EP1237849A1 - Activateurs de la guanylate cyclase soluble - Google Patents

Activateurs de la guanylate cyclase soluble

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Publication number
EP1237849A1
EP1237849A1 EP00973061A EP00973061A EP1237849A1 EP 1237849 A1 EP1237849 A1 EP 1237849A1 EP 00973061 A EP00973061 A EP 00973061A EP 00973061 A EP00973061 A EP 00973061A EP 1237849 A1 EP1237849 A1 EP 1237849A1
Authority
EP
European Patent Office
Prior art keywords
dimethylamino
propyl
phenyl
chloro
amide
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.)
Withdrawn
Application number
EP00973061A
Other languages
German (de)
English (en)
Inventor
David Uni College London The Wolfson SELWOOD
Robert Uni College London The Wolfson GLEN
Karen Uni College London The Wolfson REYNOLDS
Grant Uni College London The Wolfson WISHART
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.)
University College London
Original Assignee
University College London
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 GBGB9926286.7A external-priority patent/GB9926286D0/en
Application filed by University College London filed Critical University College London
Publication of EP1237849A1 publication Critical patent/EP1237849A1/fr
Withdrawn legal-status Critical Current

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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C07D213/643—2-Phenoxypyridines; Derivatives thereof
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    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • 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
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
    • 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
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/40—Ortho- or ortho- and peri-condensed systems containing four condensed rings
    • C07C2603/42—Ortho- or ortho- and peri-condensed systems containing four condensed rings containing only six-membered rings
    • C07C2603/50—Pyrenes; Hydrogenated pyrenes

Definitions

  • This invention relates to activators of soluble guanylate cyclase (sGC), to their preparation and to their use.
  • sGC soluble guanylate cyclase
  • Soluble guanylate cyclase is responsible for the enzymatic conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophosphate (cGMP).
  • sGC is responsible for numerous physiological processes including vascular and non-vascular smooth muscle relaxation, peripheral and central neurotransmission, platelet reactivity and phototransduction (Hobbs A.J., TiPS, December 1997, Vol 18, p.484). Activators of sGC can therefore be expected to have valuable therapeutic properties.
  • NO is known as an activator of sGC.
  • this compound has a number of different physiological effects and its use in activating sGC therefore suffers from a myriad of side effects. There is therefore a need for selective activators of sGC.
  • 3-(5'-hydroxymethyl-2'-furyl)-l-benzylindazole (YC-1) is a known NO independent activator of sGC (Hobbs, A.J., TiPS, December 1997, Vol 18, p.484). However, the activation achieved is not high.
  • the present invention provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the activation of soluble guanylate cyclase
  • R, and R 2 are the same or different and each represent a C,-C 6 alkyl group, or R, and R 2 together form a C 3 -C 6 alkylene group;
  • Z is a C,-C 4 alkylene group
  • P is a direct bond or a moiety -X-, -Y-, -W-, -XY-, -YW- or -XYW-, wherein:
  • R 4 is C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, a group -R-A wherein R is -(C,-C 6 alkyl)-, -(C 2 -C alkenyl)- or -(C 2 -C 6 alkynyl)- and A is aryl, heteroaryl, carbocycyl or heterocyclyl, or R 4 is a group -COR' * ', -CO ⁇ , -S(O) 2 R or -CONR'R" wherein R' is hydrogen, C r C 6 alkyl, C 2 -C 6 alkenyl or
  • C 2 -C 6 alkynyl and R" is is aryl, heteroaryl, carbocyclyl or heterocyclyl.
  • the moiety -X- when present, is attached to R 4 and the moiety W, when present, is attached to Z.
  • the moiety Y the moiety V is attached to W or, if W is not present, to Z, and the moiety U is attached to X or, if X is not present, to R 4 .
  • a C,-C 6 alkyl group or moiety is a linear or branched alkyl group or moiety.
  • Suitable alkyl groups and moieties include C r C 4 alkyl groups and moieties, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Methyl, ethyl, n-propyl and t-butyl are preferred.
  • a C r C 6 alkyl group or moiety can be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Suitable substituents include C r C 6 alkyl, C r C 6 alkylthio, C r C 6 alkoxy, C,-C 6 haloalkyl, for example -CF 3 and -CC1 3 , C r C 6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, oxo, -NR / R wherein R 7 and R" are the same or different and are hydrogen or C r C 6 al
  • two substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group.
  • two preferred substituents on the same carbon atom may, together with the atom to which they are attached, form a carbocyclyl group, preferably a C 3 -C 6 cycloalkyl group.
  • a C 2 -C 6 alkenyl group or moiety is a linear or branched alkenyl group or moiety.
  • Suitable alkenyl groups and moieties include C 2 -C 4 alkenyl groups and moieties such as ethenyl, propenyl and butenyl groups and moieties. Ethenyl and propenyl are preferred.
  • a C 2 -C 6 alkenyl group or moiety may be substituted or unsubstituted at any position.
  • a C 2 -C 6 alkenyl group is typically unsubstituted or carries 1, 2, 3 or 4 substituents. Preferably, it carries at least two substituents. Suitable substituents include oxo, C r C 6 alkyl, C r C 6 alkylthio, C r C 6 alkoxy, C]-C 6 haloalkyl, for example -CF 3 and -CC1 3 , C r C 6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR'R" wherein R' and R / are the same or different and are hydrogen or C r C 6 alkyl,
  • two preferred substituents on the same carbon atom may, together with the atom to which they are attached, form a carbocyclyl group, preferably a C 3 -C 8 cycloalkyl group.
  • substituents are halogen, for example chlorine and fluorine, C r C 4 alkyl, for example methyl, ethyl or t-butyl, aryl, for example phenyl, heteroaryl, for example furanyl, -CONH-aryl, for example -CONH-phenyl, -NH- CO 2 -(C,-C 4 alkyl), -NH-CO-(C,-C 4 alkyl), -NH-CO-aryl, for example -NH-CO- phenyl, heteroarylthio, for example pyrimidinethio and -CO-aryl, for example -CO- phenyl. It is also preferred that two substituents on the same carbon atom may, together with the atom to which they are attached, form a C 3 -C 8 cycloalkyl group.
  • a C 2 -C 6 alkynyl group or moiety is typically an ethynyl, propynyl or butynyl group or moiety. It may be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries 1 or 2 substituents.
  • Suitable substituents include C r C 6 alkyl, C,-C 6 alkylthio, C r C 6 alkoxy, C r C 6 haloalkyl, for example -CF 3 and -CC1 3 , C r C 6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR / R / wherein R' and R / are the same or different and are hydrogen or C r C 6 alkyl, -
  • each R / can be the same or different and represents hydrogen or C r C 6 alkyl and each R can be the same or different and represents C r C 6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(C r C 6 alkyl)-R // and -O-(Cj-C 6 alkyl)-R wherein each R" 1 can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl.
  • two substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group.
  • Preferred substituents include halogen, C r C 6 alkyl, aryl, arylthio, aryloxy, heteroaryl, heteroarylthio, heteroaryloxy and -CONHR and -NHCO 2 R wherein R is as defined above.
  • two preferred substituents on the same carbon atom may, together with the atom to which they are attached, form a carbocyclyl group, preferably a C 3 -C 6 cycloalkyl group.
  • substituents are halogen, for example chlorine and fluorine, C r C 4 alkyl, for example methyl, ethyl or t-butyl, aryl, for example phenyl, -CONH-aryl, for example -CONH-phenyl, -NH-CO 2 -(C ,-C 4 alkyl), heteroarylthio, for example pyrimidinethio and -CO-aryl, for example -CO-phenyl. It is also preferred that two substituents on the same carbon atom may, together with the atom to which they are attached, form a C 3 -C 6 cycloalkyl group.
  • a C,-C 6 alkoxy group is typically a said C,-C 6 alkyl group attached to an oxygen atom.
  • a C,-C 6 alkylthio group is typically a said C,-C 6 alkyl group attached to a sulphur atom.
  • a said alkylene group is a divalent alkyl moiety. It may be unsubstituted or substituted at any position. Typically, it is unsubstituted or monosubstituted. Suitable substituents include halogen, for example chlorine and flourine, hydroxy, C C 4 alkyl such as methyl and ethyl, C C alkoxy, for example methoxy, C r C 4 haloalkyl, for example -CF 3 and -CC1 3 and C r C 4 haloalkoxy, for example -OCF 3 and -OCCl 3 . These substituents are typically themselves unsubstituted.
  • a halogen is typically chlorine, fluorine, bromine or iodine. It is preferably chlorine.
  • a haloalkyl or haloalkoxy group is typically a said alkyl or alkoxy group substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms.
  • Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX 3 and -OCX 3 wherein X is a said halogen atom.
  • Particularly preferred haloalkyl groups are CF 3 and CC1 3 .
  • Particularly preferred haloalkoxy groups are -OCF 3 and -OCCl 3 .
  • an aryl group or moiety is typically a C 6 -C 20 aryl group or moiety. Suitable such aryl groups and moieties include phenyl, naphthyl and pyrenyl. Phenyl and pyrenyl are preferred.
  • An aryl group or moiety may be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries 1, 2, 3 or 4 substituents. Suitable substituents include C,-C 6 alkyl, C r C 6 alkylthio, C r C 6 alkoxy, C r C 6 haloalkyl, for example -CF 3 and -CC1 3 , - haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, cyano, hydroxy, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NRR wherein R' and R" are the same or different and are hydrogen or C,-C 6 alkyl, -COR, -CONR /
  • Preferred substituents include C C 6 alkyl, for example methyl and ethyl, C r C 6 alkoxy, for example methoxy, C r C 6 alkylthio, for example methylthio, C,-C 6 haloalkyl, for example -CF 3 and -CC1 3 , C r C 6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, for example chlorine and fluorine, nitro, cyano, aryl, for example phenyl, aryloxy, for example phenyloxy, arylthio, for example phenylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, -NRR / wherein R f and R are the same or different and are hydrogen or C,-C 6 alkyl, -CONH-(C,-C 6 alkyl), -NHCONH-R wherein R is aryl, for example phen
  • substituents are phenyl, in particular 4-phenyl, phenoxy, in particular 2-phenoxy, phenylthio, halogen, -CF 3 , -CC1 3 , nitro, cyano, -OCF 3 , -OCCl 3, C,-C 4 alkyl, C,-C 4 alkoxy, C,-C 4 alkylthio, -CONH-(C,-C 4 alkyl),
  • An aryl group or moiety may be fused to a further said aryl group or to a carbocyclic, heterocyclic or heteroaryl group.
  • an aryl group may be fused to a pyridine ring to form a quinoline or isoquinoline group, or to a furan ring. It may also, for example, be fused to a cyclopropyl or cyclohexyl group or to a tetrahydro furyl group, a 1,4-dioxolane group or a pyrimidone ring, for example a 4- pyrimidone ring.
  • a carbocyclic group or moiety is a non-aromatic, saturated or unsaturated carbocyclic group or moiety. Typically, it has from 3 to 10, for example from 3 to 8, carbon atoms. Preferably, it has from 3 to 8, for example 3 to 6, carbon atoms.
  • suitable carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopetadienyl, cyclohexyl, cyclohexenyl and cyclooctanyl groups.
  • Preferred carbocyclic groups include cyclohexyl, cyclooctanyl and cyclohexenyl groups.
  • substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group.
  • Preferred substituents include oxo, C,-C 6 alkyl, for example methyl and ethyl, C r C 6 alkoxy, for example methoxy, C,-C 6 alkylthio, for example methylthio, C,-C 6 haloalkyl, for example -CF 3 and -CC1 3 , - haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, for example chlorine and fluorine, nitro, cyano, aryl, for example phenyl, aryloxy, for example phenyloxy, arylthio, for example phenythio, heteroaryl, heteroarylthio, heterocyclyl, -CONH-(C,-C 6 alkyl), -NHCONH-R wherein R is aryl
  • a carbocyclic group or moiety may be fused to a further carbocyclic group or to an aryl, heteroaryl or heterocyclic group.
  • a heteroaryl group or moiety is typically a 5- to 10- membered aryl ring containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from
  • the heteroaryl group or moiety is a 5- or 6- membered ring.
  • Suitable heteroaryl groups and moieties include pyridyl, pyranyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, pyrazolyl, iso thiazolyl, isoxazolyl, furazanyl, triazolyl and thiadiazolyl groups.
  • a heteroaryl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries up to three substituents. Suitable substituents include C r C 6 alkyl, C r C 6 alkylthio, C,-C 6 alkoxy, C,-C 6 haloalkyl, for example -CF 3 and -CC1 3 , C r C 6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR / R / wherein R ; and R // are the same or different and are hydrogen or C r C 6 alkyl, -COR,
  • each R can be the same or different and represents hydrogen or C r C 6 alkyl and each R can be the same or different and represents C r C 6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(C,-C 6 alkyl)-R and -O-(C 1 -C 6 alkyl)-R / wherein each R"' can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl.
  • Preferred substituents include C r C 6 alkyl, for example methyl and ethyl,
  • C r C 6 alkoxy for example methoxy, C r C 6 alkylthio, for example methylthio, C r C 6 haloalkyl, for example -CF 3 and -CC1 3 , C,-C 6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, for example chlorine, cyano, nitro, aryl, for example phenyl, aryloxy, for example phenoxy, arylthio, for example phenylthio and -O-(C,-C 6 alkyl)-R, -S-(C,-C 6 alkyl)-R, -S-(C,-C 6 alkyl)-CONH-R, -CO-R and
  • R is an aryl group, for example a phenyl group.
  • substituents include phenyl, halogen, for example chlorine, C r C 4 alkyl, for example methyl, -CF 3 , -CC1 3 , -OCF 3 , -OCCl 3 , phenylthio, phenoxy, -S-(C C 4 alkyl)-CONH-phenyl, -S-(C,-C 4 alkyl)-phenyl, -O-(C r C 4 alkyl)-phenyl, -CO-phenyl, cyano, C r C 4 alkylthio, nitro,
  • a heteroaryl group may be fused to a said aryl or carbocyclic group or to a further heteroaryl group or to a heterocyclic group.
  • fused heteroaryl groups include quinolyl, indolyl, isoindolyl, benzothiophenyl, imidazo[l,2- ]pyridyl and ⁇ -carbolinyl groups.
  • a heterocyclic group or moiety is a non-aromatic, saturated or unsaturated cyclic group or moiety containing at least one, for example, one, two or three, heteroatoms selected from N, O and S. Typically, it is a 3- to 6- membered ring. Preferably, it is a 5- or 6- membered ring containing, as heteroatoms, one or two nitrogen atoms.
  • Suitable heterocyclic groups and moieties include pyrazolidinyl, piperidyl, piperazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolinyl, 3,4-dihydro-2H-pyranyl, tetrahydropyrimidinyl (for example 1,2,3,4- or 1,4,5,6- tetrahydrapyrimidinyl), 2-hydropyridinyl, 2-hydrothiazolyl, tetrahydropyridinyl (for example 1,2,5,6- or 2,3,4,5-tetrahydropyridinyl) and tetrahydropyridazinyl, for example 3 ,4,5 ,6-tetrahydropyridazinyl.
  • a heterocyclic group or moiety may be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries 1, 2, 3, 4 or 5 substituents. Suitable substituents include oxo, C C 6 alkyl, C,-C 6 alkylthio, C r C 6 alkoxy, C r C 6 haloalkyl, for example -CF 3 and -CC1 3 , C r C 6 haloalkoxy, for example -OCF 3 and -OCCl 3 , halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NRR / wherein R' and R /; are the same or different and are hydrogen or C,-C 6 alkyl,
  • a heterocyclic group or moiety may be fused to a further said heterocyclic group or to a said carbocyclic, aryl or heteroaryl group. Typically, it is non- fused or is fused to a benzene ring or to an iodole group. Examples of such fused heterocyclic groups include chromanyl and chromonyl groups.
  • An aryloxy, heteroaryloxy, heterocyclyloxy or carbocyclyloxy group is typically a said aryl, heteroaryl, heterocyclyl or carbocyclyl group attached to an oxygen atom.
  • An arylthio, heteroarylthio, heterocyclylthio or carbocyclylthio group is typically a said aryl, heteroaryl, heterocyclyl or carbocyclyl group attached to a sulphur atom.
  • R, and R 2 are the same or different and represent methyl, ethyl, propyl, n-butyl or t-butyl.
  • the groups represented by R, and R 2 are unsubstituted or carry one or two substituents.
  • substituents for R, and R 2 include C r C 4 alkyl, for example methyl and ethyl, C,-C alkoxy, for example methoxy and ethoxy, halogen, for example chlorine, Cj-C 4 haloalkyl, for example -CF 3 and -CC1 3 and C,-C 4 haloalkoxy, for example -OCF 3 and -OCCl 3 Typically, these substituents are themselves unsubstituted.
  • R, and R 2 are methyl or Rj and R 2 together form a n-butylene group.
  • Z is methylene, ethylene, propylene or butylene and is preferably propylene.
  • Z is unsubstituted, monosubstituted or disubstituted.
  • Preferred substituents for Z include C r C 4 alkyl, for example methyl and ethyl, C r C 4 alkoxy, for example methoxy and ethoxy, halogen, for example chlorine, C C 4 haloalkyl, for example -CF 3 and -CC1 3 and C,-C 4 haloalkoxy, for example -OCF 3 and -OCCl 3 .
  • these substituents are themselves unsubstituted.
  • Particularly preferred substituents for Z are C r C 4 alkyl groups, in particular methyl groups.
  • a preferred substituted alkylene group is 2,2-dimethylpropylene.
  • the moiety P is -Y-, -XY-, -YW- or -XY -.
  • the moiety P is -XYW- or -YW-.
  • P is typically an aryl, heteroaryl or heterocyclyl moiety and/or is typically substituted by an aryl, heteroaryl, heterocyclyl or carbocyclyl substituent.
  • W is -O- or -NR 3 .
  • R 3 is hydrogen or is methyl, ethyl, propyl, n-butyl or t-butyl.
  • R 3 is unsubstituted or carries one or two substituents.
  • Preferred substituents for R 3 include C,-C 4 alkyl, for example methyl and ethyl, Cj-C 4 alkoxy, for example methoxy and ethoxy, halogen, for example chlorine, C r C 4 haloalkyl, for example -CF 3 and -CC1 3 and C C 4 haloalkoxy, for example -OCF 3 and -OCCl 3 .
  • these substituents are themselves unsubstituted.
  • R 3 is hydrogen or methyl, most preferably hydrogen.
  • V is preferably a direct bond.
  • X is typically -NRg-.
  • R 6 is typically C r C 4 alkyl, for example methyl, ethyl, propyl, n-butyl and t-butyl, aryl, for example phenyl, or heteroaryl, for example pyridyl.
  • R ⁇ is unsubstituted or carries 1, 2 or 3 substituents.
  • substituents for R 6 include C r C 4 alkyl, for example methyl and ethyl, C r C 4 alkoxy such as methoxy or ethoxy, halogen, for example fluorine or chlorine, C,-C 4 haloalkyl, for example -CF 3 and -CC1 3 , C,-C 4 haloalkoxy, for example -OCF 3 and -OCCl 3 , cyano, nitro and -NRR / wherein R' and R" are the same or different and are hydrogen or C r C alkyl. Typically, these substituents are themselves unsubstituted.
  • X is -NH-.
  • the group R 4 has up to 30 carbon atoms and up to 10 heteroatoms selected from N, O and S. Preferably, it has up to 25 carbon atoms and up to 7 heteroatoms.
  • the group R 4 contains at least one, preferably at least two, aryl or heteroaryl rings.
  • R 4 is C r C 6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, -(C,-C 6 alkyl)-aryl, -(C,-C 6 alkyl)-heteroaryl or -COR", -CO 2 R" or -CONR'R" wherein R' is hydrogen or C r C 6 alkyl and R" is an aryl, heteroaryl, carbocyclyl or heteroaryl group.
  • R 4 is not a moiety (A) or (B).
  • R is: hydrogen, aryl, heteroaryl, 3- to 6- membered heterocyclyl, -(C r C 4 alkyl)-R wherein R is aryl, heteroaryl or 3- to 6- membered heterocyclyl, C r C 4 alkyl, -CONA' 2 , -COA" or -SO 2 A" wherein each A' is the same or different and is selected from H, C,-C 4 alkyl and aryl and each A" is the same or different and is selected from C C 4 alkyl and aryl; and R' 3 and R' 4 are either:
  • R 4 is not a 3- or 5- pyrazole or a 3- indazole group when P is a direct bond, -O- or -NH-. More preferably R 4 is not a pyrazole or indazole group when P is a direct bond, -O- or -NH-. More typically, R 4 is not a 3- or 5- pyrazole or a 3- indazole group or, more preferably, a pyrazole or indazole group when P does not contain the moiety U.
  • R 4 is a pyridyl, pyrimidyl, thiazolyl or thienyl group.
  • R 4 is typically also a pyridyl, pyrimidyl, thiazolyl or thienyl group when P does not contain the moiety U and R 4 is a heteroaryl group.
  • Suitable pyridyl, pyrimidyl, thiazolyl and thienyl groups include groups fused to a said aryl or said carbocyclic group or to a said heteroaryl or said heterocyclic group.
  • R may be substituted by one or more of the groups mentioned above as appropriate substituents for R 4 .
  • Preferred compounds of the invention are those in which X is -NRg- wherein R is as defined above, and R 4 is aryl or heteroaryl.
  • P is typically -XYW-.
  • Y is typically -CO-.
  • W is typically -NR 3 - wherein R 3 is as defined above.
  • X is preferably -NH- and/or R 4 is preferably phenyl, thienyl or pyrazolyl.
  • R 4 when R 4 is phenyl it is typically substituted by a phenoxy group or by a phenylthio group, in particular a 2-phenoxy or 2-phenylthio group, or by a further phenyl group, in particular a 4-phenyl group.
  • R 4 when R 4 is thienyl or pyrazolyl, it is typically substituted by a phenyl or phenylthio group.
  • substituents may be unsubstituted or may be further substituted at any position. Typically, they are unsubstituted or carry one, two or three further substituents.
  • Preferred further substituents include halogen, for example chlorine and fluorine, C r C alkyl, for example methyl and ethyl, C r C 4 alkoxy, for example methoxy and ethoxy, C,-C 4 haloalkyl, for example -CF 3 and -CC1 3 , and -S(O) 2 NH-phenyl.
  • R 4 is preferably
  • P is -YW- and R 4 is an aryl, heterocyclyl or heteroaryl group.
  • Y is typically -CO-.
  • W is typically -NR 3 - wherein R 3 is as defined above.
  • R 4 is preferably an oxo-substituted heterocyclic group such as a chromonyl group or is a pyrazolyl, thienyl, phenyl or indolyl group.
  • R 4 is typically unsubstituted or substituted by one or more, for example, one, two or three substituents selected from
  • C,-C 6 alkyl for example t-butyl, phenyl, thiazolyl, phenylthio, cyano, nitro, C r C 6 alkylthio, for example i-propylthio, C r C 6 alkoxy, halogen such as chlorine and -S-(C C 4 alkyl)-phenyl.
  • substituents may be unsubstituted or may be substituted at any position. Typically, they are unsubstituted or carry one, two or three further substituents.
  • Preferred further substituents include halogen, for example chlorine, C r C 4 haloalkyl, for example -CF 3 , phenyl and -S(O) 2 -NH-phenyl. These further substituents are typically themselves unsubstituted.
  • Additional preferred compounds of the invention are those in which P is -W- or -YW- wherein Y is -CO- and W is -O-.
  • Particularly preferred compounds of the invention are compounds of formula
  • R ! and R 2 are the same or different and each represent a C r C 6 alkyl group, or Rj and R 2 together form an alkylene group having from 3 to . 6 carbon atoms;
  • Z is an alkylene group having from 2 to 4 carbon atoms;
  • R 3 is hydrogen or C r C 6 alkyl;
  • Y is -CO- or -S(O) 2 -;
  • X is a direct bond or -NR ⁇ - wherein R 6 is hydrogen, C r C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl or heteroaryl; and
  • R 4 is C,-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, a group -R-A wherein R is -(C,-C 6 alkyl)-, -(C 2 -C 6 alkenyl)- or -(C 2 -C 6 alkynyl)- and A is aryl, heteroaryl, carbocycyl or heterocyclyl, or R 4 is a group -COR' or -CO 2 R' wherein R' is aryl, heteroaryl, carbocyclyl or heterocyclyl.
  • Rj and R are methyl or together form a n-butylene group
  • R 3 is hydrogen or methyl
  • R 4 is as defined in the formula (I) or in the formula (I 7 ) and X is a direct bond or is -NRg- wherein R 6 is as defined above.
  • R 4 is as defined as in the above preferred compounds of the invention.
  • R 4 is as defined in the above further preferred compounds of the invention.
  • the present invention includes pharmaceutically acceptable salts of the compounds of the invention.
  • Suitable salts include salts with pharmaceutically acceptable acids, both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succininc, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Salts may also be formed with pharmaceutically acceptable bases such as alkali metal (eg sodium or potassium) and alkali earth metal (eg calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.
  • inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid
  • organic acids such as citric, fumaric, maleic, malic, ascorbic, succininc
  • Particularly preferred compounds of the invention are: l-(3-Dimethylamino-propyl)-3-(2-phenoxy-phenyl)-urea l-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-3-(3-dimethylaminopropyl)-urea l-(3-Dimethylamino-propyl)-3-pyren-l-ylmethyl-urea l-(3-Dimethylamino-propyl)-3-[(lR,2R)-5-phenyl-2-(l-phenyl-methanoyl)- cyclohexyl]-urea l-(3-Dimethylamino-propyl)-3-[2-(4-phenoxy-phenyl)-ethyl]-urea l-(3-Dimethylamino-propyl)-3-[3-methyl-5-(4-methyl-[l,2,3]thiadiazol-5- y
  • R 4 is as defined above and U' is a group -UL wherein U is as defined above and L is a hydroxy group or a leaving group such as a halogen atom.
  • Compounds of formulae (II) and (III) are known compounds, or may be prepared by analogy with known methods.
  • the reaction takes place in the presence of a base such as diisopropylethylamine or the equivalent polymer bound resin N,N- (diisopropyl)amino-methylpolystyrene resin (PS-DIEA), and a coupling agent such as O-(7-azabenzotriazol- 1 -yl)-N,N, N, N-tetramethyluronium hexafluorophosphate (HATU).
  • a base such as diisopropylethylamine or the equivalent polymer bound resin N,N- (diisopropyl)amino-methylpolystyrene resin (PS-DIEA)
  • PS-DIEA polymer bound resin N,N- (diisopropyl)amino-methylpolystyrene resin
  • HATU O-(7-azabenzotriazol- 1 -yl)-N,N, N, N-tetramethyluronium hex
  • the work-up typically involves the use of a sequestration enabling reagent such as tetrafluorophthalic anhydride and polymer bound scavenger resins to remove unwanted starting materials.
  • a sequestration enabling reagent such as tetrafluorophthalic anhydride and polymer bound scavenger resins.
  • R 4 is as defined above.
  • the reaction takes place in a hydrocarbon solvent such as toluene at a temperature of from 0 to 100 °C.
  • a hydrocarbon solvent such as toluene
  • the work-up typically involves the use of a sequestration enabling reagent such as tetrafluorophthalic anhydride and polymer bound scavenger resins to remove unwanted starting materials.
  • the amides thereby prepared may be converted to the corresponding amidines by standard methods.
  • the compounds of formula (IV) may be prepared by techniques known in the art. For example, they may be prepared by reacting a compound of formula (V)
  • R 4 , X and U are as defined above and L is a hydroxy group or leaving group such as a 4-nitro-phenoxy group.
  • the reaction takes place in a hydrocarbon solvent such as tetrahydrofuran at a temperature of from 60 to 70 °C.
  • the work-up typically involves the use of a sequestration enabling reagent such as tetrafluorophthalic anhydride and polymer bound scavenger resins to remove unwanted starting material.
  • the compounds of formula (NI) are known compounds or may be prepared by analogy with known methods.
  • compounds of formula (VI) in which U is -CO- can be prepared by reacting a compound of formula (VII)
  • a chloroformate for example an aromatic chloroformate such as 4-nitrophenyl chloroformate.
  • the reaction takes place under reflux, in a solvent such as anhydrous THF.
  • R 4 is other than -COR", -CO 2 R", S(O) 2 R" and -CONR'R" and X is as defined above, with a compound of formula (IX)
  • Y, Z, Rj and R 2 are as defined above and L represents a hydroxy group or a leaving group such as a halogen.
  • the reaction is typically conducted in the presence of a base at from -78°C to the reflux temperature of the solvent.
  • R , X and U are as defined above and L represents a hydroxy group or a leaving group such as a halogen, with a compound of formula (XI) HWZNR,R 2 (XI)
  • A is -X- or -W-, wherein X and W are as defined above and R 4 is other than -COR", -CO 2 R", -S(O) 2 R" and -CONR'R", with a compound of formula (XIII)
  • reaction can be conducted under standard conditions. Typically, it takes place in the presence of a base in a solvent such as
  • the compounds of formula (XII) are known compounds or may be prepared by analogy with known methods.
  • the compounds of formula (XIII) are also known compounds or may be prepared by analogy with known methods. For example, they can be prepared from a corresponding compound of formula HO-Z-NR ⁇ by reaction with triflic anhydride or with PC1 5 .
  • HA-Z-NR,R 2 (IXV) wherein A, Z, R, and R 2 are as defined above, with R 4 -L, wherein R ⁇ is as defined above and L is a hydroxy group or a leaving group, for example a halogen.
  • the reaction can be conducted under standard conditions, such as those given above for the reaction of compounds of formulae (Vffl) and (IX).
  • R 4 is aryl or heteroaryl, and a compound of formula (XVI)
  • L is a hydroxy group, a group OR wherein R is alkyl, or a halogen, for example chlorine, and Z, V, R ⁇ and R 2 are as defined above.
  • the reaction can be performed under conventional conditions, in the presence of a catalyst such as A1C1 3 .
  • R 4 is as defined above, Y' is -U- or -X-U-, and L is a hydroxy group or a leaving group, for example a halogen atom, with an organometallic compound of formula (XVIII)
  • B is -V-Z- wherein V and Z are as defined above, Rj and R 2 are as defined above and M is a metal-containing moiety such as Li or -MgX wherein X is a halogen atom such as bromine.
  • M in the formula (XVIII) is Li.
  • M in the formula (XVIII) is -MgX, it may be necessary to conduct the reaction at around -78 °C and to use a large excess of the compound of formula (XVII).
  • the compounds of formula (XVII) are known compounds or may be prepared by analogy with known methods.
  • the compounds of formula (XVIII) are also known compounds or may be prepared by analogy with known methods.
  • compounds of formula (XVIII) in which M is Li can be prepared by reacting a corresponding compound of formula Br-B-N ⁇ with lithium or with magnesium.
  • R 4 -P-L (IXX) wherein R 4 and P are as defined above and L is a leaving group such as a halogen atom or a triflate group, with a compound of formula (XX)
  • the reaction can be conducted under conventional conditions. Typically, it is conducted in the presence of a base. If necessary, the NR]R 2 group can be protected during the reaction by conventional means.
  • the compounds of formulae (IXX) and (XX) are knowN compounds, or may be prepared by analogy with known methods.
  • the compounds of formula (IXX) can be prepared by reacting a corresponding compound of formula R 4 -P-OH with triflic anhydride or PC1 5 .
  • Compounds in which P is a direct bond can be prepared by conventional synthetic techniques.
  • a compound of the invention can, of course, be converted to a different compound of the invention by standard functional group intercon versions known to those of skill in the art.
  • compositions of formula (I) may be prepared by salifying a compound of formula (I) with an appropriate acid or base.
  • the compounds of the invention are activators of sGC. They can be used as selective sGC activators.
  • a compound of the invention can therefore be used as a vasodilator or to inhibit platelet aggregation. It can be used for the treatment or prevention of peripheral vascular diseases such as hypertension, angina pectoris, arteriosclerosis, or for the treatment or prevention of glaucoma, preeclampsia, Raynaud's Syndrome, stroke or erectile dysfunction. Further, the compounds of the invention are effective in improving ocular blood flow.
  • ASD age-related macular degeneration
  • AMD age-related macular degeneration
  • sGC vascular endothelial growth factor
  • the present invention also provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body, wherein R,, R 2 , Z, R 3 , Y, X and R 4 are as defined above.
  • the compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
  • the compounds of the invention may also be administered parenterally, either subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques.
  • the compounds may also be administered as suppositories.
  • a compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent.
  • solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film coating processes.
  • Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
  • the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
  • Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginte, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • the suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
  • Solutions for intravenous or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
  • a therapeutically effective amount of a compound of the invention is administered to a patient.
  • a typical daily dose is from about 0.1 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated , the type and severity of the disease and the frequency and route of administration.
  • daily dosage levels are from 5 mg to 2 g. The Examples which follow illustrate the invention.
  • Tetrafluorophthalic anhydride (65 mg, 0.3 mmol) was then added and the reaction mixture was shaken under nitrogen for 18 hours.
  • Macroporous triethylammonium methylpolystyrene carbonate resin (MP-carbonate), (610 mg, 1.96 mmol, loading 3.18 mmol/g) was then added and the reaction mixture was shaken under nitrogen for a further 48 hours.
  • the reactions were then filtered through filter syringes into vials and washed with methanol. The solvent was removed on a vacuum concentrator and each product was weighed and analysed by LC-MS.
  • Examples 70 to 99 The aryl acid (different for each reaction) (0.1 mmol) was stirred under nitrogen in anhydrous toluene (2 mL) and heated to 50 °C. Triethylamine (10 mg, 0.1 mmol) dissolved in 1 L of anhydrous toluene was then added. The temperature was raised to 80 °C and diphenylphosphorylazide (DPP A), (27.0 mg, 0.1 mmol) was added. The reaction was kept at this temperature for 1 hour then cooled to room temperature while still stirring under nitrogen.
  • DPP A diphenylphosphorylazide
  • the reaction mixture was cooled to room temperature and tetrafluorophthalic anhydride (191.0 mg, 0.87 mmol) was added.
  • the reaction was stirred at room temperature under nitrogen for 1 hour, then 6 equivalents of tris-(2-aminoethyl)amine polystyrene resin (PS-trisamine), (500 mg, 1.74 mmol, loading 3.5 mmol/g) was added and the reaction stirred for 2 hours.
  • PS-trisamine tris-(2-aminoethyl)amine polystyrene resin
  • Example 100 Prepared as in Example 100 using 4-nitrophenyl chloroformate (77.2 mg, 0.38 mmol), 4-bromoaniline (30.0 mg, 0.174 mmol) and triethylamine (38.8 mg, 0.38 mmol) to form the intermediate followed by 3-(dimethylamino)propylamine (26.6 mg, 0.26 mmol) to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using MeOH/CHCl 3 (40:60).
  • Example 100 Prepared as in Example 100 using 4-nitrophenyl chloroformate (87.0 mg, 0.436 mmol), 4-bromoaniline (50.0 mg, 0.29 mmol) and triethylamine (44.0 mg, 0.436 mmol) refluxed for 5 hours in anhydrous THF (20mL) to form the intermediate. Then N,N,N-trimethyl-l,3-propanediamine (50.5 mg, 0.436 mmol) was added and the reaction mixture refluxed for 18 hours to form the title compound. Work-up as in Example 100.
  • Example 100 Prepared as in Example 100 using 4-nitrophenyl chloroformate (45.5 mg, 0.226 mmol), 5-phenyl- ⁇ -anisidine (30.0 mg, 0.151 mmol) and triethylamine (22.8 mg, 0.226 mmol) refluxed in anhydrous THF (20 mL) for 18 hours to form the intermediate followed by 3-(dimethylamino)-propylamine (23.1 mg, 0.226 mmol) and refluxed for a further 5 hours to form the title compound. Work-up as in
  • Example 105 l-(3- ⁇ itrophenyl)-l-benzyl-3-(3-dimethylamino propyl) urea (CFM2270) Prepared as in Example 100 using 4-nitrophenyl chloroformate (66.0 mg, 0.328 mmol), N-benzyl-3-nitroaniline (50.0 mg, 0.219 mmol) and triethylamine (33.0 mg,
  • Example 106 l-Benzyl-l-(4-methyI-3-pyridinyl)-3-(3-dimethylamino propyl) urea (CFM2271) Prepared as in Example 100 using 4-nitrophenyl chloroformate (76.0 mg, 0.378 mmol), 2-benzylamino-4-methyl-pyridine (50.0 mg, 0.25 mmol) and triethylamine (38.0 mg, 0.378 mmol) refluxed in anhydrous THF (20 mL) for 5 hours to form the intermediate followed by 3-(dimethylamino)propylamine (38.0 mg, 0.378 mmol) and refluxed for a further 18 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 to 50 % MeOH (in CHC1 3 ) to give the title compound.
  • Example 100 Prepared as in Example 100 using 4-nitrophenyl chloroformate (62.0 mg, 0.308 mmol), N-methyl-3,5-bis(trifluoromethyl)aniline (50.0 mg, 0.206 mmol) and triethylamine (31.0 mg, 0.308 mmol) refluxed in anhydrous THF (20 mL) for 5 hours to form the intermediate followed by 3-(dimethylamino)propylamine (31.5 mg, 0.308 mmol) and refluxed for a further 18 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 to 40 % MeOH (in CHC1 3 ) to give the title compound.
  • Example 109 4-Nitrophenyl chloroformate (61.5 mg, 0.31 mmol), 5-chloro-2-(methylamino)- benzophenone (50.0 mg, 0.20 mmol) and triethylamine (30.80 mg, 0.31 mmol) were refluxed for 5 hours in anhydrous THF (20 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)-propylamine (32.0 mg, 0.31 mmol) was added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 - 40% MeOH (in CHC1 3 ) to give the title compound.
  • Example 109 l-(2-Chloro-4-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea
  • Example 100 4-Nitrophenyl chloroformate (77.0 mg, 0.39 mmol), 4-amino-3-chloro- benzotrifluoride (50.0 mg, 0.26 mmol) and triethylamine (38.0 mg, 0.39 mmol) were refluxed for 18 hours in anhydrous THF (20 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)-propylamine (38.0 mg, 0.39 mmol) was added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 - 40% MeOH (in CHC1 3 ) to give the title compound.
  • Example 100 4-Nitrophenyl chloroformate (84.0 mg, 4.19 mmol), 3-amino-5- fluorobenzotrifluoride (50.0 mg, 0.28 mmol) and triethylamine (42.0 mg, 4.19 mmol) were refluxed for 18 hours in anhydrous THF (20 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)-propylamine (42.0 mg, 4.19 mmol) was added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 - 40% MeOH (in CHC1 3 ) to give the title compound.
  • Example 112 4-Nitrophenyl chloroformate (3.13 g, 15.54 mmol), 3-amino-l-(N-tert-butoxy- carbonyl)benzylamine (2.30 g, 10.36 mmol) and triethylamine (1.56 g, 15.54 mmol) was refluxed for 18 hours in anhydrous THF (100 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)propylamine (1.58 g, 15.54 mmol) was added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up same as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 - 40% MeOH (in CHC1 3 ) to give the title compound.
  • Example 112 4-Nitrophenyl chloroformate (3.13 g, 15.54 mmol), 3-amino-l-(N-tert-butoxy- carbonyl)benzylamine
  • N-(3-Dimethylamino-propyl)-2-[l-(4-fluorobenzoyl]-benzamide (CFM2262) 2-(4-Fluorobenzoyl)benzoic acid (1.25 g, 5.12 mmol), N,N-(diisopropyl)amino- methylpolystyrene resin (PS-DIEA), (4.30 g, 15.36 mmol), and O-(7-azabenzotriazol-l- yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (1.95 g, 5.12 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes.
  • PS-DIEA N,N-(diisopropyl)amino- methylpolystyrene resin
  • HATU O-(7-azabenzotriazol-
  • 2-(4-Chlorobenzoyl)-benzoic acid (1.25 g, 4.80 mmol), N,N-(diisopropyl)amino- methylpolystyrene resin (PS-DIEA), (4.00 g, 14.38 mmol), and O-(7- azabenzotriazol- 1 -yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (1.82 g, 4.80 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes.
  • PS-DIEA N,N-(diisopropyl)amino- methylpolystyrene resin
  • HATU O-(7- azabenzotriazol- 1 -yl)-N,N,N,N-tetramethyluronium hexafluorophosphate
  • 2-(2-Phenylsulfamoyl-phenylsulfanyl)-benzoic acid (1.10 g, 2.60 mmol), NN- (diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (2.18g, 7.78 mmol), and O- (7-azabenzotriazol-l -yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.98 g, 2.6 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes.
  • PS-DIEA diisopropyl)amino-methylpolystyrene resin
  • HATU O- (7-azabenzotriazol-l -yl)-N,N,N,N-tetramethyluronium hexafluorophosphate
  • 2-Phenoxybenzoic acid (1.50 g, 7.00 mmol) was stirred in anhydrous toluene (50 mL) at 50 °C under nitrogen.
  • triethylamine (0.71 g, 7.00 mmol) and the temperature was increased to 80 °C at which stage diphenylphosphorylazide (DPP A) (1.92 g, 7.00 mmol) was added and the mixture was left to stir at this temperature for 5 hours.
  • DPP A diphenylphosphorylazide
  • 3- (dimethylamino)propylamine (0.71 g, 7.00 mmol) was added and the mixture was left to stir at 80 °C overnight under nitrogen.
  • Activity Example 1 Compounds of the invention were assayed to determine their ability to activate sGC.
  • the assay employed was an enzyme immunoassay to measure changes in cGMP.
  • IBMX enzyme immunoassay to measure changes in cGMP.
  • To perform the assay recombinant soluble Guanylate cyclase was added to 1.1 mg/ml IBMX, 2.6 mg/ml GTP, 667 nM DeaNO and the test compound (lO ⁇ M). The mixture was then incubated at room temperature for 10 minutes.
  • Compounds were formulated in DMSO diluted in Tris HCI (pH 7.4) buffer and with a final DMSO concentration of ⁇ 0.5%.
  • BiotrakTM cGMP enzyme immunoassay system commercially available from AmershamTM was used.
  • the assay is based on the competition between unlabelled cGMP and a fixed quantity of peroxidase labelled cGMP for a limited amount of cGMP specific antibody.
  • the peroxidase ligand that is bound to the antibody is immobilised on precoated microtitre wells.
  • the amount of labelled cGMP is determind using a one pot stabilised substrate.
  • the concentration of unlabelled cGMP in a sample is determined by interpolation from a standard curve.
  • Tables 4 to 7 The results are shown in Tables 4 to 7.
  • Tables 6 and 7 relate to commercially available compounds.
  • IC 50 values were measured as set out below.
  • PGI 2 (0.15 ⁇ g/ml) added and centrifuged at 950 g for 10 mins to sediment the platelets.
  • the resultant platelet poor plasma (PPP) was discarded and the platelet pellet was resuspended in an equal volume of Tyrodes buffer by gently pipetting up and down.
  • the suspension was centrifuged at 870 g for lOmins at 4 °C.
  • the supernatant was discarded and the platelet pellet was resuspended in an equal volume of Tyrodes buffer as before.
  • the platelets were counted (using a Coulter Counter model T540 (address)) and normalised to 250,000cells/ ⁇ l using Tyrodes.
  • the resultant suspension was placed on ice for approximately 1 hour until use.
  • Platelet A says Platelet aggregation was monitored using either a Chrono-Log model 560-CA dual channel ormodel 570-4S four channel aggregometer (Chrono-Log Co ., Havertown, PA). Aggregation was analysed by using 0.5 mL aliquots of the platelet suspension at 37 °C using % light transmittance.
  • the amplitude of each aggregatory response was used to plot dose-response curves.
  • the concentration of drug that inhibited collagen-induced platelet aggregation by 50% (IC 50 ) was calculated from the dose-response curves.

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Abstract

La présente invention concerne l'utilisation d'un composé de la formule (I), ou d'un sel pharmaceutiquement acceptable de ce dernier, dans la fabrication d'un médicament utilisé pour activer la guanylate cyclase soluble, dans laquelle : R1 et R2 sont les mêmes ou différents et chacun représente un groupe alkyle en C1-C6, ou R1 et R2 forment ensemble un groupe alkylène en C3-C6 ; Z est un groupe alkylène en C1-C4 ; P est une liaison directe ou un fragment -X-, -Y-, -W-, -XY-, -YW- ou XYW, dans laquelle W est -O-, -S-, ou -NR3, R3 étant hydrogène ou alkyle en C1-C6 ; Y est un fragment -U-V- dans lequel V est une liaison directe ou un groupe alkylène en C1-C6 et U est -CS-, -CO-, -S(O)2- or -C(=NR)-, où R est hydrogène, hydroxy ou alkyle en C1-C6 ; X est -O- or -NR6-, où R6 est hydrogène, alkyle en C1-C6, alcényle en C2-C6, alkynyle, aryle ou hétéroaryle en C2-C6 ; et R4 est alkyle en C1-C6, alcényle en C2-C6, alkynyle, aryle, hétéroaryle, carbocyclyle, hétérocyclyle, un groupe R-A en C2-C6 dans lequel R est -(C1-C6 alkyle)-, -(C2-C6 alcényle)- ou -(C2-C6 alkynyle)- et A est aryle, hétéroaryle, carbocyclyle, hétérocyclyle, ou R4 est un groupe -COR', -CO2R', -S(O)2R' or -CONR'R' dans lequel R' est hydrogène, alkyle en C1-C6, alcényle en C2-C6, ou alkynyle en C2-C6, et R'' est aryle, hétéroaryle, carbocyclyle ou hétérocyclyle.
EP00973061A 1999-11-05 2000-11-06 Activateurs de la guanylate cyclase soluble Withdrawn EP1237849A1 (fr)

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DK1300401T3 (da) 2000-06-30 2010-02-01 Dainippon Sumitomo Pharma Co Thiazolderivater til anvendelse som antiinflammatoriske midler
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