- (2-thιenyl) acetylammopropionyl, 2- cyclopentanoylammopropionyl, pyrrol-2-ylcarbonyl, 2- cyclohexylacetylammopropionyl, 2- (2- thienyl) carbonylammopropionyl, 2- (4- hydroxyphenyl ) acetylammopropionyl, 2-phenylsulfonylammo- propionyl, 2-benzylsulfonylammopropionyl, 2-naphthylmethyl and
3-chiorobenzyl . Examples of particular values for an unsubstituted or substituted non-aromatic heterocyclic group are 2,3- dihydrobenzofuran-5-yl, l-acetylpιpeπdm-4-yl, l-(2- acetylammopropionyl) pyrrolιdm-2-yl, 1- (2- (2-thιenyl) - acetylammopropionyl) pyrrolιdm-2-yl, 1- (2- cyclopentanoylammopropionyl ) pyrrolιdm-2-yl, 1- (pyrrol-2-oyl) - pyrrolιdm-2-yl, 1- (2-cyclohexylacetylammo- propionyl) pyrrolιdm-2-yl, 1- (2- (2- thienyl) carbonylammopropionyl) pyrrolιdm-2-yl, 1- (2- (4- hydroxyphenyl) acetylammopropionyl) pyrrolιdm-2-yl, 1- (2- phenylsulfonylammopropionyl )pyrrolιdm-2-yl, 1- (2- benzylsulfonylammopropionyl ) pyrrolιdm-2-yl, 6- (naphth-2- yl ) methyl-2, 5-dιoxopιperazm-3-yl and 6- (3-chlorobenzyl) -2 , 5- dιoxopιperazm-3-yl .
An unsubstituted or substituted non-aromatic heterocyclic group may be, for example, a group of formula
Figure imgf000012_0001
N- -X6-(CHR18)-X7-(CH2)h-R 19
or
Figure imgf000012_0002
in which X6, X7, R18, R19, R22, g and h are as defined above. The term (1-lOC) alkyl signifies a straight chain or branched group. It includes (1-4C) alkyl. Examples of a (1- 10C) alkyl group include methyl, ethyl, propyl, isopropyl, butyl, pentyl and hexyl . An unsubstituted or substituted (1-lOC) alkyl group may be substituted by, for example, one or two substituents selected from a halogen atom and a (l-4C)alkoxy group. An example of a substituent on a substituted (1-lOC) alkyl group is fluoro. The term (2-10C) alkenyl signifies a straight chain or branched group. It includes (2-4C) alkenyl . Examples of a (2- 10C) alkenyl group include ethenyl .
An unsubstituted or substituted (2-10C) alkenyl group may be substituted by, for example, a phenyl group that is unsubstituted or substituted by a halogen atom, a (1-4C) alkyl group or a (l-4C)alkoxy group. An example of a substituent on a substituted (2-10C) alkenyl group is phenyl.
The term (2-10C) alkynyl signifies a straight chain or branched group. It includes (2-4C) alkynyl . Examples of a (2- 10C) alkynyl group include ethynyl .
An unsubstituted or substituted (2-10C) alkynyl group may be substituted by, for example, a phenyl group that is unsubstituted or substituted by a halogen atom, a (1-4C) alkyl group or a (l-4C)alkoxy group. An example of a substituent on a substituted (2-10C) alkynyl group is phenyl.
The term ( 3-10C) cycloalkyl signifies a saturated monocyclic or polycyclic carbocyclic group. It includes (3- 6C) cycloalkyl . Examples of values for a ( 3-10C) cycloalkyl group include cyclopropyl, cyclobutyl, cyclohexyl and adamantyl .
An unsubstituted or substituted (3-10C) cycloalkyl group may be substituted by, for example, one, two or three (1- 4C) alkyl groups. An example of a substituent is methyl. The term ( 1-4C) alkylenedioxy includes methylenedioxy and ethylenedioxy .
In the compounds of formula I, the group Ar is preferably unsubstituted.
Preferably A1 represents 0, S or CH=CH . Preferably one of A2 and A3 represents CH or N and the other represents CH.
Examples of values for Ar are
Figure imgf000014_0001
Figure imgf000014_0002
Preferably A1 represents CH=CH and A2 and A3 each represents CH .
Accordingly, a preferred group of compounds of formula I is that of formula la
Figure imgf000014_0003
la in which a, R1 and R2 are as defined above, or a pharmaceutically acceptable metabolically labile amide thereof or a pharmaceutically acceptable salt of said compound of formula la or said metabolically labile amide thereof, a is preferably 0.
Accordingly, a preferred group of compounds of formula I is that of formula
Figure imgf000014_0004
lb
R1 preferably represents a group of formula NHX1 (CH2) bR3 • Accordingly, a preferred group of compounds of formula I is that of formula
Figure imgf000015_0001
lb X1 is preferably selected from CO, S02 or COO. b is preferably 0 or 1. Examples of particular values for R3 when it represents an unsubstituted or substituted (1-lOC) alkyl group are (1- 4C) alkyl groups such as methyl, ethyl, propyl and t-butyl.
Examples of particular values for R3 when it represents an unsubstituted or substituted (2-10C) alkenyl group are (2- 4C) alkenyl such as ethenyl, and styryl.
Examples of particular values for R3 when it represents an unsubstituted or substituted (2-10C) alkynyl group are (2- 4C) alkynyl such as ethynyl .
Examples of particular values for R3 when it represents an unsubstituted or substituted ( 3-10C) cycloalkyl group are cyclohexyl and adamantyl.
The aromatic group in an unsubstituted or substituted aromatic group represented by R3 may be, for example, a phenyl, 1-naphthyl or 2-naphthyl group. The heterocyclic group m an unsubstituted or substituted heterocylic group represented by R3 may be, for example a heteroaromatic group selected from furyl, benzofuryl, thienyl, benzothienyl, pyrrolyl, mdolyl, pyridyl and pyrimidyl.
An unsubstituted or substituted aromatic or heteroaromatic group represented by R3 may, for example, be unsubstituted or substituted by ( 1-4C) alkylenenedioxy or by one, two or three substituents selected independently from a halogen atom; a cyano group; a mtro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a (3-7C) cycloalkyl (1-4C) alkyl group; a halo ( 1-4C) alkyl group; a group of formula (CH2) CX2 (CH2) dχ3R13 in which c represents 0, 1 or 2, d represents 0, 1 or 2, X2 represents 0, S, SO, S02, NR14, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, X3 represents 0, S, SO, S02, NR15, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R13 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (l-4C)alkoxy group, R14 and R15 each independently represents a hydrogen atom, a (1-4C) alkyl group or, together with R13 and the nitrogen atom to which they are attached, a pyrrolidmyl, pipeπdmyl or morpholmo group; and a phenyl or naphthyl group that is unsubstituted or substituted by ( 1-4C) alkylenenedioxy, or one or two substituents selected from a halogen atom, a cyano group, a nitro group, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a group of formula (CH2) eX4 (CH2) fR16 m which e represents 0, 1 or 2, f represents 0, 1 or 2, X4 represents 0, S, SO, S02, NR17, CO, CONH, NHCO, OCONH, NHCOO,
COO, OCO, S02NH or NHS02, R16 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a ( 3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (l-4C)alkoxy group, R17 represents a hydrogen atom, a (1-4C) alkyl group or, together with R16 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperid yl or morpholmo group.
Examples of particular values for R3 when it represents an unsubstituted or substituted aromatic group are phenyl, 2- naphthyl, 4-methylphenyl, 3 , 5-dιmethylphenyl, 2,4,6- tπmethylphenyl, 4-ιsopropylphenyl, 3-methyl-4-nιtrophenyl, 3- methyl-4-ammophenyl, 4-ιsopropoxyphenyl, 3, 4-dιmethoxyphenyl, 4-phenylphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-(2- phenoxyethoxy) phenyl, 4- (N, N-dimethylammo) phenyl, 4-(N- acetylammo) phenyl , 4-methanesulphonylphenyl and 4- hydroxyphenyl .
When R3 represents an unsubstituted or substituted non- aromatic heterocyclic group, this may be, for example, a group of formula
Figure imgf000017_0001
N X6-(CHR18)-X7-(CH2)h-R19
or
Figure imgf000017_0002
Examples of particular values for R when it represents an unsubstituted or substituted heterocyclic group are 2,3- dιhydrobenzofuran-5-yl, l-acetylpιperιdm-4-yl , 1- (2- acetylammopropionyl) pyrrolidin-2-yl , 1- (2- (2-thienyl) - acetylammopropionyl )pyrrolidin-2-yl, 1- (2- cyclopentanoylammopyrrolιdm-2-yl, i- (pyrrol-2-oyl) pyrrolidm- 2-yl, 3-benzyloxycarbonylammo-6-methyl-pyπd-2-one-l-yl , l-(2- cyclohexylacetylaminopropionyl) -pyrrolιdm-2-yl, l-(2-(2- thienyl) carbonylaminopropionyl) -pyrrolιdin-2-yl, 1- (2- (4- hydroxyphenyl) acetylammopropionyl) -pyrrolidm-2-yl, 1- ( 2 - phenylsulfonylaminopropionyl ) pyrrolidin-2-yl, 1- (2- benzylsulfonylaminopropionyl )pyrrolidιn-2-yl, 3-acetylammo-6- methyl-pyrιd-2-one-l-yl, 3-benzyloxycarbonyl-amino-6- cyclohexylmethyl-pyrid-2-one-l-yl, 6- (naphth-2-yl) methyl-2, 5- dioxopiperazm-3-yl and 6- ( 3-chlorobenzyl ) -2, 5-dιoxopιperazm- 3-yl.
R2 preferably represents COR4. The heteroaromatic group represented by R4 may, for example, be unsubstituted or substituted by ( 1-4C) alkylenedioxy or by one or two substituents selected independently from a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo ( 1-4C) alkyl group; a group of formula (CH2) kX9 (CH2) mR25 in which k represents 0, 1 or 2, m represents 0, 1 or 2, X9 represents 0, S, SO, S02, NR2b, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R25 represents a hydrogen atom, an (1-4C) alkyl group, a (2- 4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3-7C) cycloalkyl group, an indanyl group, an aromatic or heteroaromatic group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a group of formula (CH2) WX14 (CH2) XR38 in which w represents 0, 1 or 2, x represents 0, 1 or 2, X14 represents 0, S, SO, S02, NH, CONH, NHCO, NHS02, or SO?NH and R38 represent a hydrogen atom, a (1-4C) alkyl group or a phenyl group that is unsubstituted or substituted by a halogen atom, a (1-4C) alkyl group or a(l-4C)alkyl group, R2° represents a hydrogen atom, a (1-4C) alkyl group or, together with R25 and the nitrogen atom to which they are attached, a pyrrolidmyl, pipeπdmyl or morpholmo group; and a phenyl or naphthyl group that is unsubstituted or substituted by ( 1-4C) alkylenedioxy or by one or two substituents selected from a halogen atom, a cyano group, a nitro group, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a group of formula (CH2) nX10 (CH2) PR27 which n represents 0, 1 or 2, p represents 0, 1 or 2, X10 represents 0, S, SO, S02, NR28, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R27 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (l-4C)alkoxy group, R28 represents a hydrogen atom, a (1-4C) lkyl group or, together with R27 and the nitrogen atom to which they are attached, a pyrrolidmyl, pipeπdmyl or morpholmo group. An aromatic or heteroaromatic group represented by R25 may be, for example, a thienyl, pyπdyl, naphthyl or phenyl group.
R2D may represent, for example, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1- 4C) alkyl group and a (l-4C)alkoxy group.
When R4 represents a heteroaromatic group, this group may, for example, be selected from groups of formula
Figure imgf000020_0001
m which :
A4 and A5 are as defined above;
R29 and R3C are together ( 1-4C) alkylenedioxy or are each selected independently from a hydrogen atom; a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo ( 1-4C) alkyl group; a group of formula (CH2) aXlλ (CH2) rR33 m which q represents 0, 1 or 2, r represents 0, 1 or 2, X11 represents 0, S, SO, S02, NR34, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R33 represents a hydrogen atom, an (1-4C) alkyl group, a (2- 4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1- 4C) alkyl group and a (l-4C)alkoxy group, R34 represents a hydrogen atom, a (1-4C) alkyl group or, together with R33 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group; and a phenyl or naphthyl group that is unsubstituted or substituted by ( 1-4C) alkylenedioxy or by one or two substituents selected from a halogen atom, a cyano group, a nitro group, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a group of formula (CH2) SX12 (CH2) tR35 m which s represents 0, 1 or 2, t represents 0, 1 or 2, X1" represents 0, S, SO, S02, NR36, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R35 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (l-4C)alkoxy group, R3€ represents a hydrogen atom, a (1-4C) alkyl group or, together with R35 and the nitrogen atom to which they are attached, a pyrrolidmyl, pipeπdmyl or morpholmo group; and R31 and R32 are together ( 1-4C) alkylenedioxy or are each selected independently from a hydrogen atom; a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo (1-4C) alkyl group; and a group of formula (CH2) UX13 (CH2) VR37 m which u represents 0, 1 or 2, v represents 0, 1 or 2, X13 represents 0, S, SO, S02, NR38, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R3^ represents a hydrogen atom, an (1-4C) alkyl group, a (2- 4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a ( 3-7C) cycloalkyl group, an mdanyl group, an aromatic or heteroaromatic group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a group of formula (CH2) WX14 (CH2) χR38 m which w represents 0, 1 or 2, x represents 0, 1 or 2, X14 represents 0, S, SO, S02, NH, CONH, NHCO, NHSO , or S02NH and R38 represent a hydrogen atom, a (1-4C) alkyl group or a phenyl group that is unsubstituted or substituted by a halogen atom, a (1-4C) alkyl group or a(l-4C)alkyl group, R38 represents a hydrogen atom, a (1-4C) alkyl group or, together with R37 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidmyl or morpholmo group.
An examples of a particular value for p is 0. Examples of particular values for r are 0 or 1.
Examples of particular values for X11 are CONH and NHCO. Examples of particular values for R3j are methyl, phenyl and cyclohexyl .
An example of a particular value for R34 is hydrogen. An example of a particular value for s is 1. An example of a particular value for t is 1. An example of a particular value for X12 is NHCO. An example of a particular value for R35 is phenyl. An example of a particular value for R36 is hydrogen. An aromatic or heteroaromatic group represented by R37 may be, for example, a thienyl, pyridyl, naphthyl or phenyl group.
R37 may represent, for example, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1- 4C) alkyl group a (l-4C)alkoxy group.
Examples of particular values for R37 are cyclohexyl, mdan-1-yl, pyrιd-4-yl, naphth-1-yl, naphth-2-yl, 2- fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-methylphenyl, 4-methylphenyl and 4-ιsopropylphenyl . A4 and A5 each preferably represents S.
Examples of particular values for R4 are methoxycarbonyl, thιazol-2-yl, benzothιazol-2-yl, 6- benzylammocarbonylbenzothiazolyl, 5-phenylthιazol-2-yl, 6- phenylcarboxamιdobenzothιazol-2-yl, 6-benzylammocarbonyl- benzothιazol-2-yl, 6- (4-methyl) benz lammocarbonylbenzothiazol- 2-yl, 6-cyclohexylmethylammo-carbonylbenzothιazol-2-yl, 6- phenylammocarbonylbenzothιazol-2-yl, 6- (3- methylbenzylammocarbonylbenzothιazol-2-yl, 6- ndan-l- ylammocarbonyl-benzothιazol-2-yl, 6- (2- fluoro) benzylammocarbonylbenzothιazol-2-yl, 6- (4- chloro) benzylcarbonylammobenzothιazol-2-yl, 6- (3- chloro) benzylcarbonylammobenzothιazol-2-yl, 6- cyclohexylcarbonylammobenzothιazol-2-yl, 6- (4- lsopropyl) phenylcarbonylammobenzothιazol-2-yl, 6-naphth-l- ylcarbonylammobenzothιazol-2-yl, 6-naphth-l- ylcarbonylammobenzothιazol-2-yl, 6- benzylsulfonylammobenzothιazol-2-yl, and 6-pyπd-4- ylammocarbonylbenzothιazol-2-yl .
Compounds of formula I m which R represents a group of formula NHX1(CH2)bR3 and R2 represents a group of formula COR4 have been found to show selectivity for tryptase over other ser e proteases and are therefore preferred. Accordingly, preferred compounds of formula I are those of general formulae
Figure imgf000023_0001
Id
Figure imgf000023_0002
I e
A particularly preferred group of compounds of formula Id is that of formula If
Figure imgf000024_0001
if
A particularly preferred group of compounds of formula Ie is that of formula Ig
Figure imgf000024_0002
ig
Preferably R29 represents a hydrogen atom and R30 is a phenyl or naphthyl group that is unsubstituted or substituted by ( 1-4C) alkylenedioxy or by one or two substituents selected from a halogen atom; a cyano group; a nitro group; an (1- 4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo (1-4C) alkyl group; and a group of formula (CH2) SX (CH2) tR ,35 which s represents 0, 1 or 2, t represents 0, 1 or 2, X 12 represents 0, S, SO, S02, NR ,36, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R35 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (l-4C)alkoxy group, R36 represents a hydrogen atom, a (1-4C) alkyl group or, together with R35 and the nitrogen atom to which they are attached, a pyrrolidmyl, pipeπdinyl or morpholmo group.
An example of a particular value for R29 is a hydrogen atom.
Examples of particular values for R 30 are phenyl, 2 naphthyl and 3, 4-ethylenedioxphenyl .
Preferably R32 represents a hydrogen atom and R31 is a hydrogen atom; a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo (1-4C) alkyl group; a group of formula
(CH2) UX13 (CH2) VR3 in which u represents 0, 1 or 2, v represents 0, 1 or 2, X13 represents 0, S, SO, S02, NR38, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R37 represents a hydrogen atom, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3-
7C) cycloalkyl group, a thienyl group, an indanyl group, a pyridyl group, a naphthyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (l-4C)alkoxy group, R38 represents a hydrogen atom, a (1-4C) alkyl group or, together with R37 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidmyl or morpholino group.
Examples of particular values are: for X13: NHCO, CONH or S02NH; for R37: cyclohexyl, mdan-2-yl, pyπd-4-yl, naphth-1-yl, naphth-2-yl, phenyl, 2-fluorophenyi, 3-chloroρhenyl, 4- chlorophenyl, 3-methylphenyl, 4-methylphenyl, 4-ιsoρropylphenyl and thιen-2-yl; for u: 0; and for v: 0 or 1.
Examples of particular values for R31 are hydrogen, benzylaminocarbonyl , phenylcarboxamido, 2- thienylmethylammocarbonyl, phenylammocarbonyl, cyclohexylammocarbonyl, cyclohexylamido, cyclohexylmethylammocarbonyl, ιndan-2-ylammocarbonyl, pyrid- 4-ylammocarbonyl, naphth-i-ylamido, naphth-2-ylamιdo, 3- methylbenzylammocarbonyl, 4-methylbenzylammocarbonyl, 2- fluorobenzyl-ammocarbonyl, 3-chlorobenzylamιdo, 4- chlorobenzylamido, benzylamido, benzylsulfonylammo and 4- lsopropylbenzamido .
An example of a particular value for R32 is a hydrogen atom.
A particular sub-group of compounds of especial interest is that of formula
Figure imgf000026_0001
(Ih) m which R1 represents a hydrogen atom or a group of formula
Figure imgf000026_0002
Compounds of formula Ih in which R1 represents a hydrogen atom have been found to be highly potent as tryptase inhibitors. Those skilled m the art will appreciate that the compounds of formula Ih m which R1 represents a hydrogen atom lack a chiral centre at the carbon atom bearing R1, and that this is highly desirable in a molecule intended for development as a pharmaceutical.
In the compounds of formula Ih, R~ preferably represents a hydrogen atom or a group of formula NHX1(CH2)bR3 m which R3 represents a ( 1-lOC) alkyl, (3-10C) cycloalkyl, phenyl or naphthyl group. Examples of preferred values for R1 in formula Ih are hydrogen, acetamido, cyclohexylmethylamido and benzamido.
The term pharmaceutically acceptable salt refers to an acid addition or base salt of a compound of formula I. Examples of acid addition salts include salts formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid or sulfuric acid, and organic acids, such as acetic acid, trifluoroacetic acid, benzoic acid, oxalic acid, succinic acid, p-toluene sulfonic acid and methanesulfonic acid. Base salts include ammonium, sodium and potassium salts.
The term pharmaceutically acceptable metabolically labile amide refers to an amide formed between a pharmaceutically acceptable carboxylic acid and the amino group in the aminomethyl group of a compound of formula I, which amide is hydrolysed m vivo to afford the aminomethyl compound of formula I and the carboxylic acid. Examples of pharmaceutically acceptable carboxylic acids include acetic acid. According to another aspect, the present invention provides a process for the preparation of a compound of formula I, or a pharmaceutically acceptable metabolically labile ester thereof or a pharmaceutically acceptable salt of said compound of formula I or said pharmaceutically acceptable metabolically labile amide thereof, which comprises deprotecting a compound of formula
Figure imgf000027_0001
II in which Ra represents a protecting group, followed if desired by
(ii) forming a pharmaceutically acceptable metabolically labile amide; or (11) forming a pharmaceutically acceptable salt.
The protection and deprotection of amme groups is well known, and is described, for example, m McOmie, Protecting Groups Organic Chemistry, Plenum Press, NY., 1973 and Greene and Wutts, Protecting Groups m Organic Synthesis, 2nd Ed., John Wiley and Sons, NY., 1991. Examples of am e protecting groups are acyl groups, for example t-butoxycarbonyl .
An acyl protecting group, such as t-butoxycarbonyl is conveniently removed by reaction with an acid, for example an inorganic acid such as hydrochloric acid, or an organic acid such as tπfluoroacetic acid. The reaction is conveniently performed at a temperature of from -10 to 100°C. Convenient solvents include halogenated hydrocarbons, such as dichloromethane . Compounds of formula II in which R2 represents COR3 and RJ represents an unsubstituted or substituted heteroaromatic group of formula
Figure imgf000028_0001
may be prepared by reacting a compound of formula
Figure imgf000028_0002
III in which Rb represents an alkoxy group, such as methoxy, or N- (1-4C) alkoxy-N- (1-4C) alkylammo, such as N-methoxy-N- methylammo with an unsubstituted or substituted compound of formula
Figure imgf000029_0001
IV V m which M represents a metal residue, such as a lithium, magnesium, copper or zinc residue. The reaction is conveniently performed at a temperature of -78 to -25°C.
Convenient solvents include ethers, such as tetrahydrofuran . The compound of formula IV or V may be generated in situ from the corresponding compound of formula IV or V m which M represents a hydrogen atom by reaction with an appropriate organometallic reagent, for example an alkyl lithium such as n- butyl lithium.
It will be appreciated that an unsubstituted or substituted compound of formula IV or V includes compounds of formula
Figure imgf000029_0002
and
Figure imgf000029_0003
Compounds of formula II in which R2 represents COR4 and R4 represents COR5 may be prepared by oxidising a compound of formula
Figure imgf000030_0001
VI The oxidation is conveniently effected using Dess-Martm reagent, 1, 1, 1-trιacetoxy-l, 1-dιhydro-l, 2-benzιodoxol-3 ( IH) - one. Other oxidizing agents include pyπdmium chlorochromate, pyridmium dichromate, potassium permanganate and dimethylsulfoxide/oxalyl chloride .
Compounds of formula III m which Rb represents N-(l- 4C) alkoxy-N- ( 1-4C) alkylammo may be prepared by reacting a corresponding compound of formula III m which Rb represents alkoxy with an N- ( 1-4C) alkoxy-N- ( 1-4C) alkylamme, or a salt thereof such as a hydrochloride m the presence of an organometallic reagent, such as dimethylalummium chloride. Alternatively, they may be prepared by reacting a compound of formula III m which Rb represents a hydroxyl group with an N- (1-4 ) alkoxy-N- ( 1-4C) alkylamme, or a salt thereof, with a carbodnmide such as 1- ( 3-dιmethylammopropyl ) -3- ethylcarbodnmide hydrochloride m the presence of a base, such as tπethylamme . A convenient solvent is dichloromethane .
Compounds of formula III in which R1 represents a group of formula NHX1 (CH2) bR3 and Rb represents alkoxy may be prepared by reacting a compound of formula III in which R1 represents an ammo group with a compound of formula Z^^CH^bR3
VII in which Z1 represents a leaving atom or group.
The leaving atom or group represented by Z1 may be, for example, a halogen atom, such as a chlorine atom. Alternatively, it may be generated in si tu, for example by reacting a compound of formula VII n which Z1 represents hydroxyl with a coupling agent, for example a carbodiimide, such as 1- [3- (dimethylamino) -propyl] -3-ethylcarbodιιmιde . The reaction is conveniently performed m the presence of a base, such as tπethylamine, dnsopropylethylamine, pyridme or 4- dimethylaminopyridme . Convenient solvents include amides, such as dimethylformamide and halogenated hydrocarbons, such as dichloromethane and chloroform. The reaction is conveniently performed at a temperature in the range of from 0 to 150°C. Compounds of formula III in which R1 represents an ammo group and Rb represents alkoxy are known or may be prepared from known compounds by methods known in the art. See, for example, Tetrahedron (1977), 33(20), 2715-7 and European patent applications, publication numbers EP 31794 and EP 580008. Compounds of formula III in which R1 represents an amino group may also be prepared by reducing a compound of formula
Figure imgf000031_0001
VIII The reduction is conveniently performed by catalytic hydrogenation in the presence of a Group VIII metal catalyst, such as Raney nickel or palladium on charcoal. Convenient solvents include esters, such as ethyl acetate. The reduction is conveniently performed at a temperature m the range of from 0 to 100°C and a pressure of from 1 to 35 x 105 Pa.
Compounds of formula IV and V are generally known or may be prepared by methods known m the art. For example, 6- carboxybenzothiazole and 6-ammobenzothiazole may readily be converted into an amide derivative by reaction with an appropriate amine or carboxylic acid.
Compounds of formula VIII may be prepared by reacting a compound of formula
Figure imgf000032_0001
IX with a strong base, such as potassium bis (tπmethylsilyl ) - amide, and a tπorganosulfonylazide, such as trnsopropyl- benzenesulfonyl azide, followed by an acid, such as acetic acid. The reactions are conveniently performed at a temperature of from -78 to 0°C. Suitable solvents include ethers, such as tetrahydrofuran .
Compounds of formula VI may be prepared by reacting a compound of formula
Figure imgf000032_0002
X m which each Rc represents a (1-6C) alkyl group, such as ethyl, with a mercury (II) chloride, mercury oxide and an alcohol of formula HOR4. The reaction is conveniently performed at a temperature the range of from 0 to 100°C. The alcohol of formula HOR4 may also serve as reaction solvent. Compounds of formula X may be prepared by reacting a compound of formula
Figure imgf000032_0003
XI with a compound of formula HC(SRC)3
XII in the presence of a strong base, such as t-butyllithium. The reaction is conveniently performed at a temperature m the range of from -78 to -25°C. Convenient solvents include ethers, such as tetrahydrofuran. Compounds of formula XI may be prepared by reacting a compound of formula III which R represents N- ( 1-4C) alkoxy- N- ( 1-4C) alkylammo with a reducing agent, such as di sobutylalummium hydride. Convenient solvents include tetrahydrofuran . Many of the intermediates described herein, including the compounds of formula II, III (where R represents N-methoxy-N- methylamme), VIII and XI are believed to be novel and are provided as further aspects of the invention.
The ability of compounds to inhibit tryptase may be determined by the method of Tapparelli et al., (1993) J. Biol. Chem., 268, 4734-4741.
The compounds exemplified herein have all been tested by this method and found to possess tryptase inhibitor activity with a Ki of less than lOOμM. The tests were performed in 0.1 M phosphate buffer (to pH 7.4) containing 0.5 mg/ml heparm at ambient temperature using purified human lung tryptase (supplied by Dr. Andrew Walls, Immunopharmacology Group, Southampton General Hospital, Southampton, UK) and the chromogenic tryptase substrate S-2366 (supplied by Quadratech, Epsom, Surrey, UK) . Compounds were dissolved dimethylsulfoxide and tested at concentrations of from lnM- lOOmM in 96 well microplates. Inhibitor activity was determined by measuring light absorption by p-nitroamlme (produced by the action of tryptase on the chromogenic substrate) at 405nm using a Dynatech MR 5000 reader (supplied by Dynex Ltd., Billmghurst , UK) . SAS software was then used to determine Km (Michaelis constant) and Ki values. S-2366 was calculated to give a Km of 216μM. The selectivity of compounds for tryptase over other seπne proteases may be determined by the same test method, but using the appropriate chromogenic serme protease substrate. As described here above, it is envisaged that a variety of mast cell mediate diseases may be treated by the compounds of the present invention through their action as tryptase inhibitors .
According to another aspect, therefore, the present invention provides a method of inhibiting tryptase in a patient requiring such treatment, which comprises administering an effective amount of a compound of formula I, or a metabolically labile amide thereof, or a pharmaceutically acceptable salt of said compound of formula I or said metabolically labile ester thereof . As used herein, the term treatment includes prophylaxis, amelioration or elimination of a condition for which a patient is being treated.
The term patient includes a warm blooded animal, such as a human, pig, horse, sheep, cow, mouse, hamster, guinea pig dog or chicken, and a reptile. Preferably, the patient is a human. The effective amount, or dose of compound administered to a patient will of course be determined by the particular circumstances surrounding the case, including the species, size, age, weight and sex of the patient, the compound to be administered, the route of administration and the particular condition being treated. The compounds can be administered by a variety of routes, such as by oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, or intranasal routes, or by inhalation. Alternatively, the compound may be administered by continuous infusion. A typical daily dose will contain from about 0.01 mg/kg to about 100 mg/kg of the active compound of this invention. Preferably, daily doses will be about 0.05 mg/kg to about 50 mg/kg, more preferably from about 0.1 mg/kg to about 25 mg/kg. The dose when administered by inhalation may be lower, for example m the range of from 0.01 to 2.0 mg for a patient weighing 70kg.
The present invention also provides the use of a compound 5 of formula I, or a metabolically labile amide thereof, or a pharmaceutically acceptable salt of said compound of formula I or said metabolically labile ester thereof for the manufacture of a medicament for use as a tryptase inhibitor.
As described heremabove, a tryptase inhibitors are
10 envisaged to be useful in the treatment of a wide variety of conditions, including asthma, allergic rhinitis, inflammatory bowel disease, chronic obstructive pulmonary disease (COPD) , Pulmonary fibrotic diseases, cirrhosis of the liver, Kimura' s disease, pre-eclampsia, bleedlmg problems associated with
15 menstruation and the menopause, Crohn' s disease, colitis, multiple sclerosis, interstitial cystitis, wound healing, eczema, psoriasis, atopic dermatitis, urticaria, conjunctivitis, neurogenic inflammation, migraine headache, rheumatoid arthritis, atherosclerosis, cancer (particularly
20 melanoma and tumour metastasis), pancreatitis and certain viral infections (Yong, Exp . Toxic Pathol, 1997, 49, 409; Stemhoff et al., Nat. Med., 2000, 6, 151; Downing and Miyan, Immunol. Today, 2000, 21, 281; Tetlow and Wooley, Ann. Rheum. Dis., 1995, 54, 549; Jeziorska, Salamonsen and Wooley, Biol . Reprod. ,
25 1995, 53, 312; Brain, Nat. Med., 2000, 6, 134, Olness et al., Headache, 1999, 39, 101.) The underlying principle is that a tryptase inhibitor should have utility where mast cells have been induced to degranulate by whatever mechanism, including anaphylactic reactions due to exogenous substances, e.g.
30 morphme- duced bronchoconstriction (Bowman and Rand, 2nd edt . , 1980.) The present invention accordingly provides the use of the compounds for the treatment of each of these conditions . The compounds according to the invention may be administered with other pharmaceutically active agents, such as a bronchodilator, for example a β-agonist such as salbutamol or terbutalme; a methylxanthme, such as theophyllme; a corticosteroid such as beclomethasone dipropionate; a chromolyn, such as sodium chromoglycate; a leukotπene antagonist such as zaf rlukast or montelukast; a 5-lιpoxygenase inhibitor, such as zileuton; or a tachykm antagonist.
The compounds of the present invention are preferably administered to patients in a pharmaceutical composition.
According to another aspect, therefore, the present invention provides a pharmaceutical composition, which comprises a compound of formula I, or a pharmaceutically acceptable metabolically labile amide thereof, or a pharmaceutically acceptable salt of said compound of formula I or said pharmaceutically acceptable metabolically labile amide thereof, and a pharmaceutically-acceptable carrier.
The pharmaceutical compositions may be prepared by methods known in the art using well-known and readily available ingredients. Generally the active ingredient is mixed with the carrier, diluted by the carrier, or enclosed within the carrier, and may be in the form of a capsule, sachet, paper, or other container. When the carrier acts as a diluent, it may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or medium for the active ingredient. The compositions can be the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 10% by weight of active compound, soft and hard gelatin capsules, suppositories, sterile mπectable solutions, and sterile packaged powders.
Examples of carriers include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum, acacia, calcium phosphate, alg ates, tragacanth, gelatin, calcium silicate, microcrystallme cellulose, polyv ylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl and propyl hydroxybenzoates, talc, magnesium stearate, and mineral oil. The compositions can additionally contain lubricating agents, wetting agents, emulsifying and suspending agents, preserving agents, sweetening agents, or flavoring agents. Compositions of the invention may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known the art.
The compositions are preferably formulated m a unit dosage form, each dosage containing from about 5 mg to about 500 mg, more preferably about 25 mg to about 300 mg of the active ingredient. The term "unit dosage form" refers to a physically discrete unit suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, m association with a suitable pharmaceutical carrier, diluent, or excipient. The following formulation examples are illustrative only and are not intended to limit the scope of the invention in any way.
Formulation 1
Hard gelatin capsules are prepared using the following ingredients :
Quantity (mg/capsule
Active Ingredient 250
Starch, dried 200
Magnesium stearate 10
Total 460 mg
Formulation 2
Tablets each containing 60 mg of active ingredient are made as follows :
Active Ingredient 60 mg Starch 45 mg
Microcrystallme cellulose 35 mg
Polyvmylpyrrolidone 4 mg
Sodium carboxymethyl starch 4.5 mg
Magnesium stearate 0.5 mg Talc 1 mg
Total 150 mg Formulation 3
Metered Dose Inhaler
Quantity (g/mhaler)
Active Ingredient 0.02
Oleic acid 0.01
Dichlorodifluoromethane 10.50
Dichlorotetrafluorethane 4.50
Total 15.3
The following Examples illustrate the invention. In the Examples, BOC refers to t-butoxycarbonyl, DMAP refers to 4-dimethylaminopyridine, DMF refers to dimethylformamide, TBTU refers to 2 ( lH-benzctrιazol-1-yl ) - 1 , 3, 3-tetramethyluronιum tetrafluoroborate, THF refers to tetrahydrofuran, TFA refers to trifluoroacetic acid, DCM refers to dichloromethane and DIBAL-H refers to diisobutylene- aluminium hydride. The term Dess-Martin reagent refers to 1, 1, 1-trιacetoxy-l, 1-dihydro-l, 2-benzιodoxol-3 ( IH) -one . Example 1
N-[α- (Benzothiazol-2-oyl) -N- (4-aminomethyl) benzyl] 4-
-Lsopropoxybenzamide trifluoroacetate salt
(I) Methyl 4-bromophenylacetate
To a solution of 4-bromophenylacetιc acid (50g; 0.23mol) in methanol (250ml), was added thionyl chloride (18ml; 0.25mol) dropwise. The resulting mixture was stirred at room temperature for 1 hour and methanol was then removed m va cuo . Ethyl acetate (300ml) was added and the resulting solution was washed with water (3 x 150ml), 1M sodium bicarbonate solution (1 x 150ml) then dried (MgS04) and evaporated to give the ester (52.8g; 100%) as an orange oil. XH nmr (CDC13) 7.38 (2H, d, J=8.4Hz, Ar) ; 7.09 (2H, d, J=8.4Hz, Ar) ; 3.63 (3H, s, OMe) ; 3.51 (2H, s, 4-CH2) .
(II) Methyl 4-cyanophenylacetate
To a solution of methyl 4-bromophenylacetate (20g; 0.088mol) m DMF (150ml) was added zinc cyanide (10.4g; 0.088mol) followed by tetrakis (triphenylphosphme) -palladium ( 0) (5g; 4.4mmol). The resulting mixture was stirred at 80°C for 5 hours, then allowed to cool to room temperature. Toluene (500ml) and 1M aqueous ammonia solution (500ml) were added and the organic layer washed with brine then dried (MgS04). Purification on silica gel afforded the cyano compound as a white solid (11.3g; 73%) . XH nmr (CDC13) 7.65 (2H,d, J=8.4Hz, Ar) ; 7.42(2H, d, J=8.1Hz, Ar) ; 3.74 (3H, s, OMe); 3.72 (2H, s, CH2) .
(III) 4-Cyanophenylacetιc acid To a solution of methyl 4-cyanophenylacetate (23.9g; 0.136mol) in ethanol (250ml) was added a solution of sodium hydroxide (6.0g; 0.15mol) m water (25ml). After 2 hours the ethanol was removed m va cuo . Ethyl acetate (300ml) and 5% aqueous HC1 solution (300ml) were added, the layers separated and the aqueous layer re-extracted with ethyl acetate (300ml) . The combined organic layers were dried (MgS04) and evaporated in va cuo to give the acid (21.6g; 99%) . τH nmr (CDC13) 7.57 (2H, d, J=8.3Hz, Ar) ; 7.34 (2H, d, J=8.2Hz, Ar) ; 3.64 (2H, s, CH2) .
(IV) 4- (BOC-aminomethyl ) phenylacetic acid
To a solution of 4-cyanophenylacet c acid (12.11g; 0.075mol) m water (163.5ml) and concentrated ammonia solution (33.9ml) was added Raney nickel (6.3g), and the resulting suspension was put under a hydrogen atmosphere. After 24 hours the reaction mixture was filtered through celite and evaporated in va cuo to give the amme (12.57g; 100%) as a pale blue solid. To a solution of 4- (aminomethyl) phenylacetic acid (12.57g; 0.075mol) m water (50ml; and 1,4-dιoxane (50ml) was added sodium hydroxide (3g; 0.075mol) and dι-tbutyl dicarbonate (16.4g; 0.075mol) simultaneously. After 24 hours the 1,4- dioxane was removed m va cuo and the residual solution acidified with saturated citric acid solution (200ml) . This was then washed with ethyl acetate (3 x 150ml), the combined organic layers dried (MgS0 ) and evaporated m va cuo to give the BOC-amme (17.6g; 88%) as a white solid. 1H nmr (CDC13) 7.0 (4H, m, Ar) ; 4.65 (IH, bs, N-H) ; 4.09 (2H, d, 4-CH2) ; 3.43 (2H, s, CH2); 1.25 (9H, s, fcBu) .
(v) Methyl 4- (BOC-ammomethyl) phenylacetate
To a solution of 4- (BOC-ammomethyl) phenylacetic acid (47.8g; O.lδmol) in methanol (200ml), was added l-[3- (dimethylammo) propyl] -3-ethylcarbodιιmιde hydrochloride
(34.8g; O.lδmol) and DMAP (catalytic). After stirring for 18 hours the methanol was removed m va cuo and the reaction mixture partitioned between ethyl acetate (200ml) and saturated citric acid solution (200ml). The organic phase was washed with sodium bicarbonate solution (200ml), brine (200ml), dried (MgS04) and evaporated to give the ester (49.8g; 99%). λti nmr (CDC13) 7.42 (4H, s, Ar) ; 5.02 (IH, bs, N-H); 4.48 (2H, d, J=5.7Hz, 4-CH2); 3.87 (3H, s, OMe); 3.79 (2H, s, CH2); 1.64 (9H, s, cBu) .
(vi) Methyl 4- (BOC-aminomethyl) -α-azidophenylacetate To a solution of methyl 4- (BOC-ammomethyl ) phenylacetate (9.34g; 0.033mol) in THF (100ml) at -78°C was added potassium bis (trimethylsilyl) amide (16.7g; 0.084mol) in THF (50 ml). After stirring for 30 minutes 2, 4 , 6-triιsopropylbenzenesulfonyl azide (31. Ig; O.lOlmol) was added as a solid. After 5 minutes, acetic acid (10ml; 0.175mol) was added and the reaction warmed to room temperature. The reaction mixture was then partitioned between ethyl acetate (500ml) and water (500ml) and the organic layer dried (MgS04) . Purification on silica gel afforded the product (7.1g; 67%) . XH nmr (CDC13) 7.28 (4H, s, Ar) ; 4.92 (IH, s, C-H); 4.25 (2H, s, 4-CH2); 3.69 (3H, s, OMe); 1.38 (9H, s, tBu) .
(vii) Methyl 4- (BOC-aminomethyl) -α-aminophenylacetate
To a solution of methyl 4- (BOC-aminomethyl) -α- azidophenylacetate (7.1g; 0.022mol) in ethyl acetate (50ml) was added palladium on carbon (5%) . The reaction vessel was taken up to 250psi (17.2 x 105 Pa) with hydrogen for 17 hours. The reaction mixture was filtered through cellite and evaporated m vacuo to give the amine (6.47g; 100%) as a pale solid.
XH nmr (CDCI3) 7.20 (2H, m, Ar) ; 7.12 (2H, m, Ar) ; 4.81 (IH, bs, N-H); 4.45 (IH, s, C-H); 4.18 (2H, d, 4-CH2) ; 3.54 (3H, s,
OMe); 2.09 (2H, bs, NH2); 1.30 (9H, s, cBu) . (vm) Methyl 4- (BOC-ammomethyl ) -α- ( 4-ιsopropoxy) - benzoylammophenylacetate
To a solution of l-hydroxy-7-azabenzotrιazole (153mg; 1.12mmol) in DMF (5ml) at 0°C was added 1- [3- (dimethylammo) propyl] -3- ethylcarbodiimide hydrochloride (215mg; 1.12mmol). The reaction mixture was allowed to warm to room temperature over 30 minutes followed by addition of 4-ιsopropoxybenzoιc acid (202mg; 1.12mmol) . After stirring for a further 30 minutes methyl 4- (BOC-aminomethyl ) -α-ammophenylacetate (300mg; 1.02mmol) was added and the reaction stirred for 18 hours. The DMF was removed in va cuo and the reaction mixture partitioned between ethyl acetate (40ml) and saturated citric acid solution (40ml) . The organic layer was washed with 1M sodium bicarbonate solution (40ml) and dried (MgS04). Purification on silica gel afforded the amide (368mg; 81%) as a white solid.
XU nmr (CDC13) 7.84 (2H, d, J=8.7Hz, Ar) ; 7.48 (2H, d, J=8.1Hz, Ar) ; 7.38 (IH, s, Ar) ; 7.11 (IH, d, J=6.1Hz, Ar) ; 6.97 (2H, d, J=8.8Hz, Ar) ; 5.82 (IH, d, J=6.8Hz, C-H); 4.69 (IH, septet, J=6.0Hz, CH(CH3)2); 4.38 (2H, d, J=5.9Hz, 4-CH2); 3.84 (3H, s, OMe); 1.53 (9H, s, tBu ); 1.43 (6H, d, J=6.0Hz, CH(CH3)2).
(IX) 4-Isopropoxy-[α- (benzothιazol-2-oyl) -N- (4-B0C- ammomethyl ) benzyl]benzamιde
To a solution of benzothiazole (309μl; 2.82mmol) m THF (5ml) at -78°C was added fcbutyl lithium (1.66ml of 1.7m solution pentane; 2.82mmol) . After 15 minutes methyl 4- (BOC- ammomethyl ) -α- ( 4-ιsopropoxy) benzoylammophenylacetate ( 368mg; 0.807mmol) was added dropwise in THF (5ml) over 20 minutes. After stirring for 3 hours ammonium carbonate solution (2ml) was added dropwise and the reaction allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate (50ml) and ammonium carbonate solution (50ml) and the organic layer dried (MgS04) . Purification on silica gel afforded the ketone (168mg; 37%).
XH nmr (CDC13) 8.11 (IH, d, J=7.9Hz, Ar) ; 7.85 (IH, d, J=8.1Hz,
Ar) ; 7.73 (2H, d, J=8.7Hz, Ar); 7.45 (4H, m, Ar); 7.14 (2H, d, J=8.0Hz, Ar) ; 7.03 (IH, d, J=6.9Hz, C-H); 6.81 (2H, d, J=8.7Hz, Ar) ; 4.53 (IH, septet, J=6.0Hz, CH(CH3)2); 4.13 (2H, d,
J=5.0Hz, 4-CH2); 1.32 (9H, s, tBu ); 1.26 (6H, d, J=6.0Hz, CH(CH3)2) .
(x) 4-Isopropoxy-[α- (benzothιazol-2-oyl) -N- (4-aminomethyl) - benzyl]benzamιde trifluoroacetate salt
To a solution of the 4-ιsopropoxy-[α- (benzothιazol-2-oyl) -N- ( 4- BOC-ammomethyl) benzyljbenzamide (168mg; 0.30mmol) m dichloromethane (10ml) was added trifluoroacetic acid (5ml). After 30 minutes the dichloromethane and trifluoroacetic acid were removed m vacuo . Purification by preparative HPLC gave the desired compound (llOmg; 64%).
XH nmr (d4methanol) 8.22 (IH, m, Ar) ; 8.13 (IH, m, Ar) ; 7.88 (2H, d, J=8.9Hz, Ar) ; 7.71 (2H, d, J=8.2Hz, Ar) ; 7.65 (2H, m, Ar) ; 7.50 (2H, d, J=8.2Hz, Ar) ; 7.11 (IH, s, C-H); 7.01 (2H, d, J=8.8Hz, Ar) ; 4.7 (IH, q, J=6.0Hz, CH(CH3)2); 4.11 (2H, s, 4- CH2); 1.37 (6H, d, J=6.0Hz, CH(CH3)2). Hplc (Magellan C8, Gradient 1, Water/acetonitrile/tπfluoroacetic acid) rt 13.29 mm.
Examples 2-27
Using methods similar to that described in Example 1, and starting from carboxylic acids that were either commercially available or were prepared using literature procedures, the following compounds were prepared.
Example 2 Benzyl alpha- (benzothiazol-2-oyl) -4- (aminomethyl)benzyl- carbamate trifluoroacetate salt λR nmr (d4 methanol) 8.22-8.19 (IH, m) ; 8.13-8.09 (IH, m) ; 7.70-7.58 (4H, m) ; 7.48-7.30 (7H, m) ; 6.79 (IH, s); 5.15 (2H, s); 4.09 (2H, s). Hplc (Magellan C8, Gradient 1,
Water/acetonitrile/trifluoroacetic acid) rt 11.55 mm.
Example 3
N- [alpha- (Benzothιazol-2-oyl) -4- (aminomethyl) benzyl] - benzylamide trifluoroacetate salt
XH nmr (d4 methanol) 8.20-8.16 (IH, m) ; 8.12-8.09 (IH, m) ;
7.70-7.58 (4H, m) ; 7.47 (2H, d) ; 7.37-7.23 (5H, m) ; 6.93 (IH, t); 4.09 (2H, s); 3.69 (2H, s). Hplc (Magellan C8, Gradient 1,
Water/acetonitrile/trifluoroacetic acid) rt 10.76 mm.
Example 4
N- [alpha- (Benzothiazol-2-oyl) -4- (aminomethyl) benzyl] -benzamide trifluoroacetate salt
XH nmr (d4 methanol) 8.24-8.20 (IH, m) ; 8.15-8.11 (IH, m) ; 7.94-7.90 (2H, m) ; 7.78 (2H, d) ; 7.70-7.58 (3H, m) ; 7.55-7.49
(4H, m) ; 7.14 (IH, s); 4.11 (2H, s). Hplc (Magellan C8,
Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 10.53 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.00 mm, 402 (M+l)+.
Example 5
N- [alpha- (Benzothiazol-2-oyl) -4- (aminomethyl) benzyl] - cyclohexylacetamide trifluoroacetate salt λn nmr (d4 methanol) 8.22-8.18 (IH, m) ; 8.13-8.09 (IH, m) ; 7.70-7.58 (4H, m) ; 7.48 (2H, d) ; 6.93 (IH, s); 4.10 (2H, s); 2.30-2.17 (2H, m) ; 1.86-1.67 (6H, m) ; 1.38-1.16 (3H, m) ; 1.10- 0.95 (2H, m) . Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 11.05 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 0.33 mm, 422 (M+l)+.
Example 6
N- [alpha- (Benzothιazol-2-oyl) -4- (aminomethyl) benzyl] - cyclohexylamide trifluoroacetate salt
XH nmr (d4 methanol) 8.22-8.18 (IH, m) ; 8.13-8.09 (IH, m) ; 7.70-7.58 (4H, m) ; 7.48 (2H, d) ; 6.90 (IH, s); 4.10 (2H, s); 2.50-2.39 (IH, m) ; 1.95-1.70 (5H, m) ; 1.56-1.23 (5H, m) . Hplc (Magellan C8, Gradient 1, Water/acetonitrile/ trifluoroacetic acid) rt 10.66 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 0.28 mm, 408 (M+l)+.
Example 7
N- [alpha- (Benzothιazol-2-oyl) -4- (aminomethyl) benzyl] -4- isopropylbenzamide trifluoroacetate salt λE nmr (d4 methanol) 8.24-8.20 (IH, m) ; 8.15-8.11 (IH, m) ; 7.86 (2H, d) ; 7.78 (2H, d) ; 7.70-7.60 (2H, m) ; 7.50 (2H, d) ; 7.40 (2H, d) ; 7.13 (IH, s); 4.11 (2H, s); 3.06-2.97 (IH, m) ; 1.33 (3H, s); 1.30 (3H, s). Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 12.62 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/ trifluoroacetic acid) rt 0.33 mm, 444 (M+l)+.
Example 8
N- [alpha- (Benzothiazol-2-oyl) -4- (aminomethyl) benzyl] -3,5- dimethylbenzamide trifluoroacetate salt XH nmr (d4 methanol) 8.24-8.20 (IH, m) ; 8.15-8.11 (IH, m) ; 7.78 (2H, d) ; 7.70-7.60 (2H, m) ; 7.54-7.46 (4H, m) ; 7.26 (IH, s); 7.12 (IH, s); 4.11 (2H, s); 2.40 (6H, s). Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 12.05 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 0.40 min, 430 (M+l)+.
Example 9
N- [alpha- (Benzothiazol-2-oyl) -4- (aminomethyl) benzyl] -1- adamantanamide trifluoroacetate salt
1H nmr (d4 methanol) 8.22-8.19 (IH, m) ; 8.14-8.10 (IH, m) ;
7.69-7.60 (4H, m) ; 7.48 (2H, d) ; 6.82 (IH, s); 4.10 (2H, s); 2.12-2.04 (3H, m) ; 1.98-1.92 (6H, m) ; 1.90-1.75 (6H, m) . Hplc
(Magellan C8, Gradient 1, Water/acetonitrile/ trifluoroacetic acid) rt 12.45 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.43 min, 460
(M+l)+.
Example 10
N- [α- (Benzothiazol-2-oyl) -4- (aminomethyl) benzyl] -2-naphthamide trifluoroacetate salt
1H nmr (d4 methanol) 8.51 (IH, s, Ar) ; 8.23 (IH, m, Ar) ; 8.13 (IH, m, Ar); 8.00 (4H, m, Ar) ; 7.84 (IH, s, Ar) ; 7.81 (IH, s, Ar) ; 7.64 (4H, m, Ar); 7.54 (IH, s, Ar) ; 7.51 (IH, s, Ar); 7.20
(IH, s, C-H); 4.12 (2H, s, 4-CH2) . Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 11.53 min.
Example 11
3-Methyl-4-nitro- [alpha- (benzothiazol-2-oyl) -4-
(aminomethyl) benzyl]benzamide trifluoroacetate salt
XH nmr (d4 methanol) 8.24-8.20 (IH, m) ; 8.16-8.12 (IH, m) ; 8.06 (IH, d) ; 7.97 (IH, s); 7.92-7.88 (IH, m) ; 7.79 (2H, d) ; 7.71- 7.60 (2H, m) ; 7.52 (2H, d) ; 7.15 (IH, t); 4.12 (2H, s); 2.64 (3H, s) . Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 17.03 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.18 mm, 461 (M+l)+.
Example 12 3 , 4-Dimethoxy-N- [alpha- (benzothiazol-2-oyl) - (4- aminomethyl) benzyl]benzamide trifluoroacetate salt
4H nmr (d4 methanol) 8.23-8.19 (IH, m) ; 8.14-8.10 (IH, m) ; 7.76 (2H, d) ; 7.70-7.56 (3H, m) ; 7.54-7.48 (3H, m) ; 7.11 (IH, s); 7.06 (IH, d) ; 4.11 (2H, s); 3.92 (3H, s); 3.90 (3H, s). Hplc (SymmetryShield Rp8, Gradient 3,
Water/acetonitrile/trifluoroacetic acid) rt 3.87 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.82 mm, 462 (M+l)+.
Example 13
4-Dιmethylamino-N- [alpha- (benzothiazol-2-oyl) -4-
(aminomethyl) benzyl] benzamide ditrifluoroacetate salt λti nmr (d4 methanol) 8.23-8.19 (IH, m) ; 8.14-8.10 (IH, m) ; 7.82 (2H, d) ; 7.77 (2H, d) ; 7.69-7.59 (2H, m) ; 7.50 (2H, d) ; 7.10 (IH, s); 6.78 (2H, d) ; 4.11 (2H, s); 3.07 (6H, s). Hplc
(Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 9.70 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.10 mm, 445 (M+l)+.
Example 14
4-Acetylamino-N- [alpha- (benzothιazol-2-oyl) -4-
(aminomethyl)benzyl]benzamide trifluoroacetate salt
1H nmr (d4 methanol) 8.24-8.20 (IH, m) ; 8.15-8.11 (IH, m) ; 7.90 (2H, d) ; 7.82-7.60 (6H, m) ; 7.50 (2H, d) ; 7.12 (IH, s); 4.11 (2H, s); 2.19 (3H, s). Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 9.34 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.73 mm, 459 (M+l)+.
Example 15 2,3-Dihydro-N- [alpha- (benzothιazol-2-oyl) -4-
(aminomethyl) benzyl]benzofuran-5-amide trifluoroacetate salt
1H nmr (d4 methanol) 8.24-8.20 (IH, m) ; 8.15-8.11 (IH, m) ; 7.82-7.72 (4H, m) ; 7.70-7.60 (2H, m) ; 7.50 (2H, d) ; 7.11 (IH, s); 6.83 (IH, d) ; 4.67 (2H, t); 4.11 (2H, s ) ; 3.29 (2H, t). Hplc (Magellan C8, Gradient 1,
Water/acetonitrile/trifluoroacetic acid) rt 10.28 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.98 mm, 444 (M+l)+.
Example 16
4-Phenoxy-N- [alpha- (benzothιazol-2-oyl) -4-
(aminomethyl) benzyl]benzamide trifluoroacetate salt
XH nmr (CD3CN) 8.23 (IH, m, Ar) ; 8.12 (IH, m, Ar) ; 7.89 (3H, m, Ar) ; 7.68 (5H, m, Ar) ; 7.47 (3H, m, Ar) ; 7.25 (IH, , C-H); 7.07 (4H, m, Ar) ; 4.12 (2H, s, 4-CH2). Hplc (Magellan C8,
Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 13.16 mm .
Example 17 4-Benzyloxy-N- [alpha- (benzothiazol-2-oyl) -4-
(aminomethyl) benzyl]benzamide trifluoroacetate salt lR nmr (d4 methanol) 8.21 (IH, m, Ar) ; 8.10 (IH, m, Ar) ; 7.88 (2H, d, J=8.9Hz, Ar) ; 7.76 (2H, d, J=8.3Hz, Ar) ; 7.64 (2H, ,
Ar) ; 7.49-7.36 (7H, m, Ar) ; 7.10 (3H, m, C-H, Ar) ; 5.18 (2H, s, CH2) ; 4.09 (2H, s, 4-CH2) . Hplc (Magellan C8, Gradient 1,
Water/acetonitrile/trifluoroacetic acid) rt 13.22 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.63 mm, 508 (M+l)+. Example 18
4- (2-Phenoxyethoxy) -N- [alpha- (benzothiazol-2-oyl) -4-
(aminomethyl) benzyl]benzamide trifluoroacetate salt :H nmr (d4 methanol) 8.21 (IH, m, Ar) ; 8.10 (IH, m, Ar) ; 7.90 (2H, d, =8.9Hz, Ar) ; 7.76 (2H, d, J=8.2Hz, Ar); 7.63 (2H, m, Ar) ; 7.48 (2H, d, J=8.2Hz, Ar) ; 7.30 (2H, m, Ar); 7.10-6.96 (6H, m, C-H, Ar) ; 4.41 (2H, m, CH2); 4.36 (2H, m, CH2); 4.09 (2H, s, CH2) • Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 4.63 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.45 mm, 538 (M+l)+.
Example 19 4-Amino-3-methyl-N- [alpha- (benzothiazol-2-oyl) -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt λR nmr (d4 methanol) 8.20 (IH, d, J=6.9Hz, Ar) ; 8.11 (IH, m, Ar) ; 7.75 (2H, d, J=8.1Hz, Ar) ; 7.63 (4H, m, Ar) ; 7.48 (2H, d, J=8.1Hz, Ar) ; 7.07 (IH, s, C-H); 6.77 (IH, d, J=8.2Hz, Ar) ; 4.09 (2H, s, 4-CH2); 2.21 (3H, s, Me). Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 3.54 mm.
Example 20
4-Methylsulfonyl-N- [alpha- (benzothiazol-2-oyl) -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt
XH nmr (d4 methanol) 8.20 (IH, m, Ar) ; 8.12 (5H, m, Ar) ; 7.77 (2H, d, =8.3Hz, Ar) ; 7.64 (2H, m, Ar) ; 7.50 (2H, d, J=8.3Hz, Ar) ; 7.14 (IH, s, C-H); 4.10 (2H, s, 4-CH2); 3.18 (3H, s, Me). Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 3.74 min, (Magellan C8, Gradient 1,
Water/acetonitrile/trifluoroacetic acid) rt 10.45 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.89 mm, 480 (M+l)+. Example 21
1-Acetyl-N- [alpha- (benzothiazol-2-oyl) -4-
(aminomethyl) benzyl] piperidin-4-amide trifluoroacetate salt 1H nmr (d4 methanol) 8.50 (2H, d, J=8.4Hz, Ar) ; 8.05 (2H, m, Ar) ; 7.56 (4H, m, Ar) ; 4.52 (IH, m, C-H); 4.23 (2H, s, CH2) ; 4.05 (IH, m, C-H); 3.38 (IH, m, C-H); 3.02 (IH, m, C-H); 2.26 (2H, m, 2C-H) ; 2.18 (3H, s, CH3) ; 1.94 (2H, m, 2C-H) ; 1.26 (2H, m, 2C-H) . Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 3.44 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.45 mm, 451 (M+l)+.
Example 22 2-{l- [2 (R) - (Acetylamino)propionyl] -N- [alpha- (benzothiazol-2- oyl) -4- (aminomethyl) benzyl] }pyrrolidinamide trifluoroacetate salt
Prepared from Ac-L-Ala-L-Pro . """H nmr (d4 methanol) 8.30 (4H, m, Ar) ; 7.71 (4H, m, Ar) ; 7.03 (IH, m, C-H); 4.72 (2H, m, 2C-H) ; 4.23 (2H, s, 4-CH2); 3.76 (2H, m, CH2) ; 2.19 (7H, m, CH3, 2CH2) ; 1.50 (3H, m, CH3) .
Example 23
2-{l-[2(S)- (Acetylamino)propionyl] -N- [alpha- (benzothiazol-2- oyl) -4- (aminomethyl) benzyl] }pyrrolidinamide trifluoroacetate salt
Prepared from Ac-D-Ala-L-Pro . λH nmr (d4 methanol) 8.02 (2H, m, Ar) ; 7.52 (4H, m, Ar) ; 7.35 (2H, m, Ar) ; 6.75 (IH, m, C-H); 4.47 (2H, m, 2C-H) ; 3.97 (2H, s, 4-CH2) ; 3.58 (2H, m, CH2); 1.91 (7H, m, CH3, 2CH2) ; 1.23 (3H, m, CH3) . Hplc (Luna7,
Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 3.24 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.58 mm, 508 (M+l)\
Example 24 2-{l- [2- (Thienylacetylamino)propionyl] -N- [alpha- (benzothiazol- 2-oyl) -4- (aminomethyl) benzyl] } -pyrrolidinamide trifluoroacetate salt
1R nmr (CDC13) 8.13-6.66 (14H, m, C-H, 2N-H, Ar); 4.75-4.42 (2H, m, 2C-H) ; 3.90-3.33 (6H, m, 3CH2); 2.20-1.92 (6H, m, 2CH2, NH2) ; 1.42-1.03 (3H, m, CH3) . Hplc (Luna7, Gradient 4,
Water/acetonitrile/trifluoroacetic acid) rt 3.82 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.73 mm, 590 (M+l)+.
Example 25
2-{l- [2- (Cyclopentanoylamino)propionyl] -N- [alpha- (benzothiazol- 2-oyl) -4- (aminomethyl) benzyl] } -pyrrolidinamide trifluoroacetate salt
1ti nmr (CDC13) 8.20 (2H, bs, NH2) ; 8.10 (2H, d, J=5.2Hz, Ar) ; 7.83 (2H, m, Ar) ; 7.43 (4H, m, Ar) ; 6.79 (IH, m) ; 6.68 (IH, d, J=5.6Hz, C-H); 4.63 (2H, m, 2C-H) ; 3.82-3.55 (4H, m, 2CH2) ; 2.60-1.05 (17H, m, Aliphatic, 2N-H) . Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 3.16 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.87 mm, 562 (M+l)+.
Example 26
2-{l- (Pyrrol-2-oyl) -N- [alpha- (benzothιazol-2-oyl) -4-
(aminomethyl) benzyl]}pyrrolidinamide trifluoroacetate salt XH nmr (d4 methanol) 8.12 (2H, m, Ar) ; 7.62 (4H, m, Ar) ; 7.45 (2H, m, Ar) ; 6.88 (3H, m, Ar) ; 6.25 (IH, s, C-H); 4.82 (IH, m, C-H); 4.07 (2H, s, CH2) ; 3.91 (2H, m, CH2); 2.05 (4H, m, 2CH2) . Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 3.80 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.78 mm, 488 (M+l)+.
Example 27
N- [alpha- (Benzothiazol-2-oyl) -4- (aminomethyl) benzyl] -3- Benzyloxycarbonylamino-6-methyl-2-pyridone-l-acetamide trifluoroacetate salt
XH nmr (d4 methanol) 8.46 (2H, d, J=8.4Hz, Ar) ; 8.05 (3H, m, Ar) ; 7.54 (5H, m, Ar) ; 7.37 (5H, m, Ar); 6.38 (IH, d, J=8.3Hz,
C-H); 5.64 (2H, s, CH2); 5.21 (2H, s, CH2); 4.19 (2H, s, CH2);
2.57 (3H, s, CH3) . Hplc (Luna7, Gradient 4,
Water/acetonitrile/trifluoroacetic acid) rt 4.44 mm. LC/MS
(Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.25 min, 596 (M+l)+.
Example 28
4-Methyl-N- [α- (benzothiazol-2-oyl) -4-
(aminomethyl) benzyl] benzenesulphonamide trifluoroacetate salt (i) Methyl 4- (BOC-aminomethyl) -α- [( -methyl) phenylsulfonyl- am o] phenylacetate
To a solution of methyl 4- (BOC-ammomethyl ) -α- aminophenylacetate (300 mg; 1.02 mmol) in pyridine (10 ml) was added tosyl chloride (214 mg; 1.12 mmol), and the reaction mixture was stirred for 18 hours. The pyridine was removed in va cuo and the reaction mixture partitioned between ethyl acetate (40 ml) and saturated citric acid solution (40 ml) . The organic layer was washed with 1M sodium bicarbonate solution (40 ml) and dried (MgS04) . Purification on silica gel afforded the sulfonamide (410 mg; 90%) as a white solid. λti nmr (d4 methanol) 7.54 (2H, d, J=8.1Hz, Ar) ; 7.16 (2H, d, J=8.1Hz, Ar); 7.07 (4H, s, Ar) ; 4.89 (IH, s, C-H); 4.06 (2H, s, 4-CH2) ; 3.37 (3H, s, OMe); 2.28 (3H, s, CH3) ; 1.33 (9H, s, cBu) . (11) 4-Methyl-[ - (benzothιazol-2-oyl ) -N- (4-BOC- ammomethyl ) benzyljbenzenesulfonamide
To a solution of benzothiazole (384 μl ; 3.5 mmol) in tetrahydrofuran (5 ml) at -78°C was added tbutyl lithium (2.07 ml of 1.7 m solution in pentane; 3.5 mmol) . After 15 minutes methyl 4- (BOC-ammomethyl) -α-
(4methyl) sulfonylammophenylacetate (410 mg; 0.92 mmol) in tetrahydrofuran (5 ml) was added dropwise over 20 minutes. After stirring for 3 hours saturated ammonium chloride solution (2 ml) was added dropwise and the reaction allowed to warm to room temperature. The reaction mixture was partitioned between ethyl acetate (50 ml) and saturated ammonium chloride solution (50 ml) and the organic layer dried (MgS04) . Purification on Biotage flash 40 afforded the ketone (110 mg; 22%) .
(m) 4-Methyl-N- [α- (benzothιazol-2-oyl) -4-
(aminomethyl ) benzyl] benzenesulphonamide trifluoroacetate salt
To a solution of 4-methyl-[α- (benzothιazol-2-oyl ) -N- (4-B0C- ammomethyl) benzyljbenzsulfonamide (110 mg; 0.2 mmol) in dichloromethane (10 ml) was added trifluoroacetic acid (5 ml). After 30 minutes the dichloromethane and trifluoroacetic acid were removed m vacuo . Purification by preparative hplc gave the desired compound (22 mg; 19%) .
XH nmr (d4 methanol) 8.26-8.23 (IH, m) ; 8.12-8.08 (IH, m) ; 7.73-7.61 (4H, m) ; 7.57 (2H, d) ; 7.41 (2H, d) ; 7.15 (2H, d) ; 6.56 (IH, s); 4.07 (2H, s); 2.29 (3H, s). Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 11.76 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.63 mm, 452 (M+l)+. Examples 29 to 33
Using methods similar to that described m Example 28, and starting from sulphonyl chlorides that were either commercially available or were prepared using literature procedures, the following compounds were prepared.
Example 29 2,4, 6-Trimethyl-N- [α- (benzothiazol-2-oyl) -4-
(aminomethyl) benzyl]benzenesulphonamide trifluoroacetate salt λti nmr (d4 methanol) 8.19 (IH, d, J=7.8Hz, Ar) ; 8.08 (IH, m, Ar) ; 7.65 (2H, m, Ar) ; 7.57 (2H, d, J=8.2Hz, Ar) ; 7.41 (2H, d,
J=8.3Hz, Ar) ; 6.71 (2H, s, Ar) ; 6.45 (IH, s, C-H); 4.07 (2H, s, 4-CH2) ; 2.62 (6H, s, 2CH3) ; 2.03 (3H, s, CH3) . Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 4.22 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.46 min, 480
(M+l)+.
Example 30
4-Isopropyl-N- [α- (benzothiazol-2-oyl) -4-
(aminomethyl)benzyl]benzensulphonamide trifluoroacetate salt XH nmr (d4 methanol) 8.02 (IH, m, Ar) ; 7.83 (IH, m, Ar) ; 7.45 (4H, m, Ar) ; 7.33 (2H, d, J=8.3Hz, Ar) ; 7.17 (2H, d, J=8.3Hz, Ar) ; 6.95 (2H, d, J=8.3Hz, Ar) ; 6.33 (IH, s, C-H); 3.82 (2H, s, 4-CH2) ; 2.60 (IH, m, 1PrC-H) ; 1.09 (6H, d, J=2.5Hz, 2CH3) . Hplc
(Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 4.24 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.27 mm, 480
(M+l)+.
Example 31 4-Phenyl-N- [ - (benzothιazol-2-oyl) -4- (aminomethyl) benzyl] - benzenesulphonamide trifluoroacetate salt
XH nmr (d4 methanol) 8.29(1H, m, Ar) ; 8.02 (IH, m, Ar) ; 7.87 (2H, m, Ar) ; 7.58 (6H, m, Ar) ; 7.43 (7H, m, Ar) ; 6.63 (IH, s, C-H); 4.02 (2H, s, 4-CH2). Hplc (Luna7, Gradient 4,
Water/acetonitrile/trifluoroacetic acid) rt 4.48 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.36 mm, 514 (M+l)+.
Example 32
4-Acetylammo-N- [ - (benzothιazol-2-oyl) -4- (aminomethyl) benzyl]benzenesulfonamide trifluoroacetate salt
1H nmr (d4 methanol) 8.19 (IH, d, J=7.9Hz, Ar) ; 8.03 (IH, d, =9.1Hz, Ar) ; 7.63 (4H, m, Ar) ; 7.47 (4H, m, Ar) ; 7.32 (2H, d, J=8.9Hz, Ar) ; 6.52 (IH, s, C-H); 3.99 (2H, s, 4-CH2) ; 2.08 (3H, s, CH3) . Hplc (MagellanC8, Gradient 1,
Water/acetonitrile/trifluoroacetic acid) rt 10.86 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.79 mm, 495 (M+l)+.
Example 33
N- [α- (Benzothιazol-2-oyl) -4- (aminomethyl) benzyl] naphth-2- ylsulphonamide tri luoroacetate salt
1R nmr (d4 methanol) 8.27-6.86 (15H, m, Ar) ; 6.07 (IH, s, C-H); 3.91 (2H, s, 4-CH2). Hplc (Luna7, Gradient 4,
Water/acetonitrile/trifluoroacetic acid) rt 3.93mm. LC/MS
(Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.79 mm, 488 (M+l)+.
Example 34
Methyl α-oxo-β-benzoylamino-4- (aminomethyl) -benzenepropionate trifluoroacetate salt
(l) Methyl 4- (BOC-ammomethyl) - -benzoylammophenylacetate To a solution of l-hydroxy-7-azabenzotπazole (153 mg; 1.12 mmol) m dimethylformamide (5 ml) at 0°C was added l-[3- (dimethylammo) propyl] -3-ethylcarbodιιmιde hydrochloride (215 mg; 1.12 mmol) . The reaction mixture was allowed to warm to room temperature over 30 minutes followed by the addition of benzoic acid (137 mg; 1.12 mmol) . After stirring for a further 30 minutes, methyl 4- (BOC-ammomethyl ) -α-ammophenylacetate (300 mg; 1.02 mmol) was added and the reaction stirred for 18 hours. The dimethylformamide was removed m va cuo and reaction mixture partitioned between ethyl acetate (40 ml) and saturated citric acid solution (40 ml) . The organic layer was washed with 1M sodium bicarbonate solution (40 ml) and dried (MgS04). Purification on silica gel afforded the amide (325 mg; 80%) as a white solid. XH nmr (CDC13) 7.84 (2H, m, Ar) ; 7.48 (5H, m, Ar) ; 7.31 (2H, m, Ar) ; 7.17 (IH, d, =6.9Hz, N-H); 5.78 (IH, d, J=6.9Hz, C-H); 4.86 (IH, bs, N-H); 4.33 (2H, d, J=5.9Hz, 4-CH2) ; 3.79 (3H, s, OMe) ; 1.47 (9H, s, fcBu) .
(n) α- [ (N-methyl-N-methoxy) amido] -4- [BOC (aminomethyl) ] -N- benzylbenzamide
To a solution of N, O-dimethylhydroxylamme hydrochloride (2.89 g; 0.03 mol) n anhydrous dichloromethane (200 ml) under argon at 0°C was added dimethylalummium chloride ( 1M solution hexane; 29.6 ml; 0.03 mol), dropwise from an addition funnel over 15 minutes. The reaction was stirred for 1 hour allowing the temperature to rise to room temperature. A solution of methyl 4- (BOC-ammomethyl) -α-benzoylammophenylacetate (2.27 g; 5.7 mmol) in anhydrous dichloromethane (50 ml) was then added dropwise and the resulting mixture stirred for 2 hours. Tris buffer (pH8.2; 30 ml; 50 mmol) was added and the aqueous layer extracted with dichloromethane (2x15 ml). The combined organic layers were dried (MgS0 ) . Purification on silica gel afforded the product (2.13 g; 88%) as a white solid. λH nmr (CDC13) 7.73 (2H, m, Ar); 7.36 (5H, m, Ar); 7.20 (2H, m, Ar) ; 6.08 (IH, d, J=7.2Hz, C-H); 4.83 (IH, bs, N-H); 4.22 (2H, d, J=5.8Hz, 4-CH2); 3.43 (3H, m, N-Me); 3.15 (3H, s, OMe); 1.37 (9H, s, lBu) .
(m) α-Carboxaldehydo-4- [BOC (aminomethyl) ] -N- benzylbenzamide To a solution of α- [ (N-methyl-N-methoxy) amiαo] -4-
[BOC (aminomethyl) ] -N-benzylbenzamide (730 mg; 1.68 mmol) in anhydrous tetrahydrofuran (40 ml) under argon at -78°C was added DIBAL-H (1M solution m toluene; 5.05 ml; 5.05 mmol) dropwise by syringe. The reaction was stirred for 1.5 hours and then quenched with Na2SO4.10H2O (1 g; 3.1 mmol) at -78°C. The mixture was stirred vigorously and allowed to warm to room temperature then filtered and reduced m va cuo to afford the product (586 mg; 93%) as a viscous yellow oil. XH nmr (CDC13) 9.55 (IH, s, C(O)-H); 7.77 (2H, m, Ar) ; 7.40 (4H, m, Ar) ; 7.34 (3H, s, Ar) ; 5.65 (IH, d, J=5.8Hz, C-H); 4.91
(IH, bs, N-H); 4.22 (2H, d, J=6.0Hz, 4-CH2); 1.37 (9H, s, ^u) .
(IV) α- [ l-Hydroxy-2-tπs ( ethylthiol) ethyl] -4- [BOC (aminomethyl) ] -N-benzylbenzamide
To a solution of tris (ethylthio) methane (670 μl; 3.47 mmol) 1n anhydrous tetrahydrofuran (10 ml) under argon at -78°C was added nBuLι (2.5M m hexane; 1.04 ml; 2.60 mmol) dropwise by syringe. After stirring for 1 hour, α-carboxaldehydo-4- [BOC (aminomethyl) ] -N-benzylbenzamide (160 mg; 0.43 mmol) tetrahydrofuran (5 ml) was added dropwise over 5 minutes. The reaction was stirred for 2 hours at -78°C and then warmed to - 45°C for a further 2 hours before being quenched with saturated aqueous ammonium chloride solution (2 ml) and allowed to warm to room temperature. Diethyl ether (10 ml) was added and the organic layer washed with brine (10 ml) and dried (MgS04) . 5 Purification on silica gel afforded the product (68 mg; 38%) as a viscous yellow oil.
XH nmr (CDC13) 7.81 (2H, m, Ar) ; 7.61 (IH, d, J=7.4Hz, Ar) ; 7.44-7.33 (5H, m, Ar) ; 7.17 (IH, s, Ar); 5.52 (IH, d, J=7.3Hz, C-H); 4.72 (IH, bs, N-H); 4.21 (2H, d, J=5.8Hz, 4-CH2); 3.91 10 (IH, s, C-H); 2.74 (6H, m, 3CH2) ; 1.38 (9H, s, tBu) ; 1.13 (9H, t, J=7.5Hz, 3CH3) .
(v) Methyl α-hydroxy-β-benzoylammo-4- (BOC (aminomethyl )) - benzenepropionate
15 To a solution of α- [l-hydroxy-2-tπs (ethylthiol ) ethyl] -4- [BOC (aminomethyl) ] -N-benzylbenzamide (68 mg; 0.12 mmol) in methanol (2 ml) and water (200 μl) was added mercury (II) oxide (24 mg; 0.11 mmol) and mercury ( II ) chloride (85 mg; 0.31 mmol). The resulting mixture was stirred at room temperature for 4
20 hours then filtered through celite, the pad was washed with methanol (1 ml) and dichloromethane (2x2 ml) . Water (5 ml) and dichloromethane (5 ml) were added to the filtrate and the layers separated. The aqueous layer was washed with dichloromethane (3x5 ml) and the combined organics washed with
25 70% aqueous ammonium acetate (10 ml) which was then re- extracted with dichloromethane (3x5 ml) and the combined organics washed with concentrated aqueous ammonium chloride solution (5 ml), dried (MgS04) and reduced m va cuo to afford the product (52 mg; 100%) as a gum.
30 XH nmr (CDC13) 7.69 (2H, d, J=8.2Hz, Ar) ; 7.44-7.0 (7H, m, Ar) ; 5.64 (IH, d, J=8.9Hz, C-H); 4.82 (IH, bs, N-H); 4.53 (IH, s, C- H) ; 4.20 (2H, d, J=5.7Hz, 4-CH2) ; 3.76 (3H, s, OMe); 1.38 (9H, s, tBu ) . (vi) Methyl α-oxo-β-benzoylammo-4- (BOC (aminomethyl )) - benzenepropionate
To a solution of methyl-α-hydroxy-β-benzoylamιno-4- (BOC (aminomethyl )) -benzenepropionate (52 mg; 0.12 mmol) in dichloromethane (5 ml) was added Dess-Martin Reagent (67 mg; 0.16 mmol) . The reaction was stirred for 45 minutes then diethyl ether (10 ml), 1M sodium bicarbonate solution (5 ml) and sodium thiosulfate (0.5 g) were added and the reaction stirred vigorously. The reaction was further diluted with diethyl ether (10 ml) and water (5 ml) and the organic layer washed with 1M sodium bicarbonate solution (5 ml), water (2x5 ml) . dried (MgS0 ) and reduced m va cuo to afford the product (44 mg; 85%) as a pale yellow solid. XH nmr (CDC13) 7.73 (2H, m, Ar) ; 7.47-7.11 (7H, m, Ar) ; 6.38 (IH, d, J=6.3Hz, C-H); 4.86 (IH, bs, N-H); 4.22 (2H, d, J=5.7Hz, 4-CH2) ; 3.74 (3H, s, OMe); 1.38 (9H, s, tBu) .
(vii) Methyl α-oxo-β-benzoylamino-4- (aminomethyl) - benzenepropionate trifluoroacetate salt
To a solution of methyl-α-oxo-β-benzoylammo-4-
(BOC (aminomethyl) ) benzenepropionate (23 mg; 0.054 mmol) m dichloromethane (1 ml) was added trifluoroacetic acid (1 ml) .
The reaction was stirred or 50 minutes and then reduced m va cuo and purified by preparative hplc to afford the product
(5.4 mg; 23%) .
XH nmr (D20) 7.50 (2H, m, Ar) ; 7.41-7.23 (7H, m, Ar) ; 5.26 (IH, s, C-H); 3.97 (2H, s, 4-CH2) ; 3.57 (3H, s, OMe). Hplc (Luna7,
Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 2.49 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.21 min, 310 (M+l-
NH3)+. Example 35
1- [2- (Cyclopentanoylamino)propionyl] -N- (4- (aminomethyl) benzyl) -
2-pyrrolidinamide trifluoroacetate salt
(l) N- [ 4-BOC (aminomethyl) benzyl] -1- (2-ammopropιonyl) -2- pyrrolidmamide was prepared using standard peptide coupling procedures from Mono-BOC-1, 4-bιs (aminomethyl) benzene which was prepared as described in the literature { J. Med. Chem, 1989, 32, 391-396) .
(n) To a solution of l-hydroxy-7-azabenzotπazole (36 mg; 0.26 mmol) in dimethylformamide (5 ml) at 0°C was added l-[3- (dimethylammo) propyl] -3-ethylcarbodιιmιde hydrochloride (50 mg; 0.26 mmol), the reaction mixture was allowed to warm to room temperature over 30 minutes followed by addition of cyclopentanecarboxylic acid (28.2 μl; 0.26 mmol). After stirring for a further 30 minutes N- [4-BOC (aminomethyl) benzyl] - 1- (2-ammopropιonyl) -2-pyrrolιdmamιde (87 mg; 0.22 mmol) was added and the reaction stirred for 18 hours. The dimethylformamide was removed m va cuo and reaction mixture partitioned between ethyl acetate (40 ml) and saturated citric acid solution (40 ml) . The organic layer was washed with 1M sodium bicarbonate solution (40 ml) and dried (MgS0 ) . The solvent was removed m va cuo and the product dissolved in anhydrous dichloromethane (10 ml) and trifluoroacetic acid (5 ml) was added. After 1 hour the solvent was removed m va cuo and the residue purified by preparative chromatography to give the product (72 mg; 64%) as a white solid. λH nmr (d4 methanol) 7.31 (4H, s, Ar) ; 4.50 (IH, m, C-H); 4.35 (3H, m, CH2, C-H); 4.00 (2H, s, CH2) ; 3.74 (IH, m, C-H); 3.58 (IH, m, C-H); 2.60 (IH, m, C-H); 2.14-1.49 (12H, m, Aliphatic); 1.25 (3H, d, J=7.0Hz, CH3) . Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 7.46 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.50 mm, 401 (M+l)+.
Examples 36 to 48 The following compounds were prepared following the method of Example 35.
Example 36
1- [2- (Cyclohexylacetylamino)propionyl] -N- (4- (aminomethyl) benzyl) -2-pyrrolidinamide trifluoroacetate salt
XH nmr (d4 methanol) 7.37 (4H, s, Ar) ; 5.48 (IH, s, C-H); 4.58 (IH, q, J=7.0Hz, C-H); 4.42 (2H, m, CH2); 4.07 (2H, s, CH2); 3.84 (IH, m, C-H); 3.65 (IH, m, C-H); 2.26-1.90 (6H, m, Aliphatic); 1.69 (6H, m, Aliphatic); 1.32 (3H, d, J=7.0Hz, CH3) ; 1.27-0.94 (5H, m, Aliphatic). Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 8.48 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.64 mm, 429 (M+l)+.
Example 37
1- [2- (Thienoylamino)propionyl] -N- (4- (aminomethyl) benzyl) -2- pyrrolidinamide trifluoroacetate salt
XH nmr (d4 methanol) 7.82 (IH, m, Ar) ; 7.69 (IH, m, Ar) ; 7.42 (4H, s, Ar); 7.16 (IH, m, Ar) ; 4.81 (IH, m, C-H); 4.47 (3H, m, CH2, C-H); 4.10 (2H, s, CH2) ; 3.92 (IH, m, C-H); 3.74 (IH, m, C-H); 2.28-1.95 (4H, m, 2CH2); 1.48 (3H, d, J=7.0Hz, CH3) . Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 7.54 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.30 mm, 415 (M+l)+.
Example 38 1- [2- (Thenoylamino)propionyl] -N- (4- (aminomethyl) benzyl) -2- pyrrolidinamide trifluoroacetate salt λH nmr (d4 methanol) 7.31 (4H, m, Ar) ; 7.18 (IH, m, Ar) ; 6.86 (2H, m, Ar) ; 4.50 (IH, q, J=7.1Hz, C-H); 4.34 (3H, m, CH2, C- H) ; 4.00 (2H, s, CH2); 3.67 (3H, m, CH2, C-H); 3.54 (IH, m, C-
H) ; 2.13 (IH, m, C-H); 1.86 (3H, m, CH2, C-H); 1.27 (3H, d,
J=7.0Hz, CH3) . Hplc (Magellan C8, Gradient 1,
Water/acetonitrile/trifluoroacetic acid) rt 7.65 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 0.58 min, 429 (M+l)+.
Example 39
1- [2- (p-Hydroxyphenylacetylamino)propionyl] -N- (4-
(aminomethyl) benzyl) -2-pyrrolidinamide trifluoroacetate salt λH nmr (d4 methanol) 7.41 (4H, s, Ar) ; 7.11 (2H, d, J=8.5Hz, Ar) ; 6.74 (2H, d, J=8.5Hz, Ar) ; 4.61 (IH, m, C-H); 4.43 (3H, m,
CH2, C-H); 4.11 (2H, s, CH2); 3.77-3.60 (2H, m, CH2); 3.45 (2H, s, CH2); 2.24-1.90 (4H, m, 2CH2) ; 1.36 (3H, d, J=7.0Hz, CH3) .
Hplc (Magellan C8, Gradient 1,
Water/acetonitrile/trifluoroacetic acid) rt 7.10 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.06 min, 439 (M+l)+.
Example 40
1- [2- (Benzenesulfonylamino)propionyl] -N- (4- (aminomethyl) benzyl) -2-pyrrolidinamide trifluoroacetate salt
XH nmr (d4 methanol) 8.00 (2H, m, Ar) ; 7.75 (3H, , Ar) ; 7.53 (4H, m, Ar) ; 4.52 (2H, m, CH2) ; 4.32 (IH, q, J=6.8Hz, C-H);
4.24 (2H, s, CH2) ; 4.19 (IH, m, C-H); 3.72 (2H, m, CH2) ; 2.22-
1.97 (4H, m, 2CH2); 1.38 (3H, d, J=6.9Hz, CH3) . Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt
8.05 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.54 min, 445 (M+l)+. Example 41
1- [2- (Benzylsulfonylamino)propionyl] -N- (4- (aminomethyl) benzyl) -
2-pyrrolidinamide trifluoroacetate salt XH nmr (d4 methanol) 7.60 (9H, m, Ar) ; 4.62 (3H, m, CH2, C-H); 4.56 (2H, s, CH2); 4.31 (2H, s, CH2) ; 4.11 (IH, m, C-H); 3.63 (2H, m, CH2) ; 2.42 (IH, m, C-H); 2.17 (3H, m, CH2, C-H); 1.46 (3H, d, J=6.9Hz, CH3) . Hplc (Magellan C8, Gradient 1, Water/acetonitrile/trifluoroacetic acid) rt 8.34 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.59 min, 459 (M+l)+.
Example 42
N- [4- (Aminomethyl) benzyl] -3-Benzyloxycarbonylamino-6-methyl-2- pyridone-1-acetamide trifluoroacetate salt
1H nmr (d4 methanol) 7.95 (IH, d, J=6.8Hz, Ar) ; 7.37 (9H, m, Ar) ; 6.27 (IH, d, J=7.7Hz, Ar) ; 5.21 (2H, s, CH2) ; 4.88 (2H, s, CH2) ; 4.45 (2H, m, CH2) ; 4.10 (2H, s, CH2) ; 2.34 (3H, s, CH3) . Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 3.56 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.73 min, 435 (M+l)+.
Example 43 N- [4- (Aminomethyl) benzyl] -3-acetylamino-6-methyl-2-pyridone-l- acetamide trifluoroacetate salt lR nmr (d4 methanol) 8.34 (IH, d, J=7.7Hz, Ar) ; 7.57 (4H, m, Ar) ; 6.40 (IH, d, =7.8Hz, Ar) ; 5.05 (2H, s, CH2) ; 4.60 (2H, s, CH2); 4.25 (2H, s, CH2) ; 2.49 (3H, s, CH3) ; 2.32 (3H, s, CH3) . Hplc (Luna7, Gradient , Water/acetonitrile/trifluoroacetic acid) rt 1.05 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 0.42 min, 343 (M+l)+. Example 44
N- [4- (Aminomethyl) benzyl] -3-Benzyloxycarbonylamino-6- cyclohexylmethyl-2-pyridone-l-acetamide trifluoroacetate salt XH nmr (CDC13) 7.88 (4H, m, 3N-H, Ar) ; 7.54 (IH, bs, N-H); 7.29 (5H, m, Ar) ; 7.02 (4H, s, Ar) ; 6.05 (IH, d, J=7.5Hz, Ar) ; 5.11 (2H, s, CH2); 4.52 (2H, s, CH2); 4.15 (2H, s, CH2); 3.68 (2H, s, CH2) ; 2.42 (2H, d, J=6.8Hz, CH2) ; 1.63 (4H, m, 2CH2) ; 1.40 (IH, m, C-H); 1.14 (4H, m, 2CH2) ; 0.87 (2H, m, CH2) . Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 4.37 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.43 min, 517 (M+l)+.
Example 45
4-Methyl-N- [4- (aminomethyl) benzyl]benzenesulphonamide trifluoroacetate salt
XH nmr (d4 methanol) 7.86 (2H, d, J=8.3Hz, Ar) ; 7.48 (6H, m, Ar) ; 4.19 (2H, s, CH2) ; 4.16 (2H, s, CH2) ; 2.55 (3H, s, CH3) . Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 3.24 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.74 min, 291 (M+l)+.
Example 46
2,4, 6-Trimethyl-N- [4- (aminomethyl)benzyl]benzenesulphonamide trifluoroacetate salt
XH nmr (d4 methanol) 7.34 (4H, m, Ar) ; 7.02 (2H, s, Ar) ; 4.08 (4H, s, 2CH2) ; 2.61 (6H, s, 2CH3) ; 2.31 (3H, s, CH3) . Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 3.67 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.83 min, 319 (M+l)+. Example 47
4-Phenyl-N- [4- (aminomethyl) benzyl] benzenesulphonamide trifluoroacetate salt lti nmr (d4 methanol) 7.95 (2H, d, J=8.5Hz, Ar) ; 7.76 (2H, d,
J=8.6Hz, Ar) ; 7.65 (2H, d, J=8.0Hz, Ar) ; 7.49 (3H, m, Ar) ; 7.35 (4H, s, Ar) ; 4.14 (2H, s, CH2); 4.02 (2H, s, CH2). Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 3.95 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.32 min, 353 (M+l)+.
Example 48
4-Acetylamino-N- [4- (aminomethyl) benzyl] benzenesulphonamide trifluoroacetate salt λR nmr (d4 methanol) 7.74 (4H, m, Ar) ; 7.35 (4H, s, Ar) ; 4.08 (2H, s, CH2) ; 4.07 (2H, s, CH2); 2.17 (3H, s, CH3). Hplc (Luna7, Gradient 4, Water/acetonitrile/trifluoroacetic acid) rt 2.60 min. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 1.45 min, 334 (M+l)+.
Example 49
N- [α- ( (6-Benzylamido)benzothiazol-2-oyl) -4- (aminomethyl) benzyl]benzamide trifluoroacetate salt
(i) N-benzyl-benzothiazole-6-carboxamide
To a solution of benzothiazole-6-carboxylic acid (1.0 g; 5.6 mmol) in anhydrous dichloromethane (5 ml) was added l-[3- (dimethylamino) propyl] -3-ethylcarbodiimide hydrochloride (1.17 g; 6.1 mmol) and benzylamine (0.66 g; 6.1 mmol) . The resulting reaction mixture was stirred at room temperature for 18 hours. Water (5 ml) and ethyl acetate (10 ml) were added, the white precipitate was filtered off and the filtrate layers were separated. The organic layer was washed with water (10 ml), brine (10 ml) and dried (MgS04). Evaporation afforded the product as a yellow solid which was combined with the white precipitate collected earlier and recrystallised from ethyl acetate and hexane to afford the product as pale yellow crystals (540 mg; 36%) . λ nmr (d4methanol) 9.25 (IH, s, Ar) ; 8.46 (IH, s, Ar) ; 8.01 (IH, d, J=8.7Hz, Ar) ; 7.90 (IH, d, J=8.6Hz, Ar) ; 7.19 (5H, m, Ar) ; 4.50 (2H, s, CH2) .
(n) N- [α- (6-Benzylamιdobenzothιazol-2-oyl) -4- (BOC- ammomethyl ) benzyl ] benzamide To a solution of N-benzyl-benzothιazole-6-carboxamιde (540 mg; 2.01 mmol) m anhydrous tetrahydrofuran (20 ml) at -78°C under argon was added tbutyl lithium (3.35 ml of 1.7m solution in pentane; 5.7 mmol) dropwise. After 10 minutes a solution of methyl 4- (BOC-ammomethyl) -α-benzoylammophenylacetate (229 mg; 0.57 mmol) in anhydrous tetrahydrofuran (5 ml) was added by cannula. The reaction was stirred for 45 minutes and then saturated aqueous ammonium chloride solution (5 ml) was added and the reaction allowed to warm to room temperature. Ethyl acetate (35 ml) and water (10 ml) were added and the layers separated, the organic layer was washed with saturated aqueous ammonium chloride solution (5 ml), water (5 ml) and brine (5 ml) and dried (MgS04) . Purification on silica gel gave the crude product as a yellow solid (111 mg; 30%) .
(m) N- [α- ( ( 6-Benzylamιdo) benzothιazol-2-oyl) -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt
To a solution of N- [α- ( ( 6-Benzylamιdo) benzothιazol-2-oyl) -4-
(BOC-aminomethyl) benzyl] benzamide (100 mg; 0.16 mmol) in anhydrous dichloromethane (5 ml) was added trifluoroacetic acid (2 ml) . After 1 hour the dichloromethane and trifluoroacetic acid were removed m vacuo . Dichloromethane (10 ml) and water
(10 ml) were added and the layers separated, the organic layer was washed with 5% aqueous hydrochloric acid solution (2x10 ml) and the combined aqueous layers washed with dichloromethane (10 ml) . The aqueous layers were purified by preparative hplc to give the desired compound (2 mg; 2%) as a white solid. XH nmr (d4methanol) 8.48 (IH, d, J=1.4Hz, Ar) ; 8.14 (IH, d, J=8.7Hz, Ar) ; 7.99 (3H, m, Ar) ; 7.77 (2H, m, Ar); 7.65 (2H, d, J=7.9Hz, Ar) ; 7.47-7.16 (8H, m, Ar) ; 6.98 (IH, s, C-H); 4.51
(2H, s, CH2) ; 3.98 (2H, s, CH2) .
Example 50
N- [alpha- (6- (Benzoylamino)benzothiazol-2-oyl) -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt
(i) 6-Aminobenzothiazole
To a solution of 6-nitrobenzothiazole (1 g; 5.6 mmol) in ethanol (10 ml) was added 5% palladium on charcoal (catalytic) . The reaction was put under a hydrogen atmosphere and stirred for 20 hours. The suspension was filtered through celite and washed through with ethanol (2x10 ml). The filtrate was reduced in va cuo and purified on silica gel to afford the product (770 mg; 92%) as a yellow crystalline solid. λH nmr (CDC13) 8.62 (IH, s, Ar) ; 7.81 (IH, d, J=8.7Hz, Ar) ; 7.08 (IH, d, J=2.4Hz, Ar) ; 6.80 (IH, m, Ar) ; 3.80 (2H, bs, NH2) .
(ii) 6- ( Benzoylamino) benzothiazole To a solution of benzoic acid (860 mg; 6.67 mmol) in dichloromethane (20 ml) was added 1- [3- (dimethylamino) propyl] - 3-ethylcarbodiimide hydrochloride (1.28 g; 6.67 mmol) and 6- aminobenzothiazole (1 g; 6.67 mmol). The reaction was stirred for 20 hours then ethyl acetate (20 ml) and brine (20 ml) were added. The organic layer was washed with brine (20 ml), 1M sodium bicarbonate solution (20 ml), dried (MgS04) and reduced in va cuo . The crude product was purified by recrystallisation from ethyl acetate to give the product (770 mg; 45%) as white crystals . λR nmr (d^methanol) 9.19 (IH, s, Ar) ; 8.64 (IH, d, J=2.0Hz, Ar) ; 8.02 (3H, m, Ar) ; 7.79 (IH, m, Ar) ; 7.57 (3H, m, Ar) .
(m) N- [α- ( 6- (Benzoylammo) benzothιazol-2-oyl) -4- (BOCaminomethyl) benzyl] benzamide
To a solution of 6- (Benzoylammo) benzothiazole (770 mg; 3.03 mmol) m dry tetrahydrofuran (20 ml) under argon at -78 °C was added fcbutyl lithium (3.6 ml of 1.7m solution m pentane; 6.06 mmol) dropwise. After stirring for 30 minutes at -78°C methyl 4- (BOC-ammomethyl ) - -benzoylammophenylacetate (327 mg; 0.82 mmol) m tetrahydrofuran (10 ml) was added dropwise over 20 minutes. After stirring for 2 hours at -78°C, saturated ammonium chloride solution (3 ml) was added dropwise and the reaction allowed to warm to room temperature. Ethyl acetate (30 ml) and saturated ammonium chloride solution (30 ml) were added ana the organic layer washed with water (30 ml), brine (30 ml) and dried (MgS04) . Purification on silica gel gave the crude product (108 mg; 21%) . XH nmr (d4methanol) 8.67-7.32 (17H, m, Ar) ; 5.51 (IH, s, C-H); 4.20 (2H, s, CH2); 1.43 (9H, s, ^u) .
(IV) N- [alpha- ( 6- (Benzoylammo) benzothιazol-2-oyl) -4- ( aminomethyl) benzyl] benzamide trifluoroacetate salt To a solution of N- [alpha- ( 6- (Benzoylammo) benzothιazol-2-oyl) - 4- (BOCam omethyl) benzyl] benzamide (108 mg; 0.17 mmol) in anhydrous dichloromethane (5 ml) was added trifluoroacetic acid (2 ml) and the reaction stirred for 1 hour then reduced m va cuo . The crude product was purified on silica gel to afford the product (53 mg; 49%) .
1H nmr (d6dmso) 9.02 (IH, d, J=1.9Hz, Ar) ; 8.42 (3H, m, Ar); 8.13 (5H, m, Ar) ; 7.85-7.64 (8H, m, Ar) ; 7.11 (IH, m, C-H); 4.20 (2H, d, J=4.9Hz, CH2). Hplc (Luna7, Gradient 4,
Water/acetonitrile/trifluoroacetic acid) rt 4.07 mm. LC/MS (Magellan C18 Gradient 2, water/acetonitrile/trifluoroacetic acid) rt 2.18 mm, 521 (M+l)+.
Example 51
N- [4- (Aminomethyl) benzyl] -6- (naphth-2-yl-methyl) -2 ,5-dioxo-3- piperazineacetamide trifluoroacetate salt
(l) β- (Benzyloxycarbonyl ) ammo-2-naphthalene propanoic acid To a solution of D-naphthylalanme (500 mg; 2.33 mmol) m dioxan and water was added benzylchloroformate (437 mg; 2.56 mmol) and sodium hydroxide (2.56 ml; 1M aqueous solution) . The reaction mixture was stirred overnight and then reduced m va cuo . Ethyl acetate (30 ml) and saturated aqueous citric acid solution (30 ml) were added, the organic layer was washed with brine (30 ml) then dried (MgS0 ) and evaporated to give the product (385 mg; 47%) .
(n) N- [ (l-methoxycarbonyl-2-tbutoxycarbonyl) ] ethyl-β- (Benzyloxycarbonyl) ammo-2-naphthalene propanamide
To a solution of β- (Benzyloxycarbonyl) ammo-2-naphthalene propanoic acid (385 mg; 1.10 mmol) m dimethylformamide (10 ml) was added diisopropylethylamme (300 mg; 2.32 mmol), HOBT (164 mg; 1.21 mmol), TBTU (390 mg; 1.21 mmol) and Asp(OtBu)OMe (246 mg; 1.21 mmol) . The reaction was stirred overnight and reduced m va cuo . Ethyl acetate (30 ml) and saturated aqueous citric acid solution (30 ml) were added, the organic layer was washed 1M sodium bicarbonate solution (30 ml) then dried (MgS04) and evaporated to give the product.
(m) N- [ ( l-methoxycarbonyl-2-tbutoxycarbonyl ) ] ethyl-β- ammo-2-naphthalene propanamide
To a solution of N- [ ( l-methoxycarbonyl-2- tbutoxycarbonyl ) ] ethyl-β- (Benzyloxycarbonyl) ammo-2-naphthalene propanamide in methanol (10 ml) was added 5% palladium on charcoal in water (5 ml) . The reaction was put under a hydrogen atmosphere and stirred for three days then filtered through celite, washed through with methanol (3x20 ml) and water (2x20 ml) and reduced in va cuo to afford the product.
(IV) tButyl-6- (naphth-2-yl-methyl) -2, 5-dιoxo-3- piperazmeacetate
A solution of N- [ ( l-methoxycarbonyl-2-tbutoxycarbonyl) ] ethyl-β- ammo-2-naphthalene propanamide m methanol (20 ml) was heated at reflux overnight and then reduced m vacuo to afford the product .
(v) 6- (naphth-2-yl-methyl) -2, 5-dιoxo-3-pιperazmeacetιc acid To a solution of tButyl 6- (naphth-2-yl-methyl) -2 , 5-dιoxo-3- piperazmeacetate in dichloromethane (5 ml) was added trifluoroacetic acid (1 ml) and the reaction stirred for 2 hours. The reaction mixture was evaporated to afford the product (100 mg; 29% over 4 steps) .
(vi) N- [4- (Aminomethyl) benzyl] -6- (naphth-2-yl-methyl ) -2, 5- dιoxo-3-pιperazmeacetamιde trifluoroacetate salt To a solution of 6- (naphth-2-yl-methyl) -2 , 5-dιoxo-3- piperazmeacetic acid (50 mg; 0.16 mmol) in dimethylformamide (2 ml) was added TBTU (52 mg; 0.16 mmol), tπethylamme (45 μl; 0.32 mmol) and p-xylenediamme (already attached to 2- chlorotπtylchloride resm (1.05 mmol/g) following literature procedures, 31 mg; 0.032 mmol) . The reaction was stirred overnight and then the resm washed with dimethylformamide (3x10 ml), dichloromethane (3x10 ml), dimethylformamide (3x10 5 ml) and dichloromethane (3x10 ml) . The resm was then taken up in trifluroacetic acid (10 ml), water (1 ml) and triethylsilane (50 μl) and left for 1 hour then filtered and evaporated. Purification by preparative hplc gave the product (17 mg; 12%). XH nmr (d4methanol) 7.89-7.31 (11H, m, Ar) ; 4.67 (2H, m, 2C-H) ; 10 4.31 (2H, m, CH2) ;
4.09 (2H, s, CH2) ; 3.42-2.53 (4H, m, 2CH2).
Example 52
N- [4- (Aminomethyl)benzyl] -6- (3-chlorobenzyl) -2 , 5-dιoxo-3- 15 piperaz neacetamide trifluoroacetate salt
The title compound was made using the route of Example 51. XH nmr (d4methanol) 7.29 (8H, m, Ar) ; 4.91-4.23 (4H, m, CH2, 2C-H) ; 4.11 (2H, d, J=1.9Hz, CH2) ; 3.52-2.50 (4H, m, 2CH2) .
20 Examples 53 to 73 General Experimental
Analytical HPLC's were performed on a Shimadzu LC6 gradient system equipped with an autosampler. Eluant A consisted of aqueous TFA (0.1 %) and eluant B consisted of 90 % acetonitπle
25 and 10 % water, containing TFA (0.1 %) . Gradient 1 elution began at 5 % B and increased to 100 % B over seven minutes. Gradient 2 elution began at 5 % B and increased to 100 % B over ten minutes. Gradient 3 elution began at 5 % B for one minute, increasing to 20 % B after the fourth minute, 40 % B after the
30 14th minute and then 100 % B after the 15th minute. Gradient 5 elution began at 5 % B and increased to 100 % B over 15 mms . The columns used were Luna 2 C18 (3 μ, 30 mm x 4.6 mm), Luna 2 C18 (5 μ, 150 mm x 2 mm) , a Symmetry Rp8 (3.5 μ, 50 x 2.1 mm) and a Jupiter 018 (2 mm x 150mm) .
LC/MS were performed on a PESCIEX single quadrupole API-150EX 5 instrument, equipped with a Luna 2 C18 column (3 μ, 30 mm x 4.6 mm) elutmg with 20 % to 100 % acetonitπle m water over five minutes (Gradient 4).
The following examples were prepared as described for Example 10 49.
Example 53
N- [a- ( (6- (4-Tolyl)methylamido)benzothiazol-2-oyl) -4-
(aminomethyl) benzyl] benzamide trifluoroacetate salt.
15 XH NMR (CDC13) : 8.70 ppm (1 H, s, benzothiazole C(7)H); 8.38 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 8.21 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 8.03 (2 H, d, J = 10 Hz, 4-ammomethylρhenyl C(2)H/C(6)H or C (3) H/C ( 5) H) ; 7.89 (2 H, d, J = 10 Hz, Ar) ; 7.70 (1 H, d, J = 8 Hz, Ph) ; 7.63 (4 H, t, J = 0 8 Hz, Ph) ; 7.40 (2 H, d, J = 9 Hz, Tolyl C(2)H/C(6)H or C(3)H/C(5)H) ; 7.30 (2 H, d, J = 9 Hz, Tolyl C(2)H/C(6)H or C(3)H/C(5)H) ; 7.20 (1 H, s, ArCH (N) C (0) ) ; 4.70 (2 H, s, CH2Tol); 4.22 (2 H, s, CH2NH2); 2.45 (3 H, s, CH3). 5 HPLC (Luna 2, Gradient 1): rt = 4.33 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.37 minutes, 549 (MH)+.
Example 54 0 N- [α- (6- (Cyclohexylmethylamido)benzothiazol-2-oyl-4- (aminomethyl) benzyl] benzamide trifluoroacetate salt. λR NMR (CDCI3) : 8.43 ppm (1 H, s, benzothiazole C(7)H); 8.12 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 7.92 (IH, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 7.77 (2 H, d, J = 10 Hz, -ammomethylphenyl C(2)H/C(6)H or C ( 3) H/C (5 ) H) ; 7.63 (2 H, d, J = 10 Hz, 4-aminomethylphenyl C(2)H/C(6)H or C ( 3 ) H/C (5 ) H) ; 7.50 - 7.35 (5 H, m, Ar) ; 6.97 (1 H, s, ArCH (N) C (0) ) ; 3.97 (2 H, s, CH2NH2); 1.76 - 1.48 (6 H, m, cHex) ; 1.26 - 1.05 (3 H, m, cHex) ; 1.01 - 0.82 (2 H, m, cHex) .
HPLC (Luna 2, Gradient 1): rt = 4.43 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.42 minutes, 542 (MH)+.
Example 55
N- [a- ( 6- (Phenylamido) benzothiazol-2 -oyl) -4-
(aminomethyl) benzyl]benzamide trifluoroacetate salt .
λR NMR (CDC13) : 8.58 ppm (1 H, s, benzothiazole C(7)H); 8.30 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 8.17 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 7.85 (2 H, d, J = 10 Hz, 4-aminomethylphenyl C(2)H/C(6)H or C (3) H/C (5) H) ; 7.76 (2 H, d, J = 10 Hz, 4-aminomethylphenyl C(2)H/C(6)H or C (3) H/C (5) H) ; 7.57 (3 H, m, Ph) ; 7.40 (2 H, t, J = 1 Hz, Ph) ; 7.30 (2 H, m, Ph) ; 7.20 (1 H, t, J = 7 Hz, Ph) ; 5.83 (1 H, s, ArCH (N) C (0) ) ; 4.04 (2 H, s, CH2NH2) .
HPLC (Luna 2, Gradient 1): rt = 4.27 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.26 minutes, 521 (MH)+.
Example 56 N- [a- ( (6- (3-Methylbenzyl) amido) benzothiazol-2-oyl) -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt. XH NMR (CDCI3) : 8.53 ppm (1 H, s, benzothiazole C(7)H); 8.20 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 8.01 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 7.82 (2 H, d, J = 10 Hz, 4-aminomethylphenyl C(2)H/C(6)H or C ( 3) H/C ( 5 ) H) ; 7.68 (2 H, d, J = 10 Hz, 4-aminomethylphenyl C(2)H/C(6)H or C ( 3 ) H/C (5) H) ;
7.55 - 7.41 (6 H, m, Ar) ; 7.15 (4 H, m, Ar); 7.02 (2 H, s, Ar); 4.52 (2 H, s, CH2NH) ; 4.03 (1 H, s, CH2NH2); 2.28 (3 H, s, CH3).
HPLC (Luna 2, Gradient 1): rt = 4.37 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.37 minutes, 550 (MH)+.
Example 57
N- [a- [6- (J?) - (Indan-l-amido)benzothiazol-2-oyl] -4- (aminomethyl)benzyl benzamide trifluoroacetate salt.
XR NMR (CDCI3) : 8.48 ppm (1 H, s, benzothiazole C(7)H); 8.15 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 7.97 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 7.75 (2 H, d, J = 10 Hz, 4-aminomethylphenyl C(2)H/C(6)H or C (3) H/C (5) H) ; 7.60 (2 H, d, J = 10 Hz, 4-aminomethylphenyl C(2)H/C(6)H or C ( 3 ) H/C ( 5) H) ; 7.5 - 7.3 (4 H, m, Ar) ; 7.25 - 7.05 (4 H, m, Ar) ; 6.96 (1 H, s, Ar) ; 5.55 (1 H, m, ArCH (N) C (0) ) ; 3.95 (1 H, s, CH2NH2); 2.95 (1 H, m, indane C(l)H); 1.92 (2 H, m, indane C(3)H2); 1.20 (2 H, m, indane C (2 ) H2) .
HPLC (Luna 2, Gradient 1): rt = 4.43 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.48 minutes, 562 (MH)+.
Example 58
N- [α- (6- (2-Fluorobenzylamido)benzothiazol-2-oyl) -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt. τR NMR (CDCI3) : 8.48 ppm (1 H, s, Ar); 8.15 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 7.97 (1 H, d, J = 9 Hz, benzothiazole C(4)H or C(5)H); 7.78 (2 H, d, J = 10 Hz, 4- aminomethylphenyl C(2)H/C(6)H or C ( 3 ) H/C (5) H) ; 7.68 (2 H, d, J = 10 Hz, 4-ammomethylphenyl C(2)H/C(6)H or C (3) H/C (5) H) ; 7.49 - 7.30 (5 H, m, Ar) ; 7.28 - 7.15 (2 H, m, Ar ) ; 7.10 - 6.96 (3 H, m, 2 x Ar and ArCH(NBz)); 4.57 (2 H, s, CH2NHC(0)); 3.98 (2 H, s, CH2NH2) .
HPLC (Luna 2, Gradient 1): rt = 4.22 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.21 minutes, 554 (MH)+.
Example 59 N- [a- (6- (Benzylamido)benzothiazol-2-oyl) -4-
(aminomethyl) benzyl] acetamide trifluoroacetate salt. λR NMR (d4 MeOH): 8.46 ppm (1 H, s, benzothiazole C(7)H); 8.13 (1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 7.95 (1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 7.52 (1 H, d, J = 7.5 Hz, Ar) ; 7.36 - 7.09 (8 H, m, Ar) ; 6.78 (1 H, s, CHNH) ; 4.51 (2 H, s, CH2NHCO) ; 3.92 (2 H, s, CH2NH2) ; 2.04 (3 H, s, NHCOCH3) .
HPLC (Luna 2, Gradient 1): rt = 3.52 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.98 minutes, 473 (MH)+.
Example 60
N- [α- (6- (Phenylamido)benzothiazol-2-oyl) -4 (aminomethyl) benzyl] acetamide trifluoroacetate salt.
XH NMR (d4 MeOH): 8.74 ppm (1 H, s, benzothiazole C(7)H); 8.37 (1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 8.24 (1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 7.82 (2 H, d, J = 7.25 Hz, 4-ammomethylphenyl C(2)H/C(6)H or C (3) H/C (5) H) ; 7.72 (2 H, d, J = 7.25 Hz, 4-ammomethylphenyl C(2)H/C(6)H or C(3)H/C(5)H) ; 7.56 - 7.21 (5 H, m, Ph); 6.98 (1 H, s, CHNH); 4.02 (2 H, s, CH2NH2) ; 2.16 (3 H, s, NHCOCH^.
HPLC (Luna 2, Gradient 1) : rt = 3.35 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.88 minutes, 459 (MH)+.
The following ten examples were prepared in an analogous manner to Example 50, using the indicated carboxylic acid to form an amide from 6-ammobenzothιazole, and the indicated derivative of 4- (aminomethyl ) phenylglycme .
Example 61
N- [α- (6- (Phenylacetylamino)benzothiazol-2-oyl) -4-
(aminomethyl) benzyl] benzamide trifluoroacetate salt.
From phenylacetic acid and methyl 4- (t-butoxycarbonylammo- methyl) -α- (benzoylammo) phenylacetate .
XH NMR (d4 MeOH): 8.54 ppm (1 H, s, benzothiazole C(7)H); 8.09
(1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 7.96 - 7.82
(4 H, m, Ar) ; 7.79 - 7.21 (11 H, m, Ar) ; 4.08 (2 H, s, CH2NH2);
3.76 (2 H, s, CH2Ph) .
HPLC (Luna 2, Gradient 1) : rt = 4.37 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.26 minutes, 535 (MH)+.
Example 62
N- [α- [ (6- (4-Chlorophenyl) cetylamino)benzothιazol-2-oyl] -4- ( minomethyl) benzyl] benzamide trifluoroacetate salt. From 4-chlorophenylacetic acid and methyl 4- (t- butoxycarbonylamino-methyl ) -α- (benzoylamino) phenylacetate .
2H NMR (d4 methanol): 8.54 ppm (1 H, s, benzothiazole C(7)H); 8.09 (1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 7.93 (2 H, d, J = 7 Hz, 4-chlorophenyl C(2)H/C(6)H or C ( 3 ) H/C ( 5 ) H) ; 7.76 (2 H, d, J = 1 Hz, 4-chlorophenyl C(2)H/C(6)H or C(3)H/C(5)H) ; 7.70 - 7.43 (6 H, m, Ar); 7.36 (4 H, s, Ar); 7.09 (1 H, s, CHNH); 4.10 (2 H, s, CH2NH2); 3.76 (2 H, s, CH2PhCl).
HPLC (Luna 2, Gradient 1) : rt = 4.60 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.56 minutes, 570 (MH)+.
Example 63
N- [ - [ (6- (3-Chlorophenyl) acetylamino)benzothiazol-2-oyl] -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt.
From 3-chlorophenylacetic acid and methyl 4-(t- butoxycarbonylamino-methyl) -α- (benzoylamino) phenylacetate .
λR NMR (d4 MeOH): 8.48 ppm (1 H, s, benzothiazole C(7)H); 8.00 (1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 7.63 - 7.27 (10 H, m, Ar) ; 7.20 (4 H, s, Ar) ; 6.95 (1 H, s, CHNH); 3.94 (2 H, s, CH2NH2) ; 3.64 (2 H, s, CH2PhCl).
HPLC (Luna 2, Gradient 1): rt = 4.58 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.42 minutes, 570 (MH)+.
Example 64
N- [α- [6- (Cyclohexanoylamino)benzothiazol-2-oyl] -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt. From cyclohexanecarboxylic acid and methyl 4-(t- butoxycarbonylamino-methyl) -α- (benzoylamino) phenylacetate .
lR NMR (d4 MeOH): 8.39 ppm (1 H, s, benzothiazole C(7)H); 7.92 (1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 7.79 (2 H, d, J = 7 Hz, 4-ammomethylphenyl C(2)H/C(6)H or C (3 ) H/C ( 5) H) ; 7.61 (8 H, m, Ar) ; 6.92 (1 H, s, CHNH); 3.78 (2 H, s, CH2NH2); 2.41 - 2.22 (1 H, m, CHCO cHex) ; 1.90 - 1.10 (10 H, m, cHex) .
HPLC (Luna 2, Gradient 1): rt = 4.52 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.34 minutes, 527 (MH)+.
Example 65 N- [α- (6- (Phenylacetylamino)benzothiazol-2-oyl) -4-
(aminomethyl) benzyl] acetamide trifluoroacetate salt.
From phenylacetic acid and methyl 4- (t-butoxycarbonylamino- methyl) -α- (acetylamino) phenylacetate .
λR NMR (d4 MeOH): 8.40 ppm (1 H, s, benzothiazole C(7)H); 7.98 (1 H, d, J= 7.5 Hz, benzothiazole C(4)H or C(5)H); 7.60 - 7.44 (3 H, m, Ar) ; 7.35 - 7.08 (7 H, m, Ar) ; 6.86 (1 H, s, CHNH); 3.86 (2 H, s, CH2NH2) ; 3.61 (2 H, s, COCH2Ph) ; 1.94 (3 H, s, NHCOCH3) .
HPLC (Luna 2, Gradient 1) : rt = 3.68 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.91 minutes, 473 (MH)+.
Example 66
N- [a- (6- (Benzoylamino) benzothiazol-2-oyl) -4-
(aminomethyl) benzyl] cyclohexylacetamide trifluoroacetate salt. From benzoic acid and methyl 4- (t-butoxycarbonylammo-methyl) - α- (cyclohexylacetylammo) phenylacetate .
λR NMR (d4 MeOH): 8.52 ppm (1 H, s, benzothiazole C(7)H); 8.08 - 7.71 (5 H, m, Ar); 7.62 - 7.29 (6 H, m, Ar); 6.76 (1 H, s, Ar) ; 3.99 (2 H, s, CH2NH2) ; 2.10 (2 H, s, COCH2cHex) ; 1.80 - 1.48 (5 H, , cHex) ; 1.28 - 0.72 (5 H, m, cHex) .
HPLC (Luna 2, Gradient 1): rt = 4.48 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.42 minutes, 541 (MH)+.
Example 67
N- [α- (6- (4-Isopropylbenzoylamino)benzothiazol-2-oyl) -4- (aminomethyl)benzyl] cyclohexylacetamide trifluoroacetate salt.
From 4-ιsopropylbenzoιc acid and methyl 4-(t- butoxycarbonylammo-methyl) -α- (cyclohexylacetylammo) phenylacetate .
λR NMR (d4 MeOH): 8.60 ppm (IH, s, benzothiazole C(7)H); 8.12
(1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 8.05 - 7.80 (3 H, m, Ar) ; 7.68 (2 H, d, J = 7 Hz, Ar) ; 7.45 (4 H, d, J = 7.5 Hz, Ar) ; 6.90 (1 H, s, CHNH); 4.10 (2 H, s, CH2NH2 ); 3.08 - 2.96 (1 H, m, CH(CH3)2); 2.30 - 2.15 (2 H, m, COCH2cHex) ; 1.87 - 1.60 (5 H, m, cHex) ; 1.43 - 1.18 (10 H, m, cHex, 2 x CH3) ; 1.10 - 0.92 (2 H, m, cHex) .
HPLC (Luna 2, Gradient 1): rt = 5.18 minutes.
LC/MS (Luna 2, Gradient 4): rt = 3.10 minutes, 583 (MH)+.
Example 68 N- [a- (6- (2-Naphthylamino)benzothiazol-2-oyl) -4- (aminomethyl) benzyl] cyclohexylacetamide trifluoroacetate salt.
From 2-naphthoιc acid and methyl 4- ( t-butoxycarbonylammo- methyl ) - - (cyclohexylacetylammo) phenylacetate .
τR NMR (d4 MeOH): 8.60 ppm (1 H, s, benzothiazole C(7)H); 8.42 (1 H, s, naphthyl C(l)H); 8.03 (1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 7.98 - 7.74 (6 H, m, Ar) ; 7.60 - 7.45 (3 H, m, Ar) ; 7.35 (2 H, d, J = 1 Hz, Ar) ; 6.77 (1 H, s, CHNH); 3.94 (2 H, s, CH2NH2) ; 2.18 - 2.02 (2 H, m, COCH2cHex) ; 1.87 - 1.50 (6 H, m, cHex) ; 1.31 - 1.04 (3 H, m, cHex) ; 1.00 - 0.77 (2 H, m, cHex) .
HPLC (Luna 2, Gradient 1): rt = 5.06 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.88 minutes, 591 (MH)+.
Example 69
N- [α- (6- (l-Naphthoylamino)benzothiazol-2-oyl) -4- (aminomethyl) benzyl] cyclohexylacetamide trifluoroacetate salt.
From 1-naphthoιc acid and methyl 4- (t-butoxycarbonylammo- methyl) -α- (cyclohexylacetylam o) phenylacetate .
λR NMR (d4 MeOH): 8.69 ppm (1 H, s, benzothiazole C(7)H); 8.38 - 7.40 (13 H, m, Ar) ; 6.88 (1 H, s, CHNH); 4.10 (2 H, s,
CH2NH2) ; 2.32 - 2.08 (2 H, m, COCH2cHex) ; 1.92 - 1.58 (6 H, m, cHex) ; 1.39 - 0.89 (5 H, m, cHex) .
HPLC (Luna 2, Gradient 1): rt = 4.95 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.66 minutes, 591 (MH)+. Example 70
N- [a- [ (6-Benzylsulfonylamino) benzothiazol-2-oyl] -4-
(aminomethyl) benzyl] acetamide trifluoroacetate salt.
From benzylsulfonic acid and methyl 4- ( t-butoxycarbonylamino- methyl) -α- (acetylamino) phenylacetate .
λR NMR (d4 MeOH): 7.80 ppm (1 H, d, J = 7.5 Hz, benzothiazole C(4)H or C(5)H); 7.56 (1 H, s, benzothiazole C(7)H); 7.41 (2 H, d, J = 7.2 Hz, Ar) ; 7.24 (2 H, d, J = 7.5 Hz, Ar) ; 7.13 - 6.80 (7 H, m, Ar) ; 6.64 (1 H, s, CHNH); 4.27 (2 H, s, CH2NH2); 3.82 (2 H, s, CH2S02) ; 1.86 (3 H, s, C0CH3) .
HPLC (Luna 2, Gradient 1) : rt = 3.55 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.78 minutes, 509 (MH)+.
Example 71
N-Phenyl-2- [ (4-aminomethyl)phenylacetyl]benzothiazol-6-amide trifluoroacetate salt.
N, O-Dimethyl [4-(N-t- butoxycarbonylaminomethyl) phenylacetyl] hydroxylamide
A solution of ( N-t-butoxycarbonyl ) -4-aminomethylphenylacetic acid (980 mg, 3.7 mmol) in dry dichloromethane (20 mL) was stirred at room temperature and 1- ( 3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (740 mg, 3.9 mmol), N, 0- dimethylhydroxylamine hydrochloride (380 mg, 3.9 mmol) and triethylamine (540 μL, 390 mg, 3.9 mmol) were added. The mixture was stirred for three days before it was diluted with dichloromethane (20 mL) , washed with water (10 mL) , 5 % aqueous HC1 (10 mL) , water (10 mL) and brine (10 mL) and dried over magnesium sulfate. After evaporation of the solvent under reduced pressure the residue was purified by flash column chromatography on silica gel (2:1 hexane / acetone) to afford the amide (1.05 g, 92 %) as a pale yellow viscous oil.
lV-Phenyl-benzothiazole-6-amide
Benzothiazole-6-carboxylic acid (1.0 g, 5.6 mmol) and l-(3- dimethylaminopropyl) -3-ethylcarbodnmide hydrochloride (1.2 g, 6.1 mmol) were stirred in dry dichloromethane (25 mL) and aniline (560 μL, 570 mg, 6.1 mmol) was added by syringe. The mixture was stirred overnight before water (10 mL) and dichloromethane (20 mL) were added. The layers were separated and the aqueous phase was extracted with ethyl acetate (25 mL) . The combined organic solvents were washed with 5 % aqueous HC1 (10 mL) , water (10 mL) and brine (10 mL) and dried over magnesium sulfate. Evaporation of the solvents under reduced pressure afforded the amide (1.31 g, 92 %) as a pale orange solid which was not purified further.
N-phenyl-2- [ (4-N-t- butoxycarbonylaminomethyl)phenylacetyl]benzothiazol-6-amide
A solution of N-phenyl benzothiazole-6-amide (214 mg, 0.84 mmol) in dry THF (5 mL) was cooled to -78 °C and n-butyllithium (2.07 M in hexane, 0.81 mL, 1.69 mmol) was added dropwise by syringe, causing the solution to turn red. After 15 minutes a solution of N, O-Dimethyl [ 4 - ( N-t- butoxycarbonylaminomethyl) phenyl-acetyl] hydroxylamide (130 mg, 0.42 mmol) in dry THF (1.5 mL) was added by cannula. The mixture was stirred for 1 hour before saturated aqueous ΝH4C1 (4 mL) was added and the mixture allowed to warm to room temperature. The layers were separated and the organic phase diluted with diethyl ether (10 mL) before being washed with water (5 L) and brine (5 mL) . The combined washings were extracted with ethyl acetate (5 mL) and the organics dried over magnesium sulfate. After evaporation of the solvents under reduced pressure, the residue was purified by flash column chromatography on silica gel (4:1 to 3:1 hexane / acetone and then methanol) to afford the benzothiazole ketone (81 mg, 38 %) as a pale yellow solid.
N-Phenyl-2- [ (4-aminomethyl)phenylacetyl]benzothiazol-6-amide trifluoracetate salt
A solution of the N-protected benzothiazole ketone (75 mg) in dichloromethane (5 mL) was stirred at room temperature and trifluoroacetic acid (1 mL) was added. After 30 minutes the dichloromethane and excess trifluoroacetic acid were evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (10 - 20 % methanol in chloroform) and then preparative HPLC to afford the free amine (14 mg, 23 %) as a pale yellow solid.
λR NMR (d6 DMSO): 8.92 ppm (1 H, s, benzothiazole C(7)H); 8.50 (1 H, d, J = 10 Hz, benzothiazole C(4)H or C(5)H); 8.27 (1 H, d, J = 10 Hz, benzothiazole C(4)H or C(5)H); 8.22 (1 H, br s, NH) ; 7.88 (2 H, d, J = 10 Hz, 4-aminomethylphenyl C(2)H/C(6)H or C(3)H/C(5)H) ; 7.48 (5 H, s, Ph) ; 7.42 (2 H, d, J = 10 Hz, 4- aminomethylphenyl C(2)H/C(6)H or C (3) H/C (5) H) ; 7.19 (1 H, t, J = 9 Hz, NH) ; 4.76 (2 H, s, ArCH2C(0)); 4.10 (2 H, q, J = 6 Hz, CH2NH3 +) .
HPLC (Luna 2, File 8): rt = 12.06 min.
LC/MS (Luna 2, Gradient 4): rt = 2.53 min, 472 (MH-NH3)+. Example 72 iV-4-Pyridyl -2- [4- (aminomethyl)phenylacetyl]benzothiazol-6-amide bis (trifluoroacetate) salt.
Prepared as in Example 71, using 4-aminopyridine instead of aniline.
lR NMR (d4 MeOH): 8.72 ppm (1 H, s, benzothiazole C(7)H); 8.59 (2 H, d, J = 9 Hz, 4-aminomethylphenyl C(2)H/C(6)H or C(3)H/C(5)H) ; 8.48 (3 H, m, 4-aminomethylphenyl C(2)H/C(6)H or C(3)H/C(5)H and benzothiazole C(4)H or C(5)H); 8.13 (1 H, d, J = 10 Hz, benzothiazole C(4)H or C(5)H); 7.37 (2 H, d, J = 9 Hz, 4-aminopirydyl C(2)H/C(6)H or C (3) H/C (5) H) ; 7.32 (2 H, d, J = 9 Hz, 4-aminopirydyl C(2)H/C(6)H or C (3) H/C (5) H) ; 4.58 (2 H, s, ArCH2C(0)); 4.02 (2 H, s, CH2NH2) .
HPLC (Luna 2, Gradient 1): rt = 2.82 min.
LC/MS (Luna 2, Gradient 4): rt = 1.35 min, 403 (MH)+.
Example 73
2- [4- (Aminomethyl)phenylacetyl] benzothiazole trifluoroacetate salt.
Prepared as in Example 71, using benzothiazole instead of 6- amidobenzothiazole
λR NMR (d4 MeOH): 8.12 (1 H, d, J = 8 Hz, benzothiazole C(7)H);
8.02 (1 H, d, J = 8 Hz, benzothiazole C(4)H); 7.52 (2 H, m, benzothiazole C(5)H, C(6)H); 7.45 (4 H, 2 x d, ammomethylphenyl) ; 4.55 (2 H, s, ArCH2C(0)); 4.01 (2 H, s, CH2NH3) .
HPLC (Jupiter C18, Gradient 5) rt = 10.2 mins Example 74
4- (Aminomethyl) benzyl thiazol-2-yl ketone trifluoroacetate salt synthesised as described for Example 71 using thiazole instead of 6-amidobenzothiazole IH NMR (d4 MeOH) 8.00 ppm (1 H, d, J = 3Hz, thiazole C(5)H); 7.91 (1 H, d, J = 3Hz, thiazole C(4)H); 7.32 (4H, s, ammomethylphenyl) ; 4.41 (2 H, s, CH2CO) ; 3.98 (2 H, s, CH2NH2) .
HPLC (Jupiter C18, Gradient 5): rt = 8.09 minutes)
Example 75
N- [a- [ (5-Naphth-2-yl) thiazol-2-oyl] -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt
i.) 2-Azido-2 ' -acetonaphthone
A solution of 2-bromo-2 ' -acetonaphthone (3.43 g, 13.8 mmol) in acetone (30 mL) was stirred at room temperature and sodium azide (1.79 g, 27.5 mmol) was added. The suspension was stirred for 18 hours, filtered and the solvent evaporated to afford the azido ketone (2.50 g, 86 %) which was not purified further .
ii.) 2-Amino-2 ' -acetonaphthone hydrochloride salt
A solution of the azide (2.0 g, 9.6 mmol) in methanol (50 mL) was stirred at room temperature and HCl (6 N, 2 mL, 12 mmol) and 10% Pd/C (0.25 g) were added. The flask was evacuated, the atmosphere replaced with hydgrogen and the suspension stirred vigorously for three hours. The catalyst was removed by filtration and the solvent evaporated to afford the amine hydrochloride as a pale yellow solid (2.10 g, 100 %).
iii . ) N-Formyl-2-amino-2 ' -acetonaphthone The a ine hydrochloride (2.09 g, 9.4 mmol) and l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (2.0 g, 10.4 mmol) were stirred in dichloromethane (50 mL) and formic acid (715 μL, 870 mg, 18.9 mmol) and triethylamine (2.63 mL, 1.91 g, 18.9 mmol) were added by syringe. The mixture was stirred for 2.5 hours when further 1- (3-dimethylaminopropyl) -3- ethylcarbodiimide hydrochloride (1.0 g, 5.2 mmol) and formic acid (500 μL, 610 mg, 13.2 mmol) were added. The mixture was stirred for a further 15 hours. Water (30 mL) was then added and the layers were separated. The organic phase was washed with saturated aqueous citric acid (30 mL) , water (30 mL) , saturated aqueous sodium bicarbonate (30 mL) and brine (30 mL) and dried over magnesium sulfate. Evaporation of the solvent afforded the formamide as a yellow-brown solid (1.85 g, 92 %) which was not purified further.
iv.) 5- (2-Naphthyl) thiazole
A solution of the formamide (1.85 g, 8.7 mmol) in dry THF (50 mL) was stirred at 0 °C under argon. Solid P2S5 (2.51 g, 11.3 mmol) was added and the mixture stirred for 75 minutes. Aqueous hydrochloric acid (2 N, 20 mL) was added and the mixture was diluted with diethyl ether (50 mL) and ethyl acetate (50 mL) , causing a precipitate to form. This was removed by filtration through Celite before the aqueous phase was separated. The organic solution was washed with water (30 mL) , saturated sodium bicarbonate (30 mL) and brine (30 mL) and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was purified by flash column chromatography on silica gel (1 % diethyl ether in dichloromethane) to afford the thiazole as a yellow solid (840 mg, 46 %) . XH NMR (CDCI3) 8.75 ppm (1 H, s, thiazole C(2)H); 8.12 (1 H, s, thiazole C(4)H); 7.97 (1 H, s, naphthyl C(l)H); 7.85 - 7.74 (3 H, m, naphthyl C(4)H, C(5)H and C(8)H); 7.64 (1 H, d, J = 11 Hz, naphthyl C(3)H); 7.48 - 7.40 (2 H, m, naphthyl C(6)H and C(7)H) .
N- [α- [ (5-Naphth-2-yl) thiazol-2-oyl] -4- (aminomethyl) benzyl] benzamide trifluoroacetate salt
The remainder of the synthesis is analogous to Example 1 using methyl 4- (BOC-aminomethyl) -α-benzoylaminophenylacetate and 5- naphthyl-thiazole λR NMR (d4 MeOH): 8.02 ppm (1 H, s, thiazole C(4)H); 8.21 (1 H, s, naphthyl C(l)H); 7.90 - 7.30 (13 H, m, Ar) ; 6.91 (1 H, s,
ArCH(N)C(0) ) ; 4.01 (2 H, s, ArCH2NH2) . HPLC (Luna 2, Gradient 2): rt = 4.75 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.75 minutes, 478 (MH)+.
Example 76
N- [α- [5- (1 , 5-Benzodioxepin-7-yl) thiazol-2-oyl] -4- (aminomethyl) benzyl]benzamide
Prepared in an analogous fashion to Example 75, starting with
7- (2-bromoacetyl) -1, 5-benzodioxepine . H NMR (d4 MeOH): 8.02 ppm (1 H, s, thiazole C(4)H); 7.86 - 7.70
(3 H, m, Ar) ; 7.53 - 7.20 (6 H, m, Ar) ; 7.14 - 7.03 (2 H, m, Ar) ; 6.90 - 6.80 (2 H, m, Ar and ArCH (N) C (0) ) ; 4.17 - 4.03 (4
H, m, benzodioxepine C(2)H2 and C(4)H2); 3.73 (2 H, s,
ArCH2NH2); 2.06 (2 H, pentet, J = 6 Hz, benzodioxepine C(3)H2).
HPLC (Luna 2, Gradient 2): rt = 4.25 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.26 minutes, 500 (MH)+. Example 77
N- [alpha- (5-Phenylthiazol-2-oyl) -4- (aminomethyl) - benzyl]benzamide TFA.
Prepared in an analogous fashion to Example 75, starting with 2-bromoacetophenone
XH NMR (d4 methanol): 8.32 (1 H, s, CH thiazole); 7.78 - 7.60 (4 H, m, Ar); 7.57 - 7.44 (5 H, m, Ar) ; 7.40 (2 H, d, J = 7.2 Hz, Ar) ; 7.19 (2 H, d, J = 7.2 Hz, Ar) ; 6.39 (1 H, s, CHNHS02) ; 4.06 (2 H, s, CH2NH2) ; 2.29 (3 H, s, CH3Tol). Hplc (Luna 2, Gradient 1) : rt = 4.61 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.03 minutes, 478 (M + H)+.
Example 78
N- [alpha- (5-Phenylthiazol-2-oyl) -4- (aminomethyl)benzyl] -4- methylbenzenesulfonamide TFA.
Prepared in an analogous manner to Example 75 starting with 2- bromoacetophenone and using methyl 4- (BOC-aminomethyl) -α- [ (4- methyl) phenylsulfonylamino] phenylacetate (see Example 27) XH NMR (d6 dmso) : 9.37 (1 H, d, J = 6.5 Hz, NH) ; 8.63 (1 H, s, CH thiazole); 8.20 (2 H, br s, NH2) ; 7.97 (2 H, d, J = 7.2 Hz, Ar) ; 7.86 (2 H, d, J = 7.2 Hz, Ar) ; 7.70 - 7.47 (10 H, m, Ar) ; 6.89 (1 H, d, J = 6.5 Hz, CHNHCO) ; 4.07 (2 H, d, J = 4.9 Hz, CH2NH2) . Hplc (Luna 2, Gradient 1): rt = 4.24 minutes. LC/MS (Luna 2, Gradient 4) : rt = 2.07 minutes, 428 (M + H)+.
Example 79
N- [alpha- (Thiazol-2-oyl) -4- (aminomethyl) benzyl]benzamide trifluoroacetate salt
Prepared as described for Example 75 using thiazole as starting material and then using α- [ (N-methyl-N-methoxy) amido] -4- (BOC- aminomethyl) -N-benzylbenzamide (see Example 33). - 90 - Claims
1. A compound of general formula I
Figure imgf000090_0001
in which : -
Ar represents an aromatic ring of formula
Figure imgf000090_0002
which is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1- 4C) alkyl group and a (1-4C) alkoxy group;
A1 represents 0, NH, S, CH or CH=CH; and A2 and A3 are each selected independently from CH, 0, S, N and NH; provided that A1, A2 and A3 are selected so that they, together with the carbon atoms to which they are attached, form an aromatic ring;
R1 represents a hydrogen atom, an amino group or a group of formula NHX1 (CH2) bR3;
R2 represents a group of formula COR4 or, when R1 represents a group of formula NHX1 (CH2) bR3, a hydrogen atom;
X1 represents a bond, CO, S02, COO or CONH;

Claims

91 a represents 0, 1 or 2;
b represents 0 or an integer of from 1 to 4;
R3 represents an unsubstituted or substituted aromatic, heterocyclic, (1-lOC) alkyl, (2-10C) alkenyl, (2-10C) alkynyl or (3-10C) cycloalkyl group;
R4 represents a group of formula COR5, a group of formula CF2R6 or an unsubstituted or substituted heteroaromatic group of formula
Figure imgf000091_0001
R represents a (1-6C) alkyl, fluoro ( 1-6C) alkyl or (3- IOC) cycloalkyl group, an unsubstituted or substituted aromatic or heterocyclic group, a group of formula OR7 or a group of formula NR8R9;
R represents a fluorine atom, a (1-6C) alkyl, fluoro ( 1-6C) alkyl or (3-10C) cycloalkyl group, an unsubstituted or substituted aromatic or heterocyc :lliicc group, a group of formula COOR10 or a group of formula CONR1:lR12;
A represents 0, NH or S;
A represents 0, NH or S; and
R7, R8, R9, R10, R11 and R12 are each selected independently from a hydrogen atom, a (1-6C) alkyl group, a (3-6C) cycloalkyl group and an unsubstituted or substituted aromatic group; or - 93 -
(i) phenyl, naphthyl, furyl, benzofuryl, thienyl, benzothienyl, pyrrolyl, indolyl, pyridyl or pyrimidyl which is unsubstituted or substituted by ( 1-4C) alkylenenedioxy or by one, two or three substituents selected independently from a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a (3-7C) cycloalkyl (1-4C) alkyl group; a halo ( 1-4C) alkyl group; a group of formula (CH2) CX2 (CH2) dX3R13 in which c represents 0, 1 or 2, d represents 0, 1 or 2, X2 represents 0, S, SO, S02, NR14, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, X3 represents a bond, 0, S, SO, S02, NR15, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R13 represents a hydrogen atom, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a ( 3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (1-4C) alkoxy group, R14 and R15 each independently represents a hydrogen atom, a (1-4C) alkyl group or, together with R13 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group; and a phenyl or naphthyl group that is unsubstituted or substituted by (1-4C) alkylenenedioxy, or one or two substituents selected from a halogen atom, a cyano group, a nitro group, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a group of formula (CH2) e 4 (CH2) fR16 in which e represents 0, 1 or 2, f represents 0, 1 or 2, X represents 0, S, SO, S02, NR17, CO, CONH, NHCO, OCONH, NHCOO, - 94 -
COO, OCO, S02NH or NHS02, R16 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (1-4C) alkoxy group, R17 represents a hydrogen atom, a (1-4C) alkyl group or, together with R16 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group;
(ii) pyrrolidmyl, piperidinyl, piperazinyl, or 2,3- dihydrobenzofuranyl unsubstituted or substituted by one, two or three of: a (1-4C) alkyl group; oxo; a group of formula -X6- (CHR18) g-X7- (CH2) h-R19 in which g represents 0, 1 or 2, h represents 0, 1 or 2, X6 represents 0, S, SO, S02, NR20, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, X7 represents a bond, 0, S, SO, S02, NR21, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R18 and R19 each independently represents a hydrogen atom, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group, a pyrrolyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group, a hydroxy group and a (1-4C) alkoxy group, and R20 and R21 each independently represents a hydrogen atom, a (1-4C) alkyl group or, together with R19 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group; and a group R22 in which R22 is (3-7C) cycloalkyl (1-4C) alkyl or a phenyl, naphthyl, phenyl (1-4C) alkyl or naphthyl (1-4C) alkyl group that is unsubstituted or substituted on any phenyl or - 95 - naphthyl moeity by (1-4C) alkylenedioxy or one or two substituents selected from a halogen atom, a cyano group, a nitro group, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2- 4C) alkynyl group, a halo (1-4C) alkyl group, a group of formula (CH2) iX8 (CH2) jR23 in which i represents 0, 1 or 2, j represents 0, 1 or 2, X8 represents 0, S, SO, S02, NR24, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R23 represents a hydrogen atom, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3- 7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (1-4C) alkoxy group, R24 represents a hydrogen atom, a (1-4C) alkyl group or, together with R23 and the nitrogen atom to which they are attached, a pyrrolidinyl, piperidinyl or morpholino group; or
(iii) a (3-10C) cycloalkyl group that is unsubstituted or substituted by one, two or three (1-4C) alkyl groups.
8. A compound as claimed in claim 7, in which R3 is a group of formula
Figure imgf000094_0001
Figure imgf000094_0002
or
Figure imgf000095_0001
9. A compound as claimed in Claim 7, in which R3 represents cyclohexyl, adamantyl, phenyl, 2-naphthyl, 4-methylphenyl, 3,5- dimethylphenyl, 2, 4 , 6-trimethylphenyl, 4-isopropylphenyl, 3- methyl-4-nitrophenyl, 3-methyl-4-aminophenyl, 4- isopropoxyphenyl, 3, 4-dimethoxyphenyl, 4-phenylphenyl, 4- phenoxyphenyl, 4-benzyloxyphenyl, 4- (2-phenoxyethoxy) phenyl, 4- (N, N-dimethylamino) phenyl, 4- (N-acetylamino) phenyl, 4- methanesulphonylphenyl, 4-hydroxyphenyl, 2 , 3-dihydrobenzofuran- 5-yl, l-acetylpiperidin-4-yl, l-(2- acetylaminopropionyl) pyrrolidin-2-yl, 1- (2- (2-thienyl) - acetylammopropionyl) pyrrolidin-2-yl, 1- (2- cyclopentanoylaminopropionyl) pyrrolidin-2-yl, 1- (pyrrol-2- oyl) pyrrolidin-2-yl, 3-benzyloxycarbonylamino-6-methyl-pyrid-2- one-l-yl, 1- (2-cyclohexylacetylaminopropionyl) -pyrrolidin-2-yl, 1- (2- (2-thienyl) carbonylaminopropionyl) -pyrrolidin-2-yl, 1- (2- ( 4-hydroxyphenyl) acetylaminopropionyl) -pyrrolidin-2-yl, 1- (2- phenylsulfonylaminopropionylpyrrolidin-2-yl, 1- (2- benzylsulfonylaminopropionylpyrrolidin-2-yl, 3-acetylamino-6- methyl-pyrid-2-one-l-yl, 3-benzyloxycarbonyl-amino-6- cyclohexylmethyl-pyrid-2-one-l-yl, 6- (naphth-2-yl) methyl-2, 5- dioxopiperazin-3-yl or 6- (3-chlorobenzyl) -2 , 5-dioxopiperazin-3- yi.
10. A compound as claimed in any one of Claims 1 to 9, in which R2 represents COR4 and R4 represents an unsubstituted substituted heteroaromatic group of formula 97 -
Figure imgf000096_0001
in which the heteroaromatic group is unsubstituted or substituted by (1-4C) alkylenedioxy or by one or two substituents selected independently from a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo (1-4C) alkyl group; a group of formula (CH2) yX9 (CH2) mR25 in which k represents 0, 1 or 2, m represents 0, 1 or 2, X9 represents 0, S, SO, S02, NR26, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R25 represents a hydrogen atom, an (1-4C) alkyl group, a (2- 4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a (3-7C) cycloalkyl group, an indanyl group, an aromatic or heteroaromatic group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a group of formula
(CH2) X14 (CH2) XR38 in which w represents 0, 1 or 2, x represents 0, 1 or 2, X14 represents 0, S, SO, S02, NH, CONH, NHCO, NHS02, or S02NH and R38 represent a hydrogen atom, a (1-4C) alkyl group or a phenyl group that is unsubstituted or substituted by a halogen atom, a (1-4C) alkyl group or a(l-4C)alkyl group, R26 represents a hydrogen atom, a (1-4C) alkyl group or, together with R25 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group; and a phenyl or naphthyl group that is unsubstituted or substituted by (1-4C) alkylenedioxy or by one or two substituents selected - 98 - from a halogen atom, a cyano group, a nitro group, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a group of formula (CH2) nX10 (CH2) PR27 in which n represents 0, 1 or 2, p represents 0, 1 or 2, X10 represents 0, S, SO, S02, NR28, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R27 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (1-4C) alkoxy group, R28 represents a hydrogen atom, a (1-4C) alkyl group or, together with R27 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group.
11. A compound as claimed in Claim 10, in which the heteroaromatic group is a group of formula
Figure imgf000097_0001
in which: R29 and R30 are together (1-4C) alkylenedioxy or are each selected independently from a hydrogen atom; a halogen atom; a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo (1-4C) alkyl group; - 99 - a group of formula (CH2) qX11 (CH2) rR33 in which q represents 0, 1 or 2, r represents 0, 1 or 2, X11 represents 0, S, SO, S0 , NR34, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R33 represents a hydrogen atom, an (1-4C) alkyl group, a (2- 4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1- 4C) alkyl group and a (1-4C) alkoxy group, R34 represents a hydrogen atom, a (1-4C) alkyl group or, together with R33 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group; and a phenyl or naphthyl group that is unsubstituted or substituted by ( 1-4C) alkylenedioxy or by one or two substituents selected from a halogen atom, a cyano group, a nitro group, an (1-
4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a group of formula (CH2) SX12 (CH2) tR35 in which s represents 0, 1 or 2, t represents 0, 1 or 2, X12 represents 0, S, SO, S02, NR36, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R35 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a (3-7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (1-4C) alkoxy group, R36 represents a hydrogen atom, a (1-4C) alkyl group or, together with R35 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group; and
R31 and R32 are together ( 1-4C) alkylenedioxy or are each selected independently from a hydrogen atom; a halogen atom; - 100 - a cyano group; a nitro group; an (1-4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo ( 1-4C) alkyl group; and a group of formula (CH2) UX13 (CH2) VR37 in which u represents 0, 1 or 2, v represents 0, 1 or 2, X13 represents 0, S, SO, S02,
NR38, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R37 represents a hydrogen atom, an (1-4C) alkyl group, a (2- 4C) alkenyl group, a (2-4C) alkynyl group, a halo (1-4C) alkyl group, a (3-7C) cycloalkyl group, an indanyl group, an aromatic or heteroaromatic group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a group of formula
(CH2) WX14 (CH2) XR38 in which w represents 0, 1 or 2, x represents 0, 1 or 2, X14 represents 0, S, SO, S02, NH, CONH, NHCO, NHS02, or S02NH and R38 represent a hydrogen atom, a (1-4C) alkyl group or a phenyl group that is unsubstituted or substituted by a halogen atom, a (1-4C) alkyl group or a(l-4C)alkyl group, R38 represents a hydrogen atom, a (1-4C) alkyl group or, together with R37 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group.
12. A compound as claimed in Claim 11, in which the heteroaromatic group is a group of formula
Figure imgf000099_0001
in which: R32 represents a hydrogen atom and R31 is a hydrogen atom; a halogen atom; a cyano group; a nitro group; an (1- - 101 -
4C) alkyl group; a (2-4C) alkenyl group; a (2-4C) alkynyl group; a halo (1-4C) alkyl group; a group of formula (CH2) UX13 (CH2) VR37 in which u represents 0, 1 or 2, v represents 0, 1 or 2, X13 represents 0, S, SO, S02, NR38, CO, CONH, NHCO, OCONH, NHCOO, COO, OCO, S02NH or NHS02, R37 represents a hydrogen atom, an (1- 4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3-7C) cycloalkyl group, an indanyl group, an aromatic or heteroaromatic group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, a (1-4C) alkyl group and a group of formula (CH2) WX14 (CH2) XR38 in which w represents 0, 1 or 2, x represents 0, 1 or 2, X14 represents 0, S, SO, S02, NH, CONH, NHCO, NHS02, or S02NH and R38 represent a hydrogen atom, a (1-4C) alkyl group or a phenyl group that is unsubstituted or substituted by a halogen atom, a (1-4C) alkyl group or a(l-4C)alkyl group, R38 represents a hydrogen atom, a (1-4C) alkyl group or, together with R37 and the nitrogen atom to which they are attached, a pyrrolidmyl, piperidinyl or morpholino group.
13. A compound as claimed in Claim 12, in which R37 represents a hydrogen atom, an (1-4C) alkyl group, a (2-4C) alkenyl group, a (2-4C) alkynyl group, a halo ( 1-4C) alkyl group, a (3-
7C) cycloalkyl group, a thienyl group or a phenyl group that is unsubstituted or substituted by one or two substituents selected independently from a halogen atom, an (1-4C) alkyl group and a (1-4C) alkoxy group.
14. A compound as claimed in any one of Claims 11 to 13, which is of the formula - 102 -
Figure imgf000101_0001
Ie
15. A compound as claimed in Claim 14, which is of the formula
Figure imgf000101_0002
(Ih) in which R1 represents a hydrogen atom or a group of formula NHX1 (CH2)bR3
16. A compound as claimed in any one of Claims 11 to 15, in which R31 is a group of formula (CH2) UX13 (CH2) VR37 in which X13 is
NHCO, CONH or S02NH, u is 0; and v is 0 or 1.
17. A compound as claimed in any one of Claims 11 to 16, in which R1 represents a hydrogen atom or a group of formula NHX^CH^bR3 in which R3 represents a (1-lOC) alkyl, (3- 10C) cycloalkyl, phenyl or naphthyl group.
18. A process for the preparation of a compound as claimed m any one of Claims 1-17, which comprises deprotecting a compound of formula
Figure imgf000102_0001
Figure imgf000103_0001
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