WO2013005045A1 - Benzylamine derivatives as inhibitors of plasma kallikrein - Google Patents

Benzylamine derivatives as inhibitors of plasma kallikrein Download PDF

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Publication number
WO2013005045A1
WO2013005045A1 PCT/GB2012/051588 GB2012051588W WO2013005045A1 WO 2013005045 A1 WO2013005045 A1 WO 2013005045A1 GB 2012051588 W GB2012051588 W GB 2012051588W WO 2013005045 A1 WO2013005045 A1 WO 2013005045A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
aminomethyl
ethoxy
ethyl
benzylcarbamoyl
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/GB2012/051588
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English (en)
French (fr)
Inventor
David Michael Evans
Rebecca Louise DAVIE
Hannah Joy EDWARDS
David Philip Rooker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Kalvista Pharmaceuticals Ltd
Original Assignee
Kalvista Pharmaceuticals Ltd
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 to MX2014000073A priority Critical patent/MX343740B/es
Priority to KR1020147003202A priority patent/KR101999195B1/ko
Priority to HK14110454.2A priority patent/HK1197055B/en
Priority to CN201280033711.8A priority patent/CN103687846B/zh
Priority to DK12735610.3T priority patent/DK2729443T6/da
Priority to BR112014000240-1A priority patent/BR112014000240B1/pt
Priority to RU2014104226A priority patent/RU2607045C2/ru
Priority to SI201230437T priority patent/SI2729443T1/sl
Priority to NZ620271A priority patent/NZ620271B2/en
Priority to ES12735610T priority patent/ES2560612T7/es
Priority to UAA201401160A priority patent/UA115427C2/uk
Priority to MYPI2013702586A priority patent/MY185103A/en
Priority to AU2012280064A priority patent/AU2012280064B2/en
Priority to US14/131,351 priority patent/US9051249B2/en
Priority to CA2841042A priority patent/CA2841042C/en
Application filed by Kalvista Pharmaceuticals Ltd filed Critical Kalvista Pharmaceuticals Ltd
Priority to RS20160011A priority patent/RS54509B2/sr
Priority to PH1/2013/502677A priority patent/PH12013502677A1/en
Priority to MEP-2016-6A priority patent/ME02308B/me
Priority to HRP20160101TT priority patent/HRP20160101T4/hr
Priority to EP12735610.3A priority patent/EP2729443B3/en
Priority to JP2014517952A priority patent/JP5921679B2/ja
Priority to PL12735610T priority patent/PL2729443T6/pl
Publication of WO2013005045A1 publication Critical patent/WO2013005045A1/en
Priority to IL230332A priority patent/IL230332A/en
Anticipated expiration legal-status Critical
Priority to ZA2014/00682A priority patent/ZA201400682B/en
Priority to US14/687,127 priority patent/US9234000B2/en
Priority to SM201600020T priority patent/SMT201600020B/it
Ceased legal-status Critical Current

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    • 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
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
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    • 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
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    • 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
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    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • alkyl is a linear saturated hydrocarbon having up to 10 carbon atoms (Ci-Cio) or a branched saturated hydrocarbon of between 3 and 10 carbon atoms (C3-C10); alkyl may optionally be substituted with 1 or 2 substituents independently selected from (C 3 - Cio)cycloalkyl, (Ci-Cg)alkoxy, OH, CN, CF 3 , COOR 11 , fluoro and NR n R 12 ;
  • R 13 is aryl or heteroaryl
  • R 14 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl
  • R 17 is H, alkyl, aryl, heteroaryl or heterocycloalkyl
  • R 3 is selected from H, alkyl, -(CH 2 )aaryl, -(CH 2 ) e heteroaryl, -(CH 2 ) f Cycloalkyl,
  • R 7 and R 8 are independently selected from H, alkyl, alkoxy, CN and halo;
  • heteroaryl is a 5, 6, 9 or 10 membered mono- or bi-cyclic aromatic ring, containing, where possible, 1, 2 or 3 ring members independently selected from N, NR 11 , S and O; heteroaryl may be optionally substituted with 1 , 2 or 3 substituents independently selected from alkyl, alkoxy, OH, halo, CN, COOR 11 , CF 3 and NR n R 12 ;
  • R 11 and R 12 are independently selected from H and alkyl; and tautomers, isomers, stereoisomers (including enantiomers, diastereoisomers and racemic and scalemic mixtures thereof), pharmaceutically acceptable salts and solvates thereof.
  • R 2 is selected from H and alkyl
  • R 7 and R 8 are independently selected from H, F, and CI;
  • R 1 is selected from -COalkyl, COheteroaryl and -COaryl.
  • R 2 is selected from H and methyl.
  • R 3 is selected from alkyl, -(CH 2 )aaryl, -(CH 2 )iCycloalkyl, and -CH(cycloalkyl) 2 ; wherein d and f are, independently, 1 or 2.
  • R 4 is H.
  • R 5 is selected from H, alkyl and OH.
  • R 4 and R 5 together with the atoms to which they are attached, join to form a piperidine moiety.
  • R 7 is selected from H, methyl and halo.
  • R 9 is selected from phenyl, 1 -naphthalene, 2,4-dichlorophenyl, 3,4- dichlorophenyl, 3,4-difluorophenyl, 4-chlorophenyl, 4-trifluoromethylphenyl and 4- ethoxyphenyl.
  • k is 0 or 1.
  • Naphthalene- 1 -carboxylic acid [(R)- 1 -[(S)- 1 -(4-aminomethyl-benzylcarbamoyl)-2-phenyl- ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide;
  • the invention comprises a compound selected from:
  • Naphthalene- 1 -carboxylic acid [(R)- 1 -[(S)- 1 -(4-aminomethyl-benzylcarbamoyl)-2-phenyl- ethylcarbamoyl]-2-(4-ethoxy-phenyl)-ethyl]-amide;
  • the invention comprises a compound selected from:
  • the present invention also provides a compound of formula (I) for use in the treatment or prevention of a disease or condition in which plasma kallikrein activity is implicated.
  • alkoxy groups include, but are not limited to, Ci - methoxy, C 2 - ethoxy, C 3 - n-propoxy and C 4 - n-butoxy.
  • excipient is used herein to describe any ingredient other than the compound(s) of the invention which may impart either a functional (i.e., drug release rate controlling) and/or a non- functional (i.e., processing aid or diluent) characteristic to the formulations.
  • a functional i.e., drug release rate controlling
  • a non- functional i.e., processing aid or diluent
  • the choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • the compounds of the invention may be administered in a form suitable for injection into the ocular region of a patient, in particular, in a form suitable for intra-vitreal injection. It is envisaged that formulations suitable for such use will take the form of sterile solutions of a compound of the invention in a suitable aqueous vehicle. The compositions may be administered to the patient under the supervision of the attending physician.
  • the compounds of the invention may also be administered directly into the blood stream, into subcutaneous tissue, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle- free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous or oily solutions. Where the solution is aqueous, excipients such as sugars (including but not restricted to glucose, manitol, sorbitol, etc.), salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen- free water.
  • excipients such as sugars (including but not restricted to glucose, manitol, sorbitol, etc.), salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen- free water.
  • solubility of compounds of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of co- solvents and/or solubility-enhancing agents such as surfactants, micelle structures and cyclodextrins.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents, 2001, 11 (6), 981-986.
  • the compounds of the present invention can be prepared according to the procedures of the following schemes and examples, using appropriate materials, and are further exemplified by the specific examples provided herein below. Moreover, by utilising the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds that fall within the scope of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • the compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above. It may be necessary to protect reactive functional groups (e.g. hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds.
  • reactive functional groups e.g. hydroxy, amino, thio or carboxy
  • Conventional protecting groups for example those described by T. W. Greene and P. G. M. Wuts in "Protective groups in organic chemistry” John Wiley and Sons, 4 th Edition, 2006, may be used.
  • a common amino protecting group suitable for use herein is tert-butoxy carbonyl (Boc), which is readily removed by treatment with an acid such as trifluoroacetic acid or hydrogen chloride in an organic solvent such as dichloromethane.
  • the amino protecting group may be a benzyloxycarbonyl (Z) group which can be removed by hydrogenation with a palladium catalyst under a hydrogen atmosphere or 9-fluorenylmethyloxycarbonyl (Fmoc) group which can be removed by solutions of secondary organic amines such as diethylamine or piperidine in an organic solvents.
  • a common hydroxy protecting group suitable for use herein is a methyl ether
  • deprotection conditions comprise refluxing in 48% aqueous HBr for 1-24 hours, or by stirring with borane tribromide in dichloromethane for 1-24 hours.
  • deprotection conditions comprise hydrogenation with a palladium catalyst under a hydrogen atmosphere.
  • the compounds according to general formula I can be prepared using conventional synthetic methods for example, but not limited to, the route outlined in Scheme 1.
  • the amine (2) is coupled using standard peptide coupling conditions to an activated alpha amino acid (1) suitably amino -protected with a standard protecting group such as tert-butyloxycarbonyl (Boc), benzyloxycarbonyl (Z) or 9-fluorenylmethyloxycarbonyl (Fmoc).
  • the activating group (X) may be N-hydroxysuccinimide. The use of such groups is well known in the art.
  • Alkylation may typically be carried by treatment with an alkyl halide or by reductive alkylation.
  • a reductive alkylation procedure the amine is allowed to react with an aldehyde or ketone in the presence of a suitable reducing agent such as sodium cyanoborohydride or sodium acetoxyborohydride in a suitable solvent such as methanol, at room temperature.
  • a suitable reducing agent such as sodium cyanoborohydride or sodium acetoxyborohydride in a suitable solvent such as methanol
  • LCMS Chrolith Speedrod RP-18e column, 50 x 4.6 mm, with a linear gradient 10% to 90% 0.1% HC0 2 H/MeCN into 0.1% HC0 2 H/H 2 0 over 11 min, flow rate 1.5 mL/min.
  • Data was collected using a Thermo finnigan Surveyor MSQ mass spectrometer with electospray ionisation in conjunction with a Thermo finnigan Surveyor LC system.
  • reaction mixture was diluted with chloroform (200 mL) and washed with NaHCC"3 (1x50 mL), water (1x50 mL), brine (1x50 mL), dried (Na 2 S0 4 ) and evaporated in vacuo giving a yellow oil. The residue was triturated with ethyl acetate and Pet.
  • reaction mixture was stirred at room temperature for 5 hrs and diluted with CHCI 3 (150 mL), this solution was washed with 0.3M KHSO 4 (1x50 mL), sat. NaHCC"3 (1x50 mL), water (1x50 mL), brine (1x50 mL), dried (Na 2 S0 4 ) and evaporated in vacuo.
  • reaction mixture was diluted with chloroform (100 mL) and washed with NaHC0 3 ( 1x30 mL), water ( 1x30 mL), brine ( 1x30 mL), dried (Na 2 S0 4 ) and evaporated in vacuo giving a yellow oil.
  • the residue was crystallised from EtO Ac/Pet. Ether (60-80°C) to give a white solid identified as [(S)-l-(4-cyano- benzylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (2.71g, 7.1mmol, 86%).
  • reaction mixture was diluted with chloroform (100 mL) and washed with NaHC0 3 (1x30 mL), water (1x30 mL), brine (1x30 mL), dried (Na 2 S0 4 ) and evaporated in vacuo giving a yellow oil.
  • CD 3 OD ⁇ 0.67-0.71 and 0.77-0.80 (3H, m), 1.19-1.24 (3H, m), 1.99-2.11 (2H, m), 2.65-2.83 (5H, m), 2.91-3.09 (2H, m), 3.81-3.88 (2H, m), 3.95 (2H, s), 4.17-4.32 (2H, m), 4.43-4.54 (IH, m), 4.77-4.82 (IH, m), 6.62-6.69 (2H, m), 6.90-6.94 (2H, m), 6.98-7.20 (7H, m), 7.21-7.26 (2H, m), 7.69 (IH, d, J 7.9Hz), 8.26-8.29 and 8.40-8.43 (IH, m)

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CA2841042A CA2841042C (en) 2011-07-07 2012-07-06 Benzylamine derivatives as inhibitors of plasma kallikrein
HK14110454.2A HK1197055B (en) 2011-07-07 2012-07-06 Benzylamine derivatives as inhibitors of plasma kallikrein
CN201280033711.8A CN103687846B (zh) 2011-07-07 2012-07-06 作为血浆激肽释放酶抑制剂的苄胺衍生物
DK12735610.3T DK2729443T6 (da) 2011-07-07 2012-07-06 Benzylaminderivater som inhibitorer af plasmakallikrein
BR112014000240-1A BR112014000240B1 (pt) 2011-07-07 2012-07-06 Derivados de benzilamina como inibidores de calicreína plasmática, seu uso, e composição farmacêutica
RU2014104226A RU2607045C2 (ru) 2011-07-07 2012-07-06 Бензиламиновые производные как ингибиторы калликреина плазмы
SI201230437T SI2729443T1 (sl) 2011-07-07 2012-07-06 Derivati benzilamina kot zaviralci plazemskega kalikreina
NZ620271A NZ620271B2 (en) 2011-07-07 2012-07-06 Benzylamine derivatives as inhibitors of plasma kallikrein
ES12735610T ES2560612T7 (es) 2011-07-07 2012-07-06 Derivados bencilamina como inhibidores de la calicreina plasmática
UAA201401160A UA115427C2 (uk) 2011-07-07 2012-07-06 Бензиламінові похідні як інгібітори калікреїну плазми
MYPI2013702586A MY185103A (en) 2011-07-07 2012-07-06 Bezylamine derivatives as inhibitors of plasma kallikrein
AU2012280064A AU2012280064B2 (en) 2011-07-07 2012-07-06 Benzylamine derivatives as inhibitors of plasma kallikrein
US14/131,351 US9051249B2 (en) 2011-07-07 2012-07-06 Benzylamine derivatives as inhibitors of plasma kallikrein
MX2014000073A MX343740B (es) 2011-07-07 2012-07-06 Derivados de bencilamina como inhibidores de calicreina plasmatica.
EP12735610.3A EP2729443B3 (en) 2011-07-07 2012-07-06 Benzylamine derivatives as inhibitors of plasma kallikrein
PL12735610T PL2729443T6 (pl) 2011-07-07 2012-07-06 Pochodne benzyloaminy jako inhibitory kalikreiny osoczowej
PH1/2013/502677A PH12013502677A1 (en) 2011-07-07 2012-07-06 Benzylamine derivatives as inhibitors of plasma kallikrein
MEP-2016-6A ME02308B (me) 2011-07-07 2012-07-06 Derivati benzilamina kao inhibitori kalikrein plazme
HRP20160101TT HRP20160101T4 (hr) 2011-07-07 2012-07-06 Derivati benzilamina kao inhibitori kalikreina plazme
KR1020147003202A KR101999195B1 (ko) 2011-07-07 2012-07-06 혈장 칼리크레인의 저해제로서의 벤질아민 유도체
JP2014517952A JP5921679B2 (ja) 2011-07-07 2012-07-06 血漿カリクレインの阻害薬としてのベンジルアミン誘導体
RS20160011A RS54509B2 (sr) 2011-07-07 2012-07-06 Derivati benzilamina kao inhibitori kalikrein plazme
IL230332A IL230332A (en) 2011-07-07 2014-01-06 History of benzylamine as cleacine plasma inhibitors
ZA2014/00682A ZA201400682B (en) 2011-07-07 2014-01-28 Benzylamine derivatives as inhibitors of plasma kallikrein
US14/687,127 US9234000B2 (en) 2011-07-07 2015-04-15 Benzylamine derivatives as inhibitors of plasma kallikrein
SM201600020T SMT201600020B (it) 2011-07-07 2016-01-20 Derivati di benzilammina come inibitori di callicreina plasmatica

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GB1111682.9A GB2494851A (en) 2011-07-07 2011-07-07 Plasma kallikrein inhibitors

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