[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2000077027A2 - Serine protease inhibitors - Google Patents

Serine protease inhibitors Download PDF

Info

Publication number
WO2000077027A2
WO2000077027A2 PCT/GB2000/002291 GB0002291W WO0077027A2 WO 2000077027 A2 WO2000077027 A2 WO 2000077027A2 GB 0002291 W GB0002291 W GB 0002291W WO 0077027 A2 WO0077027 A2 WO 0077027A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
group
dihydromdol
minutes
gradient
Prior art date
Application number
PCT/GB2000/002291
Other languages
French (fr)
Other versions
WO2000077027A3 (en
Inventor
John Walter Liebeschuetz
Stephen Clinton Young
Sarah Elizabeth Lively
Martin James Harrison
Bohdan Waszkowycz
Phillip John Morgan
Original Assignee
Tularik Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9913823.2A external-priority patent/GB9913823D0/en
Priority claimed from GBGB9918741.1A external-priority patent/GB9918741D0/en
Priority claimed from GBGB9929552.9A external-priority patent/GB9929552D0/en
Priority claimed from GBGB9929553.7A external-priority patent/GB9929553D0/en
Priority to AU55460/00A priority Critical patent/AU5546000A/en
Application filed by Tularik Limited filed Critical Tularik Limited
Priority to AU18713/01A priority patent/AU1871301A/en
Priority to US10/148,174 priority patent/US6916957B2/en
Priority to ES00981478T priority patent/ES2282152T3/en
Priority to DE60033689T priority patent/DE60033689T2/en
Priority to AT00981478T priority patent/ATE355284T1/en
Priority to CA2394276A priority patent/CA2394276C/en
Priority to PCT/GB2000/004764 priority patent/WO2001044226A1/en
Priority to EP00981478A priority patent/EP1240154B1/en
Publication of WO2000077027A2 publication Critical patent/WO2000077027A2/en
Publication of WO2000077027A3 publication Critical patent/WO2000077027A3/en
Priority to AT01938399T priority patent/ATE344795T1/en
Priority to PCT/GB2001/002566 priority patent/WO2001096305A1/en
Priority to DE60124397T priority patent/DE60124397T2/en
Priority to US10/296,245 priority patent/US7074934B2/en
Priority to EP01938399A priority patent/EP1294691B1/en
Priority to ES01938399T priority patent/ES2275683T3/en
Priority to AU2001264077A priority patent/AU2001264077B2/en
Priority to JP2002510448A priority patent/JP2004503538A/en
Priority to AU6407701A priority patent/AU6407701A/en
Priority to CA2413061A priority patent/CA2413061C/en
Priority to US09/988,082 priority patent/US6740682B2/en
Priority to US10/752,568 priority patent/US7220781B2/en
Priority to US11/126,309 priority patent/US7157585B2/en
Priority to US11/186,870 priority patent/US7381734B2/en
Priority to US11/712,906 priority patent/US7928137B2/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/36—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/53—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms 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
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • 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
    • C07D277/32—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 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles 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 in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
    • C07D333/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/36—Systems containing two condensed rings the rings having more than two atoms in common
    • C07C2602/42—Systems containing two condensed rings the rings having more than two atoms in common the bicyclo ring system containing seven carbon atoms

Definitions

  • This invention relates to compounds which are inhibitors of se ⁇ ne proteases and to pharmaceutical compositions thereof and their use in the treatment of the human or animal body. More particularly it relates to compounds for use m the treatment of mast cell mediated diseases such as asthma and other allergic and inflammatory conditions and to pharmaceutical compositions thereof and their use in the treatment of the human or animal body, and m particular to compounds which are tryptase inhibitors.
  • the serme proteases are a group of proteolytic enzymes which have a common catalytic mechanism characterized by a particularly reactive Ser residue.
  • Examples of serme proteases include trypsin, tryptase, chymotrypsm, elastase, thrombm, plasmm, kalli rem, Complement CI, acrosomal protease, lysosomal protease, cocoonase, ⁇ -lytic protease, protease A, protease B, serme carboxypeptidase II, subtilism, urokmase, Factor Vila, Factor IXa, and Factor Xa .
  • the serme proteases have been investigated extensively over a period of several decades and the therapeutic value of inhibitors of serme proteases is well understood.
  • Serme protease inhibitors play a central role m the regulation of a wide variety of physiological process including coagulation, fibrmolysis, fertilization, development, malignancy, neuromuscular patterning and inflammation. It is well known that these compounds inhibit a variety of circulating proteases as well as proteases that are activated or released m tissue. It is also becoming clear that serme protease inhibitors inhibit critical cellular processes, such as adhesion, migration, free radical production and apoptosis. In addition, animal experiments indicate that intravenously administered serme protease inhibitors, variants or cells expressing serme protease inhibitors, provide a protective effect against tissue damage.
  • Serme protease inhibitors have also been predicted to have potential beneficial uses in the treatment of disease in a wide variety of clinical areas such as oncology, neurology, haematology, pulmonary medicine, immunology, inflammation and infectious disease.
  • serme protease inhibitors may be beneficial in the treatment of thrombotic diseases, asthma, emphysema, cirrhosis, arthritis, carcinoma, melanoma, restenosis, atheroma, trauma, shock and reperfusion injury.
  • bronchoconstriction i.e. the narrowing of the airways m the lungs, was the major feature of asthma.
  • inflammation m the lungs is an integral part of the development of the disease.
  • asthma The inhalation of an allergen by an asthmatic generates a strong immune system response which triggers release of various inflammatory mediators, including histamme and leukot ⁇ enes from inflammatory cells.
  • inflammatory mediators including histamme and leukot ⁇ enes from inflammatory cells.
  • These increase the permeability of the blood vessel walls, attract inflammatory cells into the tissues and contract the smooth muscle around the airways. As a result, fluid leaks from the blood and the tissues swell, further narrowing the airways.
  • the inflammatory cells cause damage to the epithelial cells lining the airways exposing nerve endings which stimulates secretion of mucous as well as augmenting the inflammation by causing the release of neurokmms .
  • asthma is a complex disease frequently characterised by progressive developments of hyper- responsiveness of the trachea and bronchi as a result of chronic inflammation reactions which irritate the epithelium lining the airway and cause pathological thickening of the underlying tissues.
  • Leukocytes and mast cells are present in the epithelium and smootn muscle tissue of tne bronchi where they are activated initially by binding of specific inhaled antigens to IgE receptors. Activated mast cells release a number of preformed or primary chemical mediators of the inflammatory response m asthma as well as enzymes. Moreover, secondary mediators of inflammation are generated by enzymatic reactions of activated mast cells and a number of large molecules are released by degranulation of mast cells. It has therefore been proposed that chemical release from mast cells probably accounts for the early bronchiolar constriction response that occurs in susceptible individuals after exposure to airborne allergens . The early asthmatic reaction is maximal at around 15 minutes after allergen exposure, recovery occurring over the ensuing 1 to 2 hours.
  • n respiratory function which normally begins within a few hours and is maximal between 6 and 12 hours after exposure.
  • This late asthmatic reaction is accompanied by a marked increase in the number of inflammatory cells infiltrating bronchiolar smooth muscle and epithelial tissues, and spilling into the airways. These cells are attracted to the site by release of mast cell derived chemotactic agents.
  • the most straightforward way of dealing with an asthma attack is with a bronchodilator drug which causes airways to expand.
  • the most effective bronchodilators are tne ⁇ - adrenergic agonists which mimic the actions of adrenalin. These are widely used and are simply administered to the lungs by inhalers.
  • bronchoconst ⁇ ctor drugs are primarily of use m short term symptomatic relief, and do not prevent asthma attacks nor deterioration of lung function over the long term.
  • Anti- inflammatory drugs such as cromoglycate and the corticosteroids are also widely used m asthma therapy.
  • Cromoglycate has anti-inflammatory activity and has been found to be extremely safe. Although such cromolyns have minimal side effects and are currently preferred for initial preventive therapy in children, it is well known that they are of limited efficacy.
  • corticosteroids in asthma therapy was a major advance since they are very effective anti- mflammatory agents, however, steroids are very powerful, broad spectrum anti -inflammatory agents and their potency and non-specificity means that they are seriously limited by adverse side effects. Localising steroid treatment to the lungs using inhaler technology has reduced side effects but the reduced systemic exposure following inhalation still results some undesirable effects. Hence, there is a reluctance to use steroids early in the course of the disease .
  • Tryptase is the major secretory protease of human mast cells and is proposed to be involved m neuropeptide processing and tissue inflammation. Tryptase is one of a large number of serme protease enzymes which play a central role in the regulation of a wide variety of physiological processes including coagulation, flbrmolysis , fertilization, development, malignancy, neuromuscular patterning and inflammation. Although a large number of serme proteases have been widely investigated, tryptase still remains relatively unexplored.
  • Mature human tryptase is a glycosylated, heparm- associated tetramer of catalytically active subunits. Its ammo-acid structure appears to have no close counterpart among the other serme proteases which have been characterised. Tryptase is stored in mast cell secretory granules and after mast cell activation, human tryptase can be measured readily a variety of biological fluids. For example, after anaphylaxis, tryptase appears the blood stream where it is readily detectable for several hours. Tryptase also appears in samples of nasal and lung lavage fluid from atopic subjects challenged with specific antigen.
  • Tryptase has been implicated in a variety of biological processes where activation and degranulation of mast cells occur. Accordingly, mast cell tryptase inhibition may be of great value in the prophylaxis and treatment of a variety of mast cell mediated conditions.
  • Mast cells can degranulate by both IgE-dependent and independent mechanisms thereby implicating tryptase both atopic and non-atopic inflammatory conditions.
  • Tryptase can activate proteases such as pro-urokmase and pro-MMP3 (pro-matrix metalloprotease 3, pro-stromelysm) , thereby indicating a pathological role in tissue inflammation and remodelling.
  • tryptase can activate certain G-protem coupled receptors (eg PAR2 ) and induce neurogemc inflammation points to a broader physiological role, for example m modulating pain mechanisms.
  • G-protem coupled receptors eg PAR2
  • tryptase inhibitors may be beneficial m a broad range of diseases.
  • asthma chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • pulmonary fibrotic diseases rhinitis; psoriasis; urticaria; dermatitis; arthritis; Crohn's disease; colitis; angiogenesis ; atherosclerosis; multiple sclerosis; interstitial cystitis; migraine headache; neurogemc inflammation and pain mechanisms; wound healing; cirrhosis of the liver; Kimura' s disease; pre- eclampsia; bleeding problems associated with menstruation and the menopause; cancer (particularly melanoma and tumour metastasis) ; pancreatitis; and certain viral infections (Yong, Exp.
  • tryptase inhibitor should have utility where mast cells have being induced to degranulate by whatever mechanism, including anaphylactic reactions due to exogenous substances, e.g. morphine-induced bronchoconst ⁇ ction (Bowman and Rand, 2 nd edt . , 1980.)
  • WO96/09297, W095/32945, WO94/20527 and US 5,525,623 a variety of peptide based compounds are suggested as potential inhibitors of the mast cell protease tryptase.
  • a tryptase inhibitor is provided by a polypeptide ⁇ bL xric-bie from the leech hxrad ⁇ me ⁇ zcmalis .
  • W096/G8275 secretory leukocyte protease inhibitor (SLPI) and active fragments thereof have been found to inhibit the proteolytic activity of tryptase.
  • SLPI secretory leukocyte protease inhibitor
  • W099/55661 certain 4- ammomethylbenzoic ester derivatives are proposed as potential tryptase inhibitors .
  • the compounds of the invention will be useful not only in the treatment and prophylaxis of asthma but also of other allergic and inflammatory conditions mediated by tryptase such as allergic rhinitis, sk conditions such as eczema, psoriasis, atopic dermatitis and urticaria, rheumatoid arthritis, conjunctivitis, inflammatory bowel disease, neurogemc inflammation, atherosclerosis and cancer.
  • tryptase such as allergic rhinitis, sk conditions such as eczema, psoriasis, atopic dermatitis and urticaria, rheumatoid arthritis, conjunctivitis, inflammatory bowel disease, neurogemc inflammation, atherosclerosis and cancer.
  • the invention provides a serme protease inhibitor compound of formula (I)
  • R 2 represents a 5 or 6 membered aromatic carbon ring optionally interrupted by a nitrogen, oxygen or sulphur ring atom, substituted in the 3 and/or 4 position by R ⁇ r and optionally substituted in the position alpha to the X-X group (i.e.
  • each X independently is a C, N, 0 or 3 atom or a CO, CR la , C(R la ) 2 or NR la group, at least one X being C, CO, CR la or C(R la ) 2 ; each R x independently represents ammoalkyl; L is an organic linker group containing 1 to 5 backbone atoms selected from C, N, 0 and S, or a branched alkyl or cyclic group;
  • Y (the ⁇ -atom) is a nitrogen atom or a CR lb group; Cy is a saturated or unsaturated, mono or poly cyclic, homo or heterocyclic group, preferably containing 5 to 10 ring atoms and optionally substituted by groups R 3a or phenyl optionally substituted by R 3a ; each R 3a independently is R lc , ammo, halo, cyano, tro, thiol, alkylthio, alkylsulphonyl , alkylsulphenyl , t ⁇ azolyl, lmidazolyl , tetrazolyl, hydrazido, alkyl lmidazolyl, thiazolyl, alkyl thiazolyl, alkyl oxazolyl, oxazolyl , alkylsulphonamido, alkylammosulphonyl , ammosulphonyl , haloalkoxy and hal
  • Lp is a lipophilic organic group
  • D is a hydrogen bond donor group
  • n is 0, 1 or 2 ;
  • R la represents hydrogen or hydroxyl, alkoxy, alkyl, ammoalkyl , hydroxyalkyl alkoxyalkyl , alkoxycarbonyl , acyloxymethoxycarbonyl or alkylammo optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl; and
  • R lb and R lc are as defined for R la ; or a physiologically tolerable salt tnereof, e.g. a halide, phosphate or sulphate salt or a salt with ammonium or an organic am e such as ethylamme or meglumme .
  • a physiologically tolerable salt tnereof e.g. a halide, phosphate or sulphate salt or a salt with ammonium or an organic am e such as ethylamme or meglumme .
  • Compounds of formula I have surprisingly been found to be particularly effective as inhibitors of tryptase and to snow a surprising selectivity for tryptase over other serine proteases .
  • alpha atom is carbon it preferably has the conformation that would result from construction from a D- ⁇ -ammoacid NH 2 -CR lb (Cy) -COOH where the NH 2 represents part of X-X.
  • R lb at an alpha carbon is preferably a methyl or hydroxymethyl group or hydrogen.
  • aryl groups preferably contain 5 to 10 ring atoms optionally including 1, 2 or 3 heteroatoms selected from 0, N and S; alkyl, alkenyl or alkynyl groups or alkylene moieties preferably contain up to 6 carbons, e.g. C j, s or C x 3 ; cyclic groups preferably have ring sizes of 3 to 8 atoms; and fused multicyclic groups preferably contain 8 to 16 ring atoms .
  • R la is preferably hydrogen.
  • the X moiety nearest to the alpha atom is an NH or 0 atom, most preferably a NH group.
  • the X moiety alpha to the aromatic ring is preferably a carbon based group such as CH 2 or CO, preferably CO.
  • a particularly preferred linker X-X is -CONH- .
  • R lb examples of particular values for R lb are: hydrogen or (1-4C) alkyl, such as methyl.
  • R lb is preferably a hydrogen atom.
  • the alpha atom (Y) is preferably a CH or C(CH 3 ) group, especially CH.
  • R ld examples of particular values for R ld are: hydrogen ; and for alkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: (1-6C) alkyl, such as methyl or ethyl, or aryl (1-6C) alkyl , such as benzyl or phenylethyl .
  • R ld is preferably hydrogen.
  • the linker may be optionally branched, for example, to incorporate a polar functionality.
  • L are CO, CONH, CH 2 NHCO and CONHCH 2 , more preferably CO or CONH.
  • the lipophilic group comprises an alkyl group
  • this may be, for example, a (1-3C) alkyl group, such as methyl, ethyl or propyl .
  • an alkyl group is unsubstituted.
  • the lipophilic group comprises a carbocyclic group, this may be, for example, a non-aromatic or aromatic, mono or polycyclic hydrocarbon group containing up to 25, more preferably up to 10 carbon atoms.
  • the carbocyclic group may thus be, for example, a cycloalkyl, polycycloalkyl , phenyl or naphthyl group, or a cycloalkyl group fused with a phenyl group .
  • cycloalkyl group examples include (3-6C) cycloalkyl groups, such as cyclopentyl and cyclohexyi.
  • a cycloalkyl group is preferably unsubstituted or substituted by one group R 3 , preferably an ammo or alkyl group .
  • polycycloalkyl group examples include (6-10C) polycycloalkyl groups, such as bicycloalkyl, for example decalmyl, norbornyl or adamantyl.
  • a polycycloalkyl group is preferably unsubstituted or substituted by one, two or three R 3 groups, for example alkyl such as methyl .
  • An example of a polycycloalkyl group substituted by alkyl is lsopmocampheyl .
  • a phenyl group is preferably unsubstituted or substituted by one or two R 3 groups.
  • a naphthyl group is preferably unsubstituted or substituted by one R 3 group.
  • Examples of a cycloalkyl or cycloalkenyl group fused with a phenyl group are mdanyl and tetrahydronaphthyl. This group is preferably unsubstituted or substituted by oxo or one or two R 3 groups. Examples of groups substituted by oxo are l-oxomdan-5-yl , l-oxo-5 , 6 , 7 , 8-tetrahydronaphth-5-yl and l-oxo-5, 6,7, 8-tetrahydro-naphth-6-yl .
  • the lipophilic group comprises a heterocyclic group
  • this may be, for example, a non-aromatic or aromatic, mono or polycyclic group containing one or two oxygen, nitrogen or sulfur atoms in the ring system, and m total up to 25, more preferably up to 10 ring system atoms.
  • heterocyclic group when it is a non- aromatic monocyclic group examples include azacycloalkyl groups, such as pyrrolidmyl and pipe ⁇ dmyl ; azacycloalkenyl groups, such as pyrrolmyl; diazacycloalkyl groups, such as piperazmyl ; oxacycloalkyl groups, such as tetrahydropyranyl ; and thiacycloalkyl groups, such as tetrahydrothiopyranyl.
  • a non- aromatic monocyclic group preferably contains 5, 6 or 7 ring atoms and is preferably unsubstituted or substituted by one group R 3 .
  • heterocyclic group when it is a non- aromatic polycyclic group are bicyclic groups, such as azacycloalkyl fused with phenyl, for example dihydroindolyl , dihydroisomdolyl, tetra ydroquinolmyl and tetrahydroisoqumolmyl ; and azacycloalkyl fused with cycloalkyl, such as decahydroisoqumolmyl .
  • bicyclic groups such as azacycloalkyl fused with phenyl, for example dihydroindolyl , dihydroisomdolyl, tetra ydroquinolmyl and tetrahydroisoqumolmyl
  • azacycloalkyl fused with cycloalkyl such as decahydroisoqumolmyl .
  • Examples of a heterocyclic group when it is a aromatic monocyclic group are furyl , pyrrolyl, thienyl , lmidazolyl, py ⁇ dyl, pyridazmyl, pyrimid yl, pyrazmyl and triazmyl, preferably unsubstituted or substituted by one or two R 3 groups .
  • Examples of a heterocyclic group when it is an aromatic polycyclic group are bicyclic groups such as benzofuryl, qu olmyl, lsoqumolmyl , benzothienyl , mdolyl and benzothiazolyl .
  • the lipophilic group preferably comprises a cycloalkyl, azacycloalkyl, diazacycloalkyl, phenyl, naphthyl, adamantyl, bicycloalkyl , mono- or diazabicycloalkyl , mono- or bicyclo heteroaromatic or a linear or branched alkyl or alkenyl group all optionally substituted by one or more oxo or groups R 3 , or a combination of at least two such groups linked by a spiro linkage or a single or double bond or by
  • Lp comprises a combination of at least two groups, it preferably comprises a combination of two or three such groups.
  • R 3 examples of particular values for R 3 are : - for alkylam ocarbonyl : N-methyl-N-ethylammocarbonyl ; for N-alkylaminoalkanoyl : N-methylacetyl ; for N-alkanoylammoalkanonyl: 2-N-acetylammoacetyl or 2-N- acetylammopropanoyl ; for C-hydroxyammoalkanoyl : 2-ammo-3 -hydroxypropanoyl or 2- ammo-3 -hydroxybutanoyl ; hydrogen; hydroxyl ; for alkoxy optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: alkoxy such as methoxy; for alkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: alkyl, such
  • 6C) alkyl such as am omethyl , amido (CONH 2 ) , and amino (1- 6C) alkanoyl, such as ammoacetyl (COCH 2 NH 2 ) , ammopropionyl (COCH 2 CH 2 NH 2 ) or 2 -ammopropionyl (COCH (CH 3 ) NH 2 ) ;
  • hydroxyalkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: hydroxy (1- 6C) alkyl, such as hydroxymethyl or 1-hydroxyethyl , or hydroxy (1-6C) alkanoyl , such as 2-hydroxyacetyl or 2- hydroxypropanoyl ;
  • alkoxyalkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: (1-6C) alkoxy (1- 6C)
  • the lipophilic group is selected from
  • R 3 is as hereinbefore defined
  • X represents CH or N.
  • L represents CO when the Lp group is linked to L through N, or CONH when the Lp group is linked to L through C.
  • R 3 preferably represents hydrogen, hydroxyl or alkylammocarbonyl .
  • Lp m this sub-group examples are pyrrol ⁇ dm-1-yl , p ⁇ per ⁇ dm-1-yl , 3-N-methyl, N- ethylammocarbonylp ⁇ per ⁇ dm-1-yl , decahydro ⁇ soqumolm-2-yl and 2 , 3 -d ⁇ hydromdol-1-yl .
  • R 3 is preferably hydrogen, ammo, hydroxy, alkyl or ammoalkyl.
  • L represents CONH and Lp represents ln which R 3 is alkylammocarbonyl, N-alkylammoalkanoyl, N- alkanoylammoalkanonyl, C-hydroxyammoal anoyl , hydrogen, alkoxy, alkyl, ammoalkyl, ammocarbonyl, hydroxyalkyl , alkoxyalkyl, alkoxycarbonyl , acyloxymethoxycarbonyl , alkylammo, ammo, halo, cyano, mtro, thiol, alkylthio, alkylsulphonyl , alkylsulphenyl , t ⁇ azolyl, imidazolyl, tetrazolyl, hydrazido, alkyl imidazolyl, thiazolyl, alkyl thiazolyl, alkyl oxazolyl, oxazolyl, oxazolyl,
  • the phenyl group is unsubstituted or substituted by one or two R 3 groups.
  • Examples of particular values are phenyl, 3-cyano-4- methylphenyl, 3 -ammocarbonylphenyl , 4 -ammocarbonyl -phenyl , 4 -chloro-3 -ammocarbonyl -phenyl , 4-chlorophenyl , 3,5- dichlorophenyl , 3 -am omethylphenyl , 4 -methyl -3- acetylammophenyl , 4- (1-hydroxethyl) phenyl and 4- lsopropylphenyl .
  • Another particular group of compounds of formula I is that m which L represents CONH and Lp represents
  • R 3x represents R 3 or a group of formula
  • R. represents a carbocyclic or
  • heterocyclic group optionally substituted by R 3 .
  • Lp represents a group as described above, it corresponds to a group in which Lp is a combination of a heterocyclic group (2 , 3 -dihydromdolyl) , a carbocyclic or heterocyclic group (R, ) and optionally an
  • alkyl group (G x ) which groups are linked by a single bond or a carbonyl group. Accordingly, examples of particular values for R, are the examples given above for a carbocyclic or heterocyclic group forming part of Lp . Particular mention may be made of pyyrolidmyl , such as pyrrol ⁇ dm-1- yl , phenyl, thiazolyl, such as th ⁇ azol-4-yl , imidazolyl, such as ⁇ m ⁇ dazol-4-yl, and pyridyl, such as py ⁇ d-2-yl, py ⁇ d-3-yl and pyr ⁇ d-4-yl.
  • pyyrolidmyl such as pyrrol ⁇ dm-1- yl , phenyl, thiazolyl, such as th ⁇ azol-4-yl , imidazolyl, such as ⁇ m ⁇ dazol-4-yl
  • pyridyl
  • Examples of values for G are -CH 2 -, and CH 2 CH 2 .
  • the 2 , 3 -dihydromdolyl group m the above formula is preferably a 2 , 3 -d ⁇ hydromdol-5-yl or -6-yl group, especially a 2 , 3 -d ⁇ hydromdol-6-yl group.
  • Examples of structures of compounds comprising a 2,3- dihydromdolyl group as described above are :
  • R 3 is a substituent on the 1 -position of a 2,3- dihydromdolyl group, it preferably represents alkylammocarbonyl; N-alkylammoalkanoyl; N- alkanoylammoalkanonyl ; C-hydroxyaminoalkanoyl ; hydrogen; alkyl; alkanoyl; alkoxycarbonyl ; acyloxymethoxycarbonyl ; ammoalkyl; ammoalkanoyl; hydroxyalkyl; hydroxyalkanoyL; alkoxyalkyl; or alkanoylammo.
  • N-methylammoacetyl N-acetylammoacetyl , N- acetylalanmoyl , sermoyl, threonmoyl , hydrogen, methyl, acetyl, propanoyl, 2-methylpropanoyl , 3 -methylbutyryl , 2- hydroxypropanoyl , hydroxyacetyl, ammoacetyl and alanmoyl.
  • examples of particular values for Lp are: 1- (N-methylammoacetyl) -2 , 3 -d ⁇ hydromdol-6-yl ; 1- (N- acetylammoacetyl) -2 , 3-d ⁇ hydromdol-6-yl ; 1- (N- acetylalanmoyl) -2 , 3 -d ⁇ hydromdol-6-yl ; 1- (sermoyl) -2,3- d ⁇ hydromdol-6-yl ; 1- (threonmoyl) -2 , 3 -d ⁇ hydromdol-6-yl ; 2 , 3-d ⁇ hydromdol-5-yl ; l-methyl-2 , 3 -dihydromdol -6-yl ; 1- acetyl-2 , 3 -dihydromdol -6-yl ; l-propanoyl
  • R 3 is a substituent on a phenyl, thiazolyl, imidazolyl or pyridyl group, it is preferably hydrogen, ammo, alkyl or ammoalkyl. Examples of particular values are hydrogen, ammo, alkyl or ammomethyl .
  • Lp further examples of particular values for Lp are: 2 , 3 -dihydromdol -5 -yl , l-prolmoyl-2 , 3 -dihydromdol - 6-yl, l-phenylacetyl-2 , 3 -dihydromdol -6-yl , l-(2- hydroxy) phenylacetyl-2 , 3 -dihydromdol -6-yl , 1- (3 - hydroxy) phenylacetyl-2 , 3 -dihydromdol -6-yl , 1- (4- hydroxy) phenylacetyl-2 , 3 -dihydromdol -6-yl , 1- (4- hydroxy) phenylacetyl-2 , 3 -dihydromdol -6-yl , 1- (4- pyridyl) acetyl-2 , 3 -d
  • the cyclic group attached to the alpha carbon is preferably an optionally R 3a substituted cycloalkyl (such as cyclohexyi), piperldmyl (such as p ⁇ pe ⁇ dm-4 -yl) , phenyl, thienyl (such as th ⁇ en-2-yl or th ⁇ en-3-yl) , thiazolyl (such as th ⁇ azol-4-yl or th ⁇ azol-5-yl) , pyridyl (such as pyr ⁇ d-3- yl or py ⁇ d-4-yl) or naphthyl (such as naphth-1-yl) group.
  • R 3a substituted cycloalkyl such as cyclohexyi
  • piperldmyl such as p ⁇ pe ⁇ dm-4 -yl
  • phenyl such as p ⁇ pe ⁇ dm-4 -yl
  • thienyl such as th ⁇ en-2-y
  • R 3a examples of particular values for R 3a are : - hydrogen; hydroxyl ; for alkoxy: methoxy or ethoxy; for alkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or ethyl, or alkylammoalkyl , such as methylammomethyl or dimethylammomethyl ; for hydroxyalkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: hydroxymethyl; for alkoxyalkyl : methoxymethyl ; for alkoxycarbonyl : methoxycarbonyl or ethoxycarbonyl; for alkylammocarbonyl : methylammocarbonyl or dimethylammocarbonyl ; for ammoalkyl optionally substituted by hydroxy, alkylammo, alk
  • alkylammo optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: (1- 6C) alkanoylammo, such as formylammo or acetylamino; for alkoxycarbonylam o : methoxycarbonylammo, ethoxycarbonylammo or t-butoxycarbonylammo; am o ; for halo: fluoro or chloro; cyano ; mtro; thiol ; for alkylthio: methylthio; for alkylsulphonyl : methylsulphonyl or ethylsulphonyl ; for alkylsulphenyl : methylsulphenyl ; for imidazolyl: imidazol-4-yl ; hydrazido; for alkylim
  • R_ c examples of particular values for R_ c are: hydrogen; hydroxyl ; for alkoxy: methoxy or ethoxy; for alkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or ethyl, or alkylaminoalkyl , such as methylaminomethyl or dimethylaminomethyl ; for hydroxyalkyl : hydroxymethyl ; for alkoxyalkyl: methoxymethyl ; for alkoxycarbonyl: methoxycarbonyl or ethoxycarbonyl; for alkylammocarbonyl : methylaminocarbonyl or dimethylaminocarbonyl ; for alkoxycarbonylamino : methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino; for alkylamino optionally substituted by hydroxy, alky
  • Cy is preferably unsubstituted or substituted by one or two R3 a groups.
  • R3 a is hydrogen, hydroxyl, ammo, aminomethyl, hydroxymethyl, amido, formylammo, acetylammo or ammoacetyl .
  • Cy examples are cyclohexyi, p ⁇ per ⁇ dm-4-yl , phenyl, 4-ammophenyl , 4-hydroxphenyl , 3- ammomethylphenyl , 4-ammomethylphenyl , 4- hydroxmethylphenyl , 3-hydroxyrnethylphenyl , 2- hydroxymethylphenyl, 4-phenylphenyl , 2-ammoth ⁇ azol-4-yl , 2- formylammoth ⁇ azol-4-yl , 2-ammoth ⁇ azol-5-yl , 2- formylammoth ⁇ azol-5-yl , 4-ammopyr ⁇ d-3 -yl , 3 -ammo-pyr ⁇ d-4 - yl and naphth-1-yl.
  • the group R x is preferably a group of formula -CH(R 6a )NH 2 in which R 6a is hydrogen or methyl.
  • R 6a is hydrogen or methyl.
  • R 2 represents a 5 or 6 membered aromatic carbon ring optionally interrupted by a nitrogen, oxygen or sulphur ring atom, substituted m the 3 position by R x .
  • the 5 or 6 membered aromatic ring is preferably unsubstituted or substituted in the position alpha to the X- X.. group (i.e. 6 position for a six membered aromatic ring etc) by ammo, hydroxy, halo, alkyl, carboxy, cyano, amido, ammoalkyl, alkoxy or alkylthio. More preferably it is unsubstituted or substituted by ammo. Most preferably it is unsubstituted.
  • R 2 is preferably a group of formula
  • R 5 is amino, hydroxy, aminomethyl, hydroxymethyl or hydrogen
  • R 6 and R 7 which may be the same or different represent hydrogen or R x .
  • R 5 is preferably amino or hydrogen. Most preferably it is hydrogen.
  • R 2 is a group of formula
  • R 5 is amino, hydroxy, aminomethyl, hydroxymethyl or hydrogen
  • R 6a is hydrogen or methyl
  • R 2 is 3-aminomethylphenyl .
  • L-Lp(D) ⁇ represents CO-L x ;
  • R s represents ammo, hydroxy, aminomethyl, hydroxymethyl or hydrogen
  • R 6a represents hydrogen or methyl
  • Cy is a saturated or unsaturated, mono or poly cyclic, homo or heterocyclic group, preferably containing 5 to 10 ring atoms and optionally substituted by groups R 3a or phenyl optionally substituted by R 3a ; each R 3a independently is R lc , ammo, halo, cyano, tro, thiol, alkylthio, alkylsulphonyl , alkylsulphenyl , hydrazido, alkylsulphonamido, alkylammo-sulphonyl , aminosulphonyl, haloalkoxy, and haloalkyl ; each R lc independently represents hydrogen or hydroxyl, alkoxy, alkyl, ammoalkyl, hydroxyalkyl alkoxyalkyl, alkoxycarbonyl, acyloxymethoxycarbonyl or alkylammo optionally substituted by hydroxy, alkylammo, alkoxy, o
  • L x is a mono or bicyclic group bound to the carbonyl via a pendent nitrogen atom or nitrogen atom which forms part of the mono or bicyclic ring; or a physiologically tolerable salt thereof, e.g. a halide, phosphate or sulphate salt or a salt with ammonium or an organic amme such as ethylamme or meglumme .
  • the group CO-L x corresponds with the group L-Lp(D) n in which L is CONH and Lp is a mono or bicyclic group.
  • the group CO-Lx corresponds with the group L-Lp(D) n in which L ⁇ s CO and Lp is a mono or bicyclic group containing a nitrogen atom in the ring and bound to L via this nitrogen.
  • R 5 and R s are both preferably hydrogen.
  • the Lx group comprises
  • a and B are independently chosen from NH, N, 0, S, CH, CH 2 ;
  • R lx and R 2x are independently chosen from hydrogen, alkoxy, alkyl, ammoalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, ammo, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl , oxo, heterocyclo optionally substituted by R 3x , cycloalkyl optionally substituted by R 3x or aryl optionally substituted by R 3x ; and
  • R 3x is hydrogen, alkoxy, alkyl, ammo, hydroxy, alkoxy, alkoxycaroonyl , halo, cyano, nitro, thiol, sulphonyl, or sulphenyl.
  • heterocyclic R lx and R 2x groups are pipe ⁇ dine, piperazme and pyrrolldme.
  • the cyclic group attached to the alpha atom is preferably an optionally R 3a substituted phenyl.
  • one group compounds of the invention are those of formula (II)
  • Lx is as hereinbefore defined. It is envisaged that especially preferred Lx groups will be those in which a cyclic or bicyclic ring is substituted by hydrogen bond donating and/or acceptor groups.
  • phenyl -based functionality on the left side of the compounds of the invention may be replaced by an optionally substituted, e.g. R substituted, 2 -aminomethylthiophene .
  • the compounds of the invention may be prepared by conventional chemical synthetic routes, e.g. by amide bond formation to couple the aromatic function to the alpha atom and to couple the lipophilic function to the alpha atom.
  • the alpha atom is a carbon
  • the cyclic group-alpha atom combination may conveniently derive from an alpha ammo acid (preferably of D configuration) with the aromatic deriving from for example an acid derivative of a compound based on R 2 , e.g. an ammomethylbenzoic acid (which is readily available; .
  • Amide formation from sucn reagents in which any ammo or hydroxyl function (especially in an aminomethyl group) may if desired be protected during some or all of the synthesis steps) yields a compound of formula
  • the ammo group in an ammoalkyl group Prior to reaction the ammo group in an ammoalkyl group should be protected by an appropriate protecting group e.g. Boc, Z, Fmoc or Bpoc .
  • an appropriate protecting group e.g. Boc, Z, Fmoc or Bpoc .
  • the use of protecting groups is described m McOmie, "Protective Groups in Organic Chemistry", Plenum, 1973 and Greene, “Protective Groups in Organic Synthesis", Wiley Interscience, 1981. According to another aspect therefore, the present mvention provides compounds of formula ( I ' )
  • R x is replaced by a protected ammoalkyl group of formula PG-NH (alkyl) - in which PG la an ammo protecting group (defined in more detail below) .
  • the lipophilic group (and optionally simultaneously the hydrogen bond donor) may then conveniently be introduced by reaction of a compound of formula (V) (or another analogous carboxylic acid) optionally after transformation into an activated form, e.g. an acid chloride or active ester, with a lipophilic group carrying an amine, hydroxylamme, hydrazme or hydroxyl group, e.g. to produce compounds with linkages of -CO-NR ⁇ , -C0-NR ld -0- , -CO-NR ld -NR ld - and -CO-O- from the alpha atom (where it is a carbon) to the lipophilic group.
  • a compound of formula (V) or another analogous carboxylic acid
  • an activated form e.g. an acid chloride or active ester
  • a lipophilic group carrying an amine, hydroxylamme, hydrazme or hydroxyl group e.g. to produce compounds with linkages of -CO-NR ⁇
  • the amide linkage can be reduced using an appropriate reducing agent employing the necessary protection depending on whether concurrent reduction of the carboxylic acid moiety is also desired.
  • a compound of formula V or another analogous carboxylic acid may be transformed into an alcohol by reaction with isobutylchloroformate and reduction with sodium borohyd ⁇ de .
  • Such an alcohol e.g.
  • R 2 - CONH - CH(Cy)CH 2 OH (VI) can be reacted to introduce the lipophilic group by reactions such as: alkylation with an alkyl halide in the presence of a base ; reaction under Mitsunobu conditions, such as with diethyl azodicarboxylate/triphenylphosphine and a hydroxylated aryl compound; by reaction with an activated carboxylic acid (e.g.
  • an acid chloride or with a carboxylic acid and diethylazodicarboxylate/triphenylphosphine; by reaction with an isocyanate; and by treatment with methanesulphonyl chloride or trifluoromethanesulphonic anhydride and reaction with an amine, or with a thiol optionally followed by oxidation, e.g. with potassium metaperiodate or hydrogen peroxide.
  • the alcohol can be oxidized to form a corresponding aldehyde (e.g. by oxidation with manganese dioxide or DMSO/oxalyl chloride or DMSO/S0 3 or Dess-Martin reagent) which may be reacted to introduce the lipophilic group by reactions such as: reaction with Wittig reagents or Horner-Emmons reagents, optionally followed by reduction of the resulting carbon: carbon double bond using H 2 /Pd-carbon; reaction with an organometallic , eg a Grignard reagent, optionally followed by reaction on the resulting hydroxyl group, such as oxidation (eg with Mn0 2 , DMSO/oxalyl chloride or Dess-Martin reagent) , alkylation (eg with an alkyl halide in the presence of a base in a solvent such as DMF) , arylation (eg with diethylazo dicarboxylate/triphenyl pho
  • Such an amine reagent may be reacted to introduce the lipophilic group, e.g. by acylation with an acid halide or activated ester, by reaction with isocyanate, by reaction with an isothiocyanate, or by reaction with a sulphonyl chloride.
  • Such amides may be reacted to introduce lipophilic groups, e.g. by reaction with a haloketone (e.g. phenacyl bromide) . This provides a linkage
  • the amide may be transformed to a thioamide by reaction with Lawesson's reagent and then reacted with a haloketone to form a linkage
  • the amide reagent may likewise be transformed to a nitrile reagent by dehydration, e.g. with trifluoroacetic anhydride.
  • the nitrile reagent may be reacted with hydrazine then with acyl halide and then cyclized, (e.g. with trifluoroacetic anhydride) to produce a linkage
  • the hydrazide produced by reaction of a carboxylic acid reagent with hydrazine discussed above may likewise be used as a reagent for lipophilic group introduction, e.g. as a compound of formula
  • the hydrazide may be transformed by reaction with Lawesson's reagent and then reacted with an acyl halide and cyclized (e.g. with trifluoroacetic anhydride) to produce the linkage
  • PG Protecting group The protecting group may then be removed before coupling of the for example o-ammo benzoic acid (optionally protected) .
  • the protection of ammo and carboxylic acid groups is described in McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973, and Greene and Wuts, Protecting Groups Organic Synthesis, 2nd. Ed., John Wiley Sc Sons, NY, 1991.
  • carboxy protecting groups include C x - C 6 alkyl groups such as methyl, ethyl, t-butyl and t-amyl; aryl (C 1 -C 4 ) alkyl groups such as benzyl, 4-n ⁇ trobenzyl , 4- methoxybenzyl , 3 , 4-d ⁇ methoxybenzyl , 2 , 4-d ⁇ methoxybenzyl , 2 , 4 , 6-tr ⁇ methoxybenzyl , 2 , 4 , 6-tr ⁇ methylbenzyl , benzhydryl and t ⁇ tyl; silyl groups such as t ⁇ methylsilyl and t- butyldimethylsilyl ; and allyl groups such as allyl and 1- (trimethyls lylmethyl) prop-l-en-3 -yl .
  • aryl (C 1 -C 4 ) alkyl groups such as benzyl, 4-n ⁇ trobenzyl ,
  • amine protecting groups include acyl groups, such as groups of formula RCO in which R represents C 1-s alkyl, C 3 . 10 cycloalkyl, phenyl C x 6 alkyl, phenyl, C ⁇ alkoxy, phenyl C 1-6 alkoxy, or a C 3 . 10 cycloalkoxy, wherein a phenyl group may oe optionally substituted, for example by one or two of halogen, C 1 -C 4 alkyl and C 1 -C 4 alkoxy.
  • Preferred ammo protecting groups include t-butoxycarbonyl (Boc) and benzyl.
  • ⁇ -Ammo acids of formula (VII) which are not commercially available can be synthesized by methods known in the art, for example as described m "Synthesis of Optically Active ⁇ -Amino Acids” by Robert M. Williams (Pergamon Press, 1989) and “Asymmetric Synthesis of ArylGlycmes” , Chem. Rev. 1992, 889-917.
  • a starting reagent for lipophilic group introduction where the alpha atom is nitrogen may be produced for example by reaction of a beta protected hydrazine (such protection to be chosen as to be compatible with the subsequent reagents to be employed) with phosgene, diphosgene, t ⁇ phosgene or N,N' carbonyl dnmidazole to give a reactive compound of the type:
  • PG Protecting group This intermediate may be used as has been described above for the carboxylic starting reagents where the alpha atom is carbon.
  • the invention provides a process for the preparation of a compound according to the invention which process comprises coupling a lipophilic group to a compound of formula (VIII)
  • the compounds of formula I may alternatively be prepared by a process in which the group R 2 is introduced in the final process step.
  • the invention provides a process for the preparation of a compound according to the invention which process comprises coupling a lipophilic group to a compound of formula (IX)
  • R 2 is as defined above and Z3 is XH or an appropriate reactive group
  • Z3 is XH or an appropriate reactive group
  • H 2 N may be reacted with a compounds of formula (X) in which Z3 is COOH or a reactive derivative thereof, such as a acyl halide or an anhydride, for example as described the Examples herein.
  • Z3 is COOH or a reactive derivative thereof, such as a acyl halide or an anhydride, for example as described the Examples herein.
  • the lipophilic group Lp comprises more than one group
  • it may generally be formed by coupling these groups together at an appropriate stage in the preparation of the compound of formula I using conventional methods or as described in the Examples .
  • the compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature or transdermally.
  • the compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc.
  • Such compositions may contain components conventional pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • the compositions will be sterile and in a solution or suspension form suitable for injection or infusion.
  • Such compositions form a further aspect of the invention.
  • Hard gelatin capsules are prepared using the followmg ingredients :
  • Tablets each containing 60 mg of active ingredient are made as follows:
  • the active ingredient, starch, and cellulose are passed through a No . 45 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvmylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve.
  • the granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
  • the compounds of the invention will have excellent oral bioavailability .
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a serme protease (tryptase) inhibitor according to the invention together with at least one pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may also optionally comprise at least one further anti -inflammatory
  • the invention provides the use of a serine protease (tryptase) inhibitor according to the invention for the manufacture of a medicament for use in a method of treatment of the human or non-human animal body (e.g. a mammalian, avian or reptilian body) to combat (i.e. treat or prevent) a condition responsive to said inhibitor.
  • the invention provides a method of treatment of tne numan or non-numan animal body (e.g. a mammalian, avian or reptilian body) to combat a condition responsive to a serine protease (tryptase) inhibitor.
  • tne numan or non-numan animal body e.g. a mammalian, avian or reptilian body
  • tryptase serine protease
  • the dosage of the inhibitor compound of the invention will depend upon the nature and severity of the condition being treated, the administration route and the size and species of the patient. However m general, quantities of from 0.01 to 100 ⁇ mol/kg bodyweight will be administered. All publications referred to herein are hereby incorporated by reference.
  • Flash column chromatography was carried out using Merck silica gel S ⁇ 60 (40-63 ⁇ m, 230-400 mesh) . Purification of final products was by crystallisation, flash column chromatography or gradient reverse phase HPLC on a Waters Deltaprep 4000 at a flow rate of 50 mL/mmute using a Deltapak C18 radial compression column (40 mm x 210 mm, 10- 15 mm particle size) .
  • Eluant A consisted of aqueous trifluoroacetic acid (0.1 %) and eluant B 90% acetomtrile in aqueous trifluoroacetic acid (0.1 %) with gradient elution (Gradient, 0 minutes 5 % B for 1 minutes, then 5 % B to 20 % B over 4 minutes, then 20 % B to 60 % B over 32 minutes) . Fractions were analysed by analytical HPLC and LC/MS before pooling those with >95 % purity for lyophilisa ion.
  • LC/MS were performed on a PESCIEX single quadrupole API- 150EX instrument, equipped with a Luna 2 C18 column (3 ⁇ , 30 mm x 4.6 mm) eluting with 20 % to 100 % acetonitrile in water over five minutes.
  • 2-Ammo-6-mtrobenzoth ⁇ azole 500 mg, 2.56 mmol was dissolved methanol (20 mL) and 10 % palladium on carbon (50 mg) was added as a slurry in methanol (1 mL) . The atmosphere was replaced with hydrogen and the suspension was stirred overnight. The catalyst was removed by suction filtration and the solvent evaporated to afford 2,6- diammobenzothiazole (420 mg, 99 %) as a pale yellow solid.
  • .W-BOC-3-aminomethylbenzoic acid 250 mg, 1.0 mmol
  • l-(3- dimethylaminopropyl) -3-ethylcarbod ⁇ mide hydrochloride 190 mg, 1.0 mmol
  • 7-aza-l-hydroxybenzotriazole 140 mg, 1.0 mmol
  • D-Phenylglycine 2-aminobenzothiazol-6-amide trifluoroacetate salt 350 mg, 0.85 mmol
  • Examples 2 - 34 were prepared in the same fashion as Example 1, starting with the indicated nitro-compound or amine. Other functional groups present were protected appropriately.
  • N-BOC-D-phenylglycine l-benzyloxycarbonyl-2, 3 -dihydroindol- 6 -amide A solution of N-BOC-D-phenylglycme (0.83 g, 3.28 mmol), 1- [3- (dimethyl -ammo) propyl] -3-ethylcarbod ⁇ m ⁇ de hydrochlo ⁇ de (0.75 g, 3.9 mmol), 1 -hydroxy- 7 -azabenzot ⁇ azole (0.54 g, 3.9 mmol) and 4- (N, N-dimethylammo) py ⁇ dme (10 mg, cat.) in dimethylformamide (20 mL) was stirred at room temperature and a solution of the above amme (0.88 g, 3.28 mmol) in dimethylformamide (20 mL) was added and the mixture allowed to stir overnight.
  • the dimethylformamide was evaporated under reduced pressure and the resulting oil partitioned between water (50 mL) and ethyl acetate (50 mL) .
  • the ethyl acetate was washed with 5% aqueous HCl (10 mL) and saturated aqueous NaHC0 3 (10 mL) , dried (MgSO and evaporated under reduced pressure to give the amide as a golden foam (1.6 g, 97 %) .
  • Examples 36 - 60 were prepared from the intermediate 3 - ⁇ N- BOC-aminomethyl) -benzoyl -D-phenylglycme 2 , 3 -dihydromdol -5- amide, described for Example 29, and the appropriate carboxylic acid or derivative, using standard chemical methods and protecting other functionality where required.
  • Example 59 3- (Aminomethyl) benzoyl-D-phenylglycine l-(2- aminothiazol-4-yl) - cetyl-2,3-dihydroindol- 6-amide dihydrochloride .
  • Zinc cyanide (10.4 g, 0.088 mol) and tetrakis- (triphenylphosphme) pallad ⁇ um(O) (5 g, 4.4 mmol) were added to a solution of methyl 4-bromophenylacetate (20 g, 0.088 mol) in dimethylformamide (150 mL) . The resulting mixture was stirred at 80°C for 5 hours, then allowed to cool to room temperature. Toluene (500 mL) and 1M aqueous ammonia (500 mL) were added, the layers were separated and the organic layer washed with brine (100 mL) and dried (MgS0 4 ) .
  • the solution was partitioned between ethyl acetate (25 mL) and water (25 mL) and the organic phase was separated and washed with 5 % aqueous HCl (25 mL) , saturated aqueous NaHC0 3 (25 mL) and water (25 mL) before being dried (MgS0 4 ) and concentrated under reduced pressure to afford a yellow solid.
  • the residue was purified by flash chromatography on silica gel (ethyl acetate / hexane 1 : 1) to give the diprotected bis -amide as a colourless solid (103 mg, 61 %) .
  • Examples 62 - 64 were prepared in a similar fashion to
  • Example 61 using the specified amine in place of 5- aminoindane .
  • Examples 65 - 68 were prepared in a similar manner to
  • Example 61 except that the indicated protected amino acid was used in the place of D/L-4- (iV-BOC-aminomethyl) - ⁇ - (27- benzyloxycarbonyl ) phenylglycine .
  • 2,6-Lut ⁇ dme (9.44 ml, 8.68 g, 81.0 mmol) and 4- dimethylammopyridme (1.65 g, 13.5 mmol) were added to a stirred solution of 27-BOC-D- (4 -hydroxyphenyl) glycine methyl ester (19 g, 67.5 mmol) in dichloromethane (400 mL) and the mixture cooled in an ice bath.
  • Trifluoromethananesulphonic anhydride (13.7 mL, 23.0 g, 81.4 mmol) was added over a period of five minutes and then the mixture was allowed to warm to room temperature over four hours.
  • the vessel was pressurised to -10 psi with nitrogen and the gas released (repeated five times to remove all oxygen from the system) . Carbon monoxide gas was then carefully introduced to -20 psi and released three times. Carbon monoxide was then added to -100 psi and the stirrer started. The vessel was slowly heated to 65 °C internal temperature and then stirred, monitoring by tic. When complete (after - 18 hours) the reaction was cooled to 30°C, the gas released and the vessel flushed five times with nitrogen as before.
  • reaction mixture was partitioned between ethyl acetate (250 mL) and water (100 mL) and the organic layer washed with 1M hydrochloric acid (30 mL) and saturated aqueous NaHC0 3 (30 mL) and dried (MgS0 4 ) and evaporated. Purification of the resulting oil by column chromatography (ethyl acetate / hexane; 1:4) gave the benzyl ester (18.7 g, 70%).
  • the mixture was partitioned between ethyl acetate (25 mL) and water (25 mL) and the organic solution was washed with saturated aqueous citric acid (25 mL) , saturated aqueous NaHC0 3 (25 mL) and water (25 mL) , dried (MgSO and concentrated under reduced pressure.
  • the crude product was purified by column chromatography (ethyl acetate) to yield 2 -ammo-5 -cyanobenzoyl -D-phenylglycme 4- hydroxypiperidmamide (90 mg, 23 %) .
  • Boc D-phenylglycme (251 mg, 1 mmol.) was dissolved in dimethylformamdide (3ml) with HATU [0- (7-azabenzotr ⁇ azol-l- yl) -1, 1, 3 , 3-tetramethyluron ⁇ um hexafluorophosphate] (380 mg., 1 mmol.) and diisopropylethylam e (350 ⁇ l., 2 mmol.). To this mixture was added 4-methylbenzylamme (121mg., 1 mmol.) and diisopropylethylamme (170 ⁇ l., 1 mmol.). The mixture was stirred overnight.
  • H nmr (CD 3 CN) 7.95 (2H, m) ; 7.80 (2H, m) ; 7.50 (5H, m) ; 5.65 (IH, s) ; 4.45 (2H, s); 3.30 (2H, m) ; 3.00 (2H,m); 2.00-1.00 (10H,m) .
  • MS TOF 409 (M+l + ) .
  • Hplc Magneticellan C8 , Gradient 3, water/acetonitrile/TFA) rt 12.68 min.
  • Di- E butyl dicarbonate (0.9 g, 0.004 mol) and 5% palladium on carbon (catalytic amount) were added to a solution of the azide (0.95 g, 0.0037 mol) in methanol (25 mL) .
  • the mixture was stirred at room temperature under an atmosphere of hydrogen for 8 hours. After this time the mixture was filtered through celite, washing through with methanol (25 mL) .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Compounds of formula (I) where R2, each X, L, Y, Cy, Lp, D and n are as defined in the specification, are serine protease (especially tryptase) inhibitors useful as antiinflammatory agents.

Description

Compounds
This invention relates to compounds which are inhibitors of seπne proteases and to pharmaceutical compositions thereof and their use in the treatment of the human or animal body. More particularly it relates to compounds for use m the treatment of mast cell mediated diseases such as asthma and other allergic and inflammatory conditions and to pharmaceutical compositions thereof and their use in the treatment of the human or animal body, and m particular to compounds which are tryptase inhibitors.
The serme proteases are a group of proteolytic enzymes which have a common catalytic mechanism characterized by a particularly reactive Ser residue. Examples of serme proteases include trypsin, tryptase, chymotrypsm, elastase, thrombm, plasmm, kalli rem, Complement CI, acrosomal protease, lysosomal protease, cocoonase, α-lytic protease, protease A, protease B, serme carboxypeptidase II, subtilism, urokmase, Factor Vila, Factor IXa, and Factor Xa . The serme proteases have been investigated extensively over a period of several decades and the therapeutic value of inhibitors of serme proteases is well understood.
Serme protease inhibitors play a central role m the regulation of a wide variety of physiological process including coagulation, fibrmolysis, fertilization, development, malignancy, neuromuscular patterning and inflammation. It is well known that these compounds inhibit a variety of circulating proteases as well as proteases that are activated or released m tissue. It is also becoming clear that serme protease inhibitors inhibit critical cellular processes, such as adhesion, migration, free radical production and apoptosis. In addition, animal experiments indicate that intravenously administered serme protease inhibitors, variants or cells expressing serme protease inhibitors, provide a protective effect against tissue damage.
Serme protease inhibitors have also been predicted to have potential beneficial uses in the treatment of disease in a wide variety of clinical areas such as oncology, neurology, haematology, pulmonary medicine, immunology, inflammation and infectious disease.
In particular serme protease inhibitors may be beneficial in the treatment of thrombotic diseases, asthma, emphysema, cirrhosis, arthritis, carcinoma, melanoma, restenosis, atheroma, trauma, shock and reperfusion injury.
Asthma, the most prevalent of all mast cell mediated conditions affects about 5% of the population m industrialised countries and there s evidence that its incidence and severity are on the increase. Furthermore, the incidence of childhood asthma is rising and there are suggestions of a link between environmental pollutants and the onset of the disease.
Initially, it was believed that bronchoconstriction, i.e. the narrowing of the airways m the lungs, was the major feature of asthma. However, it is now recognised that inflammation m the lungs is an integral part of the development of the disease.
The inhalation of an allergen by an asthmatic generates a strong immune system response which triggers release of various inflammatory mediators, including histamme and leukotπenes from inflammatory cells. These increase the permeability of the blood vessel walls, attract inflammatory cells into the tissues and contract the smooth muscle around the airways. As a result, fluid leaks from the blood and the tissues swell, further narrowing the airways. The inflammatory cells cause damage to the epithelial cells lining the airways exposing nerve endings which stimulates secretion of mucous as well as augmenting the inflammation by causing the release of neurokmms . Thus asthma is a complex disease frequently characterised by progressive developments of hyper- responsiveness of the trachea and bronchi as a result of chronic inflammation reactions which irritate the epithelium lining the airway and cause pathological thickening of the underlying tissues.
Leukocytes and mast cells are present in the epithelium and smootn muscle tissue of tne bronchi where they are activated initially by binding of specific inhaled antigens to IgE receptors. Activated mast cells release a number of preformed or primary chemical mediators of the inflammatory response m asthma as well as enzymes. Moreover, secondary mediators of inflammation are generated by enzymatic reactions of activated mast cells and a number of large molecules are released by degranulation of mast cells. It has therefore been proposed that chemical release from mast cells probably accounts for the early bronchiolar constriction response that occurs in susceptible individuals after exposure to airborne allergens . The early asthmatic reaction is maximal at around 15 minutes after allergen exposure, recovery occurring over the ensuing 1 to 2 hours. In approximately 30% of individuals, the early asthmatic reaction is followed by a further decline n respiratory function which normally begins within a few hours and is maximal between 6 and 12 hours after exposure. This late asthmatic reaction is accompanied by a marked increase in the number of inflammatory cells infiltrating bronchiolar smooth muscle and epithelial tissues, and spilling into the airways. These cells are attracted to the site by release of mast cell derived chemotactic agents. The most straightforward way of dealing with an asthma attack is with a bronchodilator drug which causes airways to expand. The most effective bronchodilators are tne β- adrenergic agonists which mimic the actions of adrenalin. These are widely used and are simply administered to the lungs by inhalers. However, bronchoconstπctor drugs are primarily of use m short term symptomatic relief, and do not prevent asthma attacks nor deterioration of lung function over the long term.
Anti- inflammatory drugs such as cromoglycate and the corticosteroids are also widely used m asthma therapy. Cromoglycate has anti-inflammatory activity and has been found to be extremely safe. Although such cromolyns have minimal side effects and are currently preferred for initial preventive therapy in children, it is well known that they are of limited efficacy.
The use of corticosteroids in asthma therapy was a major advance since they are very effective anti- mflammatory agents, however, steroids are very powerful, broad spectrum anti -inflammatory agents and their potency and non-specificity means that they are seriously limited by adverse side effects. Localising steroid treatment to the lungs using inhaler technology has reduced side effects but the reduced systemic exposure following inhalation still results some undesirable effects. Hence, there is a reluctance to use steroids early in the course of the disease .
There therefore still remains a need for an alternative asthma therapy which is a safe, effective, anti -inflammatory or immunomodulatory agent which can be taken to treat chronic asthma.
Tryptase is the major secretory protease of human mast cells and is proposed to be involved m neuropeptide processing and tissue inflammation. Tryptase is one of a large number of serme protease enzymes which play a central role in the regulation of a wide variety of physiological processes including coagulation, flbrmolysis , fertilization, development, malignancy, neuromuscular patterning and inflammation. Although a large number of serme proteases have been widely investigated, tryptase still remains relatively unexplored.
Mature human tryptase is a glycosylated, heparm- associated tetramer of catalytically active subunits. Its ammo-acid structure appears to have no close counterpart among the other serme proteases which have been characterised. Tryptase is stored in mast cell secretory granules and after mast cell activation, human tryptase can be measured readily a variety of biological fluids. For example, after anaphylaxis, tryptase appears the blood stream where it is readily detectable for several hours. Tryptase also appears in samples of nasal and lung lavage fluid from atopic subjects challenged with specific antigen. Tryptase has been implicated in a variety of biological processes where activation and degranulation of mast cells occur. Accordingly, mast cell tryptase inhibition may be of great value in the prophylaxis and treatment of a variety of mast cell mediated conditions. Mast cells can degranulate by both IgE-dependent and independent mechanisms thereby implicating tryptase both atopic and non-atopic inflammatory conditions. Tryptase can activate proteases such as pro-urokmase and pro-MMP3 (pro-matrix metalloprotease 3, pro-stromelysm) , thereby indicating a pathological role in tissue inflammation and remodelling. Furthermore, the recent evidence that tryptase can activate certain G-protem coupled receptors (eg PAR2 ) and induce neurogemc inflammation points to a broader physiological role, for example m modulating pain mechanisms. Given C-y cϊtoά ' i multiple mechanisms of action, it nas oeen proposed that tryptase inhibitors may be beneficial m a broad range of diseases. These include conditions such as: asthma (specifically influencing the inflammatory component, the underlying hyperreactivity, and the chronic fibrotic damage due to smooth muscle thickening) ; chronic obstructive pulmonary disease (COPD) and pulmonary fibrotic diseases; rhinitis; psoriasis; urticaria; dermatitis; arthritis; Crohn's disease; colitis; angiogenesis ; atherosclerosis; multiple sclerosis; interstitial cystitis; migraine headache; neurogemc inflammation and pain mechanisms; wound healing; cirrhosis of the liver; Kimura' s disease; pre- eclampsia; bleeding problems associated with menstruation and the menopause; cancer (particularly 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., 1995, 53, 312; Bram, 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 being induced to degranulate by whatever mechanism, including anaphylactic reactions due to exogenous substances, e.g. morphine-induced bronchoconstπction (Bowman and Rand, 2nd edt . , 1980.)
In WO96/09297, W095/32945, WO94/20527 and US 5,525,623 a variety of peptide based compounds are suggested as potential inhibitors of the mast cell protease tryptase. In WO95/03333 a tryptase inhibitor is provided by a polypeptide αbL xric-bie from the leech hxradό meάzcmalis . In W096/G8275 secretory leukocyte protease inhibitor (SLPI) and active fragments thereof have been found to inhibit the proteolytic activity of tryptase. In W099/55661 certain 4- ammomethylbenzoic ester derivatives are proposed as potential tryptase inhibitors .
We have now found that certain aromatic compounds carrying lipophilic side chains are particularly effective as inhibitors of the serme protease, tryptase.
It is envisaged that the compounds of the invention will be useful not only in the treatment and prophylaxis of asthma but also of other allergic and inflammatory conditions mediated by tryptase such as allergic rhinitis, sk conditions such as eczema, psoriasis, atopic dermatitis and urticaria, rheumatoid arthritis, conjunctivitis, inflammatory bowel disease, neurogemc inflammation, atherosclerosis and cancer.
Thus viewed from one aspect the invention provides a serme protease inhibitor compound of formula (I)
Figure imgf000009_0001
(I) where R2 represents a 5 or 6 membered aromatic carbon ring optionally interrupted by a nitrogen, oxygen or sulphur ring atom, substituted in the 3 and/or 4 position by Rι r and optionally substituted in the position alpha to the X-X group (i.e. 6 position for a six membered aromatic ring etc) by ammo, hydroxy, halo, alkyl, carboxy, cyano, amido, ammoalkyl, hydroxyalkyl , alkoxy or alkylthio; each X independently is a C, N, 0 or 3 atom or a CO, CRla, C(Rla)2 or NRla group, at least one X being C, CO, CRla or C(Rla)2; each Rx independently represents ammoalkyl; L is an organic linker group containing 1 to 5 backbone atoms selected from C, N, 0 and S, or a branched alkyl or cyclic group;
Y (the α-atom) is a nitrogen atom or a CRlb group; Cy is a saturated or unsaturated, mono or poly cyclic, homo or heterocyclic group, preferably containing 5 to 10 ring atoms and optionally substituted by groups R3a or phenyl optionally substituted by R3a; each R3a independently is Rlc, ammo, halo, cyano, tro, thiol, alkylthio, alkylsulphonyl , alkylsulphenyl , tπazolyl, lmidazolyl , tetrazolyl, hydrazido, alkyl lmidazolyl, thiazolyl, alkyl thiazolyl, alkyl oxazolyl, oxazolyl , alkylsulphonamido, alkylammosulphonyl , ammosulphonyl , haloalkoxy and haloalkyl ;
Lp is a lipophilic organic group; D is a hydrogen bond donor group; n is 0, 1 or 2 ;
Rla represents hydrogen or hydroxyl, alkoxy, alkyl, ammoalkyl , hydroxyalkyl alkoxyalkyl , alkoxycarbonyl , acyloxymethoxycarbonyl or alkylammo optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl; and
Rlb and Rlc are as defined for Rla; or a physiologically tolerable salt tnereof, e.g. a halide, phosphate or sulphate salt or a salt with ammonium or an organic am e such as ethylamme or meglumme . Compounds of formula I have surprisingly been found to be particularly effective as inhibitors of tryptase and to snow a surprising selectivity for tryptase over other serine proteases .
In the compounds of the invention, where the alpha atom is carbon it preferably has the conformation that would result from construction from a D-α-ammoacid NH2-CRlb (Cy) -COOH where the NH2 represents part of X-X. Likewise the fourth substituent Rlb at an alpha carbon is preferably a methyl or hydroxymethyl group or hydrogen. In the compounds of the invention, unless otherwise indicated, aryl groups preferably contain 5 to 10 ring atoms optionally including 1, 2 or 3 heteroatoms selected from 0, N and S; alkyl, alkenyl or alkynyl groups or alkylene moieties preferably contain up to 6 carbons, e.g. Cj, s or Cx 3; cyclic groups preferably have ring sizes of 3 to 8 atoms; and fused multicyclic groups preferably contain 8 to 16 ring atoms .
Rla is preferably hydrogen.
The linker group from the R2 group to the alpha atom is preferably selected from -CH=CH- , -CONH-, -CONRla-, -NH- CO-, -NH-CH2-, -CH2-NH-, -CH20-, -OCH2-, -COO-, -OC=0- and -CH2CH2-. Preferably, the X moiety nearest to the alpha atom is an NH or 0 atom, most preferably a NH group. The X moiety alpha to the aromatic ring is preferably a carbon based group such as CH2 or CO, preferably CO. Thus a particularly preferred linker X-X is -CONH- .
Examples of particular values for Rlb are: hydrogen or (1-4C) alkyl, such as methyl. Rlb is preferably a hydrogen atom. The alpha atom (Y) is preferably a CH or C(CH3) group, especially CH.
The linker group from the alpha atom to the lipophilic group is preferably CO, CH2NH, CONRld (CH2) m, (CH2)mN(Rld)CO(CH2)m, (CH2)m+2, CO(CH2)m, (CH2)mCO, (CH2)mOC=0, (CH2)m0, CH=CH(CH2)m, S02, S02NRld, S02(CH2)m, (CH2)raS02 or
(CH2)mS02NRld (where each m is independently 0 or 1 and Rld is as defined for Rla) .
Examples of particular values for Rld are: hydrogen ; and for alkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: (1-6C) alkyl, such as methyl or ethyl, or aryl (1-6C) alkyl , such as benzyl or phenylethyl .
Rld is preferably hydrogen.
The linker may be optionally branched, for example, to incorporate a polar functionality. Examples of particular values for L are CO, CONH, CH2NHCO and CONHCH2, more preferably CO or CONH.
It will be appreciated by those skilled in the art that a diverse range of organic groups are lipophilic, and that it is therefore impractical to define with precision each and every structure that may be incorporated into a serine protease inhibitor according to the invention. Accordingly, it is being assumed that the addressee of this specification will not require an exhaustive computer listing of structures of lipophilic groups, but will instead make use of the structures of lipophilic groups disclosed in the specification, especially those exemplified; the test systems described herein for identifying serine protease inhibitors; and common general knowledge of the lipophilicity, synthesis and stability of organic compounds, to obtain novel serine protease inhibitor compounds of formula (I) .
The lipophilic group may be, for example, an alkyl, alkenyl, carbocyclic or heterocyclic group, or a combination of two or more such groups linked by a spiro linkage or a single or double bond or by C=0, 0, S, SO, S02 , CONRle, NRle- CO-, NRle linkage (where Rle is as defined for Rla) , optionally substituted by one or more oxo or R3 groups in which R3 is alkylaminocarbonyl , alkoxycarbonylamino, N- alkylammoalkanoyl, N-alkanoylaminoalkanonyl , C- hydroxyaminoalkanoyl or is as defined for R3a.
When the lipophilic group comprises an alkyl group, this may be, for example, a (1-3C) alkyl group, such as methyl, ethyl or propyl . Preferably an alkyl group is unsubstituted. When the lipophilic group comprises a carbocyclic group, this may be, for example, a non-aromatic or aromatic, mono or polycyclic hydrocarbon group containing up to 25, more preferably up to 10 carbon atoms. The carbocyclic group may thus be, for example, a cycloalkyl, polycycloalkyl , phenyl or naphthyl group, or a cycloalkyl group fused with a phenyl group .
Examples of particular values for a cycloalkyl group are (3-6C) cycloalkyl groups, such as cyclopentyl and cyclohexyi. A cycloalkyl group is preferably unsubstituted or substituted by one group R3 , preferably an ammo or alkyl group .
Examples of particular values for a polycycloalkyl group are (6-10C) polycycloalkyl groups, such as bicycloalkyl, for example decalmyl, norbornyl or adamantyl. A polycycloalkyl group is preferably unsubstituted or substituted by one, two or three R3 groups, for example alkyl such as methyl . An example of a polycycloalkyl group substituted by alkyl is lsopmocampheyl . A phenyl group is preferably unsubstituted or substituted by one or two R3 groups.
A naphthyl group is preferably unsubstituted or substituted by one R3 group.
Examples of a cycloalkyl or cycloalkenyl group fused with a phenyl group are mdanyl and tetrahydronaphthyl. This group is preferably unsubstituted or substituted by oxo or one or two R3 groups. Examples of groups substituted by oxo are l-oxomdan-5-yl , l-oxo-5 , 6 , 7 , 8-tetrahydronaphth-5-yl and l-oxo-5, 6,7, 8-tetrahydro-naphth-6-yl . When the lipophilic group comprises a heterocyclic group, this may be, for example, a non-aromatic or aromatic, mono or polycyclic group containing one or two oxygen, nitrogen or sulfur atoms in the ring system, and m total up to 25, more preferably up to 10 ring system atoms. Examples of a heterocyclic group when it is a non- aromatic monocyclic group are azacycloalkyl groups, such as pyrrolidmyl and pipeπdmyl ; azacycloalkenyl groups, such as pyrrolmyl; diazacycloalkyl groups, such as piperazmyl ; oxacycloalkyl groups, such as tetrahydropyranyl ; and thiacycloalkyl groups, such as tetrahydrothiopyranyl. A non- aromatic monocyclic group preferably contains 5, 6 or 7 ring atoms and is preferably unsubstituted or substituted by one group R3.
Examples of a heterocyclic group when it is a non- aromatic polycyclic group are bicyclic groups, such as azacycloalkyl fused with phenyl, for example dihydroindolyl , dihydroisomdolyl, tetra ydroquinolmyl and tetrahydroisoqumolmyl ; and azacycloalkyl fused with cycloalkyl, such as decahydroisoqumolmyl . Examples of a heterocyclic group when it is a aromatic monocyclic group are furyl , pyrrolyl, thienyl , lmidazolyl, pyπdyl, pyridazmyl, pyrimid yl, pyrazmyl and triazmyl, preferably unsubstituted or substituted by one or two R3 groups . Examples of a heterocyclic group when it is an aromatic polycyclic group are bicyclic groups such as benzofuryl, qu olmyl, lsoqumolmyl , benzothienyl , mdolyl and benzothiazolyl .
The lipophilic group preferably comprises a cycloalkyl, azacycloalkyl, diazacycloalkyl, phenyl, naphthyl, adamantyl, bicycloalkyl , mono- or diazabicycloalkyl , mono- or bicyclo heteroaromatic or a linear or branched alkyl or alkenyl group all optionally substituted by one or more oxo or groups R3 , or a combination of at least two such groups linked by a spiro linkage or a single or double bond or by
C=0, 0, S, SO, S02, CONRle, NRle-CO- or NRle linkage (where Rle is as defined for Rla) .
Where Lp comprises a combination of at least two groups, it preferably comprises a combination of two or three such groups. The groups are preferably linked by a single bond, C=0, 0 or NRle .
Examples of particular values for R3 are : - for alkylam ocarbonyl : N-methyl-N-ethylammocarbonyl ; for N-alkylaminoalkanoyl : N-methylacetyl ; for N-alkanoylammoalkanonyl: 2-N-acetylammoacetyl or 2-N- acetylammopropanoyl ; for C-hydroxyammoalkanoyl : 2-ammo-3 -hydroxypropanoyl or 2- ammo-3 -hydroxybutanoyl ; hydrogen; hydroxyl ; for alkoxy optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: alkoxy such as methoxy; for alkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl, ethyl, propyl, and 2-propyl, or (1-6C) alkanoyl , such as acetyl, propionyl or isobutyryl; for ammoalkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: ammo(l-
6C) alkyl, such as am omethyl , amido (CONH2) , and amino (1- 6C) alkanoyl, such as ammoacetyl (COCH2NH2) , ammopropionyl (COCH2CH2NH2) or 2 -ammopropionyl (COCH (CH3) NH2) ; for hydroxyalkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: hydroxy (1- 6C) alkyl, such as hydroxymethyl or 1-hydroxyethyl , or hydroxy (1-6C) alkanoyl , such as 2-hydroxyacetyl or 2- hydroxypropanoyl ; for alkoxyalkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: (1-6C) alkoxy (1- 6C) alkyl such as methoxymethyl ; for alkylammo optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: (1- 6C) alkanoylammo, such as formylammo or acetylammo; am o ; for halo: chloro; cyano ; nitro; thiol ; for alkylthio: methylthio; for alkylsulphonyl : methylsulphonyl ; for alkylsulphenyl : methylsulphenyl ; and hydrazido .
Most preferably, the lipophilic group is selected from
Figure imgf000016_0001
Figure imgf000017_0001
Figure imgf000017_0002
Figure imgf000017_0003
Figure imgf000018_0001
Figure imgf000018_0002
Figure imgf000018_0003
Figure imgf000019_0001
wherein R3 is as hereinbefore defined; and
X represents CH or N.
In the Lp groups depicted above, preferably L represents CO when the Lp group is linked to L through N, or CONH when the Lp group is linked to L through C.
One group of compounds of particular interest is that in which L represents CO and Lp represents
Figure imgf000019_0002
Figure imgf000020_0001
In t s group of compounds, R3 preferably represents hydrogen, hydroxyl or alkylammocarbonyl .
Examples of particular values for Lp m this sub-group are pyrrolιdm-1-yl , pιperιdm-1-yl , 3-N-methyl, N- ethylammocarbonylpιperιdm-1-yl , decahydroιsoqumolm-2-yl and 2 , 3 -dιhydromdol-1-yl .
Another group of compounds of particular interest is that in which L represents CONH and Lp represents
Figure imgf000020_0002
Figure imgf000021_0001
rn which X is CH or N.
In this group of compounds, R3 is preferably hydrogen, ammo, hydroxy, alkyl or ammoalkyl.
Examples of particular values are: (l) 2-ammocyclohexyl or 4 -ammomethyl cyclohexyi ; (ii) adamantyl;
(m) 2-ammobenzothιazol-6-yl ; (IV) quιnolm-3 -yl ;
(v) 4-pιperιdm-l-ylphenyl or 4-pιperazm-l-ylphenyl ; (vi) l-oxomdan-5-yl; (vn) mdan-5-yl;
(vm) tetrahydronaphth-6-yl or l-methyltetrahydronaphth-6- yl;
(ix) l-oxotetrahydronaphth-6-yl or l-oxotetrahydronaphth-7- yi;
(x) 2 , 3-dιmethylmdol-5-yl ; and
(xi) (N-benzyl-3-acetylmdol-5-yl or N-benzyl-3 -acetylmdol - 7-yl.
Another group of compounds of particular interest is that which L represents CONH and Lp represents
Figure imgf000022_0001
ln which R3 is alkylammocarbonyl, N-alkylammoalkanoyl, N- alkanoylammoalkanonyl, C-hydroxyammoal anoyl , hydrogen, alkoxy, alkyl, ammoalkyl, ammocarbonyl, hydroxyalkyl , alkoxyalkyl, alkoxycarbonyl , acyloxymethoxycarbonyl , alkylammo, ammo, halo, cyano, mtro, thiol, alkylthio, alkylsulphonyl , alkylsulphenyl , tπazolyl, imidazolyl, tetrazolyl, hydrazido, alkyl imidazolyl, thiazolyl, alkyl thiazolyl, alkyl oxazolyl, oxazolyl, alkylsulphonamido, alkylammosulphonyl , ammosulphonyl , haloalkoxy or haloalkyl .
Preferably the phenyl group is unsubstituted or substituted by one or two R3 groups.
Examples of particular values are phenyl, 3-cyano-4- methylphenyl, 3 -ammocarbonylphenyl , 4 -ammocarbonyl -phenyl , 4 -chloro-3 -ammocarbonyl -phenyl , 4-chlorophenyl , 3,5- dichlorophenyl , 3 -am omethylphenyl , 4 -methyl -3- acetylammophenyl , 4- (1-hydroxethyl) phenyl and 4- lsopropylphenyl . Another particular group of compounds of formula I is that m which L represents CONH and Lp represents
Figure imgf000022_0002
in which R3x represents R3 or a group of formula
-(CO)p- (G^-R., m which p is 0 or 1; Gx represents (1-3C) alkanediyl or,
when p is 1, a bond; and R. represents a carbocyclic or
heterocyclic group, optionally substituted by R3.
It will be appreciated that when Lp represents a group as described above, it corresponds to a group in which Lp is a combination of a heterocyclic group (2 , 3 -dihydromdolyl) , a carbocyclic or heterocyclic group (R, ) and optionally an
alkyl group (Gx) , which groups are linked by a single bond or a carbonyl group. Accordingly, examples of particular values for R, are the examples given above for a carbocyclic or heterocyclic group forming part of Lp . Particular mention may be made of pyyrolidmyl , such as pyrrolιdm-1- yl , phenyl, thiazolyl, such as thιazol-4-yl , imidazolyl, such as ιmιdazol-4-yl, and pyridyl, such as pyπd-2-yl, pyπd-3-yl and pyrιd-4-yl.
Examples of values for G are -CH2-, and CH2CH2.
The 2 , 3 -dihydromdolyl group m the above formula is preferably a 2 , 3 -dιhydromdol-5-yl or -6-yl group, especially a 2 , 3 -dιhydromdol-6-yl group. Examples of structures of compounds comprising a 2,3- dihydromdolyl group as described above are :
Figure imgf000023_0001
Figure imgf000024_0001
When R3 is a substituent on the 1 -position of a 2,3- dihydromdolyl group, it preferably represents alkylammocarbonyl; N-alkylammoalkanoyl; N- alkanoylammoalkanonyl ; C-hydroxyaminoalkanoyl ; hydrogen; alkyl; alkanoyl; alkoxycarbonyl ; acyloxymethoxycarbonyl ; ammoalkyl; ammoalkanoyl; hydroxyalkyl; hydroxyalkanoyL; alkoxyalkyl; or alkanoylammo. Examples of particular values are: N-methylammoacetyl , N-acetylammoacetyl , N- acetylalanmoyl , sermoyl, threonmoyl , hydrogen, methyl, acetyl, propanoyl, 2-methylpropanoyl , 3 -methylbutyryl , 2- hydroxypropanoyl , hydroxyacetyl, ammoacetyl and alanmoyl. Accordingly, examples of particular values for Lp are: 1- (N-methylammoacetyl) -2 , 3 -dιhydromdol-6-yl ; 1- (N- acetylammoacetyl) -2 , 3-dιhydromdol-6-yl ; 1- (N- acetylalanmoyl) -2 , 3 -dιhydromdol-6-yl ; 1- (sermoyl) -2,3- dιhydromdol-6-yl ; 1- (threonmoyl) -2 , 3 -dιhydromdol-6-yl ; 2 , 3-dιhydromdol-5-yl ; l-methyl-2 , 3 -dihydromdol -6-yl ; 1- acetyl-2 , 3 -dihydromdol -6-yl ; l-propanoyl-2 , 3 -dihydromdol - 6-yl; 1- (2 -methylpropanoyl ) -2 , 3 -dihydromdol - 6 -yl ; ; l-(3- methylbutyryl ) -2 , 3 -dihydromdol -6-yl ,- 1- (2 -hydroxpropanoyl) - 2 , 3 -dihydromdol -6-yl ; l-hydroxacetyl-2 , 3 -dihydromdol -6-yl ; 1 -ammoacetyl -2 , 3 -dihydromdol -6-yl and l-alamnoyl-2 , 3- dihydro dol - 6-yl . When R3 is a substituent on a phenyl, thiazolyl, imidazolyl or pyridyl group, it is preferably hydrogen, ammo, alkyl or ammoalkyl. Examples of particular values are hydrogen, ammo, alkyl or ammomethyl .
Accordingly, further examples of particular values for Lp are: 2 , 3 -dihydromdol -5 -yl , l-prolmoyl-2 , 3 -dihydromdol - 6-yl, l-phenylacetyl-2 , 3 -dihydromdol -6-yl , l-(2- hydroxy) phenylacetyl-2 , 3 -dihydromdol -6-yl , 1- (3 - hydroxy) phenylacetyl-2 , 3 -dihydromdol -6-yl , 1- (4- hydroxy) phenylacetyl-2 , 3 -dihydromdol -6-yl , 1- (4- pyridyl) acetyl-2 , 3 -dihydromdol -6-yl, 1- (3 -pyridyl ) acetyl - 2 , 3 -dihydromdol -6-yl , l-ιmιdazol-4-ylacetyl-2 , 3 - dihydromdol -6-yl, 1- (2-ammothιazol-4-yl ) acetyl-2 , 3 - dihydromdol -6-yl, and 1- (2 -formamιdothιazol-4-yl) acetyl - 2 , 3 -dihydromdol -6-yl . The cyclic group attached to the alpha carbon is preferably an optionally R3a substituted cycloalkyl (such as cyclohexyi), piperldmyl (such as pιpeπdm-4 -yl) , phenyl, thienyl (such as thιen-2-yl or thιen-3-yl) , thiazolyl (such as thιazol-4-yl or thιazol-5-yl) , pyridyl (such as pyrιd-3- yl or pyπd-4-yl) or naphthyl (such as naphth-1-yl) group. Examples of particular values for R3a are : - hydrogen; hydroxyl ; for alkoxy: methoxy or ethoxy; for alkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or ethyl, or alkylammoalkyl , such as methylammomethyl or dimethylammomethyl ; for hydroxyalkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: hydroxymethyl; for alkoxyalkyl : methoxymethyl ; for alkoxycarbonyl : methoxycarbonyl or ethoxycarbonyl; for alkylammocarbonyl : methylammocarbonyl or dimethylammocarbonyl ; for ammoalkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: am omethyl ,
CONH2, CH2CONH2 or ammoacetyl; for alkylammo optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: (1- 6C) alkanoylammo, such as formylammo or acetylamino; for alkoxycarbonylam o : methoxycarbonylammo, ethoxycarbonylammo or t-butoxycarbonylammo; am o ; for halo: fluoro or chloro; cyano ; mtro; thiol ; for alkylthio: methylthio; for alkylsulphonyl : methylsulphonyl or ethylsulphonyl ; for alkylsulphenyl : methylsulphenyl ; for imidazolyl: imidazol-4-yl ; hydrazido; for alkylimidazolyl : 2-methylimidazol-4-yl ; for alkylsulphonamido : methylsulphonylamido or ethylsulphonylamido; for alkylaminosulphonyl : methylaminosulphonyl or ethylaminosulphonyl ; aminosulphonyl ; for haloalkoxy: trifluoromethoxy; and for haloalkyl : trifluoromethyl .
Examples of particular values for R_c are: hydrogen; hydroxyl ; for alkoxy: methoxy or ethoxy; for alkyl optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: alkyl, such as methyl or ethyl, or alkylaminoalkyl , such as methylaminomethyl or dimethylaminomethyl ; for hydroxyalkyl : hydroxymethyl ; for alkoxyalkyl: methoxymethyl ; for alkoxycarbonyl: methoxycarbonyl or ethoxycarbonyl; for alkylammocarbonyl : methylaminocarbonyl or dimethylaminocarbonyl ; for alkoxycarbonylamino : methoxycarbonylamino, ethoxycarbonylamino or t-butoxycarbonylamino; for alkylamino optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl: (1- 6C) alkanoylamino, such as formylamino or acetylamino; and for ammoalkyl substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl: aminomethyl, CONH2, CH2CONH2 or am oacetyl ;
Cy is preferably unsubstituted or substituted by one or two R3a groups.
Preferably R3a is hydrogen, hydroxyl, ammo, aminomethyl, hydroxymethyl, amido, formylammo, acetylammo or ammoacetyl .
Examples of particular values for Cy are cyclohexyi, pιperιdm-4-yl , phenyl, 4-ammophenyl , 4-hydroxphenyl , 3- ammomethylphenyl , 4-ammomethylphenyl , 4- hydroxmethylphenyl , 3-hydroxyrnethylphenyl , 2- hydroxymethylphenyl, 4-phenylphenyl , 2-ammothιazol-4-yl , 2- formylammothιazol-4-yl , 2-ammothιazol-5-yl , 2- formylammothιazol-5-yl , 4-ammopyrιd-3 -yl , 3 -ammo-pyrιd-4 - yl and naphth-1-yl. Referring to the group R2, the group Rx is preferably a group of formula -CH(R6a)NH2 in which R6a is hydrogen or methyl. Most preferably it is aminomethyl.
Preferably R2 represents a 5 or 6 membered aromatic carbon ring optionally interrupted by a nitrogen, oxygen or sulphur ring atom, substituted m the 3 position by Rx . The 5 or 6 membered aromatic ring is preferably unsubstituted or substituted in the position alpha to the X- X.. group (i.e. 6 position for a six membered aromatic ring etc) by ammo, hydroxy, halo, alkyl, carboxy, cyano, amido, ammoalkyl, alkoxy or alkylthio. More preferably it is unsubstituted or substituted by ammo. Most preferably it is unsubstituted.
R2 is preferably a group of formula
Figure imgf000029_0001
wherein R5 is amino, hydroxy, aminomethyl, hydroxymethyl or hydrogen, and R6 and R7 which may be the same or different represent hydrogen or Rx .
R5 is preferably amino or hydrogen. Most preferably it is hydrogen.
Preferably, R2 is a group of formula
Figure imgf000029_0002
in which R5 is amino, hydroxy, aminomethyl, hydroxymethyl or hydrogen, and R6a is hydrogen or methyl.
Most preferably, R2 is 3-aminomethylphenyl .
A group of compounds of particular interest is that of formula
Figure imgf000029_0003
ln which :
L-Lp(D)π represents CO-Lx;
Rs represents ammo, hydroxy, aminomethyl, hydroxymethyl or hydrogen; R6a represents hydrogen or methyl;
Cy is a saturated or unsaturated, mono or poly cyclic, homo or heterocyclic group, preferably containing 5 to 10 ring atoms and optionally substituted by groups R3a or phenyl optionally substituted by R3a; each R3a independently is Rlc, ammo, halo, cyano, tro, thiol, alkylthio, alkylsulphonyl , alkylsulphenyl , hydrazido, alkylsulphonamido, alkylammo-sulphonyl , aminosulphonyl, haloalkoxy, and haloalkyl ; each Rlc independently represents hydrogen or hydroxyl, alkoxy, alkyl, ammoalkyl, hydroxyalkyl alkoxyalkyl, alkoxycarbonyl, acyloxymethoxycarbonyl or alkylammo optionally substituted by hydroxy, alkylammo, alkoxy, oxo, aryl or cycloalkyl;
Lx is a mono or bicyclic group bound to the carbonyl via a pendent nitrogen atom or nitrogen atom which forms part of the mono or bicyclic ring; or a physiologically tolerable salt thereof, e.g. a halide, phosphate or sulphate salt or a salt with ammonium or an organic amme such as ethylamme or meglumme . It will be appreciated that when Lx is bound to the carbonyl via a pendant nitrogen, the group CO-Lx corresponds with the group L-Lp(D)n in which L is CONH and Lp is a mono or bicyclic group. When Lx is bound to the carbonyl via a nitrogen that forms part of the mono or bicyclic ring, the group CO-Lx corresponds with the group L-Lp(D)n in which L ιs CO and Lp is a mono or bicyclic group containing a nitrogen atom in the ring and bound to L via this nitrogen.
It is believed that an aminomethyl group positioned on the 3 position of the phenyl ring will give rise to excellent binding within the SI binding pocket of tryptase.
Without wishing to be limited by theory it is believed that the presence of a hydrogen bond donating group attached to the phenyl group will be essential for successful inhibition of tryptase .
R5 and Rs are both preferably hydrogen.
Most preferably the Lx group comprises
Figure imgf000031_0001
Figure imgf000031_0002
Figure imgf000031_0003
wherein :
A and B are independently chosen from NH, N, 0, S, CH, CH2 ; Xlx and X2x are independently chosen from (CH2)m, (CH2)mCH=CH(CH2)p, CO(CH2)m, NH(CH2)m, NHCO(CH2)m, CONH(CH2)m, S02NH(CH2)Ε,NHS02(CH2)m;
Figure imgf000032_0001
m is 0 to 2
Figure imgf000032_0002
Rlx and R2x are independently chosen from hydrogen, alkoxy, alkyl, ammoalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, ammo, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl , oxo, heterocyclo optionally substituted by R3x, cycloalkyl optionally substituted by R3x or aryl optionally substituted by R3x; and
R3x is hydrogen, alkoxy, alkyl, ammo, hydroxy, alkoxy, alkoxycaroonyl , halo, cyano, nitro, thiol, sulphonyl, or sulphenyl.
Examples of heterocyclic Rlx and R2x groups are pipeπdine, piperazme and pyrrolldme.
The cyclic group attached to the alpha atom is preferably an optionally R3a substituted phenyl. Thus, one group compounds of the invention are those of formula (II)
Figure imgf000032_0003
* the alpha atom II wherein Lx is as hereinbefore defined. It is envisaged that especially preferred Lx groups will be those in which a cyclic or bicyclic ring is substituted by hydrogen bond donating and/or acceptor groups.
In another embodiment of the invention it is envisaged that the phenyl -based functionality on the left side of the compounds of the invention may be replaced by an optionally substituted, e.g. R substituted, 2 -aminomethylthiophene .
The compounds of the invention may be prepared by conventional chemical synthetic routes, e.g. by amide bond formation to couple the aromatic function to the alpha atom and to couple the lipophilic function to the alpha atom. Where the alpha atom is a carbon, the cyclic group-alpha atom combination may conveniently derive from an alpha ammo acid (preferably of D configuration) with the aromatic deriving from for example an acid derivative of a compound based on R2, e.g. an ammomethylbenzoic acid (which is readily available; . Amide formation from sucn reagents (in which any ammo or hydroxyl function (especially in an aminomethyl group) may if desired be protected during some or all of the synthesis steps) yields a compound of formula
(V) .
R2-CONH-CH(Cy) -COOH (V) (where Cy and R2 are as defined above) .
Prior to reaction the ammo group in an ammoalkyl group should be protected by an appropriate protecting group e.g. Boc, Z, Fmoc or Bpoc . The use of protecting groups is described m McOmie, "Protective Groups in Organic Chemistry", Plenum, 1973 and Greene, "Protective Groups in Organic Synthesis", Wiley Interscience, 1981. According to another aspect therefore, the present mvention provides compounds of formula ( I ' )
Figure imgf000034_0001
(I') in which R2 , is as defined for R2 except that the ammoalkyl
group Rx is replaced by a protected ammoalkyl group of formula PG-NH (alkyl) - in which PG la an ammo protecting group (defined in more detail below) .
The lipophilic group (and optionally simultaneously the hydrogen bond donor) may then conveniently be introduced by reaction of a compound of formula (V) (or another analogous carboxylic acid) optionally after transformation into an activated form, e.g. an acid chloride or active ester, with a lipophilic group carrying an amine, hydroxylamme, hydrazme or hydroxyl group, e.g. to produce compounds with linkages of -CO-NR^, -C0-NRld-0- , -CO-NRld-NRld- and -CO-O- from the alpha atom (where it is a carbon) to the lipophilic group. If necessary the amide linkage can be reduced using an appropriate reducing agent employing the necessary protection depending on whether concurrent reduction of the carboxylic acid moiety is also desired. Alternatively a compound of formula V or another analogous carboxylic acid may be transformed into an alcohol by reaction with isobutylchloroformate and reduction with sodium borohydπde . Such an alcohol, e.g. of formula (VI) R2 - CONH - CH(Cy)CH2OH (VI) can be reacted to introduce the lipophilic group by reactions such as: alkylation with an alkyl halide in the presence of a base ; reaction under Mitsunobu conditions, such as with diethyl azodicarboxylate/triphenylphosphine and a hydroxylated aryl compound; by reaction with an activated carboxylic acid (e.g. an acid chloride) or with a carboxylic acid and diethylazodicarboxylate/triphenylphosphine; by reaction with an isocyanate; and by treatment with methanesulphonyl chloride or trifluoromethanesulphonic anhydride and reaction with an amine, or with a thiol optionally followed by oxidation, e.g. with potassium metaperiodate or hydrogen peroxide.
In this way compounds with linkages of -CH2-0-, -CH2-0-CO-, -CH2-0-CO-NRld-, -CH2-NRxd-, -CH--S-, -CH2-SO- and -CH2-S02- between the alpha carbon and the lipophilic group may be produced.
Alternatively the alcohol can be oxidized to form a corresponding aldehyde (e.g. by oxidation with manganese dioxide or DMSO/oxalyl chloride or DMSO/S03 or Dess-Martin reagent) which may be reacted to introduce the lipophilic group by reactions such as: reaction with Wittig reagents or Horner-Emmons reagents, optionally followed by reduction of the resulting carbon: carbon double bond using H2/Pd-carbon; reaction with an organometallic , eg a Grignard reagent, optionally followed by reaction on the resulting hydroxyl group, such as oxidation (eg with Mn02, DMSO/oxalyl chloride or Dess-Martin reagent) , alkylation (eg with an alkyl halide in the presence of a base in a solvent such as DMF) , arylation (eg with diethylazo dicarboxylate/triphenyl phosphine and a hydroxyaryl compound) , ester formation (eg with an acid chloride or with a carboxylic acid and diethylazido dicarboxylate/triphenyl phosphine) , or carbamate formation (eg with an isocyanate) ; by reaction with an amine followed by reduction, e.g. with sodium cyanoborohydride; by reaction with a hydrazine; or by reaction with a carbazide.
In this way compounds with linkages of -CH=CRld-, -CH2-CHRld-, -CHOH-, -CHRld-0- , -CHRld-0-CO- , -CHRld-0-CO-NRld- , -CO-, -CH2-NRld-, -CH=N-NRld- and -CH=N-NR1-CO-NRld- between the alpha carbon and the lipophilic group may be produced.
The transformation of alcohol to amine referred to above may be used to produce an amine reagent for lipophilic group introduction, e.g. a compound
R2-CONH-CH(Cy) -CH2-NRldH. Such an amine reagent may be reacted to introduce the lipophilic group, e.g. by acylation with an acid halide or activated ester, by reaction with isocyanate, by reaction with an isothiocyanate, or by reaction with a sulphonyl chloride. In this way compounds with linkages of -CH2NRld- CO-, -CH2-NRld-CO-NRld-, -CH2NRld-CS-NRld- and -CH2NRld-S02- between the alpha carbon and the lipophilic groups may be produced. The transformation of acid to amide referred to above may be used to produce an amide reagent for introduction of the lipophilic group, e.g. a compound
R2-CONH-CH(Cy) -C0N(Rld)2. Such amides may be reacted to introduce lipophilic groups, e.g. by reaction with a haloketone (e.g. phenacyl bromide) . This provides a linkage
Figure imgf000037_0001
from alpha carbon to lipophilic group.
Analogously the amide may be transformed to a thioamide by reaction with Lawesson's reagent and then reacted with a haloketone to form a linkage
Figure imgf000037_0002
The amide reagent may likewise be transformed to a nitrile reagent by dehydration, e.g. with trifluoroacetic anhydride. The nitrile reagent may be reacted with hydrazine then with acyl halide and then cyclized, (e.g. with trifluoroacetic anhydride) to produce a linkage
Figure imgf000037_0003
Alternatively it may be treated with hydroxylamine then reacted with acyl halide and cyclized (e.g. with trifluoroacetic anhydride) to produce a linkage
Figure imgf000037_0004
The hydrazide produced by reaction of a carboxylic acid reagent with hydrazine discussed above may likewise be used as a reagent for lipophilic group introduction, e.g. as a compound of formula
R2-CONH-CH(Cy) -CO-NRld-N (Rld)2. Thus the hydrazide reagent can be reacted with an acyl halide and cyclized, e.g. with trifluoroacetic anhydride to yield a linkage
Figure imgf000038_0001
or reacted with an acyl halide or an isocyanate to yield linkages -CO-NR^NR^-CO- and -CO-NRld-NRld-CO-NRld- respectively .
Alternatively the hydrazide may be transformed by reaction with Lawesson's reagent and then reacted with an acyl halide and cyclized (e.g. with trifluoroacetic anhydride) to produce the linkage
Figure imgf000038_0002
An alternative route to these compounds is to carry out any of the above chemical reactions to incorporate the lipophilic group (an optional H bond donor) into a protected intermediate such as a compound of formula (VII) .
Figure imgf000038_0003
PG = Protecting group The protecting group may then be removed before coupling of the for example o-ammo benzoic acid (optionally protected) . The protection of ammo and carboxylic acid groups is described in McOmie, Protecting Groups in Organic Chemistry, Plenum Press, NY, 1973, and Greene and Wuts, Protecting Groups Organic Synthesis, 2nd. Ed., John Wiley Sc Sons, NY, 1991. Examples of carboxy protecting groups include Cx- C6 alkyl groups such as methyl, ethyl, t-butyl and t-amyl; aryl (C1-C4) alkyl groups such as benzyl, 4-nιtrobenzyl , 4- methoxybenzyl , 3 , 4-dιmethoxybenzyl , 2 , 4-dιmethoxybenzyl , 2 , 4 , 6-trιmethoxybenzyl , 2 , 4 , 6-trιmethylbenzyl , benzhydryl and tπtyl; silyl groups such as tπmethylsilyl and t- butyldimethylsilyl ; and allyl groups such as allyl and 1- (trimethyls lylmethyl) prop-l-en-3 -yl .
Examples of amine protecting groups (PG) include acyl groups, such as groups of formula RCO in which R represents C1-s alkyl, C3.10 cycloalkyl, phenyl Cx 6 alkyl, phenyl, C^ alkoxy, phenyl C1-6 alkoxy, or a C3.10 cycloalkoxy, wherein a phenyl group may oe optionally substituted, for example by one or two of halogen, C1-C4 alkyl and C1-C4 alkoxy. Preferred ammo protecting groups include t-butoxycarbonyl (Boc) and benzyl. α-Ammo acids of formula (VII) which are not commercially available can be synthesized by methods known in the art, for example as described m "Synthesis of Optically Active α-Amino Acids" by Robert M. Williams (Pergamon Press, 1989) and "Asymmetric Synthesis of ArylGlycmes" , Chem. Rev. 1992, 889-917.
Compounds of the type (VII) made be prepared (for example) by one or more of the following methods.
(l) from aryl or heteroaryl aldehydes via the Strecker synthesis or modifications thereof, via Bucherer-Bergs hydantom synthesis, or via the Ugi methodology (Isomtrile Chemistry, Ugi I. Ed.; Academic: New York, 1971; ppl45-199) with removal and replacement of protecting groups;
(ii) from styrenes via Sharpless methodology (J. Am. Chem. Soc. 1998,120, 1207-1217)
(m) from aryl boronic acids via Petasis methodology (Tetrahedron, 1997, 53, 16463-16470) with removal and replacement of protecting groups;
(IV) from aryl and heteroaryl acetic acids - via Evan's azidation (Synthesis, 1997, 536-540) or by oximation, followed by reduction and addition of protecting groups;
(v) from existing aryl glycmes by manipulation of functional groups, for example, alkylation of hydroxy groups, palladium assisted carbonylation of triflates derived from hydroxy groups and further manipulation of the carboxylic esters to give carboxylic acids by hydrolysis, carboxamides by activation of the carboxylic acid and coupling with amines, amines via Curtius reaction on the carboxylic acid; or (vi) from aliphatic, carbocylic and non-aromatic heterocyclic aldehydes and ketones using a Horner-Emmons reaction with N-benzyloxycarbonyl) -α-phosphonoglycme tπmethyl ester (Synthesis, 1992, 487-490).
Examples of synthetic schemes are shown below: )2
Figure imgf000041_0001
EDC, DMAP MeOH
Figure imgf000041_0002
Figure imgf000041_0003
Figure imgf000041_0004
ZCI, NEt3 THF
Figure imgf000041_0005
Synthesis of protected 4-piperidylglycine
Figure imgf000042_0001
Synthesis of protected 2-aminothiaz-4-ylglycine
Figure imgf000042_0002
N j HCHO NHCHO
LiOH, THF, H20
S N S^N
\ /
\— / — c -NHBoc
Et0 V -NHBoc V 2C H02C
A starting reagent for lipophilic group introduction where the alpha atom is nitrogen may be produced for example by reaction of a beta protected hydrazine (such protection to be chosen as to be compatible with the subsequent reagents to be employed) with phosgene, diphosgene, tπphosgene or N,N' carbonyl dnmidazole to give a reactive compound of the type:
or imidazole
Figure imgf000043_0001
PG = Protecting group This intermediate may be used as has been described above for the carboxylic starting reagents where the alpha atom is carbon.
Removal of the protecting group by standard methods and coupling with an activated aryl carboxylic acid will give compounds of the type
R2-CONH-N(Cy) -L-Lp(D)n
(where R2 , X, Y, Cy, L, Lp and D are as defined above) . Thus viewed from a further aspect the invention provides a process for the preparation of a compound according to the invention which process comprises coupling a lipophilic group to a compound of formula (VIII)
R2- (X)--Y(Cy) -Zj. (VIII)
(wherein R2, X, Y and Cy are as defined above and Zx is a reactive functional group) , and optionally subsequently coupling a hydrogen bond donor group to said lipophilic group.
Instead of introducing the group L-Lp(D)^ as the final stage process step, the compounds of formula I may alternatively be prepared by a process in which the group R2 is introduced in the final process step.
Thus viewed from another aspect the invention provides a process for the preparation of a compound according to the invention which process comprises coupling a lipophilic group to a compound of formula (IX)
Z2-Y(Cy) -L-Lp(D)n (IX)
(wherein Y, Cy, L, Lp D, and n are as defined above and Z2 is HX or a reactive functional group) , or a protected derivative thereof, with a compound of formula (X)
R2- Z3
(wherein R2 is as defined above and Z3 is XH or an appropriate reactive group) , or a protected derivative thereof, followed if necessary by the removal of any protecting groups.
Thus, for a compound of formula I in which X-X represents CONH, a compound of formula (IX) m which Z2 is
H2N may be reacted with a compounds of formula (X) in which Z3 is COOH or a reactive derivative thereof, such as a acyl halide or an anhydride, for example as described the Examples herein.
Where the lipophilic group Lp comprises more than one group, it may generally be formed by coupling these groups together at an appropriate stage in the preparation of the compound of formula I using conventional methods or as described in the Examples .
The compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature or transdermally. The compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc. Such compositions may contain components conventional pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. Preferably the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.
The following are examples of pharmaceutical compositions of compounds according to the invention.
Formulation 1
Hard gelatin capsules are prepared using the followmg ingredients :
Quantity (mg/capsule)
Active Ingredient 250
Starch, dried 200
Magnesium stearate 10
Total 460 mg The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities.
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 l ma
Total 150 mg
The active ingredient, starch, and cellulose are passed through a No . 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvmylpyrrolidone is mixed with the resultant powders which are then passed through a No . 14 mesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
In particular, it is believed that the compounds of the invention will have excellent oral bioavailability .
Viewed from this aspect the invention provides a pharmaceutical composition comprising a serme protease (tryptase) inhibitor according to the invention together with at least one pharmaceutically acceptable carrier or excipient. The pharmaceutical composition may also optionally comprise at least one further anti -inflammatory Viewed from a further aspect the invention provides the use of a serine protease (tryptase) inhibitor according to the invention for the manufacture of a medicament for use in a method of treatment of the human or non-human animal body (e.g. a mammalian, avian or reptilian body) to combat (i.e. treat or prevent) a condition responsive to said inhibitor. Viewed from a further aspect the invention provides a method of treatment of tne numan or non-numan animal body (e.g. a mammalian, avian or reptilian body) to combat a condition responsive to a serine protease (tryptase) inhibitor.
The dosage of the inhibitor compound of the invention will depend upon the nature and severity of the condition being treated, the administration route and the size and species of the patient. However m general, quantities of from 0.01 to 100 μmol/kg bodyweight will be administered. All publications referred to herein are hereby incorporated by reference.
The invention will now be described further with reference to the following non-limitmg Examples. Experimental : Abbreviations used follow IUPAC-IUB nomenclature. Additional abbreviations are HPLC, high-performance liquid chromatography; LC/MS , liquid chromatography / mass spectrometry; rt , retention time; NMR, nuclear magnetic resonance, TBTU, 2 - (1H- (benzotrιazol-1-yl) -1 , 1 , 3 , 3 - tetramethyluromumtetrafluoroborate . Starting materials were purchased from Aldrich (Gillmgham, UK) , Lancaster (Morecambe, UK), Avocado (Heysham, UK), Maybridge (Tmtagel, UK) , Nova Biochem (Nottingham, UK) or Bachem.
Purification .-
Flash column chromatography was carried out using Merck silica gel Sι60 (40-63 μm, 230-400 mesh) . Purification of final products was by crystallisation, flash column chromatography or gradient reverse phase HPLC on a Waters Deltaprep 4000 at a flow rate of 50 mL/mmute using a Deltapak C18 radial compression column (40 mm x 210 mm, 10- 15 mm particle size) . Eluant A consisted of aqueous trifluoroacetic acid (0.1 %) and eluant B 90% acetomtrile in aqueous trifluoroacetic acid (0.1 %) with gradient elution (Gradient, 0 minutes 5 % B for 1 minutes, then 5 % B to 20 % B over 4 minutes, then 20 % B to 60 % B over 32 minutes) . Fractions were analysed by analytical HPLC and LC/MS before pooling those with >95 % purity for lyophilisa ion.
Analysis :
Proton nuclear magnetic resonance (XH NMR) spectra were recorded on a Bruker DPX300 (300 MHz) . Analytical HPLC ' s were performed on a Shimadzu LC6 gradient system equipped with an autosampler. Eluant A consisted of aqueous trifluoroacetic acid (0.1 %) and eluant B consisted of 90 % acetonitrile and 10 % water, containing trifluoroacetic acid (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 14th minute and then 100 % B after the 15ch minute. 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) and a Symmetry Rp8 (3.5 μ, 50 x 2.1 mm) .
LC/MS were performed on a PESCIEX single quadrupole API- 150EX instrument, equipped with a Luna 2 C18 column (3 μ, 30 mm x 4.6 mm) eluting with 20 % to 100 % acetonitrile in water over five minutes.
Example 1
3- (Aminomethyl) benzoyl-D-phenylglycine 2- aminobenzothiazol-6-amide bis (trifluoroacetate) salt
2 , 6-Diaminobenzothiazole
2-Ammo-6-mtrobenzothιazole (500 mg, 2.56 mmol) was dissolved methanol (20 mL) and 10 % palladium on carbon (50 mg) was added as a slurry in methanol (1 mL) . The atmosphere was replaced with hydrogen and the suspension was stirred overnight. The catalyst was removed by suction filtration and the solvent evaporated to afford 2,6- diammobenzothiazole (420 mg, 99 %) as a pale yellow solid.
iV-BOC-D-Phenylglycine 2-aminobenzoth.iazol-6-amide N-BOC-D- Phenylglycme (250 mg, 1.0 mmol), l-(3- dimethylammopropyl) -3-ethylcarbodιιmιde hydrochloride (190 mg, 1.0 mmol) and 7-aza-l-hydroxybenzotrιazole (140 mg, 1.0 mmol) were stirred in dimethylformamide (3 mL) for ten minutes. 2 , 6-Dιammobenzothιazole (160 mg, 1.0 mmol) was then added and the solution was stirred overnight at room temperature. Ethyl acetate (15 mL) was added and the solution was washed with water (5 mL) , saturated citric acid solution (5 mL) , saturated NaHC03 (5 mL) and water (5 mL) , and dried over MgS04. The solvent was removed under reduced pressure to afford N-BOC-D-phenylglycme 2- ammobenzothιazol-6-amιde .
lE NMR (CDC13) : 8.93 (1 H, br s, C(O)NHAr); 7.72 (1 H, s, benzothiazole C(7)H); 7.35 (2 H, br s, Ph) ; 7.23 - 7.05 (3 H, m, Ph) ; 6.93 (1 H, d, J" = 10 Hz, benzothiazole C(4)H or C(5)H); 6.72 (1 H, d, J = 10 Hz, benzothiazole C(4)H or C(5)H) ; 6.05 (1 H, d, J = 1 Hz, CHPh) ; 5.92 (2 H, br s, NH2) ; 5.45 (1 H, br s, BOCNH); 1.27 (9 H, s, cBu) .
D-Phenylglycine 2 -aminobenzothiazol-6-amide
A solution of N-BOC-D-phenylglycine 2-aminobenzothiazol-5- amide m dichloromethane (5 mL) was treated with trifluoroacetic acid (5 mL) and stirred for 30 minutes. The dichloromethane and excess trifluoroacetic acid were removed under reduced pressure and the residue was triturated with diethyl ether to afford D-phenylglycine 2 -ammobenzothiazol- 6-amide as its trifluoroacetate salt (350 mg, 89 %) .
3- (Aminomethyl) benzoyl-D-phenylglycine 2-aminobenzothiazol- 6 -amide trifluoroacetate salt
.W-BOC-3-aminomethylbenzoic acid (250 mg, 1.0 mmol), l-(3- dimethylaminopropyl) -3-ethylcarbodιιmide hydrochloride (190 mg, 1.0 mmol) and 7-aza-l-hydroxybenzotriazole (140 mg, 1.0 mmol) were stirred in dimethylformamide (10 mL) for five minutes. D-Phenylglycine 2-aminobenzothiazol-6-amide trifluoroacetate salt (350 mg, 0.85 mmol) was then added and the mixture was stirred overnight. The solution was poured into ethyl acetate (20 mL) and washed with 5 % HC1 (5 mL) , saturated NaHC03 (5 mL) and water (5 mL) , dried over MgS04 and the solvent removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (60 % ethyl acetate / 40 % hexane to 100 % ethyl acetate) to afford JV-BOC-3- (aminomethyl) benzoyl-D- phenylglycine 2-aminobenzothiazol-6-amide . This was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) was added. The solution was stirred at room temperature for 30 minutes before the dichloromethane and excess trifluoroacetic acid were removed under reduced pressure. The residue was triturated with diethyl ether to afford 3 - (aminomethyl) benzoyl-D-phenylglycme 2- a inobenzothiazol -6 -amide as its trifluoroacetate salt (150 mg, 32 %) .
XH NMR (d4 MeOH): 8.21 ppm (1 H, s, benzothiazole C(7)H); 7.97 (1 H, s, ammomethylbenzoyl C(2)H); 7.94 (1 H, d, J = 5
Hz, 3- (aminomethyl) benzoyl C(6)H); 7.80 - 7.48 (5 H, m, Ar) ;
7.47 - 7.32 (4 H, m, Ar) ; 5.81 (1 H, s, CHPh); 4.22 (2 H, s,
CH2NH2) .
HPLC (Luna 2, Gradient 1) : rt = 2.80 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.40 minutes, 432 (MH) \
Examples 2 - 34 were prepared in the same fashion as Example 1, starting with the indicated nitro-compound or amine. Other functional groups present were protected appropriately.
Example 2
3- (Aminomethyl) benzoyl-D-phenylglycine phenylamide trifluoroacetate salt Prepared from aniline.
'H NMR (d4 MeOH): 7.85 ppm (2 H, br s, Ar) ; 7.49 (6 H, m,
Ar) ; 7.27 (5 H, m, Ar) 7.01 (1 H, t, J = 9 Hz, Ar) ; 5.70 (1
H, s, CHPh); 4.12 (2 H, s, CH2NH2) .
HPLC (Luna 2, Gradient 1): rt = 3.59 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.99 minutes, 360 (MH)\ Example 3
2 -Amino- 5- (aminomethyl) benzoyl-D-phenylglycine
(IS , 2S , 3S , 5R) -isopinocamphamide dihydroc loride salt Prepared from { IS, 2S, 3S, 5R) - (+) -isopinocampheylamine .
XH NMR (d4 MeOH): 7.52 ppm (1 H, s, Ar-C(6)H); 7.42 (2 H, d, J = 10, 2 x Ph-o-CH) ; 7.32 - 7.2 (3 H, m, 2 x Ph-m-CH, Ph-p- CH) ; 7.12 (1 H, d, J = 11 Hz, Ar-C(4)H) ; 6.67 (1 H, d, J = 11 Hz, Ar-C(3)H); 5.53 (1 H, s, NCH(Ph)); 4.18 (1 H, quintet, J = 8 Hz, ipc-C(l)H); 3.90 (2 H, s, CH2NH2) ; 2.42 - 2.23 (2 H, m, ipc-C(3)H and ipc- (C (2) H) ; 1.91 (1 H, m, ipc- (C) 6H) ; 1.80 (1 H, br s, ipc- (C) 5H) ; 1.74 (1 H, t, J" = 5 Hz, ipc-(C)6H); 1.32 (1 H, dd, J = 14, 8 Hz, ipc-C(7)H); 1.14 (3 H, s, ipc-C(8)H3); 1.02 (3 H, d, J" = 8 Hz, ipc-C (10) H3) ; 0.95 (3 H, s, ipc-C(9)H3) ; 0.87 (1 H, d, J = 11 Hz, ipc-C(7)H). HPLC (Luna 2, Gradient 1): rt = 4.21 minutes. LC/MS (Luna 2, Gradient 4): rt = 2.10 minutes, 418 (MH-NH3)\
Example 4 3- (Aminomethyl) benzoyl-D-phenylglycine quinolin-3- ylamide trifluoroacetate salt
Prepared from 3 -aminoquinoline .
'H NMR (d4 MeOH) : 9.21 and 8.88 ppm (1 H each, s, quinoline C(2)H and C(4)H) ; 8.10 - 7.90 (4 H, m, Ar) ; 7.81 (1H, t , J" = 7 Hz, Ar) ; 7.77 - 7.55 (5 H, m, Ar) ; 7.53 - 7.25 (3 H, m, Ar) ; 5.91 (1 H, s, CHPh); 4.20 (2 H, s, CH2NH2) . HPLC (Luna 2, Gradient 1): rt = 2.98 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.83 minutes, 411 (MH) \
Example 5 3- (Aminomethyl) benzoyl-D-phenylglycine 4- (1- piperidyl) phenylamide trifluoroacetate salt
Prepared from 4- (1-pιperιdyl) aniline .
*H NMR (d4 MeOH) : 7.97 ppm (2 H, m, Ar) ; 7.8 (2 H, d, J = 9
Hz, Ar) ; 7.7 - 7.35 (9 H, m, Ar) ; 5.8 (1 H, s, CHPh); 4.2 (2
H, s, CH2NH2) ; 3.55 (4 H, m, pip); 2.0 (4 H, m, pip); 1.8 (2
H, m. pip) .
HPLC (Luna 2, Gradient 1): rt = 2.81 minutes
LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 443 (MHT
Example 6: 3 - (Aminomethyl) benzoyl-D-phenylglycine 1- oxoindan-5-amide trifluoroacetate salt
Prepared from 5 -ammo- 1 -oxomdane .
XH NMR (d4 MeOH): 7.98 ppm (1 H, s, (aminomethyl) benzoyl C(2)H); 7.96 ppm (1 H, d, J" = 10 Hz, (aminomethyl) benzoyl
C(6)H); 7.94 (1 H, s, indanone C(4)H); 7.70 - 7.52 (6 H, m,
Ar) ; 7.47 - 7.33 (3 H, m, Ar) ; 5.84 (1 H, s, CHPh); 4.22 (2
H, s, CH2NH2) ; 3.12 (2 H, t, J = 5 Hz , indanone C(3)H2); 2.82
- 2.75 (2 H, m, indanone C(2)H2). HPLC (Luna 2, Gradient 1): rt = 3.35 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.78 minutes, 414 (MH)+.
Example 7
3- (Aminomethyl) benzoyl-D-phenylglycine 3 -cyano-4 - methylphenyl-amide trifluoroacetate salt
Prepared from 3 -cyano-4 -methylanilme .
XH NMR (d4 MeOH): 8.01 ppm (1 H, s, 3 -cyano-4 -methylphenyl C(2)H); 7.98 (1, s, 3 - (aminomethyl) benzoyl C(2)H); 7.94 (1 H, d, J = 9 Hz, 3- (aminomethyl) benzoyl C(6)H); 7.72 - 7.52 (5 H, m, Ar) ; 7.48 - 7.28 (4 H, m, Ar) ; 5.82 (1 H, s, CHPh); 4.19 (2 H, s, CH2NH2) ; 2.47 (3 H, S, CH3) . HPLC (Luna 2, Gradient 1) : rt = 3.72 minutes. LC/MS (Luna 2, Gradient 4): rt = 2.05 minutes, 399 (MH)\
Example 8
3- (Aminomethyl) benzoyl-D-phenylglycine 4 -amido phenylamide trifluoroacetate salt
Prepared from 4-mtrobenzamιde .
XH NMR (d4 MeOH): 8.20 - 8.05 ppm (2 H, m, 3- (aminomethyl) benzoyl C(2)H and C(6)H); 7.97 (2 H, d, J = 9
Hz, 4- (amidocarbonyl) phenyl C(2)H and C(6)H); 7.86 (2 H, d,
J = 9 Hz, 4- (amidocarbonyl) phenyl C(3)H and C(5)H); 7.82 -
7.65 (4 H, m, Ar) ; 7.63 - 7.47 (3 H, m, Ar) ; 6.01, (1 H, s,
CHPh); 4.32 (2 H, br s, CH2NH2) . HPLC (Symmetry C8 , Gradient 2) : rt = 4.84 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.51 minutes, 403 (MH) \
Example 9
3- (Aminomethyl) benzoyl-D-phenylglycine 3- amidophenylamide trifluoroacetate salt
Prepared from 3 -nitrobenzamide . lK NMR (d4 MeOH): 8.30 ppm (1, s, 3 - (amidocarbonyl) phenyl
C(2)H); 8.17 (1 H, s, 3 - (aminomethyl ) benzoyl C(2)H); 8.12 (1
H, d, J = 8 Hz, 3- (aminomethyl) benzoyl C(6)H); 7.93 (1 H, d, J = 1 Hz, 3- (amidocarbonyl) phenyl C(6)H); 7.85 - 7.68 (5 H, m, Ar) ; 7.65 - 7.52 (4 H, m, Ar) ; 6.03 (1 H, s, CHPh); 4.37 (2 H, br s, CH2NH2) .
HPLC (Luna 2, Gradient 1): rt = 2.95 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.78 minutes, 403 (MH)+. Example 10
3- (Aminomethyl) benzoyl-D-phenylglycine 1,2,3,4- tetrahydro-l-oxonaphthyl-6-amide trifluoroacetate salt.
Prepared from 6-amino-l , 2 , 3 , 4 -tetrahydro-1-oxonaphthalene . Η NMR (d4 MeOH): 7.72 ppm (3 H, m, Ar) ; 7.40 (6 H, m, Ar) ; 7.20 (3 H, m, Ar) ; 5.65 (1 H, s, CHPh); 4.02 (2 H, s, CH2NH2) ; 2.78 (2 H, t, J = 6 Hz, tetrahydronaphthyl C(4)H2); 2.42 (2 H, t, J = 7 Hz, tetrahydronaphthyl C(2)H2); 1.95 (2H, m, tetrahydronaphthyl C(3)H2). HPLC (Luna 2, gradient 1) : rt = 3.57 minutes.
LC/MS (Luna 2, gradient 4): rt = 1.88 minutes; 428 (MH)+.
Example 11
3- (Aminomethyl) benzoyl-D-phenylglycine 1,2,3,4- tetrahydro-l-oxonaphthyl-7 -amide trifluoroacetate salt
Prepared from 7-nitro-l , 2 , 3 , 4-tetrahydro-l-oxonaphthalene . XH NMR (d4 MeOH): 8.04 ppm (1 H, s, tetrahydronaphthyl C(8)H); 7.82 (2 H, dd, J = 1 , 10 Hz, Ar) ; 7.60 (2 H, dd, Ar) ; 7.45 (4 H, m, Ar) ; 7.28 (3 H, m, Ar) ; 7.16 (1 H, m, Ar) ; 5.68 (1 H, br s, CHPh); 4.03 (2 H, s, CH2NH2), 2.83 (2 H, t, J = 7 Hz, tetrahydronaphthyl C(4)H2); 2.40 (2 H, t, J = 7 Hz, tetrahydronaphthyl C(2)H2); 2.00 (2 H, m, tetrahydronaphthyl C(3)H2). HPLC (Luna 2, gradient 1): rt = 3.65 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.94 minutes, 428 (MH) \
Example 12
3 - (Aminomethyl) benzoyl-D-phenylglycine 1,2,3,4- tetrahydro-naphthyl-6-amide trifluoroacetate salt Prepared from 6-amino-l, 2 , 3 , 4-tetrahydronaphthalene . :H NMR (d4 MeOH): 7.72 ppm (1 H, s, 3 - (aminomethyl ) benzoyl C(2)H); 7.70 (1 H, d, J = 7 Hz, 3 - (aminomethyl ) benzoyl C(6)H); 7.40 (4 H, m, Ar) ; 7.22 (3 H, m, Ar) ; 7.09 (1 H, m, Ar) ; 6.82 (1 H, m, Ar) ; 5.62 (1 H, s, CHPh); 4.00 (2 H, s, CH2NH2) ; 2.50 (4 H, s , ) ; 1.58 (4 H, s, tetrahydronaphthyl C(4)H2 and C(5)H2) .
HPLC (Luna 2, Gradient 4) : rt = 4.21 minutes. LC/MS (Luna 2, Gradient 4): rt = 2.21 minutes, 414 (MH) \
Example 13
3- (Aminomethyl) benzoyl-D-phenylglycine 4- (piperazin-1- yl) phenyl-amide bis (trifluoroacetate) salt
Prepared from 4- (piperazin-1-yl) aniline . lR NMR (d4 MeOH): 8.00 ppm (2 H, m, Ar) ; 7.70 - 7.35 (9 H, m, Ar) ; 7.02 (2 H, d, J = 10 Hz, Ar) ; 5.80 (1 H, s, CHPh); 4.21 (2 H, s, CH2NH2) ; 3.30 (8 H, m, pip). HPLC (Luna 2, Gradient 1) : rt = 2.71 minutes. LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 444 (MH)*.
Example 14
3- (Aminomethyl) benzoyl-D-phenylglycine 2 , 3 -dihydroindol 5-amide bis (trifluoroacetate) salt
Prepared from 2 , 3 -dihydro-5-nitroindole . lU NMR (d4 MeOH): 7.97 ppm (2 H, m, Ar) ; 7.82 (1 H, s, Ar) ; 7.65 (5 H, m, Ar) ; 7.45 (4 H, m, Ar) ; 5.80 (1 H, s, CHPh);
4.20 (2 H, s, CH2NH2) ; 3.85 (2 H, t, J = 7.5 Hz, dihydroindole C(2)H2); 3.30 (2 H, t, J = 7.5 Hz, dihydroindole C(3)H2).
HPLC (Luna 2, Gradient 1): rt = 2.59 minutes. LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 401 (MH)*. Example 15
3- (Aminomethyl) benzoyl-D-phenylglycine 4-chloro-3- amidophenylamide trifluoroacetate salt Prepared from 2 -chloro-5-nitrobenzamide .
XH NMR (d4 MeOH): 7.98 ppm (1, s, 3 - (aminomethyl ) benzoyl C(2)H); 7.94 (1 H, d, J" = 9 Hz, 3 - (aminomethyl ) benzoyl C(6)H); 7.83 (1 H, s, 2 -chloro-3 - (amidocarbonyl ) -phenyl C(6)H); 7.70 - 7.50 (5 H, m, Ar) ; 7.45 - 7.35 (4 H, m, Ar) ; 5.58 (1 H, s, CHPh); 4.21 (2 H, s, CH2NH2) .
HPLC (Luna 2, Gradient 1) : rt = 3.09 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.62 minutes, 437/439
(MH)\
Example 16
3- (Aminomethyl) benzoyl-D-phenylglycine 3,5- dichlorophenylamide trifluoroacetate salt
Prepared from 3 , 5-dichloroaniline .
XH NMR (d4 MeOH): 7.98 ppm (1, s, 3 - (aminomethyl) benzoyl C(2)H); 7.94 (1 H, d, J = 9 Hz, 3 - (aminomethyl ) benzoyl
C(6)H); 7.73 - 7.51 (4 H, m, Ar) ; 7.64 (2 H, s, 3,5- dichlorophenyl C(2)H and C(6)H) ; 7.49 - 7.32 (3 H, m, Ar) ;
7.18 (1 H, s, 3,5-dichlorophenyl C(4)H) ; 5.80 (1 H, s,
CHPh) ; 4.20 (2 H, s, CH2NH2) . HPLC (Luna 2, Gradient 1) : rt = 4.31 minutes.
LC/MS (Luna 2, Gradient 4) : rt = 2.29 minutes, 428/430/432
(MH)+.
Example 17 3- (Aminomethyl) benzoyl-D-phenylglycine 3- (aminomethyl) phenyl-amide bis (trifluoroacetate) salt
Prepared from 3 -nitrobenzylam e .
Η NMR (d4 MeOH): 7.97 ppm (2 H, Ar) ; 7.82 (1 H, s, Ar) ; 7.61 (5 H, m, Ar) ; 7.40 (4 H, m, Ar) ; 7.22 (1 H, d, J = 11 Hz, Ar) ; 5.81 (1 H, s, CHPh); 4.22 (2 H, s, CH2NH2); 4.10 (2 H, s, CH2NH2) .
HPLC (Luna 2, Gradient 1) : rt = 2.67 minutes. LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 389 (MH)\
Example 18
3- (Aminomethyl) benzoyl-D-phenylglycine 2,3- dimethylindol-5-amide bis (trifluoroacetate) salt
Prepared from 2 , 3 -dιmethyl-5-nιtromdole .
XH NMR (d3 acetonitrile): 9.12 ppm (1 H, br s, NH) ; 9.08 (1H, bs, NH) ; 8.40 (1 H, d, J = 1 Hz, Ar) , 8.20 (1 H, s,
Ar) ; 8.0 (1 H, d, J = 7 Hz, Ar) ; 7.88-7.50 (7 H, m, Ar) ;
7.30 (2 H, m, Ar) ; 6.0 (1 H, d, J = 6.5 Hz, CHPh); 4.30 (2
H, s, CH2 H2) ; 2.71 (2 H, br s, CH2NH2) ; 2.50 (3 H, s, mdole
C(3)CH3) ; 2.31 (3 H, s, mdole C(2)CH3) . HPLC (Luna 2, Gradient 1) : rt = 3.76 minutes.
LC/MS (Luna 2, Gradient 4) : rt = 1.99 minutes, 427 (MH) \
Example 19
3- (Aminomethyl) benzoyl-D-phenylglycine 4- chlorophenylamide trifluoroacetate salt
Prepared from 4-chloroanιlme . λE NMR (d4 MeOH): 7.97 ppm (2 H, m, Ar) ; 7.70 - 7.50 (13 H, m, Ar) ; 5.80 (1 H, s, CHPh); 4.21 (2 H, s, CH2NH2) . HPLC (Luna 2, Gradient 1): rt = 3.95 minutes. LC/MS (Luna 2, Gradient 4): rt = 2.05 minutes, 394 (MH) \ Exa ple 20
1- [3- (Aminomethyl) benzoyl-D-phenylglycinyl] piperidine trifluoroacetate salt Prepared from piperidine. lE NMR (d4 MeOH) : 7.97 ppm (2 H, m Ar) ; 7.65 - 7.30 (7 H, m, Ar) ; 6.10 (1 H, s, CHPh); 4.21 (2H, s, CH2NH2) ; 3.79 (1H, m, pip); 3.50 (3H, m, pip); 1.70 - 1.21 (5 H, m, pip). HPLC (Luna 2, Gradient 1) : rt = 3.36 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.78 minutes, 394 (MH) \
Example 21
1- [3- (Aminomethyl) benzoyl-D-phenylglycinyl] -3- [ (iV-ethyl- iV-methyl) amido] piperidine trifluoroacetate salt Prepared from 3 -[ (N-ethyl -N-methyl) amidocarbonyl] - piperidine .
:H NMR (CD3CN) : The compound contains two chiral centres and is therefore a mixture of diastereomers , as well as exhibiting rotamers due to the N-ethyl -N-methyl amide. 8.45 - 7.78 ppm (5 H, m, Ar and NH) ; 7.72 - 7.28 (5 H, m, Ph) ;
6.10 - 5.90 (1 H, m, CHPh); 4.61 - 4.35 (1 H, m, piperidine H) ; 4.14 (2 H, br s, CH2NH2); 3.97 - 3.66 (1 H, m, piperidine H) ; 3.50 - 2.35 (12 H, m) 1.90 - 0.75 (4 H, m) . HPLC (Luna 2, Gradient 1): rt = 3.13 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.72 minutes, 437 (MH) \
Example 22
1- [3- (Aminomethyl) benzoyl-D-phenylglycinyl] pyrrolidine trifluoroacetate salt Prepared from pyrrolidine. XH NMR (d4 MeOH): 7.95 ppm (2 H, m, Ar) ; 7.72-7.34 (7 H, m, Ar) ; 5.91 (1 H, m, CHPh); 4.20 (2 H, s, CH2NH2); 3.80 (2 H, , pyr); 3.61 (2 H, m, pyr); 3.50 (2 H, m, pyr); 3.19 (2 H, m, pyr) . HPLC (Luna 2, Gradient 1): rt = 3.06 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.57 minutes, 338 (MH)+.
Example 23
2- [3- (Aminomethyl) benzoyl-D-phenylglycinyl] decahydroisoquinoline trifluoroacetate salt
Prepared from decahydroisoquinoline.
XH NMR (d4 MeOH): 7.70 ppm (2 H, br s, Ar) ; 7.41 -7.09 (7 H, m, Ar) ; 5.95-5.78 (1H, m, CHPh); 3.95 (2H, s, CH2NH2); 1.7 - 0.65 (16 H, m, decahydroisoquinoline C(H) 's) . HPLC (Luna 2, Gradient 1): rt = 4.11 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.15 minutes, 406 (MH) \
Example 24
3- (Aminomethyl) benzoyl-D-phenylglycine 2 , 3 -dihydroindol- 6 -amide trifluoroacetate salt
Prepared from 2 , 3 -dihydro-6-nitroindole .
XH NMR (d4 MeOH): 7.91 ppm (2 H, , Ar) ; 7.75 (1 H, s, Ar) ; 7.57 (4 H, m, Ar) ; 7.34 (5 H, m, Ar) ; 5.75 (1 H, s, CHPh); 4.15 (2 H, s, CH2NH2) ; 3.75 (2 H, t, J = 7.5 Hz, dihydroindole C(2)H2); 3.20 (2 H, t, J = 7.5 Hz, dihydroindole C(3)H2).
HPLC (Luna 2, Gradient 1): rt = 2.54 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.24 minutes, 401 (MH)*.
Example 25 s' (Aminomethyl) benzoyl-D-phenylglycine 2,3- dihydroindolamide trifluoroacetate salt
Prepared from 2 , 3 -dihydroindole .
'H NMR (d4 MeOH) : 8.92 ppm (1 H, d, J" = 7 Hz , NH) ; 8.22 (1 H, d, J" = 9.5 Hz, dihydroindole C(7)H); 7.97 (2 H, m, Ar) ; 7.48 (3 H, m, Ar) ; 7.19 (2 H, m, Ar) ; 7.08 (1 H, m, Ar) ; 6.02 (1 H, m, CHPh); 4.41 (1 H, m, dihydroindole C(2)H); 4.19 (2H, s, CH2NH2) ; 3.78 (IH, m, dihydroindole C(2)H); 3.23 (IH, m, dihydroindole C(3)H); 3.07 (IH, m, dihydroindole C(3)H) .
HPLC (Luna 2, Gradient 1): rt = 3.79 minutes.
LC/MS (Luna 2, gradient 4): rt = 2.21minutes, 386 (MH)*.
Example 26 3- (Aminomethyl) benzoyl-D-phenylglycine l-methyl-2 , 3- dihydro-indol-6-amide bis (trifluoracetate salt)
Prepared from 6-amino-2 , 3 -dihydro-1-methylindole .
LH NMR (d4 MeOH): 8.0 ppm (2 H, m, Ar) ; 7.65 (4 H, m, Ar) ;
7.40 (3 H, m, Ar) ; 7.15 (2 H, m, Ar) ; 6.95 (1 H, m, Ar) ; 5.83 (1 H, s, CHPh); 4.20 (2 H, s, CH2NH2) ; 3.42 (2 H, m, dihydroindole C(2)H); 2.98 (2H, m, dihydroindole C(3)H);
2.82 (3H, s, NCH3) .
HPLC (Luna 2, Gradient 1): rt = 2.80 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.88 minutes, 415 (MH)*.
Example 27
3 - (Aminomethyl ) benzoyl-D-phenylglycine 3 -acetylamino-4 - methylphenyla ide trif luoroacetate salt
Prepared from 2 -methyl - 5 -nitroacetanilide . *H NMR (D20) : 7 . 78 - 7 . 19 ( 12 H , m, Ar) , 5 . 64 ( IH , s , α-CH) , 4.17 (2 H, s, CH2NH2) , 2.12 (6H, s, 2 x CH3) HPLC (Luna 2, Gradient 1): rt = 3.10 minutes. LC/MS (Luna 2, Gradient 4) : rt = 1.56 minutes, 431 (MH+) .
Example 28
3- (Aminomethyl) benzoyl-D-phenylglycine (R/S) - 8-methyl-
5, 6, 7 , 8-tetrahydronaphth-2-ylamide trifluoroacetate salt
Prepared from (R/S) -8-methyl-5 , 6 , 7 , 8-tetrahydronaphth-2- ylam e, synthesised as described below.
(R/S) -8 -methyl- 5, 6,7, 8-tetrahydronaphth-2-ylamine
A suspension of methyltriphenylphosphonium iodide (680 mg, 1.68 mmol) in tetrahydrofuran (7 mL) was cooled to -45°C. n- Butyllithium (1.0 mL, 1.6 M in hexane, 1.60 mmol) was then added dropwise, and the solution was stirred for 1 hour. 1, 2, 3, 4-Tetrahydro-7-mtro-l-oxonaphthalene (200 mg, 1.05 mmol) in tetrahydrofuran (3 mL) was then added over 5 minutes. The reaction mixture was allowed to warm to room temperature before being quenched with water (20 mL) . The solution was then extracted with dichloromethane (2 x 25 mL) , the solvent was dried (MgSO and concentrated under reduced pressure to give a black oil . The crude product was then purified by flash chromatography (ethyl acetate / hexane; 1:40) to afford 5 , 6 , 7 , 8-tetrahydro-8 -methylene-2 - tro-naphthalene as a white solid (150 mg, 76%) .
A solution of the olefin (100 mg, 0.53 mmol) m methanol (2 mL) was stirred over 10% palladium on carbon (20 mg) . The mixture was purged with hydrogen and stirred for 18 hrs under a balloon of hydrogen. The reaction mixture was then filtered through celite, washing with additional methanol, and concentrated under reduced pressure to afford (R/S) -8- methyl-5 , 6 , 7 , 8-tetrahydronaphth-2 -ylamine as a colourless oil (75 mg, 82%) . lE NMR (CDC13) : 7.53 ppm (1 H, d, J" = 8 Hz, C(4)H) ; 7.21 (1 H, d, J = 2 Hz, C(l)H) ; 7.18 (1 H, dd, J = 8, 2 Hz, C(3)H) ; 4.16 (2 H, br s, NH2) ; 3.52 (1 H, sextet, J" = 7 Hz, CHCH3) ; 3.41-3.25 (2 H, m, C(5)H2); 2.61-2.45 (2 H, m, tetrahydronaphthalene C(6)H and/or C(7)H); 2.43-2.32 (1 H, m, tetrahydronaphthalene C ( 6 ) or C(7)H); 2.23-2.12 (1 H, m, tetrahydronaphthalene C(6)H or C(7)H); 1.96 (3 H, d, J = 7 Hz, CH3) .
3- (Aminomethyl) benzoyl-D-phenylglycine (R/S) -8-methyl-
5, 6,7, 8-tetrahydro-naphth-2-ylamide trifluoroacetate salt. XH NMR (MeOH): 7.95 ppm (2 H, br s, Ar) ; 7.76 - 7.60 (4 H, m, Ar) ; 7.48 - 7.31 (4 H, m, Ar) ; 7.29 - 7.21 (1 H, m, Ar) ; 6.97 (1 H, d, J = 8 Hz, Ar) ; 5.80 (1 H, s, CHPh); 4.18 (2 H, s, CH2NH2) ; 2.90 - 2.69 (3 H, m, tetrahydronaphthalene C(5)H and C(8)H2); 1.99-1.80 (2 H, m, tetrahydronaphthalene C(6)H and/or C(7)H); 1.75 - 1.63 (1 H, m, tetrahydronaphthalene
C(6) or C(7)H); 1.58 - 1.40 (1 H, m, tetrahydro-naphthalene
C(6)H or C(7)H) ; 1.27 (3 H, d, J = 7 Hz, CH3 ) .
HPLC (Symmetry, Gradient 2): rt = 6.73 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.53 minutes, 428 (MH)*.
Example 29
3- (Aminomethyl) benzoyl-D-phenylglycine indan-5-ylamide trifluoroacetate salt
Prepared from 5-aminoindane. lE NMR (d4 MeOH): 8.16 ppm (1 H, s, 3 - (aminomethyl) benzoyl C(2)H); 8.15 (1 H, m, 3 - (aminomethyl ) benzoyl C(6)H); 7.96 - 7.54 (8 H, m, Ar) ; 7.45 (1 H, d, J" = 8 Hz, mdane C(6)H or C(7)H); 7.33 (1 H, d, J = 8 Hz, ndane C(6)H or C(7)H); 6.0 (1 H, s, CHPh); 4.39 (2 H, s, CH2NH2) ; 3.06 (4 H, q, J = 1 Hz, indane C(1)H2 and C(3)H2); 2.26 (2 H, quintet, J = 7 Hz, indane C (2)H2) .
HPLC (Luna 2, Gradient 1): rt = 4.02 minutes. LC/MS (Luna 2, Gradient 4): rt = 2.42 minutes, 400 (MH)*.
Example 30
3- (Aminomethyl) benzoyl-D-phenylglycine 4- isopropylphenylamide trifluoroacetate salt
Prepared from 4 -lsopropylanil e .
XH NMR (d4 MeOH): 8.17 ppm (1 H, s, 3 - (aminomethyl ) benzoyl C(2)H); 8.15 (1 H, m, 3 - (aminomethyl) benzoyl C(6)H); 7.83 -
7.59 (9 H, m, Ar) ; 7.38 (2 H, d, J = 8.5 Hz, Ar) ; 6.0 (1 H, s, CHPh); 4.38 (2 H, s, CH2NH2) ; 3.09 (1 H, septet, J" = 7 Hz,
CH(CH3)2); 1.42 (6 H, d, J = 1 Hz, CH(CH3)2).
HPLC (Luna 2, Gradient 1): rt = 4.21 minutes. LC/MS (Luna 2, Gradient 4): rt = 2.48 minutes, 402 (MH)*.
Example 31
3- (Aminomethyl) benzoyl-D-phenylglycine (IS ,2S ,3S ,5R) - isopinocamphamide trif luoroacetate salt Prepared from {IS, 2S, 3S, 5R) - ( + ) -lsopmocampheylamme .
'H NMR (d4 MeOH) : 7.96 ppm (1 H, s, 3 - (aminomethyl) benzoyl C(2)H) ; 7.95 (1 H, m, 3 - (aminomethyl ) benzoyl C(6)H) ; 1.61 - 7.25 (7 H, m, Ar) ; 5.70 (1 H, s, CHPh) ; 4.28 (1 H, m, isopmocampheyl C(l)H) ; 4.20 (2 H, s, CH2NH2) ; 2.55 - 1.77 (5 H, m, isopmocampheyl H's) ; 1.26 (3 H, s, CH3) ; 1.14 (3 H, d, J = 7Hz, isopmocampheyl C(10)H3); 1.08 (3 H, s, CH3) ,
1.04 - 0.94 (2 H, m, isopmocampheyl H's). HPLC (Luna 2, Gradient 1): rt = 4.34 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.34 minutes, 420 (MH)*.
Example 32
3- (Aminomethyl) benzoyl-D-phenylglycine 4- (1- hydroxy ethyl) phenyl amide trif luoroacetate salt Prepared from 1- (4 -ammophenyl) ethanol . lE NMR (d4 MeOH) : 7.85 ppm (1 H, s, 3 - (aminomethyl ) benzoyl C(2)H) ; 7.84 (1 H, m, 3 - (aminomethyl) benzoyl C(6)H) ; 7.56 -
7.05 (11 H, m, Ar) ; 5.72 (1 H, s, CHPh) ; 4.69 (1 H, q, J = 6.5 Hz, CH(OH)CH3) ; 4.08 (2 H, s, CH2NH2) ; 1.31 (3 H, d, J = 6.5 Hz, CH3) . HPLC (Luna 2, Gradient 1): rt = 3.0 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.83 minutes, 404 (MH)*.
Example 33
3- (Aminomethyl) benzoyl-D-phenylglycine cis-2- aminocyclohexyl-amide bis (trifluoroacetate) salt
Prepared from cιs-1 , 2-dιammocyclohexane .
XH NMR (d4 MeOH): 8.08 ppm (1 H, s, 3 - (aminomethyl ) benzoyl C(2)H); 8.06 (1 H, m, 3 - (aminomethyl ) benzoyl C(6)H); 7.79 - 7.48 (7 H, m, Ar) ; 5.87 (1 H, s, CHPh); 4.46 (1 H, m, cyclohexyi C(l)H); 4.30 (2 H, s, CH2NH2) ; 3.54 (1 H, m, cyclohexyi C(2)H); 2.11 - 1.52 (8 H, m, cyclohexyi H's).
HPLC (Luna 2, Gradient 1); rt = 2.40 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.08 minutes, 381 (MH)*.
Example 34 1- [3- (Aminomethyl) benzoyl-D-phenylglycinyl] 4- hydroxypiperidine hydrochloride salt
Prepared from 4-hydroxypιperιdme .
XE NMR (d4 MeOH): 7.84 ppm (1 H, s, 3 - (aminomethyl) benzoyl C(2)H); 7.80 (1 H, m, 3 - (aminomethyl) benzoyl C(6)H); 7.59 - 7.17 (7 H, m, Ar) ; 6.03 (1 H, s, CHPh); 4.11 (2 H, s, CH2NH2) ; 3.90 (1 H, m, pipeπdyl C(4)H); 3.62 (2 H, m, piperidyl C(2)H and C(6)H); 3.14 - 2.94 (2 H, m, pipeπdyl C(2)H and C(6)H); 1.93 - 1.16 (4 H, m, piperidyl C(3)H2 and C ( 5 ) H2) .
HPLC (Luna 2, Gradient 1): rt = 2.56 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.36 minutes, 368 (MH)*.
Example 35 3- (Aminomethyl) benzoyl-D-phenylglycine l-acetyl-2 , 3- dihydro-indol-β-amide trifluoroacetate salt
l-Benzyloxycarbonyl-2 , 3 -dihydro-6-nitroindole
A solution of 6-nιtromdolme (10.0 g, 0.061 mol), triethylamme (22.7 mL, 0.16 mol) and dimethylammopyridme (50 mg, cat.) dichloromethane (130 mL) was stirred at 0°C and benzyl chloroformate (18 mL, 0.12 mol) was added slowly. The mixture was allowed to warm to room temperature overnight. The mixture was washed with water (50 mL) , 5% aqueous HCl (100 mL) , saturated aqueous NaHC03 (50 mL) and water (50 mL) . The dichloromethane was dried (MgS04) and evaporated under reduced pressure to give an orange solid. This was triturated in diethyl ether (150 ml) to give a yellow solid (12.34 g, 68%). XH NMR (CDC13) : 7.80 ppm (1 H, dd, J = 8 , 2 Hz, C(7)H); 7.35 (5 H, m, Ph) ; 7.20 (2 H, m, C(4)H and C(5)H); 5.25 (2 H, br s, CH2Ph) ; 4.11 (2 H, t, J = 8 Hz, dihydroindole C(2)H2); 3.15 (2 H, t, J = 8 Hz, dihydroindole C(3)H2).
6-amino-l-benzyloxycarbonyl-2 , 3 -dihydroindole
A mixture of l-benzyloxycarbonyl-2 , 3 -dιhydro-6-nιtromdole (1.0 g, 3.36 mmol) and tin (II) chloride dihydrate (3.78 g, 16.75 mmol) in ethanol (70 mL) was heated at 70°C, under an atmosphere of nitrogen, for 3 hours. The solution was cooled and the solvent evaporated under reduced pressure to give an off-white solid. The solid was partitioned between water (50 mL) and ethyl actate (100 mL) and the aqueous layer basified (pH 11) with 1M sodium hydroxide solution. The mixture was filtered to remove tin salts and the ethyl acetate was separated, dried (MgS04) and evaporated under reduced pressure to give the amine as a yellow oil (0.89 g, 99 %) :H NMR (CDC13) : 7.51 - 7.33 ppm ( 6 H, m, Ph + C(7)H); 6.93 (1 H, d, J = 8 Hz, C(4)H) ; 6.32 (1 H, dd, J = 8, 2 Hz, C(5)H) ; 5.28 (2 H, br s, CH2Ph) ; 4.01 (2 H, t, J = 7.5 Hz, dihydroindole C(2)H2); 3.66 (2 H, bs , NH2) ; 3.05 (2 H, t, J = 7.5 Hz, dihydroindole C(3)H2).
N-BOC-D-phenylglycine l-benzyloxycarbonyl-2, 3 -dihydroindol- 6 -amide A solution of N-BOC-D-phenylglycme (0.83 g, 3.28 mmol), 1- [3- (dimethyl -ammo) propyl] -3-ethylcarbodιιmιde hydrochloπde (0.75 g, 3.9 mmol), 1 -hydroxy- 7 -azabenzotπazole (0.54 g, 3.9 mmol) and 4- (N, N-dimethylammo) pyπdme (10 mg, cat.) in dimethylformamide (20 mL) was stirred at room temperature and a solution of the above amme (0.88 g, 3.28 mmol) in dimethylformamide (20 mL) was added and the mixture allowed to stir overnight. The dimethylformamide was evaporated under reduced pressure and the resulting oil partitioned between water (50 mL) and ethyl acetate (50 mL) . The ethyl acetate was washed with 5% aqueous HCl (10 mL) and saturated aqueous NaHC03 (10 mL) , dried (MgSO and evaporated under reduced pressure to give the amide as a golden foam (1.6 g, 97 %) . λE NMR (CDClj) : 7.43 - 7.10 ppm (13 H, m, Ar) : 6.85 (1 H, d, J = 6 Hz, NH) ; 5.61 (1 H, br s, NH) ; 5.03 (2 H, br s,
CH2Ph) ; 3.85 (2 H, t, J = 7 Hz, dihydroindole C(2)H2); 2.85 (2 H, t, J = 8 Hz, dihydroindole C(3)H2); 1.19 (9 H, s, cBu) .
D-phenylglycine l-benzyloxycarbonyl-2, 3-dihydroindol-6-amide trifluoroacetate salt
Tπfluoroacetic acid (5 mL) was added to a solution of the above foam in dichloromethane (20 mL) and the solution was allowed to stir for 2 hours at room temperature. The solvent was evaporated under reduced pressure to give the amme trifluoracetate salt as a red foam (1.5 g, 91 %) which was used without further purification.
3- (iV-BOC-Aminomethyl) benzoyl-D-phenylglycine (1- benzyloxycarbonyl-2 , 3-dihydro) -indol-6-amide A solution of 3 - (N-BOC-aminomethyl) benzoic acid (0.798 g, 3.2 mmol) , 1- [3- (dimethylammo) propyl] -3 -ethylcarbodiimide hydrochloride (0.73 g, 3.8 mmol), l-hydroxy-7- azabenzotπazole (0.52 g, 3.8 mmol) and triethylamme (1.0 mL, 7.2 mmol) m dimethylformamide (10 mL) was stirred at room temperature and a solution of the above amme (1.5 g, 3.0 mmol) in dimethylformamide (5 mL) was added. The mixture was stirred overnight before the dimethylformamide was evaporated under reduced pressure, and the resulting oil partitioned between water (50 mL) and ethyl acetate (50 L) . The ethyl acetate layer was washed with 5% aqueous HCl (10 mL) and saturated aqueous NaHC03 (10 mL) , dried (MgSO„) and evaporated under reduced pressure to give a yellow solid. XH NMR (CDC13) : 7.75 - 7.22 ppm (17 H, m, Ar) : 7.05 (1 H, d, J = 5.5 Hz, NH) ; 5.74 (IH, d, J = 6 Hz , CHPh) ; 5.21 (2 H, s, 0CH2Ph) ; 4.89 (1 H, br s, NH) ; 4.32 (2 H, d, J = 6 Hz,
CH2NHBOC) ; 4.02 (2H, t, J = 8 Hz, dihydroindole C(2)H2); 3.05 (2H, t, J = 8 Hz, dihydroindole C(3)H2); 1.4 (9 H. s, r"Bu) .
3- (iV-BOC-Aminomethyl) benzoyl-D-phenylglycine 2,3- dihydroindol-6-amide
A solution of the above solid in methanol (50 mL) was stirred over 10%Pd/C (500 mg) under an atmosphere of H2 and heated under reflux for 2 hours. The mixture was cooled, filtered and the solvent evaporated under reduced pressure to provide the unprotected dihydroindole as a yellow foam
(1.4g, 88%) which was used without further purification.
3- (Aminomethyl) benzoyl-D-phenylglycine 1-acetyl-2 , 3 - dihydroindol-6-amide trifluoroacetate salt A solution of the dihydroindole (500 mg, 1.0 mmol) and triethylamme (0.28 L, 2 mmol) in dichloromethane (20 mL) was stirred at 0°C and acetyl chloride (86 mg, 1.1 mmol) was added dropwise, then left to stir overnight. The mixture was washed with 5% aqueous HCl (10 mL) and the organic phase was dried (MgSO and evaporated. The residue was purified by flash column chromatography (ethyl acetate / hexane, 1:1) to give a yellow oil. The oil was dissolved m dichloromethane (20 mL) and treated with trifluoroacetic aid (5 mL) . After stirring for 2 hours the solvent was evaporated under redued pressure to an oil, which after triturating with diethyl ether gave the amme as its trifluoroacetate salt as a white solid (337 mg, 61 %) .
XH NMR (d4 MeOH): 8.30 ppm (1 H, s, Ar) ; 7.97 (2 H, m, Ar) ; 7.60 (4 H, m, Ar) ; 7.39 (4 H, 3, m, Ar) ; 7.22 (1 H, d, J = 10 Hz, Ar) ; 5.82 (1 H, s, CHPh); 4.2 (2 H, s, CH2NH2) ; 4.15 (2 H, t, J = 7 Hz, dihydroindole C(2)H2); 3.17 (2 H, t, J" = 7 Hz, dihydroindole C(3)H2); 2.25 (3 H, s, CH3) . HPLC (Luna 2, Gradient 1): rt = 3.39 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.72 minutes, 443 (MH)*.
Examples 36 - 60 were prepared from the intermediate 3 - {N- BOC-aminomethyl) -benzoyl -D-phenylglycme 2 , 3 -dihydromdol -5- amide, described for Example 29, and the appropriate carboxylic acid or derivative, using standard chemical methods and protecting other functionality where required.
Example 36
3- (Aminomethyl) benzoyl-D-phenylglycine l-propanoyl-2 , 3- dihydro-indol-6-amide trifluoroacetate salt Prepared using propanoyl chloride.
XH NMR (d4 MeOH) : 8.58 ppm (1 H, d, J = 1.2 Hz, dihydroindole C(7)H); 8.18 (2 H, m, Ar) ; 7.82 (4 H, m, Ar) ;
7.59 (4 H, m, Ar) ; 7.37 (1 H, m, Ar) ; 6.03 (1 H, s, CHPh);
4.39 (2 H, s, CH2NH2) ; 4.31 (2 H, t, J = 9 Hz, dihydroindole C(2)H); 3.37 (2 H, t, J = 9 Hz, dihydroindole C(3)H); 2.73 (2 H, q, J = 7.5 Hz, CH2CH3) ; 1.47 (3 H, t, J = 7.5 Hz,
CH2CH3) .
HPLC (Luna 2, Gradient 1) : rt = 3.55 minutes.
LC/MS (Luna 2, Gradient 4):rt = 1.94 minutes, 457 (MH)*.
Example 37
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (2 -methyl- propanoyl) -2 , 3 -dihydroindol-6-amide trifluoroacetate salt Prepared using 2 -methylpropanoyl chloride. lE NMR (d4 MeOH): 8.32 ppm (1 H, s, dihydroindole C(7)H);
7.98 (2 H, m, Ar) ; 7.60 (4 H, m, Ar) ; 7.43 (4 H, m, Ar) ;
7.18 (1 H, m, Ar) ; 5.83 (1 H, s, CHPh); 4.21 (4 H, m, CH2NH2 and dihydroindole C(2)H); 3.18 (2 H, t, J = 9 Hz, dihydroindole C(3)H), 2.95 (1 H, m, CH(CH3)2); 1.22 (6 H, d,
J = 8 Hz, CH(CH3)2) •
HPLC (Luna 2, Gradient 1): rt = 3.74 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.05 minutes, 471 (MH)*.
Example 38
3- (Aminomethyl) benzoyl-D-phenylglycine 1-D-alaninoyl- 2, 3-dihydroindol-6-amide bis (trifluoroacetate) salt
Prepared using D-alanme.
XH NMR (d4 MeOH): 8.40 ppm (1 H, s, Ar) ; 8.01 (2 H, m, Ar) ; 7.65 (4 H, m, Ar) ; 7.45 (4 H, m, Ar) ; 7.25 (1 H, d, J" = 10 Hz, Ar) ; 5.85 (1 H, s, CHPh); 4.4 (1 H, q, J = 1 Hz, alanmyl CHNH2) ; 4.25 (2 H, s, ArCH2NH2) ; 4.25 (2 H, t, J" = 8 Hz, dihydroindole C(2)H2); 3.28 (2 H, t, J = 8 Hz, dihydroindole C(3)H2); 1.65 (3 H, d, J = 1 Hz, CH3) . HPLC (Luna 2, Gradient 1) : rt = 2.85 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.35 minutes, 472 (MH)*.
Example 39
3- (Aminomethyl) benzoyl-D-phenylglycine 1-L-alaninoyl- 2 , 3-dihydroindol-6-amide bis (trifluoroacetate) salt
Prepared using L-alanme. lE NMR (d4 MeOH): 8.43 ppm (1 H, s, Ar) ; 7.97 (2 H, m, Ar) ;
7.63 (4 H, m, Ar) ; 7.45 (4 H, m, Ar) ; 7.25 (1 H, d, J = 10
Hz, Ar) ; 5.85 (1 H, s, CHPh) ; 4.35 (1 H, q, J = 1 Hz, alanmyl CHNH2) ; 4.25 (2H, t, J = 7.5 Hz, mdolme C(2)H2) ;
4.2 (2 H, s, CH2NH2) ; 3.25 (2H, t, J" = 8 Hz, mdolme
C(3)H2) ; 1.6 (3 H, d, J = 7 Hz, CH3) ■
HPLC (Luna 2, Gradient 1) : rt = 2.84 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 472 (MH)*.
Example 40
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (iV-acetyl-D- alaninoyl) -2 , 3-dihydroindol-6-amide trifluoroacetate salt Prepared using N-acetyl-D-alamne .
XH NMR (d4 MeOH): 8.33 ppm (1 H, s, Ar) ; 7.97 (2 H, m, Ar) ; 7.61 (4 H, m, Ar) ; 7.40 (4 H, m, Ar) ; 7.18 (1 H, d, J = 9 Hz, Ar) ; 5.83 (1 H, s, CHPh); 4.70 (1 H, br m, CHNHAc); 4.38 (1 H, m, mdolme C(2)H); 4.21 (2H, s, CH2NH2) ; 4.20 (1 H, t, J" = 8 Hz mdoline C(2)H); 3.2 (2 H, t, J" = 8 Hz, mdoline C(3)H2); 2.01 (3 H, s, COCH3); 1.4 (3 H, d, J = 7 Hz, CH3) . HPLC (Luna 2, Gradient 1): rt = 3.24 minutes. LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 514 (MH)*.
Example 41 3- (Aminomethyl) benzoyl-D-phenylglycine 1- (27-acetyl-L- alaninoyl) -2 , 3-dihydroindol-6-amide trifluoroacetate salt
Prepared using N-acetyl -L-alanine . XH NMR (d4 MeOH): 8.33 ppm (1 H, s, Ar) ; 7.97 (2 H, m, Ar) ; 7.62 (4 H, m, Ar) ; 7.38 (4 H, m, Ar) ; 7.18 (1 H, d, Ar) ; 5.83 (1 H, s, CHPh); 4.70 (1 H, m, CHNHAc); 4.35 (1 H, m, dihydroindole C(2)H); 4.2 (2H, s, CH2NH2) ; 4.2 (IH, m, dihydroindole C(2)H); 3.2 (2 H, t, J = 8 Hz, dihydroindole C(3)H2); 2.0 (3 H, s, COCH3); 1.4 (3 H, d, J = 7 Hz, CH3). HPLC (Luna 2, Gradient 1): rt = 3.19 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.67 minutes, 514 (MH)*.
Example 42 3- (Aminomethyl) benzoyl-D-phenylglycine 1-aminoacetyl- 2,3-dihydroindol-6-amide bis (trifluoroacetate) salt
Prepared using glycine. λE NMR (d4 MeOH): 8.41 (1 H, s, dihydroindole C(7)H); 7.97 (2 H, br S, Ar) ; 7.58 (4 H, m, Ar) ; 7.22 (1 H, d, J = 8 Hz, Ar) ; 5.84 (1 H, s, CHPh); 4.20 (2 H, s, CH2NH2); 4.15 (2 H, t, J = 9 Hz, dihydroindole C(2)H); 4.04 (2 H, s, COCH2NH2) ;
3.23 (2H, t, J = 9 Hz, dihydroindole C(3)H).
HPLC (Luna 2, Gradient 1): rt = 2.77 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.24 minutes, 458 (MH)*.
Example 43
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (3- methylbutanoyl) -2,3 -dihydroindol-6-amide trifluoroacetate salt Prepared using 3-methylbutanoyl chloride. *H NMR (d4 MeOH): 8.40 ppm (1 H, s, Ar) ; 8.02 (2 H, m, Ar) ; 7.67 (4 H, m, Ar) ; 7.22 (1 H, d, J = 11 Hz, Ar) ; 5.90 (1 H, s, CHPh); 4.27 (2 H, s, CH2NH2); 4.22 (2 H, t, J = 8 Hz, indoline C(2)H2); 3.22 (2H, t , J" = 8 Hz, indoline C(3)H2); 2.45 (2 H, d, J" = 7 Hz, COCH2) ; 2.28 (1 H, septet, J" = 7 Hz, CHMe2) ; 1.1 (6 H, d, J = 1 Hz, CH(CH3)2). HPLC (Luna 2, Gradient 1): rt = 4.18 minutes. LC/MS (Luna 2, Gradient 4): rt = 2.15 minutes, 485 (MH)*.
Example 44
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (benzyloxy) - acetyl-2 , 3 -dihydroindol-6 -amide trifluoroacetate salt
Prepared using 2-benzyloxyacetyl chloride.
XH NMR (d4 MeOH): 8.40 ppm (1 H, s, Ar) ; 8.02 (2 H, m, Ar) ; 7.65 (5 H, m, Ar) ; 7.45 (10 H, m, Ar) ; 7.22 (1 H, d, J = 10
Hz, Ar) ; 5.91 (1 H, s, CHPh); 4.73 (2 H, S, COCH) ; 4.35 (1
H, q, CHNH2) ; 4.37 (2 H, s, CH2Ph) ; 4.25 (2 H, s, CH2NH2) ;
4.12 (2 H, t, J = 7.5 Hz, indoline C(2)H2); 3.2 (2 H, t, J =
7.5 Hz, indoline C(3)H2). HPLC (Luna 2, Gradient 1): rt = 4.25 minutes.
LC/MS (Luna 2, Gradient 4) : rt = 2.15 minutes, 549 (MH)*.
Example 45
3- (Aminomethyl) benzoyl-D-phenylglycine 1-L-threoninoyl- 2, 3 -dihydroindol-6 -amide bis (trifluoroacetate) salt
Prepared using L-threonine.
XH NMR (d4 MeOH): 8.31 ppm (1 H, s, Ar) ; 7.80 (2 H, m, Ar) ; 7.45 (4 H, m, Ar) ; 7.25 (4 H, m, Ar) ; 7.05 (1 H, d, Ar) ; 5.65 (1 H, s, CHPh); 4.10 (2 H, t, J = 8 Hz, indoline C(2)H2); 4.02 (2 H, s, CH2NH2) ; 3.11 (2 H, t, J = 8 Hz, indoline C(3)H2); 1.21 (3H, d, CH3) ; other signals obscured by solvent .
HPLC (Luna 2, Gradient 1) : rt = 2.84 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.65 minutes, 502 (MH)*.
Example 46
3- (Aminomethyl) benzoyl-D-phenylglycine 1-L-prolinoyl-
2, 3 -dihydroindol-6 -amide bis (trifluoroacetate) salt
Prepared using L-proline. lE NMR (d4 MeOH) : 8.47 ppm (1 H, s, Ar) / 8.05 (2 H, m, Ar) ;
7.75 - 7.65 (4 H, m, Ar) ; 7.56 - 7.47 (4 H, m, Ar) ; 7.30 (1
H, d, J = 9 Hz, Ar) ; 5.91 (1 H, s, CHPh) ; 4.73 (1 H, t, J =
6.5 Hz, proline C(2)H); 4.25 (4 H, m, CH2NH2 and indoline
C(2)H2); 3.65-3.32 (3 H, m, indoline C(3)H2 and proline C(5)H); 2.70 (1 H, m, proline C(5)H); 2.33 - 2.15 (4 H, m, proline C(3)H2 and C(4)H2).
HPLC (Luna 2, Gradient 1): rt = 2.98 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 498 (MH)*.
Example 47
3- (Aminomethyl) benzoyl-D-phenylglycine 1- ( (S) -2-hydroxy- propanoyl) -2 , 3 -dihydroindol-6 -amide trifluoroacetate salt
Prepared using (S) -2-hydroxypropanoic acid. 'H NMR (d4 MeOH): 8.33 ppm (1 H, s, Ar) ; 7.97 (2 H, m, Ar) ; 7.66 - 7.56 (4 H, m, Ar) ; 7.45 - 7.37 (4 H, m, Ar) ; 7.18 (1 H, d, J = 9 Hz, Ar) ; 5.83 (1 H, s, CHPh); 4.58 (IH, m, CHOH); 4.31 (IH, m, indoline C(2)H); 4.21 (2 H, s, CH2NH2) ; 4.15 (1 H, m, indoline C(2)H); 3.18 (2 H, t, J = 8 Hz, indoline C(3)Ha); 1.4 (3 H, d, J = 7 Hz, CH3) . HPLC (Luna 2, Gradient 1): rt = 3.31 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.72 minutes, 473 (MH)*.
Example 48 3- (Aminomethyl) benzoyl-D-phenylglycine 1-D-prolinoyl- 2, 3 -dihydroindol-6 -amide bis (trifluoroacetate) salt
Prepared using D-proline. lE NMR (d4 MeOH): 8.41 ppm (1 H, s, Ar) ; 7.97 (2 H, m, Ar) ,-
7.64 - 7.57 (4 H, m, Ar) ; 7.48 - 7.39 (4 H, m, Ar) ; 7.23 (1 H, d, J" = 11 Hz, Ar) ; 5.82 (1 H, s, CHPh); 4.63 (1 H, m, proline C(2)H); 4.24 (4 H, m, CH2NH2 and indoline C(2)H2);
3.52-3.24 (3 H, m, indoline C(3)H2 and proline C(5)H); 2.63
(1 H, m, proline C(5)H); 2.23 - 2.08 (4 H, m, proline C(3)H2 and C(4)H2) . HPLC (Luna 2, Gradient 1) : rt = 2.98 minutes.
HPLC (Symmetry, Gradient 2): rt = 4.87 minutes.
LC/MS (Luna 2, Gradient 4): rc = 0.59 minuces, 498 (MK) \
Example 49 3- (Aminomethyl) benzoyl-D-phenylglycine l-L-serinoyl-2 , 3 - dihydroindol-6 -amide bis (trifluoroacetate) salt
Prepared using L-serine. lE NMR (d4 MeOH): 8.40 ppm (1 H, s, Ar) ; 7.95 (2 H, m, Ar) ;
7.64 - 7.57 (4 H, m, Ar) ; 7.47 - 7.39 (4 H, m, Ar) ; 7.23 (1 H, d, J = 10 Hz, Ar) ; 5.81 (1 H, s, CHPh); 4.4 (1 H, dd, J =
12 Hz, 4 Hz, serine CHaHbOH) ; 4.25 (2 H, t, J" = 7 Hz, indoline C(2)H2); 4.20 (2 H, s, CH2NH2) ; 4.05 (1 H, dd, J =
12, 6 Hz, serine CHaHbOH) ; 3.91 (1 H, m, serine CHNH2) ; 3.25
(2 H, t, J = 7 Hz, indoline C(3)H2). HPLC (Luna 2, Gradient 1) : rt = 2.84 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.35 minutes, 488 (MH)*.
Example 50
3- (Aminomethyl) benzoyl-D-phenylglycine l-D-serinoyl-2 , 3 - dihydroindol-6 -amide bis (trifluoroacetate) salt
Prepared using D-serme. lE NMR (d4 MeOH): 8.42 ppm (1 H, s, Ar) ; 7.97 (2 H, m, Ar) ;
7.64 - 7.57 (4 H, m, Ar) ; 7.47 - 7.39 (4 H, m, Ar) ; 7.23
(IH, d, J = 9 Hz, Ar) ; 5.82 (1 H, s, CHPh) ; 4.41 (1 H, dd, J = 12, 4 Hz, serine CHaHbOH) ; 4.25 (2 H, t, J = 7.5 Hz, mdolme C(2)H2) ; 4.2 (2 H, s, CH2NH2) ; 4.05 (1 H, dd, J =
12, 6 Hz, serine CHaHbOH) ; 3.9 (1 H, mseπne CHNH2) ; 3.25 (2
H, t, J" = 7.5 Hz, mdoline C(3)H2) .
HPLC (Luna 2, Gradient 1): rt = 2.78 minutes. HPLC (Symmetry, Gradient 2): rt = 4.61 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.65 minutes, 488 (MH)*.
Example 51
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (3 -pyridyl- acetyl) -2 , 3 -dihydroindol- 6 -amide bis (trifluoroacetate) salt
Prepared using 3 -pyπdylacetic acid. lE NMR (d3 acetonitrile): 8.91 ppm (1 H, br s, Ar) , 8.73-8.55
(2 H, m, Ar) , 8.35 (1 H, br s, Ar) , 8.15 (1 H, d, J = 10 Hz, Ar) , 8.05-7.95 (2 H, m, Ar) , 7.80 (IH, d, J = 10 Hz, Ar) ,
7.74 - 7.15 (10 H, m, Ar Sc 2 x amide NH) , 5.69 (1 H, d, J = 7 Hz, CHPh), 4.25 - 4.12 (4 H, m, ArCH2N & dihydroindole C(2)H2), 3.98 (2 H, s, C(0)CH2Py), 3.17 (2 H, t, J = 8 Hz, dihydroindole C(3)H2). HPLC (Luna 2, Gradient 1): rt = 2.96 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.35 minutes, 520 (MH*) .
Example 52
3- (Aminomethyl) benzoyl -D-phenylglycine 1- (27-acetyl) - aminoacetyl-2 , 3 -dihydroindol-6 -amide trifluoroacetate salt
Prepared using N-acetylglycine .
XH NMR (d4 MeOH): 8.31 ppm (1 H, s, Ar) ; 7.95 (2 H, m, Ar) ;
7.64 - 7.57 (4 H, m, Ar) ; 7.43 - 7.38 (4 H, m, Ar) ; 7.18 (IH, d, J = 10 Hz, Ar) ; 5.81 (IH, s, CHPh); 4.23 - 4.11 (6
H, m, ArCH2NH2, ammoacetyl CH2 and dihydroindole C(2)H2) ;
3.21 (2 H, t, J - 7 Hz, dihydroindole C(3)H2) ; 2.07 (3H, s,
C0CH3) .
HPLC (Luna 2, Gradient 1): rt = 3.33 minutes. HPLC (Symmetry, Gradient 2): rt = 5.20 minutes.
LC/MS (Luna 2, Gradient 4): rt = 0.59 minutes, 500 (MH)*.
Example 53
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (hydroxyacetyl) -2 , 3 -dihydroindol-6-amide trifluoroacetate salt
Prepared using 2-benzyloxyacetic acid. lE NMR (d4 MeOH): 8.25 ppm (1 H, s, Ar) ; 7.85 (2 H, m, Ar) ;
7.54 - 7.47 (4 H, m, Ar) ; 7.35 - 7.26 (4 H, m, Ar) ; 7.10 (1 H, d, J = 11 Hz, Ar) ; 4.21 (2 H, s, CH2OH ) ; 4.10 (2 H, s,
CH2NH2) ; 3.95 (2 H, t, J = 7.5 Hz, dihydroindole C(2)H2);
3.21 (2 H, t, J = 7.5 Hz, dihydroindole C(3)H2).
HPLC (Luna 2, Gradient 1) : rt = 3.23 minutes.
HPLC (Symmetry, Gradient 2): rt = 5.26 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.67 minutes, 500 (MH)*. Example 54
3- (Aminomethyl) benzoyl-D-phenylglycine 1-phenylacetyl-
2, 3 -dihydroindol-6 -amide trifluoroacetate salt Prepared using phenylacetic acid.
XH NMR (d3 acetonitrile): 8.78 (1 H, br s, Ar) , 8.23 (1 H, br s, Ar) , 7.90 (2 H, s, Ar) , 7.73 (IH, d, J" = 10 Hz, Ar) , 7.60 - 7.01 (14 H, m, Ar S. 2 x amide NH) , 5.60 (1 H, d, J = 7 Hz, CHPh), 4.10 - 3.97 (4 H, m, ArCH2N Sc dihydroindole C(2)H2), 3.71 (2 H, s, PhCH2) , 2.99 (2 H, t, J = 8 Hz, dihydroindole C(3)Ha) .
HPLC (Luna 2, Gradient 1): rt = 4.17 minutes. LC/MS (Luna 2, Gradient 4): rt = 2.26 minutes, 519 (MH+) .
Example 55
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (methylamino) - acetyl-2, 3 -dihydroindol-6-amide bis (trifluoroacetate) salt
Prepared using sarcosine. lE NMR (d4 MeOH): 8.39 ppm (1 H, s, indoline C(7)H); 7.95 (2 H, br s, 3- (aminomethyl) phenyl C(2)H and C(6)H); 7.72 - 7.53
(4 H, m, Ar) ; 7.47 - 7.31 (4 H, m, Ar) / 7.24 (1 H, d, J = 10 Hz, indoline C(4)H or C(5)H); 5.82 (1 H, br s , CHPh); 4.20
(2 H, s, CH2NH2 or C (0) CH2NHMe) ; 4.15 (2 H, s, CH2NH2 or C(0)CH2NHMe) ; 4.10 (2 H, t, J = 9 Hz , indoline C(2)H2); 3.25
(2 H, t, J = 9 Hz, indoline C(3)H2); 2.81 (3 H, s, CH3) . HPLC (Symmetry C8 , Gradient 2) : rt = 4.75 min. LCMS (Luna 2, Gradient 4): rt = 1.45 min, 472 (MH)*.
Example 56 3- (Aminomethyl) benzoyl-D-phenylglycine 3-aminopropionyl- 2 , 3 -dihydroindol- 6 -amide bis (trifluoracetate) salt
Prepared using β-alanine. lH NMR (D-O) : 7.98 ppm (1 H, s, indoline C(7)H); 7.72 (2 H, br s, 3- (aminomethyl) phenyl C(2)H and C(6)H); 7.60 - 7.30 (7 H, m, Ar) ; 7.08 (1 H, d, J = 10 Hz, indoline C(4)H or C(5)H) ; 6.95 (1 H, d, J = 10 Hz, indoline C(4)H or C(5)H) ; 5.57 (1 H, s, CHPh); 4.09 (2 H, s, ArCH2NH2) ; 3.82 (2 H, t, J = 7 Hz, indoline C(3)H2); 3.20 (2 H, t, J = 4.5 Hz, C(0)CH2CH2NH2) ; 2.95 (2 H, t, J = 7 Hz, indoline C(3)H2); 2.71 (2 H, t, J = 4.5 Hz, C (0) CH2CH2NH2) . HPLC (Symmetry C8 , Gradient 2) : rt = 4.80 minutes. LCMS (Luna 2, Gradient 4): rt = 1.53 minutes, 472 (MH)*.
Example 57
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (4-pyridyl- acetyl) -2 , 3 -dihydroindol-6 -amide bis-trifluoroacetate salt
Prepared using 4 -pyridylacetic acid. XE NMR (CD3CN) : 8.91 (I H, br s , Ar) , 8.73-8.55 (2 H, m, Ar) , 8.35 (1 H, br s, Ar) , 8.15 (1 H, d, J = 10 Hz, Ar) , 8.05- 7.95 (2 H, m, Ar) , 7.80 (IH, d, J" = 10 Hz, Ar) , 7.74 - 7.15 (10 H, m, Ar Sc 2 x amide NH) , 5.69 (1 H, d, J = 7 Hz, CHPh), 4.25 - 4.12 (4 H, m, PhCH2N Sc dihydroindole C(2)H2), 3.98 (2 H, s, C(0)CH2Py), 3.17 (2 H, t, J = 8 Hz, dihydroindole C(3)H2) .
HPLC (Symmetry, Gradient 2): rt = 5.43 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.56 minutes, 520 (MH)*.
Example 58 3- (Aminomethyl) benzoyl-D-phenylglycine 1- (imidazol-4- ylacetyl) -2 , 3 -dihydroindol-6 -amide bis (trifluoroacetate) salt
Prepared using imidazol-4-ylacetic acid. lE NMR (D20) : 7.75 ppm (1 H, br s, NH) ; 7.49 (2 H, br s, Ar) ; 7.28 (1 H, d, J" = 8 Hz, Ar) ; 7.24-7.12 (9 H, m, Ar) ; 6.92 (1 H, d, J = 8 Hz, Ar) ; 6.74 (1 H, d, J" = 8 Hz, Ar) ; 6.28 (IH, s, NH) ; 5.38 (1 H, s, CHPh); 3.87 (2 H, s, ArCH2NH2) ; 3.72 (2 H, d, J 8 = Hz, dihydroindole C(2)H2); 3.52 (2 H, br s, CH2Im) ; 2.70 (2 H, t, J = 8 Hz, dihydroindole C(3)H2). HPLC (Symmetry, Gradient 2): rt = 4.89 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.45 minutes, 509 (MH)*.
Example 59 3- (Aminomethyl) benzoyl-D-phenylglycine l-(2- aminothiazol-4-yl) - cetyl-2,3-dihydroindol- 6-amide dihydrochloride .
Prepared using (2-formamidothiazol-4-yl) acetic acid.
X NMR (DjO) : 7.77 ppm (1 H, br s, NH) ; 7.51 (2 H, br s, Ar) ; 7.29 (1 H, d, J = 8 Hz, Ar) ; 7.24-7.03 (9 H, m, Ar) ; 6.91 (1 H, d, J = 8 Hz, Ar) ; 6.72 (1 H, d, J = 8 Hz, Ar) ; 6.22 (IH, s, NH) ; 5.32 (1 H, s, CHPh); 3.85 (2 H, s, ArCH2NH2) ; 3.73 (2 H, d, J = 8 Hz, dihydroindole C(2)H2); 3.56 (2 H, br s, CH2Thz) ; 2.76 (2 H, t, J" = 8 Hz, dihydroindole C(3)H2). HPLC (Symmetry, Gradient 2): rt = 5.03 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.51 minutes, 541 (MH)*.
Example 60
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (2- formylaminothiazol-4-yl) acetyl-2 , 3 -dihydroindol -6 -amide trifluoroacetate salt
Prepared using (2-formylammothιazol-4-yl) acetic acid. lE NMR (D20) : 8.30 ppm (1 H, s, NCHO) ; 7.90 (1 H, br S, ArNH) ; 7.64 (2 H, br s, Ar) ; 7.42 (1 H, d, J = 8 Hz, Ar) ; 7.38 - 7.26 (9 H, m, Ar Sc NH) ; 7.01 (1 H, d, J = 8 Hz, Ar) ; 6.96 (1 H, d, J = 8 Hz, Ar) ; 6.82 (IH, s, NH) ; 5.50 (1 H, s, CHPh); 4.06 (2 H, s, ArCH2NH2) ; 3.90 (2 H, d, J" = 8 Hz, dihydroindole C(2)H2); 3.64 (2 H, br s, CH2Thz) ; 2.90 (2 H, t, J = 8 Hz, dihydroindole C(3)H2). HPLC (Symmetry, Gradient 2): rt = 5.75 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.10 minutes, 569 (MH)*.
Example 61
3- (Aminomethyl) benzoyl-D/L- (4-aminomethyl) phenylglycine indan-5-amide bis (trifluoroacetate) salt.
Methyl 4-bromophenylacetate
Thionyl chloride (18 mL, 0.25 mol) was added dropwise to a solution of 4-bromo-phenylacetιc acid (50 g; 0.23 mol) m methanol (250 mL) . The resulting mixture was stirred at room temperature for 1 hour before the methanol was removed in vacuo . Ethyl acetate (300 mL) was added and the resulting solution was washed with water (3 x 150 mL) and 1M aqueous NaHC03 (1 x 150 mL) , dried (MgS04) and evaporated to give the ester (52.8 g; 100 %) as an orange oil which was used without further purification. lE NMR (CDC13) : 7.38 ppm (2 H, d, J = 8.4 Hz, C(2)H and C(6)H) ; 7.09 (2 H, d, J" = 8.4 Hz, C(3)H and C(5)H) ; 3.63 (3 H, s, OMe) ; 3.51 (2 H, s, CH2) . Methyl 4-cyanophenylacetate
Zinc cyanide (10.4 g, 0.088 mol) and tetrakis- (triphenylphosphme) palladιum(O) (5 g, 4.4 mmol) were added to a solution of methyl 4-bromophenylacetate (20 g, 0.088 mol) in dimethylformamide (150 mL) . The resulting mixture was stirred at 80°C for 5 hours, then allowed to cool to room temperature. Toluene (500 mL) and 1M aqueous ammonia (500 mL) were added, the layers were separated and the organic layer washed with brine (100 mL) and dried (MgS04) . Evaporation of the solvents afforded an off-white solid, which was purified by silica gel chromatorgraphy to afford the cyano-compound as a white solid (11.3 g; 73 %) . 'H NMR (CDC13) : 7.65 ppm (2 H, d, J" = 8.4 Hz, C(3)H and C(5)H) ; 7.42 (2 H, d, J = 8.1 Hz, C(2)H and C(6)H) ; 3.74 (3H, S, OMe) ; 3.72 (2H, S, CH2) .
4-Cyanophenylacetic acid
A solution of methyl 4-cyanophenylacetate (23.9 g; 0.136 mol) in ethanol (250 L) was stirred at room temperature and a solution of sodium hydroxide (6.0 g; 0.15 mol) in water
(25 mL) was added. After 2 hours the ethanol was removed in vacuo . Ethyl acetate (300 mL) and 5% aqueous HCl (300 mL) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (300 mL) and the combined organic layers were dried (MgS04) and evaporated m vacuo to give the acid (21.6 g; 99 %) which was used without further purification. lH NMR (CDCI3) : 7.57 ppm (2 H, d, J = 8.3 Hz, C(3)H and C(5)H) ; 7.34 (2 H, d, J = 8.2 Hz, C(2)H and C(6)H) ; 3.64 (2 H, s, CH2) . 4- (iV-BOC-aminomethyl)phenylacetic acid
A solution of 4-cyanophenylacetic acid (12.11 g, 0.075 mol) in water (163 mL) and concentrated aqueous ammonia (40 mL) was stirred at room temperature and Raney nickel (6.3 g) was added. The resulting suspension was stuirred under a hydrogen atmosphere for 24 hours before the reaction mixture was filtered through celite and evaporated in vacuo to give crude 4- (aminomethyl) -phenylacetic acid (12.57 g; 100 %) as a pale blue solid.
A solution of the crude amino acid (12.57 g, 0.075 mol) in water (50 mL) and 1,4-dioxane (50 mL) was stirred at room temperature and sodium hydroxide (3 g, 0.075 mol) and di- cbutyl dicarbonate (16.4 g, 0.075 mol) were added simultaneously. After 24 hours the 1,4-dioxane was removed in vacuo and the aqueous layer was acidified with saturated aqueous citric acid (200 mL) . The solution was extracted with ethyl acetate (3 x 150 mL) and the combined organic layers were dried (MgS04) and evaporated in vacuo to give the W-BOC-amine (17.6 g, 88 %) as a white solid which was used without further purification.
*H NMR (CDC13) : 7.00 ppm (4 H, m, Ar) ; 4.65 (1 H, br s, N-H) ; 4.09 (2 H, d, J = 6 Hz, CH2NH) ; 3.43 (2H, s, CH2) ; 1.25 (9H, s, sBu) .
Methyl 4- (27-BOC-aminomethyl) phenylacetate 1- [3- (Dimethylamino) propyl] -3 -ethylcarbodiimide hydrochloride (34.8 g, 0.18 mol) and 4 - (N, N- dimethylamino) yridine (220 mg, 1.8 mmol) were added to a solution of 4- (N-BOC-aminomethyl) phenylacetic acid (47.8 g, 0.18 mol) in methanol (200 ml) . After stirring for 18 hours the methanol was removed in vacuo and the reaction mixture partitioned between ethyl acetate (200 mL) and saturated aqueous citric acid (200 mL) . The organic phase was separated and washed with saturated aqueous NaHC03 (200 mL) and brine (200 mL) , dried (MgS04) and evaporated to give the methyl ester (49.8 g; 99 %) .
XH NMR (CDClj) : 7.42 ppm (4 H, s, Ar) ; 5.02 (1 H, br s, N-H) ; 4.48 (2 H, d, J = 5.7 Hz, CH2NH) ; 3.87 (3 H, s, OMe) ; 3.79 (2 H, s, CH2) ; 1.64 (9 H, s, cBu) .
Methyl [4- (27-BOC-aminomethyl) phenyl] -α-azidoacetate
A solution of methyl 4- (N-BOC-aminomethyl ) phenylacetate (9.34 g; 0.033 mol) in THF (100 mL) was stirred under argon at -78°C and potassium bis (trimethylsilyl) amide (16.7 g,
0.084 mol) in THF (50 mL) was added. After stirring for 30 minutes, 2 , 4 , 6-triisopropylbenzene-sulfonyl azide (31.1 g, 0.101 mol) was added as a solid. After 5 minutes, acetic acid (10 mL, 0.175 mol) was added and the reaction warmed to room temperature. The reaction mixture was then partitioned between ethyl acetate (500 mL) and water (500 mL) , separated and the organic layer dried (MgS04) . Evaporation of the solvent and purification of the residue by silica gel chromatography afforded the azide (7.1 g, 67 %) . lE NMR (CDClj) : 7.28 ppm (4 H, s, Ar) ; 4.92 (1 H, s, CHN3) ;
4.25 (2 H, s, CH2NH) ; 3.69 (3 H, s, OMe); 1.38 (9 H, s, cBu) .
Methyl α-amino- [4- (27-BOC-aminomethyl) phenylacetate
A solution of methyl [4- (7-BOC-aminomethyl) phenyl] -α- azidoacetate (7.1 g, 0.022 mol) in ethyl acetate (50 mL) was stirred over palladium on carbon (5%) . The reaction vessel was taken up to 250 psi with hydrogen for 17 hours. The reaction mixture was filtered through celite and evaporated m vacuo to give the amme (6.47 g, 100 %) as a pale solid. 'H NMR (CDC13) : 7.20 ppm (2 H, m, Ar) ; 7.12 (2 H, m, Ar) ;
4.81 (1 H, br s, NH) ; 4.45 (1 H, s, CH) ; 4.18 (2 H, d, J = 6 Hz, CH2NH) ; 3.54 (3 H, s, OMe); 2.09 (2 H, br s, NH2); 1.30 (9 H, s, cBu) .
Methyl - (27-benzyloxycarbonyl-amino) - [4- (27-BOC- aminomethy1) phenyl] acetate
A solution of the amme (530 mg, 1.8 mmol) in tetrahydrofuran (15 mL) was treated with triethylamme (0.25 mL, 1.8 mmol) and benzyl chloroformate (0.26 mL, 1.8 mmol) and allowed to stir at room temperature for 1 hour. The reaction was diluted with ethyl acetate (40 mL) , washed with brine (2 x 25 mL) , dried (MgS04) and concentrated under reduced pressure to afford a yellow oil. The benzyloxycarbonyl ester was purified by flash chromatography on silica gel (ethyl acetate / hexane 1 : 1) to give a yellow solid (312 mg, 66 %) . λH NMR (CDCI3) : 7.32 - 7.15 ppm (9 H, m, 9 Ar) ; 5.80 (1 H, br s, NH) ; 5.30 (1 H, d, J = 9.6 Hz, CH) ; 5.01 (2 H, s, CH2Ph) ; 4.22 (2 H, d, J" = 7.2 Hz, CH2NHBoc) ; 3.63 (3 H, s, OCH3 ) ; 1.39 (9 H, s, cBu) .
D/L-α- (27-benzyloxycarbonyl) - [4- (27-BOC-aminomethyl) phenyl] glycine
A solution of the ester (356 mg, 0.83 mmol) in tetrahydrofuran (15 mL) was treated with 1 M LiOH (1.7 mL, 1.7 mmol) and heated at reflux for 3 hours. The solvent was removed under reduced pressure and the residue diluted with water (20 mL) . The pH was reduced to 4 using 5 % aqueous HCl and the aqueous phase was extracted with ethyl acetate (3 x 20 mL) . The combined organic extracts were dried (MgS04) and concentrated under reduced pressure to afford the acid as a yellow solid (273 mg, 79 %) which was carried forward without further purification.
D/L-α- (27-benzyloxycarbonyl) - [4- (27-BOC- a inomethyl) phenyl] glycine indan-5-amide.
A solution of the acid (173 mg, 0.42 mmol) in dimethylformamide (15 ml) was treated with l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (80 mg, 0.42 mmol), l-hydroxy-7-azabenzotriazole (57 mg, 0.42 mmol), 5-aminoindane (56 mg, 0.42 mmol) and 4 - (N, N- dimethylamino) pyridine (5 mg) and stirred overnight at room temperature before being partitioned between ethyl acetate (50 mL) and water (50 mL) . The layers were separated and the organic phase was washed with 5 % aqueous HCl (25 mL) , saturated aqueous NaHC03 (25 mL) and water (25 mL) , dried (MgS04) and concentrated under reduced pressure to afford the indanamide as a colourless solid (160 mg, 72 %) which was used without further purification. lE NMR (CDC13) : 7.39 - 7.09 ppm (12 H, m, 10 Ar and 2 NH) ; 6.99 (2 H, s, Ar) ; 5.38 (1 H, br s, CHAr) ; 5.01 (2 H, s, CH2Ph) ; 4.81 (1 H, m, NH) ; 4.19 (2 H, s, CH2NHBOC) ; 2.85 - 2.68 (4 H, m, indane C(1)H2 and C(3)H2); 2.04 - 1.88 (2 H, m, indane C(2)H2); 1.39 (9 H, s, cBu) . 3- (27-BOC-Aminomethyl) benzoyl-D/L-4- (27-BOC-aminomethyl) - phenylglycine indan-5-amide
10 % Palladium on carbon (50 mg) , was added to a solution of the mdanamide (160 mg, 0.3 mmol) in ethanol (20 mL) and the suspension was stirred under a hydrogen atmosphere overnight . The mixture was filtered and the filter was washed with ethanol (20 ml) . The combined filtrates were concentrated under reduced pressure to afford the amme as a colourless solid (107 mg, 90 %) which was carried forward without further purification.
A solution of the amme (107 mg, 0.27 mmol) in dimethylformamide (15 mL) was treated with l-(3- dimethylammopropyl) -3-ethylcarbodιιmιde hydrochloπde (52 mg, 0.27 mmol), l-hydroxy-7-azabenzotπazole (37 mg, 0.27 mmol), AT-BOC-3- (aminomethyl) benzoic acid (68 mg, 0.27 mmol) and 4- (N/ N-dimethylammoJ pyridme (5 mg) and stirred overnight at room temperature. The solution was partitioned between ethyl acetate (25 mL) and water (25 mL) and the organic phase was separated and washed with 5 % aqueous HCl (25 mL) , saturated aqueous NaHC03 (25 mL) and water (25 mL) before being dried (MgS04) and concentrated under reduced pressure to afford a yellow solid. The residue was purified by flash chromatography on silica gel (ethyl acetate / hexane 1 : 1) to give the diprotected bis -amide as a colourless solid (103 mg, 61 %) .
XH NMR (CDC13) : 9.25 ppm (1 H, s, NH) ; 7.94 (1 H, d, J" = 7.2 Hz, Ar) ; 7.62 (2 H, s, Ar) ; 7.43 - 7.24 (5 H, m, 4 Ar, NH) ; 7.05 (3 H, d, J = 7.2 Hz, Ar) ; 6.94 (1 H, d, J" = 7.2 Hz, Ar) ; 6.14 (1 H, d, J = 7.2 Hz, CH) ; 5.07 (1 H, m, NH) ; 4.99 (1 H, m, NH) ; 4.16 (2 H, s, CH2 HB0C) ; 4.10 (2 H, S, CH2NHBOC) ; 2.77 - 2.61 (4 H, m, indane C(1)H2 and C(3)H2); 1.98 - 1.87 (2 H, m, indane C(2)H2); 1.35 (9 H, s, cBu) .
3- (Aminomethyl)benzoyl-D/L-4- (aminomethyl) phenylglycine indan-5-amide bis (trifluoroacetate) salt.
A solution of the diprotected bis-amide (103 mg, 0.16 mmol) in dichloromethane (5 mL) was stirred at room temperature and trifluoroacetic acid (3 mL) was added. Stirring was continued for a further hour before the solvents were removed under reduced pressure to afford the bis (trifluoroacetate) salt as a colourless solid (92 mg, 88
%) • lE NMR (d4 MeOH): 7.90 ppm (1 H, s, Ar) ; 7.84 (1 H, s, Ar) ;
7.65 - 7.54 (4 H, m, Ar) ; 7.49 - 7.32 (3 H, m, Ar) ; 7.12 (1 H, d, J = 7.2 Hz, Ar) ; 7.02 (1 H, d, J" = 7.2 Hz, Ar) ; 5.78
(1 H, S, CHAr); 4.08 (2 H, s, CH2 H2) ; 4.01 (2 H, s, CH2NH2) ;
2.79 - 2.70 (4 H, m, indane C(1)H2 and C(3)H2); 2.03 - 1.90
(2 H, m, indane C(2)H2) .
HPLC (Luna 2, Gradient 1): rt = 3.13 minutes. LCMS (Luna 2, Gradient 4): rt = 1.45 minutes, 429 (MH)*.
Examples 62 - 64 were prepared in a similar fashion to
Example 61, using the specified amine in place of 5- aminoindane .
Example 62
3- (Aminomethyl) benzoyl-D/L-4- (aminomethyl) phenylglycine l-aminoacetyl-2 , 3 -dihydroindol-6 -amide tris (trifluoroacetate salt) Prepared from 6-amino-l- (N-BOC-aminoacetyl ) -2 , 3 - dihydromdole . lE NMR (d4 MeOH) : 8.23 ppm (1 H, s, Ar) ; 7.84 - 7.74 (2 H, m, Ar) ; 7.56 - 7.30 (6 H, m, Ar) ; 7.17 (1 H, d, J = 7.2 Hz, Ar) ; 7.02 (1 H, d, J = 7.2 Hz, Ar) ; 5.68 (1 H, s, CHAr) ; 4.02 (2 H, s, CH2NH2) ; 3.99 - 3.79 (6 H, m, CH2NH2 , dihydroindole C(2)H2, CH2NH2 glycme) ,- 3.06 - 2.97 (2 H, m, dihydroindole C(3)H2) .
HPLC (Luna 2, Gradient 1) : rt = 2.13 minutes. LCMS (Luna 2, Gradient 4): rt = 0.51 minutes, 487 (MH)*.
Example 63
3- (Aminomethyl) benzoyl-D/L-4- (aminomethyl) phenylglycine 1- acetyl-2 , 3 -dihydroindole bis (trifluoroacetate) salt
Prepared from l-acetyl-6-ammo-2 , 3 -dihydroindole . *H NMR (d4 MeOH): 8.21 ppm (1 H, s, Ar) ; 7.97 - 7.86 (2 H, m,
Ar) ; 7.72 - 7.43 (6 H, m, Ar) ; 7.32 (1 H, d, J = 7.2 Hz,
Ar) ; 7.12 (1 H, d, J" = 7.2 Hz, Ar) ; 5.81 (1 H, Ξ, CHAr);
4.17 (1 H, s, CH2NH2) ; 4.15 - 4.04 (4 H, m, CH2NH2 , dihydroindole C(2)H2); 3.19 - 3.07 (2 H, m, dihydroindole C(3)H2); 2.20 (3 H, s, NCOCH3 ) .
HPLC (Luna 2, Gradient 1) : rt = 2.72 minutes.
LCMS (Luna 2, Gradient 4): rt = 1.18 minutes, 472 (MH)*.
Example 64 3- (Aminomethyl) benzoyl-D/L-4- (aminomethyl) phenylglycine 4- (isopropyl) phenylamide bis (trifluoroacetate salt)
Prepared from 4-ιsopropylanιlme .
*H NMR (d4 MeOH): 8.01 - 7.92 ppm (2 H, m, Ar) ; 7.75 - 7.43 (8 H, m, Ar) ; 7.18 (2 H, d, J" = 9.6 Hz, Ar) ; 5.87 (1 H, s, CHAr); 4.21 (2 H, s, CH2NH2) ; 4.14 (2 H, s, CH2NH2); 2.96 - 2.81 (1 H, m, CH(CH3)2); 1.24 (6 H, d, J = 1 Hz, CH(CH3)2). HPLC (Luna 2, Gradient 1): rt = 3.39 minutes. LCMS (Luna 2, Gradient 4) : rt = 1.59 minutes, 431 (MH)*.
Examples 65 - 68 were prepared in a similar manner to
Example 61 except that the indicated protected amino acid was used in the place of D/L-4- (iV-BOC-aminomethyl) -α- (27- benzyloxycarbonyl ) phenylglycine .
Example 65
3- (Aminomethyl) benzoyl-D-cyclohexylglycine indan-5-amide trifluoroacetate salt
Prepared from 27-BOC-D-cyclohexylglycine .
LH NMR (d4 MeOH): 7.88 - 7.02 ppm (7 H, m, Ar) ; 4.43 (1 H, d, J = 9 Hz, CH(cHex)); 4.04 (2 H, S, CH2NH2) ; 2.78 - 2.68 (4 H, m, indane C(1)H2 and C(3)H2); 2.04 - 1.82 (4 H, m, indane
C(2)H2, cHex CH2) ; 1.77 - 1.56 (4 H, m, 2 x cHex CH2) ; 1.36 -
0.95 (5 H, m, 2 x cHex CH2 and CH) .
HPLC (Luna 2, Gradient 1): rt = 4.27 minutes. LCMS (Luna 2, Gradient 4): rt = 2.21 minutes, 406 (MH)*.
Example 66
3- (Aminomethyl) benzoyl-D/L-1-naphthylglycine indan-5- amide trifluoroacetate salt Prepared from 27-BOC-D/L-l-naphthylglycine . λE NMR (d4 MeOH) : 8.25 ppm (1 H, d, J = 7.2 Hz, Ar) ; 8.04 - 7.84 (4 H, m Ar) ; 7.75 - 7.44 (7 H, m, Ar) ; 7.33 (1 H, d, J = 7.25 Hz, Ar) ; 7.16 (1 H, d, J = 7.25 Hz, Ar) ; 6.72 (1 H, s, CHAr); 4.15 (2 H, s, CH2NH2) ; 2.94 - 2.78 (4 H, m, indane C(1)H2 C(3)H2); 2.17 - 1.98 (2 H, m, indane C(2)H2). HPLC (Luna 2, Gradient 1): rt = 4.37 minutes. LCMS (Luna 2, Gradient 4): rt = 2.37 minutes, 450 (MH)*.
Example 67 3- (Aminomethyl) benzoyl-D/L- (4 -phenyl) phenylglycine indan-5-amide trifluoroacetate salt
Prepared from 27-Fmoc-D/L- (4-phenyl) phenylglycine . lE NMR (d4 MeOH): 7.94 - 7.83 ppm (2 H, m, Ar) ; 7.64 - 7.15 (13 H, m, Ar) ; 7.02 (1 H, d, J = 7.2 Hz, Ar) ; 5.80 (1 H, s, CH) ; 4.08 (2 H, s, CH2NH2) ; 2.81 - 2.77 (4 H, m, indane C(1)H2 and C(3)H2); 2.01 - 1.88 (2 H, m, indane C(2)H2). HPLC (Luna 2, Gradient 1) : rt = 4.87 minutes. LCMS (Luna 2, Gradient 4): rt = 2.56 minutes, 476 (MH)*.
Example 68
3- (Aminomethyl) benzoyl-D- (4-aminophenyl) glycine indan-5- amide bis (trifluoroacetate) salt
Prepared from 27-BOC-D- (4-Benzyloxycarbonylammophenyl ) - glycine (prepared as described below) .
D- (4-Hydroxyphenyl) glycine methyl ester hydrochloride
D-4-Hydroxyphenylglycme (12.5 g, 74.8 mmol) and dry methanol (24 mL) were stirred in a dry 250 mL three necked round bottom flask, equipped with a low temperature thermometer. The mixture was stirred under nitrogen and cooled to an internal temperature of below -20°C. Using a syringe, thionyl chloride (6 mL, 9,78 g, 82.2 mmol) was added dropwise to the cooled mixture over a period of 10 minutes at such a rate that the internal temperature did not exceed -20°C. Once the addition was complete the mixture was allowed to warm to room temperature and stirred overnight. Dry ether (150 mL) was added and the white precipitate that formed was collected by suction filtration, washed w th a little more ether and dried (15.5g, 95%) .
27-BOC-D- (4-Hydroxyphenyl) glycine methyl ester Di-t-butyl dicarbonate (15.9 g, 72.8 mmol) was added to a stirred mixture of D-4-hydroxyphenylglycme methyl ester hydrochloride (14 g, 64.3 mmol) and NaHC03 (11.7 g, 0.14 mol) in tetrahydrofuran (150 mL) and water (50 mL) , in one portion. The mixture was stirred rapidly for 4h. Hexane (75 mL) was added and the organic layer separated and washed with saturated aqueous NaHC03 (20 mL) and brine (20 mL) and dried (MgS04) . Evaporation of the solvent afforded the 27- BOC-protected amme (19.7g, 96%).
27-BOC-D- (4-Trifluoromethylsulphonyloxyphenyl) glycine methyl ester
2,6-Lutιdme (9.44 ml, 8.68 g, 81.0 mmol) and 4- dimethylammopyridme (1.65 g, 13.5 mmol) were added to a stirred solution of 27-BOC-D- (4 -hydroxyphenyl) glycine methyl ester (19 g, 67.5 mmol) in dichloromethane (400 mL) and the mixture cooled in an ice bath. Trifluoromethananesulphonic anhydride (13.7 mL, 23.0 g, 81.4 mmol) was added over a period of five minutes and then the mixture was allowed to warm to room temperature over four hours. The solution was washed with water (2 x 150 mL) , IN HCl (2 x 150 mL) and saturated aqueous NaHC03 (150 mL) and dried (MgS04) . Evaporation of the solvent afforded an oil which was purified by flash chromatography on silica gel (hexane / dichloromethane 1:1 and then neat dichloromethane) affording the tπflate as a white solid (19 g, 77%) .
27-BOC-D- (4 -benzyloxycarbonylphenyl) glycine methyl ester 27-BOC-D- (4 -trifluoromethylsulphonyloxyphenyl) glycine methyl ester (27.6 g, 77.0 mmol), benzyl alcohol (32.6 mL, 34.1 g, 315 mmol), palladium (II) acetate (255 mg, 1.13 mmol), bis- 1, 3-dιphenylphosphmylpropane (448 mg, 1.09 mmol) and triethylamme (10.2 mL, 7.40 g, 73.2 mmol) in dimethylformamide (72 mL) were placed m a Parr reactor and the reactor assembled. The vessel was pressurised to -10 psi with nitrogen and the gas released (repeated five times to remove all oxygen from the system) . Carbon monoxide gas was then carefully introduced to -20 psi and released three times. Carbon monoxide was then added to -100 psi and the stirrer started. The vessel was slowly heated to 65 °C internal temperature and then stirred, monitoring by tic. When complete (after - 18 hours) the reaction was cooled to 30°C, the gas released and the vessel flushed five times with nitrogen as before. The reaction mixture was partitioned between ethyl acetate (250 mL) and water (100 mL) and the organic layer washed with 1M hydrochloric acid (30 mL) and saturated aqueous NaHC03 (30 mL) and dried (MgS04) and evaporated. Purification of the resulting oil by column chromatography (ethyl acetate / hexane; 1:4) gave the benzyl ester (18.7 g, 70%).
27-BOC-D- (4 -hydroxycarbonylphenyl) glycine methyl ester
10 % Palladium on carbon (100 mg) was added to a solution of the benzyl ester (500 mg, 1.25 mmol) in ethanol (15 mL) and the suspension was stirred under a hydrogen atmosphere overnight. The mixture was filtered and the residue was washed with ethanol (20 mL) and the combined organic solvents were evaporated under reduced pressure to afford the acid as a colourless solid (363 mg, 94 %) . lE NMR (CDC13) : 8.08 ppm (2 H, br s, Ar) ; 7.49 (2 H, d, J = 7.2 Hz, Ar) ; 5.87 (1 H, d, J = 9 Hz, NHCH) ; 3.73 (3 H, s, OCH3) ; 1-41 (9 H, s, sBu) .
27-BOC-D- (4-Benzyloxycarbonylaminophenyl) glycine methyl ester.
The acid (218 mg, 0.7 mmol) in tetrahydrofuran (20 mL) was treated with triethylamine (108 μl , 0.78 mmol) and diphenylphosphonic azide (161 μl , 0.78 mmol) and stirred at room temperature for 1.5 hours. Benzyl alcohol (116 μl , 1.12 mmol) was then added and the mixture was heated at reflux for 18 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (ethyl acetate / hexane, 1:1) to give the 27- benzyloxycarbonylaniline as a brown solid (87 mg, 30 %) . λE NMR (CDCI3) : 7.35 - 7.23 ppm (7 H, m, Ar) ; 7.16 (2 H, d, J = 9 Hz, Ar); 7.06 (1 H, s, NH) ; 5.53 (1 H, d, J = 9 Hz, CHAr); 5.18 (1 H, d, J = 9 Hz, NH) ; 5.10 (2 H, s, CH2Ph) ; 3.59 (3 H, s, 0CH3) ; 1.31 (9 H, s, cBu) .
27-BOC-D- (4-Benzyloxycarbonylaminophenyl) glycine A solution of the ester (87 mg, 0.21 mmol) in tetrahydrofuran (5 mL) was treated with 1 M LiOH (0.84 ml, 0.84 mmol) and heated at reflux for four hours. The solvent was removed under reduced pressure and the residue was diluted with water (10 mL) . The aqueous solution was acidified to pH 4 using 5 % aqueous HCl and extracted with ethyl acetate (3 x 10 mL) . The combined extracts were dried (MgS04) and evaporated under reduced pressure to afford the crude acid (80 mg, 95 %) as a colourless solid which was carried forward without further purification.
3- (Aminomethyl) benzoyl-D- (4 -aminopheny1) glycine indan-5- a ide bis (trifluoroacetate) salt. lE NMR (d4 MeOH) : 7.92 - 7.80 ppm (2 H, m, Ar) ; 7.69 (2 H, d, J = 7.3 Hz, Ar) ; 7.60 - 7.40 (2 H, m, Ar) ; 7.34 (3 H, d, J = 12 Hz, Ar) ; 7.15 (1 H, d, J" = 7.2 Hz, Ar) ; 7.02 (1 H, d, J = 7.2 Hz, Ar) ; 5.79 (1 H, s, CHAr); 4.07 (2 H, s, CH2NH2) ; 2.80 - 2.69 (4 H, m, indane C(1)H2 and C(3)H2); 2.01 - 1.88 (2 H, m, dane C (2)H2) .
HPLC (Luna 2, Gradient 1) : rt = 3.17 minutes.
LCMS (Luna 2, Gradient 4): rt = 1.59 minutes, 415 (MH)*.
Example 69 3- (Aminomethyl) benzoyl-D/L-piperidin-4-ylglycine indan- 5-amide bis (trifluoroacetate) salt
(27-BOC-Piperidin-4-ylidene) - (27-benzyloxycarbonyl) glycine methyl ester 27-BOC-4-Pιpeπdone (2.0 g, 10 mmol), 27- (benzyloxy-carbonyl ) - α-phosphonoglycme trimethyl ester (3.64 g, 2.20 mmol) and 1, 8-dιazabιcyclo [5.4.0] undec-7-ene (1.57 mL, 2.10 mmol) were stirred in acetonitrile overnight. The solvent was removed and the residue taken up in ethyl acetate (50 mL) and washed with water (2 x 10 mL) , dried (MgS04) and evaporated under reduced pressure. The residual oil was purified by chromatography on silica gel (ethyl acetate / hexane, 40 % / 60 %) to afford the unsaturated ester (3.63 g, 90 %) . XH NMR (CDC13) : 7.36 ppm (5 H, br s, Ph) ; 6.05 (1 H, br s, NH) ; 5.12 (2 H, s, CH2Ph) ; 3.73 (3 H, br s, OMe); 3.50 (4 H, br s, piperidine C(2)H2 and C(6)H2); 2.86 (2 H, br s, piperidine C(3) H2 or C(5) H2) ; 2.45 - 2.36 (2 H, m, piperidine C(3) H2 or C(5) H2) ; 1.47 (9 H, s, cBu) .
(27-BOC-Piperidin-4-ylidene) - (27-benzyloxycarbonyl) glycine
A solution of the methyl ester (391 mg, 1 mmol) in tetrahydrofuran (10 mL) was treated with 1 M LiOH (2 mL, 2 mmol) and heated at reflux for 4 hours. The solvent was removed under reduced pressure and the residue diluted with water (20 mL) . The aqueous solution was acidified to pH 4 with 5 % aqueous HCl and extracted with ethyl acetate (3 x 20 mL) . The combined organic extracts were dried (MgS04) and concentrated under reduced pressure to afford the acid as a brown solid (305 mg, 78 %) which was carried forward without further purification.
(27-B0C-Piperidin-4-ylidene) - (27-benzyloxycarbonyl) glycine indan-5 -amide
A solution of the acid (253 mg, 0.65 mmol) in dimethylformamide (20 mL) was treated with l-(3- dimethylaminopropyl) -3 -ethylcarbodiimide hydrochloride (124 mg, 0.65 mmol), l-hydroxy-7-azabenzotriazole (88 mg, 0.65 mmol), 5-aminoindane (86 mg, 0.65 mmol) and 4- (27,27- dimethylamino) pyridine (10 mg) and stirred overnight at room temperature. The solution was partitioned between ethyl acetate (30 mL) and water (30 mL) , separated, and the organic phase was washed with 5 % aqueous HCl (30 mL) , saturated aqueous NaHC03 (30 mL) and water (30 mL) , dried (MgS04) and concentrated under reduced pressure to afford a colourless solid. The crude product was purified by flash chromatography (ethyl acetate / hexane 1 : 1) to afford the indanamide as a colourless solid (215 mg, 65 %) . lE NMR (CDC13) : 8.31 (1 H, br s, NH) ; 7.43 (9 H, m, 8 Ar, NH) ; 5.01 (2 H, s, CH2Ph) ; 3.34 (4 H, br s , piperidine C(2)H2 and C(6)H2); 2.83 - 2.71 (4 H, m, indane C(1)H2 and C(3)H2);
2.54 (2 H, br s, piperidine C(3)H2 or C(5)H2); 2.23 - 2.14 (2 H, m, piperidine C(3)H2 or C(5)H2); 2.05 - 1.92 (2 H, m, indane C(2)H2); 1.38 (9 H, s, cBu) .
D/L- (27-B0C-Piperidin-4-yl) glycine indan-5-amide
10 % Palladium on carbon (50 mg) was added to a solution of the alkene (215 mg, 0.43 mmol) in ethanol (20 mL) and the suspension was stirred under a hydrogen atmosphere overnight. The mixture was filtered and the filtrand was washed with ethanol (20 ml) before the combined solvents were concentrated under reduced pressure to afford the deprotected saturated amine as a colourless oil (97 mg, 60 %) . The crude amine was carried forward without further purification.
The remaining steps of the synthesis are identical to those of Example 61.
3- (Aminomethyl) benzoyl-D/L-piperidin-4-ylglycine indan-5- amide bis (trifluoroacetate) salt. lE NMR (d4 MeOH): 8.04 - 7.92 ppm (2 H, m, Ar) ; 7.73 - 7.55 (2 H, m, Ar) ; 7.49 (1 H, s, Ar) ; 7.32 (1 H, d, J = 7.2 Hz, Ar) ; 7.18 (1 H, d, J = 7.2 Hz, Ar) ; 4.68 (1 H, d, J = 9 Hz, CH(Pip)); 4.21 (2 H, s, CH2NH2) ; 3.54 - 3.40 (2 H, m, piperidine C(2)H and C(6)H); 3.13 - 2.96 (2 H, m, piperidine C(2)H and C(6)H); 2.94 - 2.81 (4 H, m, indane C(1)H2 and C(3)H2); 2.41 - 2.23 (1 H, m, piperidine C(4)H); 2.20 - 1.95 (4 H, m, indane C(2)H2, piperidine C(3)H and C(4)H); 1.84 - 1.60 (2 H, m, piperidine C(3)H and C(4)H). HPLC (Luna 2, Gradient 1) : rt = 3.08 minutes.
LCMS (Luna 2, Gradient 4): rt = 1.27 minutes, 407 (MH)*.
Example 70
2-Amino-5- (aminomethyl) benzoyl-D-phenylglycine indan-5- ylamide bis (trifluoroacetate) salt
2-Amino-5-cyanobenzoic acid
A solution of 2 -amino-5-bromobenzoic acid (6.9 g, 31.9 mmol) in 27-methyl-2-pyrrolidinone (100 mL) was treated with copper cyanide (4.14 g, 46 mmol) and the mixture was heated at
190°C for 4.5 hours before being cooled to room temperature and allowed to stand overnight. The mixture was diluted with water (500 mL) , acidified with 6N aqueous HCl (100 mL) and extracted with ethyl acetate (6 x 40 mL) . The organic extracts were dried (MgSO and concentrated under reduced pressure to yield the crude nitrile (4.35 g, 84 %) .
2-Amino-5-cyanobenzoyl-D-phenylglycine methyl ester
A solution of 2 -amino-5-cyanobenzoic acid (1.0 g, 6.17 mmol) in dimethylformamide (50 mL) was treated with l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.18 g, 6.17 mmol) and 1 -hydroxy- 7 -azabenzotriazole (0.84 g, 6.17 mmol) . After stirring for 10 minutes, D-phenylglycine methyl ester (1.24 g, 6.17 mmol) was added and the resulting solution was stirred overnight at room temperature. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL) and the organic solution was washed with saturated aqueous citric acid (50 mL) , saturated aqueous NaHC03 (50 mL) and water (50 mL) , dried (MgS04) and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate / hexane, 1:1) to yield 2 -amino- 5 -cyanobenzoyl -D-phenylglycine methyl ester (1.3 g, 68 %) . LC/MS (Luna 2, Gradient 4): rt = 3.28 minutes, 310 (MH)*.
2 - (Di-1-butoxycarbonyl) amino- 5 -cyanobenzoyl-D-phenylglycine methyl ester
A solution of 2 -amino-5 -cyanobenzoyl -D-phenylglycine methyl ester (800 mg, 2.6 mmol) in dimethylformamide (20 mL) was treated with 4-dimethylaminopyridine (30 mg; 0.3 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (500 mg; 2.6 mmol) and di-t-butyldicarbonate (570 mg; 2.6 mmol) . The mixture was stirred overnight at room temperature and then partitioned between ethyl acetate (25 mL) and water (25 mL) . The organic extracts were dried
(MgSO , concentrated under reduced pressure and the residue was purified by flash column chromatography (ethyl acetate / hexane 3:7) to yield the bis-protected amine (150 mg, 11 %) .
2- (Di-t-butoxycarbonyl) amino-5-cyanobenzoyl-D-phenylglycine The ester (150 mg, 0.29 mmol) was dissolved in tetrahydrofuran (20 mL) and treated with 1 M lithium hydroxide (0.6 mL, 0.6 mmol) . The mixture was heated at reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (10 mL) , acidified with 5% aqueous HCl (10 mL) and the product extracted into ethyl acetate (25 mL) . The organic extracts were then dried (MgS04) and concentrated under reduced pressure and the crude acid (110 mg, 75 %) was carried forward without further purification.
2- (Di-t-butoxycarbonyl) amino- 5 -cyanobenzoyl-D-phenylglycine indan-5-y1amide
A solution of the acid (110 mg, 0.20 mmol) in dimethylformamide (10 mL) was treated with l-(3- dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (30 mg, 0.2 mmol) and l-hydroxy-7-azabenzo-triazole (30 mg, 0.2 mmol) . After stirring for 10 minutes, 5-aminoindane (30 mg, 0.2 mmol) was added and the resulting solution stirred overnight at room temperature. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL) and the organic solution was washed with saturated aqueous citric acid (25 mL) , saturated aqueous NaHC03 (25 mL) and water (25ml) , dried (MgSO and concentrated under reduced pressure. The crude product was purified by flash column chromatography (ethyl acetate / hexane, 3:7) to yield 2- (di- t-butoxycarbonyl) amino- 5 -cyanobenzoyl -D-phenylglycine indan- 5-ylamide as an off-white solid (50 mg, 40 %) .
2-Amino-5- (aminomethyl)benzoyl-D-phenylglycine indan-5- ylamide bis (trifluoroacetate) salt.
A solution of the nitrile (50 mg, 0.08 mmol) in methanol (10 mL) and 36% aqueous HCl (0.5ml) was stirred over 10% palladium on carbon (20 mg) under a hydrogen atmosphere for 16 hours. The mixture was filtered and the residue was washed with methanol (10 mL) before concentrating the extracts under reduced pressure.
The residue was dissolved in a mixture of trifluoroacetic acid (5 ml) and dichloromethane (5ml) and stirred for one hour. The mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to afford 2- amino-5- (aminomethyl) benzoyl-D-phenylglycine indan-5-ylamide ditrifluoroacetate salt (2 mg, 6 %) . λE NMR (d4 MeOH): 7.98-7.37 ppm (10 H, m, Ar) ; 7.02 (IH, d, J = 7.5 Hz, Ar) ; 6.03 (IH, s, CHPh); 3.92 (2 H, Ξ, CH2NH2) ;
3.09 (4H, q, J = 7.5Hz, indane C(1)H2 and C(3)H2); 2.29 (2H, quintet, J" = 7.5 Hz, indane C(2)H2).
HPLC (Luna 2, Gradient 1): rt = 4.04 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.10 minutes, 398 (MH-NH3)*.
Example 71
1- (2 -Amino-5- (aminomethyl) benzoyl-D-phenylglycinyl) 4- hydroxypiperidine dihydrochloride salt
D-Phenylglycine 4-hydroxypiperidinamide trifluoroacetate salt
A solution of 4-hydroxypiperidine (330 mg, 1.4 mmol) in dimethylformamide (10 mL) was treated with 2-(lH- benzotriazole-1-yl) -1,1,3,3 -tetramethyluronium tetrafluoroborate (450 mg; 1.4 mmol) and 27- ethyldiisopropylamine (0.74 mL, 4.2 mmol). After stirring for 10 minutes, 27-butoxycarbonyl-D-phenylglycme (330 mg, 1.4 mmol) was added and the resulting solution stirred overnight at room temperature. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL) and the organic solution was washed with saturated aqueous citric acid (25 mL) , saturated aqueous NaHC03 (25 mL) and water (25 mL) , dried (MgS04) and concentrated under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and tπfluoroacetic acid (5 mL) and stirred for one hour before the solvents were removed under reduced pressure, giving D- phenylglycme-4 -hydroxypiperidmamide as its trifluoracetate salt (150 mg, 43 %) . LC/MS (Luna 2, Gradient 4): rt = 2.64 mm, 235 (MH)*.
2 -amino-5-cyanobenzoyl-D-phenylglycine 4 - hydroxypiperidinamide
A solution of 2-ammo-5-cyanobenzoic acid (170 mg, 1.0 mmol) in dimethylformamide (10 mL) was treated with l-(3- dimethylammopropyl) -3 -ethylcarbodiimide hydrochloride (210 mg, 1.1 mmol) and 1 -hydroxy- 7 -azabenzotπazole (150 mg, 1.1 mmol). After stirring for 10 minutes, D-phenylglycme 4- hydroxypipeπdmamide trifluoroacetate salt (250 mg; 1.1 mmol) was added and the resulting solution stirred overnight at room temperature. The mixture was partitioned between ethyl acetate (25 mL) and water (25 mL) and the organic solution was washed with saturated aqueous citric acid (25 mL) , saturated aqueous NaHC03 (25 mL) and water (25 mL) , dried (MgSO and concentrated under reduced pressure. The crude product was purified by column chromatography (ethyl acetate) to yield 2 -ammo-5 -cyanobenzoyl -D-phenylglycme 4- hydroxypiperidmamide (90 mg, 23 %) .
1- (2-amino-5- (aminomethyl) benzoyl-D-phenylglycinyl 4- hydroxypiperidine dihydrochloride salt
A solution of the nitrile in methanol (10 mL) and 36% hydrochloric acid (0.5 mL) was stirred over 10 % palladium on carbon (20 mg) under an atmosphere of hydrogen for 16 hours. The mixture was filtered and the residue washed with methanol (10 mL) before concentrating the filtrate under reduced pressure. Purification by preparative HPLC afforded 2-amιno-5- (aminomethyl) benzoyl-D-phenylglycme 4-hydroxy- pipeπdmamide dihydrochloride salt (30 mg, 33 %) . XH NMR (d4 MeOH): 7.84 ppm (1 H, s, Ar) ; 7.61-7.17 (7 H, m, Ar) ; 6.85 (1 H, d, J" = 8 Hz , Ar) ; 6.12 (1 H, s, CHPh); 4.26 (1 H, m, piperidine C(4)H); 3.99 (2 H, s, CH2 H2) ; 3.79 (2 H, m, piperidine C(2)H and C(6)H); 3.42-3.08 (2H, m, piperidine C(2)H and C(6)H); 1.86-0.72 (4H, m, piperidine C(3)H2 and C(5)H2) . HPLC (Luna 2, Gradient 1): rt = 2.49 minutes.
LC/MS (Luna 2, Gradient 4): rt = 1.35 minutes, 366 (MH-NH3)*.
Examples 72 and 73
The compounds of Examples 72 and 73 were prepared by the method described below, but using the appropriate starting materials .
Boc D-phenylglycme (251 mg, 1 mmol.) was dissolved in dimethylformamdide (3ml) with HATU [0- (7-azabenzotrιazol-l- yl) -1, 1, 3 , 3-tetramethyluronιum hexafluorophosphate] (380 mg., 1 mmol.) and diisopropylethylam e (350μl., 2 mmol.). To this mixture was added 4-methylbenzylamme (121mg., 1 mmol.) and diisopropylethylamme (170μl., 1 mmol.). The mixture was stirred overnight. The mixture was then taken up into ethylacetate and washed with water, sodium carbonate solution, water, 10% hydrochloric acid solution and water. The ethylacetate was evaporated without drying and treated immediately with trifluoroacetic acid (TFA) for 30 mm. The TFA was then evaporated to dryness and the product triturated with diethylether. Triethylamme (1ml) was added and evaporated to dryness. A solution of 3- hydroxymethylbenzoic acid (76mg, 0.5mmole) in dry dimethylformamide (DMF) was treated with TBTU (161mg., 0.5mmol . ) and diisopropylethylamme (1.5 mmol.). The mixture was then added to the D-phenylglycιne-4-methylbenzylamιde (0.5mmol.) and stirred overnight. The crude product was dissolved in water/acetonitπle (20ml) , filtered and purified by preparative Hplc to yield pure product. XH nmr (CD3CN) 7.75 (IH, m) ; 7.65 (2H, m) ; 7.30 (7H, broad m) ; 6.80 (3H, m) ; 5.40 (IH, s) ; 4.45 (2H,s); 4.10 (2H, m) ; 2.10 (3H, s) . MS TOF 389 (M+l*) . Hplc (Magellan C8 , Gradient 3, water/acetonitrile/TFA) rt 13.51 mm.
Compounds made by the above method: -
Example 72.
3-Aminomethylbenzoyl-D-phenylglycine-4-aminomethylcyclohexyl methylamide
:H nmr (CD3CN) 7.95 (2H, m) ; 7.80 (2H, m) ; 7.50 (5H, m) ; 5.65 (IH, s) ; 4.45 (2H, s); 3.30 (2H, m) ; 3.00 (2H,m); 2.00-1.00 (10H,m) . MS TOF 409 (M+l+) . Hplc (Magellan C8 , Gradient 3, water/acetonitrile/TFA) rt 12.68 min.
Example 73.
3 -Aminomethylbenzoyl-D-phenylglycine- 1-adamantylamide lE nmr (CD3CN) 7.95 (IH, s) ; 7.85 (2H, d) ; 7.60 (IH, m) ; 7.50 (2H,m); 7.40 (3H,m); 5.65 (IH, s); 4.20 (2H, s); 2.50-1.50 (15H,m) . MS TOF 418 (M+l*) . Hplc (Magellan C8 , Gradient 1, water/acetonitrile/TFA) rt 18.36 min.
Example 74
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (2- hydroxyphenyl) acetyl-2 , 3 -dihydroindol-6 -amide trifluoroacetate salt. Prepared in a similar manner to Example 35, using (2- hydroxyphenyl) acetic acid. lE NMR (CD3CN) : 8.91 ppm (1 H, s, OH), 8.30 (1 H, s, NH) , 7.94 (2 H, br s, Ar) , 7.73 (1 H, d, J = 10 Hz, Ar) , 7.54- 7.06 (12 H, m, Ar Sc NH) , 7.01 (1 H, d, J = 8 Hz, Ar) , 6.74 (2 H, m, Ar) , 5.61 (1 H, d, J = 8 Hz, ArCH) , 4.21 (2 H, t, J = 8 Hz, dihydroindole C(2)H2), 4.10 (2 H, s, ArCH2N) , 3.73 (2H, s, ArCH2CO) , 3.10 (2 H, d, J" = 8 Hz, dihydroindole C(3)H2) . HPLC (Symmetry, Gradient 2) : rt = 6.24 minutes. LC/MS (Luna 2, Gradient 4): rt = 2.10 minutes, 535 (MH)*.
Example 75
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (3- hydroxyphenyl) acetyl-2 , 3 -dihydroindol- 6-amide trifluoroacetate salt. Prepared m a similar manner to Example 35, using (3- hydroxyphenyl) acetic acid.
XH NMR (d4 MeOH) : 8.21 ppm (1 H, s, Ar) , 7.71 (2 H, br s, Ar) , 7.50-7.16 (8 H, m, Ar) , 7.05-6.95 (2 H, m, Ar) , 6.64- 6.50 (3 H, m, Ar) , 5.62 (1 H, s, ArCH) , 4.09 (2 H, s,
ArCH2N) , 4.04 (2 H, t, J" = 8 Hz, dihydroindole C(2)H2), 3.68 (2H, s, ArCH2C0) , 2.91 (2 H, d, J = 8 Hz, dihydroindole C(3)H2) .
HPLC (Symmetry, Gradient 2): rt = 5.95 minutes. LC/MS (Luna 2, Gradient 4): rt = 2.05 minutes, 535 (MH*) .
Example 76
3- (Aminomethyl) benzoyl-D-phenylglycine 1- (4- hydroxyphenyl) acetyl-2 , 3 -dihydroindol- 6 -amide trifluoroacetate salt.
Prepared in a similar manner to Example 35, using (4- hydroxyphenyl) acetic acid.
XH NMR (d4 MeOH) : 8.32 ppm (1 H, s, Ar) , 8.04 (2 H, br s ,
Ar) , 7.66-7.34 (8 H, m, Ar) , 7.22-7.11 (3 H, , Ar) , 6.80 (2 H, d, J" = 10 Hz, Ar) , 5.85 (1 H, s, ArCH) , 4.21 (2 H, s,
ArCH2N) , 4.15 (2 H, t, J" = 8 Hz, dihydroindole C(2)H2), 3.81
(2 H, s, ArCH2CO) , 3.20 (2 H, d, J = 8 Hz, dihydroindole
C(3)H2) .
HPLC (Symmetry, Gradient 2): rt = 5.97 minutes. LC/MS (Luna 2, Gradient 4) : rt = 2.02 minutes, 535 (MH*) .
Example 77
3- (Aminomethyl) benzoyl-D-phenylglycine l-benzyl-3- acetylindol-5-amide trifluoroacetate salt. Prepared a similar fashion to Example 1, starting from 3 -acetyl-5-amino-l-benzylindole, which was prepared as described below.
3-Acetyl-5-nitroindole and 3 -acetyl-7 -nitroindole
Prepared by the method described by Ottoni, Cruz and Kramer in Tetrahedron Letters, 40, 1999, 1117-1120, as a mixture of isomers .
3-Acetyl-l-benzyl-5-nitroindole and 3-acetyl-l-benzyl-7- nitroindole
Potassium carbonate (940 mg, 6.8 mmol) was added to a stirred solution of the above indoles (695 mg, 3.4 mmol) in dimethylformamide (30 mL) . Benzyl bromide (0.61 mL, 5.1 mmol) was then added dropwise and the mixture left to stir over the weekend. The dimethylformamide was removed under reduced pressure and the residue partitioned between ethyl acetate (30 mL) and water (20 mL) . The ethyl acetate layer was dried (MgS04) and evaporated to give the benzylamines as a golden oil .
3 -Acetyl- 5-amino- 1-benzylindole and 3-acetyl-7-amino-l- benzylindole
A mixture of the indoles (1.0 g, 3.4 mmol), tin(ll) chloride dihydrate (3.48 g, 15.4 mmol) and ethanol (20 mL) was heated at reflux, under an atmosphere of nitrogen, for 3 hours. The mixture was cooled and the solvent evaporated to give a brown oil. To this was added water (50 mL) , which was then made basic with 1 N aqueous sodium hydroxide. The aqueous solution was then extracted with ethyl acetate (2 x 30 mL) . The whole biphasic mixture was filtered through celite to remove tin salts, separated and the organic solvent dried (MgS04) . The solvent was removed under reduced pressure to give a brown oil which was purified by flash chromatography on silica gel (hexane / ethyl acetate; 3:1) to afford, in order of elution,
3 -acetyl-7 -amino- 1-benzylindole H NMR (CDC13) : 7.67 ppm (1 H, s, indole C(2)H); 7.39 - 7.13 (3 H, m, Ph) ; 7.15 (2 H, m, Ph) ; 7.05 (1 H, t, J = 6 Hz, indole C(5)H); 6.57 (1 H, d, J = 6.5 Hz, indole C(4)H); 6.41 (1 H, d, J = 6 Hz, indole C(6)H); 5.95 (2 H, br s, NH2) ; 5.27 (2 H, s, PhCH2) ; 2.50 (3 H, s, CH3)
and 3 -acetyl-5-amino-l-benzylindole lE NMR (CDCI3) : 8.08 ppm (1 H, d, J" = 6 Hz, indole C(7)H); 7.50 (1 H, s, indole C(2)H); 7.31 - 7.22 (3 H, m, Ph) ; 7.05 (2 H, m, Ph) ; 6.63 (1 H, dd, J = 6 , 2 Hz, indole C(6)H);
6.45 (1 H, s, indole 4-H) ; 5.25 (2 H, s, PhCH2) ; 3.62 (2 H, br s, NH2) ; 2.5 (3 H, s, CH3) .
3- (Aminomethyl) benzoyl-D-phenylglycine l-benzyl-3- acetylindol-5-amide trifluoroacetate salt. lH NMR (d4 MeOH): 8.28 ppm (1 H, s, Ar) ; 8.20 (1 H, d, J = 5 Hz, Ar) ; 7.97 (3 H, m, Ar) ; 7.71 - 7.56 (4 H, m, Ar) ; 7.47 - 7.19 (9 H, m, Ar) ; 5.85 (1 H, s, CHPh); 5.45 (2 H, s, CH2Ph) ; 4.21 (2 H, CH2NH2) ; 2.53 (3 H, s, CH3). HPLC (Luna 2, Gradient 1) : rt = 4.15 minutes. HPLC (Symmetry, Gradient 2): rt = 6.77 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.48 minutes, 531 (MH)*.
Example 78
3- (Aminomethyl) benzoyl-D-phenylglycine l-benzyl-3- acetylindol-7-amide trifluoroacetate salt.
Prepared in a similar fashion to Example 1, starting from 3- acetyl-7-amino-l-benzylindole, which was prepared as described above. lE NMR (d4 MeOH) : 8.46 ppm (1 H, s, Ar) ; 8.34 (1 H, d, J" = 6
Hz, Ar) ; 8.11 - 7.95 (3 H, m, Ar) ; 7.75 - 7.48 (4 H, m, Ar) ;
7.46 - 7.12 (9 H, m, Ar) ; 5.85 (1 H, s, CHPh); 5.48 (2 H, s, CH2Ph) ; 4.21 (2 H, s, CH2NH2) ; 2.62 (3 H, s, CH3) •
HPLC (Luna 2, Gradient 1): rt = 4.58 minutes.
HPLC (Symmetry, Gradient 2): rt = 6.80 minutes.
LC/MS (Luna 2, Gradient 4): rt = 2.80 minutes, 531 (MH)*.
Example 79
3- (Aminomethyl) benzoyl-D- (4 -hydroxyphenyl) glycine indan-5- amide trifluoroacetate salt.
Prepared in a similar fashion to Example 61, using (4- hydroxyphenyl) glycine and protecting as appropriate. lE NMR (d4 MeOH): 8.00 ppm (2 H, s, Ar) ; 7.72 - 7.55 (2 H, m, Ar) ; 7.47 (3 H, t, J = 8.6 Hz, Ar) ; 7.31 (1 H, d, J = 7.5 Hz, Ar) ; 7.18 (1 H, d, J = 8 Hz, Ar) ; 6.86 (2 H, d, J" = 8.6 Hz, Ar) ; 5.75 (1 H, s, CHPh); 4.23 (2 H, s, CH2NH2) ; 2.94 (4 H, m, indane C(1)H2 and C(3)H2); 2.12 (2 H, m, indane C(2)H2) • HPLC (Luna 2, Gradient 1) : rt = 3.78 minutes. HPLC (Symmetry, Gradient 2) : rt = 5.80 minutes. LC/MS (Luna 2, Gradient 4): rt = 1.83 minutes, 416 (MH)*.
Example 80
3 - (Aminomethyl) benzoyl-D/L-2 - (27-formylamino) thiazol-4- yl] glycine 5-indanamide trifluoroacetate salt
Prepared using the same method as described for Example 61 from D/L- - (27-εbutyloxycarbonyl) - [2- (27-formylammo) thιaz-4- yl]glycme (synthesised as described below) .
Ethyl α-azido- [2- (N-formylamino) thiaz-4 -yl] acetate
A solution of ethyl [2- (27-formylammo) thιaz-4-yl] acetate (1 g, 0.0047 mol) in THF (10 L) was stirred under argon at - 78°C and potassium bis (trimethylsilyl) amide (2.8 g, 0.014 mol) in THF (10 mL) was added. After stirring for 30 minutes, 2 , 4 , 6-trιιsopropylbenzenesulfonyl azide (3.6 g, 0.012 mol) was added as a solid in one portion. After 5 minutes, acetic acid (1.4 mL, 0.018 mol) was added and the mixture warmed to room temperature. The reaction mixture was then partitioned between ethyl acetate (100 mL) and water (100 mL) , separated and the organic layer dried (MgSO . Evaporation of the solvent and purification of the residue by silica gel chromotography afforded the azide (0.95 g, 80 %) . lE NMR (CDC13) : 8.78 ppm (1 H, s, NHCHO) ; 6.98 (1 H, s, C(5)H) ; 5.95 (1 H, s, CHN3) ; 4.18 (2 H, m, CH2CH3) ; 1.20 (3 H, m, CH2CH3) •
Ethyl α- (27- jbutyloxycarbonylamino) - [2- (27-formylamino) thiaz- 4-yl] acetate
Di-Ebutyl dicarbonate (0.9 g, 0.004 mol) and 5% palladium on carbon (catalytic amount) were added to a solution of the azide (0.95 g, 0.0037 mol) in methanol (25 mL) . The mixture was stirred at room temperature under an atmosphere of hydrogen for 8 hours. After this time the mixture was filtered through celite, washing through with methanol (25 mL) . Evaporation of the solvent and purification of the residue by silica gel chromotography afforded the cbutyloxycarbonyl amine as a pale oily solid (1.1 g, 90 %) XH NMR (CDC13) : 8.53 ppm (1 H, s, NHCHO); 6.89 (1 H, s, C(5)H) ; 6.18 (1 H, d, J = 8 Hz, NHBoc) ; 5.38 (1 H, d, J = 8 Hz, CHN) ; 4.06 (2 H, m, CH2CH3); 1.28 (9 H, s, tBu) ; 1.12 (3 H, m, CH2CH3) •
D/L-α-27-tbutyloxycarbonyl- [2- (27-formylamino) thiaz-4- yl] glycine
A solution of the ester (1.1 g, 0.0031 g) in THF (25 mL) was treated with 1 M aqueous LiOH (5 ml, 0.005 mol) and heated at reflux for 1 hour. The solvent was removed under reduced pressure and the residue diluted with water (100 mL) . The pH was reduced to 2 using 5% aqueous HCl and the aqueous phase was extracted with ethyl acetate (3 x 50 mL) . The combined organic extracts were dried (MgS04) and concentrated under reduced pressure to afford the acid as a white solid (0.8 g, 84 %) . lE NMR (d4 MeOH) : 8.38 ppm (1 H, s, NHCHO); 7.01(1 H, s, C(5)H); 5.21 (1 H, s, CHN); 1.39 (9 H, s, cBu) .
3- (Aminomethyl) benzoyl-D/L- [2- (formylamino) thiazol-4- yl] glycine 5-indanamide trifluoroacetate salt
LH NMR (d4 MeOH): 10.10 ppm (1 H, s, NHCHO); 8.80 (1 H, d, J = 8 Hz, NH) ; 8.48 (1 H, s, NHCHO); 7.97 (2 H, br s, Ar) ; 7.58 (2 H, m, Ar) ; 7.42 (1 H, s, ammothiazole C(5)H); 7.37 (1 H, d, J" = 7 Hz, mdane C(6)H); 7.18 (1 H, s, indane
C(4)H); 7.10 (1 H, d, J" = 7Hz , mdane C(7)H); 5.92 (1 H, m, CHAr); 4.18 (2 H,s, CH2NH2); 2.83 (4 H, m, mdane C(1)H2 and C(3)H2); 2.02 (2 H, m, mdane C(2)H2) HPLC (Luna 2, gradient 1): rt = 3.71 minutes. LC/MS (Luna 2, gradient 4): rt = 2.05 minutes; 450 (MH)*.
Example 81
3 - (Aminomethyl) benzoyl-D/L-2 -aminothiazol-4 -ylglycine-5- indanamide bis (hydrochloride) salt. Prepared from D/L-α-27-cbutyloxycarbonyl- [2- (27- formylammo) thiaz-4-yl] glycine and synthesised using the method of Example 80 except that the final deprotection was effected using 3 M aqueous HCl in THF, order to remove both the cbutyloxycarbonyl and formyl protecting groups. XH NMR (d4 MeOH): 7.87 ppm (2 H, m, Ar) ; 7.51 (1 H, m, Ar) ;
7.48 (1 H, t, J = 7 Hz, (aminomethyl) benzoyl C(3)H); 7.40 (1 H, s, ammothiazole C(5)H); 7.20 (1 H, d, J = 8 Hz, mdane C(6)H); 7.05 (1 H, d, J = 8 Hz, mdane C(7)H); 6.73 (1 H, s, mdane C(4)H); 5.78 (1 H, s, CHAr); 4.12 (2 H, s, CH2NH2) ; 2.79 (4 H, m, indane C(1)H2 and C(3)H2); 2.00 (2 H, m, mdane C(2)H2) .
HPLC (Luna 2, gradient 1): rt = 3.21 minutes. LC/MS (Luna 2, gradient 4): rt = 1.78 minutes; 422 (MH)*.
The compounds exemplified hereinabove have been found to be inhibitors of tryptase by the method of Tapparelli et al . , (1993) J. Biol. Chem., 268, 4734 to 4741.

Claims

1. A serine protease inhibitor compound of formula (I)
Figure imgf000116_0001
(I) where R2 represents a 5 or 6 membered aromatic carbon ring optionally interrupted by a nitrogen, oxygen or sulphur ring atom, substituted m the 3 and/or 4 position by R , and optionally substituted the position alpha to the X-X group by ammo, hydroxy, halo, alkyl, carboxy, cyano, amido, ammoalkyl, alkoxy or alkylthio; each X independently is a C, N, 0 or S atom or a CO, CRla, C(Rla)2 or NRla group, at least one X being C, CO, CRla or C(Rla)2; each Rx independently represents ammoalkyl;
L is an organic linker group containing 1 to 5 backbone atoms selected from C, N, 0 and S, or a branched alkyl or cyclic group;
Y (the α-atom) is a nitrogen atom or a CRlb group; Cy is a saturated or unsaturated, mono or poly cyclic, homo or heterocyclic group optionally substituted by groups R3a or phenyl optionally substituted by R3a; each R3a independently is Rlc, ammo, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl , tπazolyl, imidazolyl, tetrazolyl, hydrazido, alkyl imidazolyl, thiazolyl, alkyl thiazolyl, alkyl oxazolyl, oxazolyl, alkylsulphonamido, alkylammosulphonyl , aminosulphonyl , haloalkoxy and haloalkyl ;
Lp is a lipophilic organic group; D is a hydrogen bond donor group; n is 0, 1 or 2 ;
Rla represents hydrogen or hydroxyl, alkoxy, alkyl, ammoalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, acyloxymethoxycarbonyl or alkylamino optionally substituted by hydroxy, alkylamino, alkoxy, oxo, aryl or cycloalkyl; and
Rlb and Rlc are as defined for Rla; or a physiologically tolerable salt thereof.
2. A compound as claimed in Claim 1, in which n is 0.
3. A compound as claimed in Claim 1 or Claim 2 , in which X-X is selected from -CH=CH-, -CONH-, -CONRx-, -NH-C0-, -NH-CH2-, -CH2-NH-, -CH20-, -OCH2-, -COO-, -OC=0- and -CH2CH2- is CONH.
4. A compound as claimed in Claim 3, in which X-X is CONH.
5. A compound as claimed in any one of Claims 1 to 4 , in which Y is a CRlb group and has the conformation that would result from construction from a D-α-aminoacid NH2-CRlb(Cy) -COOH where the NH2 represents part of X-X.
6. A compound as claimed in any one of Claims 1 to 5 , in which Y is CH.
7. A compound as claimed in any one of Claims 1 to 6, in which Cy represents an optionally R3a substituted cycloalkyl, piperidinyl, phenyl, thienyl, thiazolyl, pyridyl, or naphthyl group .
8. A compound as claimed in Claim 7, m which R3a is selected from: hydrogen, hydroxyl, methoxy, ethoxy, methyl, ethyl, methylammomethyl , d methylammomethyl , hydroxymethyl, methoxymethyl , methylammocarbonyl , dimethylammocarbonyl, aminomethyl, C0NH2 , CH2CONH2, ammoacetyl, formylammo, acetylammo, methoxycarbonylammo, ethoxycarbonylammo, t-butoxycarbonylammo, ammo, fluoro, chloro, cyano, nitro, thiol, methylthio, methylsulphenyl , ιmιdazol-4-yl, hydrazido, 2-methylιmιdazol-4-yl , methylsulphonylamido, ethylsulphonylamido, methylaminosulphonyl , ethylammosulphonyl , aminosulphonyl, trifluoromethoxy or trifluoromethyl .
9. A compound as claimed in Claim 8, in which Cy is selected from cyclohexyi, pιpeπdm-4-yl , phenyl, 4- ammophenyl , 4-hydroxphenyl , 3 -ammomethylphenyl , 4- ammomethylphenyl , 4 -hydroxmethylphenyl , 3 - hydroxymethylphenyl , 2-hydroxymethylphenyl , 4-phenylphenyl , 2-ammothιazol-4-yl, 2-formylammothιazol-4 -yl , 2- ammothιazol-5-yl , 2 -formylammothιazol-5-yl , 4-ammopyπd- 3-yl, 3-ammo-pyπd-4-yl and naphth-1-yl.
10. A compound as claimed m any one of Claims 1 to 9, in which L represents CO, CH2NH, CONRld (CH2) m,
(CH2)mN(Rld)CO(CH2)m, (CH2)m+2, CO(CH2)m, (CH2)mCO, (CH2)mOC=0, (CH2)m0, CH=CH(CH2)m, S02, S02NRld, S02(CH2)m, (CH2)mS02 or (CH2)mS02NRld (where each m is independently 0 or 1 and Rld is as defined for Rla) .
11. A compound as claimed in Claim 10, in which L is CO, CONH, CH2NHCO or CONHCH2.
12. A compound as claimed in any one of Claims 1 to 11, in which Lp is an alkyl, alkenyl, carbocyclic or heterocyclic group, or a combination of two or more such groups linked by a spiro linkage or a single or double bond or by C=0, O, S, SO, S02, CONRle, NRle-CO-, NRle linkage (where Rle is as defined for Rla) , optionally substituted by one or more oxo or R3 groups in which R3 is alkylammocarbonyl, alkoxycarbonylammo, N-alkylammoalkanoyl, N- alkanoylammoalkanonyl , C-hydroxyammoalkanoyl or is as defined for R,a .
13. A compound as claimed in Claim 12, in which m which L represents CO and Lp represents
Figure imgf000119_0001
Figure imgf000119_0002
14. A compound as claimed in Claim 13, in which R3 represents hydrogen, hydroxyl or alkylammocarbonyl.
15. A compound as claimed in Claim 12, in which L represents CONH and Lp represents
Figure imgf000120_0001
in which X is CH or N.
16. A compound as claimed in Claim 15, in which R3 is hydrogen, amino, hydroxy, alkyl or aminoalkyl.
17. A compound as claimed in Claim 12, in which L represents CONH and Lp represents
Figure imgf000120_0002
m which R3 is alkylammocarbonyl, N-alkylammoalkanoyl, N- alkanoylammoalkanonyl , C-hydroxyammoalkanoyl , hydrogen, alkoxy, alkyl, ammoalkyl, ammocarbonyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, acyloxymethoxycarbonyl, alkylammo, ammo, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl , triazolyl, imidazolyl, tetrazolyl, hydrazido, alkyl imidazolyl, thiazolyl, alkyl thiazolyl, alkyl oxazolyl, oxazolyl, alkylsulphonamido, alkylaminosulphonyl , aminosulphonyl, haloalkoxy or haloalkyl .
18. A compound as claimed in Claim 17, m which Lp is phenyl, 3 -cyano-4 -methylphenyl , 3 -ammocarbonylphenyl , 4- ammocarbonyl -phenyl , 4 -chloro-3 -ammocarbonyl -phenyl , 4- chlorophenyl, 3 , 5-dιchlorophenyl , 3-ammomethylphenyl , 4- methyl-3-acetylammophenyl , 4- (1-hydroxethyl) phenyl and 4- lsopropylphenyl .
19. A compound as claimed in Claim 12, in which L represents CONH and Lp represents
Figure imgf000121_0001
in which R3x represents R3 or a group of formula
-(CO)p-(G1) -RD
m which p is 0 or 1; Gx represents (1-3C) alkanediyl or,
when p is 1, a bond; and R- represents a carbocyclic or heterocyclic group, optionally substituted by R3.
20. A compound as claimed in Claim 19, in which Lp is selected from
Figure imgf000122_0001
in which (i) when R3 is a substituent on the 1 -position of a 2, 3-dihydroindolyl group, it represents alkylammocarbonyl; N-alkylaminoalkanoyl ; N-alkanoylaminoalkanonyl ; C- hydroxyaminoalkanoyl ; hydrogen; alkyl; alkanoyl; alkoxycarbonyl; acyloxymethoxycarbonyl; aminoalkyl; ammoalkanoyl ; hydroxyalkyl ; hydroxyalkanoyl ; alkoxyalkyl ; or alkanoylammo; and (11) when R3 is a substituent on a phenyl, thiazolyl, imidazolyl or pyridyl group, it is hydrogen, am o, alkyl or ammoalkyl.
21. A compound as claimed in Claim 12, m which Lp is selected from: 1- (N-methylammoacetyl) -2 , 3 -dihydromdol -6- yl; 1- (N-acetylammoacetyl) -2 , 3 -dihydromdol -6-yl ; 1- (N- acetylalanmoyl) -2, 3 -dihydro dol -6-yl ; 1- (sermoyl) -2,3- dihydromdol -6-yl; 1- (threonmoyl) -2 , 3 -dihydromdol -6-yl ; 2 , 3 -dihydromdol-5 -yl; 1 -methyl-2 , 3 -dihydromdol -6-yl ; 1- acetyl-2 , 3 -dihydromdol -6-yl ; l-propanoyl-2 , 3 -dihydromdol- 6-yl; 1- (2 -methylpropanoyl) -2 , 3 -dihydromdol -6-yl; ; l-(3- methylbutyryl) -2 , 3 -dihydromdol -6-yl ; 1- (2 -hydroxpropanoyl) - 2 , 3 -dihydromdol -6-yl; l-hydroxacetyl-2, 3 -dihydromdol -6-yl ; 1 -ammoacetyl -2, 3 -dihydromdol -6-yl and l-alanmoyl-2,3- dιhydromdol-6-yl; 2 , 3 -dihydromdol -5 -yl , l-prolmoyl-2 , 3 - dihydromdol -6-yl, 1-phenylacetyl -2 , 3 -dihydro dol -6-yl , 1- (2 -hydroxy) phenylacetyl-2, 3 -dihydromdol -6-yl , 1- (3- hydroxy) phenylacetyl-2, 3 -dihydromdol-6 -yl , l-(4- hydroxy) phenylacetyl-2 , 3 -dihydromdol -6-yl , 1- (4- pyπdyl) acetyl-2, 3 -dihydromdol -6-yl , 1- (3 -pyridyl) acetyl - 2, 3 -dihydromdol -6-yl, l-ιmιdazol-4-ylacetyl-2 , 3- dιhydromdol-6-yl, 1- (2-ammothιazol-4-yl) acetyl-2 , 3- dihydromdol - 6 -yl , and 1- (2-formamιdothιazol-4 -yl) acetyl - 2 , 3 -dihydromdol -6-yl .
22. A compound as claimed in any one of Claims 1 to 21, in which R2 is a group of formula
Figure imgf000124_0001
wherein R5 is ammo, hydroxy, aminome hyl, hydroxymethyl or hydrogen, and Rs and R7 which may be the same or different represent hydrogen or Rx .
23. A compound as claimed in Claim 22, in which Rx is a group of formula -CH(RSa)NH2 m which RSa is hydrogen or methyl .
24. A compound as claimed in Claim 22 or Claim 23, in which R5 is ammo or hydrogen.
25. A compound as claimed in Claim 24, in which Rs is hydrogen .
26. A compound as claimed in Claim 25, in which R2 is 3-ammomethylphenyl .
27. A compound as claimed m any one of Claims 1 to 27, m which L-Lp(D)n is COLx- and Lx is
Figure imgf000124_0002
Figure imgf000125_0001
Figure imgf000125_0002
wherein: A and B are independently chosen from NH, N, 0, S, CH, CH2 ;
Xlx and X2x are independently chosen from (CH2)m, (CH2)mCH=CH(CH2)p, C0(CH2)m, NH(CH2)m, NHC0(CH2)ra, CONH(CH2)m, S02NH(CH2)m,NHΞ02(CH2)m; n is 1 or 2 m is 0 to 2 p is 0 to 2
Rlx and R2x are independently chosen from hydrogen, alkoxy, alkyl, aminoalkyl, hydroxyalkyl, alkoxyalkyl, alkoxycarbonyl, amino, halo, cyano, nitro, thiol, alkylthio, alkylsulphonyl, alkylsulphenyl, oxo, heterocyclo optionally substituted by R3x, cycloalkyl optionally substituted by R3x or aryl optionally substituted by R3x; and
R3x is hydrogen, alkoxy, alkyl, amino, hydroxy, alkoxy, alkoxycarbonyl, halo, cyano, nitro, thiol, sulphonyl, or sulphenyl .
28. A compound of formula I as claimed in Claim 1 and as named in any one of the Examples herein, or a physiologically tolerable salt thereof.
29. A pharmaceutical composition, which comprises a compound as claimed in any one of Claims 1 to 27 together with at least one pharmaceutically acceptable carrier or excipient .
PCT/GB2000/002291 1997-08-29 2000-06-13 Serine protease inhibitors WO2000077027A2 (en)

Priority Applications (24)

Application Number Priority Date Filing Date Title
AU55460/00A AU5546000A (en) 1999-06-14 2000-06-13 Compounds
EP00981478A EP1240154B1 (en) 1999-12-14 2000-12-13 Serine protease inhibitors
PCT/GB2000/004764 WO2001044226A1 (en) 1999-12-14 2000-12-13 Serine protease inhibitors
AU18713/01A AU1871301A (en) 1999-12-14 2000-12-13 Serine protease inhibitors
CA2394276A CA2394276C (en) 1999-12-14 2000-12-13 Serine protease inhibitors
AT00981478T ATE355284T1 (en) 1999-12-14 2000-12-13 INHIBITORS OF SERINE PROTEASES
US10/148,174 US6916957B2 (en) 1999-12-14 2000-12-13 Serine protease inhibitors
ES00981478T ES2282152T3 (en) 1999-12-14 2000-12-13 SERINA PROTEASA INHIBITORS.
DE60033689T DE60033689T2 (en) 1999-12-14 2000-12-13 INHIBITORS OF SERIN PROTEASES
ES01938399T ES2275683T3 (en) 2000-06-13 2001-06-12 INHIBITORS OF SERINO PROTEASA.
AU2001264077A AU2001264077B2 (en) 2000-06-13 2001-06-12 Serine protease inhibitors
JP2002510448A JP2004503538A (en) 2000-06-13 2001-06-12 Serine protease inhibitor
AU6407701A AU6407701A (en) 2000-06-13 2001-06-12 Serine protease inhibitors
AT01938399T ATE344795T1 (en) 2000-06-13 2001-06-12 INHIBITORS OF SERINE PROTEASES
PCT/GB2001/002566 WO2001096305A1 (en) 2000-06-13 2001-06-12 Serine protease inhibitors
CA2413061A CA2413061C (en) 2000-06-13 2001-06-12 Serine protease inhibitors
EP01938399A EP1294691B1 (en) 2000-06-13 2001-06-12 Serine protease inhibitors
DE60124397T DE60124397T2 (en) 2000-06-13 2001-06-12 INHIBITORS OF SERIN PROTEASES
US10/296,245 US7074934B2 (en) 2000-06-13 2001-06-12 Serine protease inhibitors
US09/988,082 US6740682B2 (en) 1997-08-29 2001-11-19 Meta-benzamidine derivatives as serine protease inhibitors
US10/752,568 US7220781B2 (en) 1997-08-29 2004-01-08 Meta-benzamidine derivatives as serine protease inhibitors
US11/126,309 US7157585B2 (en) 1999-12-14 2005-05-11 Serine protease inhibitors
US11/186,870 US7381734B2 (en) 2000-06-13 2005-07-22 Serine protease inhibitors
US11/712,906 US7928137B2 (en) 1997-08-29 2007-03-02 Meta-benzamidine derivatives as serine protease inhibitors

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
GB9913823.2 1999-06-14
GBGB9913823.2A GB9913823D0 (en) 1999-06-14 1999-06-14 Compounds
US14206499P 1999-07-02 1999-07-02
US60/142,064 1999-07-02
GB9918741.1 1999-08-09
GBGB9918741.1A GB9918741D0 (en) 1999-08-09 1999-08-09 Compounds
GBGB9929553.7A GB9929553D0 (en) 1999-12-14 1999-12-14 Compounds
GB9929552.9 1999-12-14
GB9929553.7 1999-12-14
GBGB9929552.9A GB9929552D0 (en) 1999-12-14 1999-12-14 Compounds

Related Parent Applications (2)

Application Number Title Priority Date Filing Date
PCT/GB1998/002605 Continuation-In-Part WO1999011658A1 (en) 1997-08-29 1998-08-28 Meta-benzamidine derivatives as serin protease inhibitors
US48567800A Continuation-In-Part 1997-08-29 2000-02-25

Related Child Applications (3)

Application Number Title Priority Date Filing Date
PCT/GB1998/002605 Continuation-In-Part WO1999011658A1 (en) 1997-08-29 1998-08-28 Meta-benzamidine derivatives as serin protease inhibitors
US09485678 Continuation-In-Part 2000-02-25
US09/988,082 Continuation-In-Part US6740682B2 (en) 1997-08-29 2001-11-19 Meta-benzamidine derivatives as serine protease inhibitors

Publications (2)

Publication Number Publication Date
WO2000077027A2 true WO2000077027A2 (en) 2000-12-21
WO2000077027A3 WO2000077027A3 (en) 2001-05-25

Family

ID=56290032

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/GB2000/002291 WO2000077027A2 (en) 1997-08-29 2000-06-13 Serine protease inhibitors
PCT/GB2000/002296 WO2000076970A2 (en) 1999-06-14 2000-06-13 Serine protease inhibitors

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/GB2000/002296 WO2000076970A2 (en) 1999-06-14 2000-06-13 Serine protease inhibitors

Country Status (4)

Country Link
EP (1) EP1192135A2 (en)
AU (2) AU5546000A (en)
CA (1) CA2383008A1 (en)
WO (2) WO2000077027A2 (en)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001087834A1 (en) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Melanin-concentrating hormone antagonist
WO2001096305A1 (en) * 2000-06-13 2001-12-20 Tularik Limited Serine protease inhibitors
WO2002047762A1 (en) * 2000-12-13 2002-06-20 Tularik Limited Serine protease inhibitors
US6784182B2 (en) 2000-06-13 2004-08-31 Eli Lilly And Company Serine protease inhibitors
US6878725B2 (en) 2000-06-13 2005-04-12 Eli Lilly And Company Serine protease inhibitors
US6900196B2 (en) 2000-06-13 2005-05-31 Eli Lilly And Company Serine protease inhibitors
US6936611B2 (en) 2000-06-13 2005-08-30 Eli Lilly And Company Serine protease inhibitors
US7074934B2 (en) 2000-06-13 2006-07-11 Tularik Limited Serine protease inhibitors
EP1240154B1 (en) * 1999-12-14 2007-02-28 Tularik Limited Serine protease inhibitors
US7271280B2 (en) 2002-03-05 2007-09-18 Sumitomo Chemical Company, Limited Process for preparing a biaryl compound
US7378409B2 (en) 2003-08-21 2008-05-27 Bristol-Myers Squibb Company Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity

Families Citing this family (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7208497B2 (en) 2001-07-02 2007-04-24 Novo Nordisk A/S Substituted piperazines and diazepanes
WO2003010160A2 (en) 2001-07-26 2003-02-06 Eli Lilly And Company 1-glycinyl-4 (methylpiperidin-4-yl) piperazines and -piperridines as factor xa antagonists
NZ535402A (en) 2002-04-01 2006-02-24 Lilly Co Eli Certain 1-(d-cyclopropylglycinyl)-4-(piperidin-4-yl) piperazine compounds as inhibitors of the serine protease factor Xa
DK1569912T3 (en) 2002-12-03 2015-06-29 Pharmacyclics Inc 2- (2-hydroxybiphenyl-3-yl) -1h-benzoimidazole-5-carboxamidine derivatives as factor VIIa inhibitors.
PE20040804A1 (en) 2002-12-19 2004-12-31 Boehringer Ingelheim Pharma CARBOXAMID DERIVATIVES AS INHIBITORS OF THE Xa FACTOR
US7405210B2 (en) 2003-05-21 2008-07-29 Osi Pharmaceuticals, Inc. Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phosphorylase
WO2005112922A2 (en) * 2004-04-22 2005-12-01 Samaritan Pharmaceuticals Benzamide compounds
US7371743B2 (en) 2004-02-28 2008-05-13 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
DE602005023965D1 (en) 2004-03-08 2010-11-18 Prosidion Ltd PYRROLOPYRIDINE-2-CARBOXYLIC HYDRAZIDE AS INHIBITORS OF GLYCOPE PHOSPHORYLASE
US7550499B2 (en) 2004-05-12 2009-06-23 Bristol-Myers Squibb Company Urea antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
EP1819332B1 (en) 2004-12-02 2009-03-11 Prosidion Limited Pyrrolopyridine-2-carboxylic acid amides
KR20070100894A (en) 2005-01-19 2007-10-12 브리스톨-마이어스 스큅 컴퍼니 2-phenoxy-n-(1,3,4-thiadizol-2-yl)pyridin-3-amine derivatives and related compounds as p2y1 receptor inhibitors for the treatment of thromboembolic disorders
DE602006020871D1 (en) 2005-06-27 2011-05-05 Bristol Myers Squibb Co LINEAR UREA MIMETIC ANTAGONISTS OF THE P2Y1 RECEPTOR FOR THE TREATMENT OF THROMBOSELEIDES
WO2007002634A1 (en) 2005-06-27 2007-01-04 Bristol-Myers Squibb Company Carbocycle and heterocycle antagonists of p2y1 receptor useful in the treatment of thrombotic conditions
EP1896466B1 (en) 2005-06-27 2011-04-13 Bristol-Myers Squibb Company N-linked heterocyclic antagonists of p2y1 receptor useful in the treatment of thrombotic conditions
US7700620B2 (en) 2005-06-27 2010-04-20 Bristol-Myers Squibb Company C-linked cyclic antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
EP1757290A1 (en) 2005-08-16 2007-02-28 Zentaris GmbH Novel triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors
CN102988362B (en) 2005-12-07 2014-11-05 巴斯利尔药物股份公司 Useful combinations of monobactam antibiotics with beta-lactamase inhibitors
JP5235887B2 (en) 2006-09-20 2013-07-10 アエリー ファーマシューティカルズ インコーポレイテッド Rho kinase inhibitor
US7960569B2 (en) 2006-10-17 2011-06-14 Bristol-Myers Squibb Company Indole antagonists of P2Y1 receptor useful in the treatment of thrombotic conditions
EP2091944B1 (en) 2006-11-17 2011-05-18 Pfizer Inc. Substituted bicyclocarboxyamide compounds
US8410155B2 (en) 2006-12-15 2013-04-02 Bristol-Myers Squibb Company Arylpropionamide, arylacrylamide, arylpropynamide, or arylmethylurea analogs as factor XIA inhibitors
PE20081775A1 (en) 2006-12-20 2008-12-18 Bristol Myers Squibb Co MACROCYCLIC COMPOUNDS AS INHIBITORS OF FACTOR VIIA
US8455513B2 (en) 2007-01-10 2013-06-04 Aerie Pharmaceuticals, Inc. 6-aminoisoquinoline compounds
WO2008128647A1 (en) 2007-04-23 2008-10-30 Sanofi-Aventis Quinoline-carboxamide derivatives as p2y12 antagonists
JP5504171B2 (en) 2007-12-26 2014-05-28 サノフイ Heterocyclic pyrazole-carboxamides as P2Y12 antagonists
US8455514B2 (en) 2008-01-17 2013-06-04 Aerie Pharmaceuticals, Inc. 6-and 7-amino isoquinoline compounds and methods for making and using the same
WO2009134666A1 (en) 2008-04-29 2009-11-05 Boehringer Ingelheim International Gmbh Indazole compounds as ccr1 receptor antagonists
CA2722811C (en) 2008-05-06 2016-07-05 Boehringer Ingelheim International Gmbh Pyrazole compounds as ccr1 antagonists
US8450344B2 (en) 2008-07-25 2013-05-28 Aerie Pharmaceuticals, Inc. Beta- and gamma-amino-isoquinoline amide compounds and substituted benzamide compounds
BRPI0919844A2 (en) 2008-09-26 2019-09-24 Boehringer Ingelheim Int azaindazole compounds as ccr1 receptor antagonists
EP2424842B1 (en) 2009-05-01 2015-10-28 Aerie Pharmaceuticals, Inc. Dual mechanism inhibitors for the treatment of disease
CN102666526A (en) 2009-10-21 2012-09-12 贝林格尔.英格海姆国际有限公司 Indazole and pyrazolopyridine compounds as ccr1 receptor antagonists
JP5542214B2 (en) 2009-10-27 2014-07-09 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング Heterocyclic compounds as CCR1 receptor antagonists
EP3786165A1 (en) 2010-02-11 2021-03-03 Bristol-Myers Squibb Company Synthetic intermediates for producing macrocycles as factor xia inhibitors
EP2563787B1 (en) 2010-04-30 2014-11-26 Boehringer Ingelheim International GmbH Azaindazole amide compounds as ccr1 receptor antagonists
EP2431035A1 (en) 2010-09-16 2012-03-21 Æterna Zentaris GmbH Novel Triazole Derivatives with Improved Receptor Activity and Bioavailability Properties as Ghrelin Antagonists of Growth Hormone Secretagogue Receptors
WO2012087782A1 (en) 2010-12-23 2012-06-28 Boehringer Ingelheim International Gmbh Pyrazolopiperidine compounds as ccr1 receptor antagonists
TW201319068A (en) 2011-08-05 2013-05-16 必治妥美雅史谷比公司 Cyclic P1 linkers as factor XIa inhibitors
TW201311689A (en) 2011-08-05 2013-03-16 必治妥美雅史谷比公司 Novel macrocycles as factor XIa inhibitors
EP2766347B1 (en) 2011-10-14 2016-05-04 Bristol-Myers Squibb Company Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
KR101937514B1 (en) 2011-10-14 2019-01-10 브리스톨-마이어스 스큅 컴퍼니 Substituted tetrahydroisoquinoline compounds as factor xia inhibitors
ES2572908T3 (en) 2011-10-14 2016-06-03 Bristol-Myers Squibb Company Tetrahydroisoquinoline compounds substituted as factor XIa inhibitors
HUE032622T2 (en) 2012-08-03 2017-10-30 Bristol Myers Squibb Co Dihydropyridone p1 as factor xia inhibitors
KR20150038369A (en) 2012-08-03 2015-04-08 브리스톨-마이어스 스큅 컴퍼니 Dihydropyridone p1 as factor xia inhibitors
EP3461484B9 (en) 2013-03-15 2021-06-09 Aerie Pharmaceuticals, Inc. Dimesylate salts of 4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl, their combinations with prostaglandins and the use thereof in the treatment of ocular disorders
JP6479763B2 (en) 2013-03-25 2019-03-06 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Substituted azole containing tetrahydroisoquinolines as factor XIA inhibitors
JP2016152772A (en) * 2013-06-27 2016-08-25 味の素株式会社 Novel umami-taste imparting agent
US20170002006A1 (en) 2014-01-31 2017-01-05 Bristol-Myers Squibb Company Macrocycles with hetrocyclic p2' groups as factor xia inhibitors
NO2760821T3 (en) 2014-01-31 2018-03-10
NO2721243T3 (en) 2014-10-01 2018-10-20
US10160750B2 (en) 2015-06-19 2018-12-25 Bristol-Myers Squibb Company Diamide macrocycles as factor XIa inhibitors
US10676477B2 (en) 2015-07-29 2020-06-09 Bristol-Myers Squibb Company Factor XIa macrocycle inhibitors bearing a non-aromatic P2' group
EP3331872B1 (en) 2015-08-05 2019-09-25 Bristol-Myers Squibb Company Novel substituted glycine derived fxia inhibitors
WO2017086941A1 (en) 2015-11-17 2017-05-26 Aerie Pharmaceuticals, Inc. Process for the preparation of kinase inhibitors and intermediates thereof
US9643927B1 (en) 2015-11-17 2017-05-09 Aerie Pharmaceuticals, Inc. Process for the preparation of kinase inhibitors and intermediates thereof
EP3423458A1 (en) 2016-03-02 2019-01-09 Bristol-Myers Squibb Company Diamide macrocycles having factor xia inhibiting activity
EP3506890A1 (en) 2016-08-31 2019-07-10 Aerie Pharmaceuticals, Inc. Ophthalmic compositions
JP2020515583A (en) 2017-03-31 2020-05-28 アエリエ ファーマシューティカルズ インコーポレイテッド Aryl cyclopropyl-amino-isoquinolinyl amide compound
EP3849555A4 (en) 2018-09-14 2022-05-04 Aerie Pharmaceuticals, Inc. Aryl cyclopropyl-amino-isoquinolinyl amide compounds

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047876A1 (en) * 1997-04-24 1998-10-29 Akzo Nobel N.V. Heterocyclic derivatives and their use as antithrombotic agents
WO1999011657A1 (en) * 1997-08-29 1999-03-11 Proteus Molecular Design Ltd. 1-amino-7-isoquinoline derivatives as serine protease inhibitors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2062943B1 (en) * 1993-03-23 1995-11-16 Uriach & Cia Sa J NEW DERIVATIVES OF (2-METHYL-3-PIRIDIL) CYANOMETILPIPERAZINES.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998047876A1 (en) * 1997-04-24 1998-10-29 Akzo Nobel N.V. Heterocyclic derivatives and their use as antithrombotic agents
WO1999011657A1 (en) * 1997-08-29 1999-03-11 Proteus Molecular Design Ltd. 1-amino-7-isoquinoline derivatives as serine protease inhibitors
WO1999011658A1 (en) * 1997-08-29 1999-03-11 Proteus Molecular Design Ltd. Meta-benzamidine derivatives as serin protease inhibitors

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1240154B1 (en) * 1999-12-14 2007-02-28 Tularik Limited Serine protease inhibitors
WO2001087834A1 (en) * 2000-05-16 2001-11-22 Takeda Chemical Industries, Ltd. Melanin-concentrating hormone antagonist
US6878725B2 (en) 2000-06-13 2005-04-12 Eli Lilly And Company Serine protease inhibitors
US7053078B2 (en) 2000-06-13 2006-05-30 Eli Lilly And Company Serine protease inhibitors
US7381734B2 (en) 2000-06-13 2008-06-03 Tularik Limited Serine protease inhibitors
US6900196B2 (en) 2000-06-13 2005-05-31 Eli Lilly And Company Serine protease inhibitors
US6936611B2 (en) 2000-06-13 2005-08-30 Eli Lilly And Company Serine protease inhibitors
EP1289954B1 (en) * 2000-06-13 2005-09-14 Eli Lilly And Company Serine protease inhibitors
US6946467B2 (en) 2000-06-13 2005-09-20 Eli Lilly And Company Serine protease inhibitors
US6784182B2 (en) 2000-06-13 2004-08-31 Eli Lilly And Company Serine protease inhibitors
US7351822B2 (en) 2000-06-13 2008-04-01 Eli Lilly And Company Serine protease inhibitors
US7074934B2 (en) 2000-06-13 2006-07-11 Tularik Limited Serine protease inhibitors
WO2001096305A1 (en) * 2000-06-13 2001-12-20 Tularik Limited Serine protease inhibitors
US7067516B2 (en) 2000-12-13 2006-06-27 Tularik Limited Serine protease inhibitors
WO2002047762A1 (en) * 2000-12-13 2002-06-20 Tularik Limited Serine protease inhibitors
US7271280B2 (en) 2002-03-05 2007-09-18 Sumitomo Chemical Company, Limited Process for preparing a biaryl compound
US7714157B2 (en) 2002-03-05 2010-05-11 Sumitomo Chemical Company, Limited Process for preparing a biaryl compound
US7378409B2 (en) 2003-08-21 2008-05-27 Bristol-Myers Squibb Company Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity

Also Published As

Publication number Publication date
AU5413600A (en) 2001-01-02
AU5546000A (en) 2001-01-02
WO2000076970A2 (en) 2000-12-21
CA2383008A1 (en) 2000-12-21
EP1192135A2 (en) 2002-04-03
WO2000077027A3 (en) 2001-05-25
WO2000076970A3 (en) 2001-07-19

Similar Documents

Publication Publication Date Title
WO2000077027A2 (en) Serine protease inhibitors
EP1240154B1 (en) Serine protease inhibitors
EP1192132B1 (en) Serine protease inhibitors
ES2282192T3 (en) SERINA PROTEASA INHIBITORS.
US6703379B2 (en) Benzene derivatives and pharmaceutical use thereof
AU2002222207A1 (en) Serine protease inhibitors
US7074934B2 (en) Serine protease inhibitors
AU2001264077C1 (en) Serine protease inhibitors
AU2001264077A1 (en) Serine protease inhibitors
EP1294691B1 (en) Serine protease inhibitors
MXPA01002563A (en) Benzene derivatives and medicinal use thereof
FR2666335A1 (en) Arylalkylamines, process for their preparation and pharmaceutical compositions containing them

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase in:

Ref country code: JP