WO2000027394A1 - Activateurs de guanylate cyclase soluble - Google Patents

Activateurs de guanylate cyclase soluble Download PDF

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WO2000027394A1
WO2000027394A1 PCT/GB1999/003663 GB9903663W WO0027394A1 WO 2000027394 A1 WO2000027394 A1 WO 2000027394A1 GB 9903663 W GB9903663 W GB 9903663W WO 0027394 A1 WO0027394 A1 WO 0027394A1
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Prior art keywords
pyrazole
benzyl
dimethylamino
propoxy
phenyl
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PCT/GB1999/003663
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English (en)
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David Selwood
Robert Glen
Qian Liu
Marcel Kling
David Madge
Karen Reynolds
Grant Wishart
Ken Powell
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University College London
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Priority to AU64816/99A priority Critical patent/AU6481699A/en
Publication of WO2000027394A1 publication Critical patent/WO2000027394A1/fr

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    • 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
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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    • A61K31/415—1,2-Diazoles
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
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    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C07D231/28—Two oxygen or sulfur atoms
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    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
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Definitions

  • This invention relates to activators of soluble guanylate cyclase (sGC), to their preparation and to their use.
  • Soluble guanylate cyclase is responsible for the enzymatic conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine-3',5'-monophosphate (cGMP).
  • GTP guanosine-5'-triphosphate
  • cGMP cyclic guanosine-3',5'-monophosphate
  • the enzyme is stimulated by NO binding to the enzyme.
  • 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,
  • 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. Certain pyrazoles and indazoles are known er se. Thus, Palazzo et al, J.
  • Med. Chem. 9, 38 (1966) discloses certain indazoles substituted at the 1- position with alkyl, phenyl or 2-phenylethyl and at the 3- position with -O(CH 2 ) n -NMe 2 wherein n is 2 or 3. These compounds are said to be analgesics and anti- inflammatory and antispasmodic agents.
  • FR-A-7505524 discloses particular pyrazoles substituted at the 1- and 4- positions with optionally substituted phenyl groups and at the 3- position with a group -O-(CH 2 ) n -NR 3 R 4 wherein n is 2 or 3 and R 3 and R 4 are various radicals or, together with the N atom to which they are attached, form a heterocyclic ring. Such compounds are also said to be anti-inflammatory agents and analgesics. Bull. Chem. Soc. Jpn., 53, 825-826 (1980) discloses 3-(3-
  • the present invention provides the use of a compound of the formula (la) or (lb), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the activation of soluble guanylate cyclase:.
  • Y is: -0-, -C ⁇ 2 - or -NH-;
  • R is: hydrogen, aryl, heteroaryl, 3- to 6- membered heterocyclyl, -(C,-C 4 alkyl)-R wherein R is aryl, heteroaryl or 3- to 6- membered heterocyclyl, C,-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;
  • R 2 is: (a) when Y is -O-: -XNMe 2 or -XNHMe wherein X is an alkylene group having from 3 to 5 carbon atoms or R 2 is 2-hydroxymethylfuran-5-yl-methyl or -WB wherein W is an alkylene group having from 1 to 5 carbon atoms and B is a N-containing heterocyclic group;
  • R 3 and R 4 are either: (a) the same or different and selected from -CO 2 A' wherein A 1 is as defined above, -CF 3 , -CC1 3 , halogen, C,-C 4 alkoxy, -(C,-C 4 alkyl)- aryl, -(C,-C 4 alkyl)-heteroaryl, hydrogen, C,-C 4 alkyl, C 3 -C 6 carbocyclyl, 3- to 6- membered heterocyclyl, -SO 2 NA' 2 wherein A' is as defined above, or -CONZ,Z 2 wherein Z, and Z 2 , which are the same or different, represent H, C,-C 4 alkyl, aryl, heteroaryl, C,-C () carbocyclyl, 3- to 6- membered heterocyclyl or -(C,-C 4
  • a C,-C 4 alkyl group or moiety can, unless specified otherwise, be linear or branched but is preferably linear. Suitable such alkyl groups and moieties include methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Methyl is preferred. Unless specified otherwise, a C,-C 4 alkyl group or moiety can be substituted or unsubstituted at any position. Typically, it carries up to 3 substituents.
  • Suitable substituents include C,-C 4 alkyl such as methyl or ethyl, C,-C 4 alkoxy such as methoxy or ethoxy, hydroxy, halogen, -CF 3 , -CC1 3 , -NA' 2 , -CO 2 A' or -NH-CO-(C,-C 4 alkyl) in which A' is as defined above.
  • Preferred substituents are halogen, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, dimethylamino, -NH-CO-CH 3 , -CO 2 H and -CO 2 Me.
  • a C,-C 4 alkoxy group is typically a said C,-C 4 alkyl group attached to an oxygen atom.
  • a C,-C 4 haloalkyl or haloalkoxy group is typically a said C,-C 4 alkyl or alkoxy group substituted by one or more halogen atoms. Typically, it is substituted by one, two or three halogen atoms.
  • Preferred haloalkyl and haloalkoxy groups include perhaloalkyl and perhaloalkoxy groups such as -CX 3 and -OCX 3 wherein X is a halogen atom.
  • Particularly preferred haloalkyl groups are CF 3 and CC1 3 .
  • Particularly preferred haloalkoxy groups are -OCF 3 and -OCCl 3 .
  • a -(C,-C 4 alkyl)-aryl group is-typically a said C,-C 4 alkyl group joined to an aryl group, as defined below. It is preferably benzyl or 2-phenylethyl.
  • a halogen atom is typically a chlorine, fluorine, bromine or iodine atom. It is preferably chlorine.
  • An aryl group or moiety is typically a C 6 -C, 0 aryl group or moiety. Suitable such aryl groups and moieties include phenyl and naphthyl. Phenyl is preferred.
  • An aryl group or moiety may be substituted or unsubstituted at any position.
  • an aryl group or moiety carries 1, 2, 3 or 4 substituents.
  • substituents include aryl, for example phenyl, heteroaryl, 3- to 6- membered heterocyclyl, C 3 -C 6 carbocyclyl, -(C,-C 4 alkyl)-aryl, for example benzyl, -(C,-C 4 alkyl)-heteroaryl, halogen, nitro, cyano, hydroxyl, C,-C 4 haloalkyl, C,-C 4 alkyl such as methyl or ethyl, C,-C 4 alkoxy such as methoxy or ethoxy, C,-C 4 haloalkoxy, C,-C 4 alkylthio such as methylthio or ethylthio, -NA',, -C0 2 A' and -NH-CO-A' in which A' is as defined above and -COA" wherein A" is as defined above.
  • Preferred heteroaryl and heterocyclic substituents are 5- or 6- membered heteroaryl or heterocyclic rings containing 1, 2 or 3 heteroatoms selected from N, O and S.
  • Examples include thiadiazole, for example 1,2,3-thiadiazole, thiazole, imidazole, isoxazole, isothiazole, furan, pyrazole, pyrrole and thiophene substituents.
  • Other preferred substituents include phenyl, methyl, ethyl, methoxy, ethoxy, hydroxy, nitro, cyano, dimethylamino, methylthio, ethylthio, -NH-CO-CH 3 and -CO- (C,-C 4 alkyl).
  • An aryl group may optionally be fused to a further said aryl group, to a C 3 -C 6 carbocyclic group, to a heteroaryl group, for example a pyrrole group or a thiadiazole group such as a 1,2,5-thiadiazole group, or to a 3- to 6- membered heterocyclic group, for example a 1 ,4-dioxolane group, for example a 5,5-difiuoro-l,4-dioxolane group, a tetrahydrofuran group, for example a 2,2-dimethyl-tetrahydrofuran group, or a pyrrolidine group, for example a 2,5-dioxo-pyrrolidine group.
  • a 1 ,4-dioxolane group for example a 5,5-difiuoro-l,4-dioxolane group
  • a tetrahydrofuran group for example a 2,2-di
  • a preferred pyrrolidine group is a l-methyl-2,5-dioxopyrrolidine group.
  • the alkylene group X typically has 3 or 4 carbon atoms. It may be unsubstituted or substituted at any position. Typically it is unsubstituted or monosubstituted.
  • Y is -CH 2 - or -NH-
  • X is typically unsubstituted to the amine moiety. Suitable substituents include C r C 4 alkyl such as methyl or ethyl.
  • the alkylene group W typically has from 2 to 4 carbon atoms. It may be substituted or unsubstituted at any position. Typically, it is unsubstituted or monosubstituted.
  • Suitable substituents include C,-C 4 alkyl such as methyl or ethyl.
  • a C 3 -C 6 carbocyclic group is a non-aromatic saturated or unsaturated hydrocarbon ring having from 3 to 6 carbon atoms. Preferably, it is a saturated hydrocarbon ring (i.e. a cycloalkyl group) having from 3 to 6 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. It is preferably cyclohexyl.
  • a C 3 -C 6 carbocyclic group may be fused to a said aryl group, to a further
  • a C 3 -C 6 carbocyclic group may be unsubstituted or substituted at any position. Typically, it carries up to 3 substituents. Suitable substituents include halogen, hydroxyl, nitro, cyano, CF 3 , CC1 3 C,-C 4 alkyl such as methyl or ethyl, C,-C 4 alkoxy such as methoxy or ethoxy, C,-C 4 alkylthio such as methylthio or ethylthio,
  • substituents include methyl, ethyl, methoxy, ethoxy, hydroxy, dimethylamino, and -NH-CO-CH 3 .
  • a heteroaryl group is typically a 5- to 10- membered aryl ring containing at least one heteroatom selected from O, S and N. It may be unsubsituted or substituted at any position. Typically, it carries up to three substituents.
  • Suitable substituents include aryl, for example phenyl, heteroaryl, 3- to 6- membered heterocyclyl, C 3 -C 6 carbocyclyl, -(C,-C 4 alkyl)-aryl, for example benzyl, -(C,-C 4 alkyl)-heteroaryl, halogen, hydroxyl, C,-C 4 alkyl such as methyl or ethyl, C,-C 4 haloalkyl, C,-C 4 alkoxy such as methoxy or ethoxy, C,-C 4 haloalkoxy, C,-C 4 alkylthio such as methylthio and ethylthio, nitro, cyano, -COA" wherein A 7 is as defined above, -NA' 2 , -CO 2 A' and -NH-CO-A' in which A' is as defined above.
  • Preferred substituents include phenyl, benzyl, methyl, ethyl, methoxy, ethoxy, hydroxy, dimethylamino and -NH-CO-CH 3 .
  • the heteroaryl group is a 5- or 6- membered ring.
  • Suitable heteroaryl groups include thiadiazolyl, for example 1,2,3- thiadiazolyl and 1,2,5-thiadiazolyl, oxadiazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, pyridyl, furanyl, thienyl, pyrazolidinyl, pyrazolyl and pyrrolyl groups.
  • a heteroaryl group may optionally be fused to a said aryl group, for example to a phenyl group, to a said C 3 -C 6 carbocyclic group, for example to a cyclohexyl group, to a further heteroaryl group or to a 3- to 6- membered heterocyclic group.
  • fused heteroaryl groups include quinoline, and thiazole and imidazole groups fused to phenyl or cyclohexyl groups.
  • Particularly preferred fused heteroaryl groups are quinoline groups.
  • a 3- to 6- membered heterocyclic group may be a substituted or unsubstituted 3- to 6- membered ring containing at least one heteroatom selected from N, O and S.
  • a 3- to 6- membered heterocyclic group may be fused to a said aryl, heteroaryl or C 3 -C 6 carbocyclic group or to a further 3- to 6- membered heterocyclic group.
  • a 3- to 6- membered heterocyclic group typically carries up to 3 substituents.
  • Suitable substituents include oxo, aryl, for example phenyl, heteroaryl, -(C,-C 4 alkyl)-aryl for example benzyl, -(C,-C 4 alkyl)-heteroaryl, halogen, hydroxyl, CF 3 , CC1 3 C,-C 4 alkyl such as methyl or ethyl, C,-C 4 alkoxy such as methoxy or ethoxy, -NA' 2 , -C0 2 A' and -NH-CO-A' in which A' is as defined above.
  • Preferred substituents include oxo, aryl, -(C,-C 4 alkyl)-aryl, methyl, ethyl, methoxy, ethoxy, hydroxy, amino, dimethylamino, and -NH-CO-CH 3 .
  • Suitable 3- to 6- membered heterocyclic groups include 1,4-dioxolane, tetrahydrofuran, pyrrolidyl, pyrazolidinyl, piperidyl, piperazinyl and hydantoin groups.
  • Preferred heterocyclic groups are 2,5-dioxopyrrolidinyl groups and N linked hydantoin groups of the formula
  • R is a C,-C 4 alkyl group or a (C,-C 4 alkyl)-aryl group.
  • the N-containing heterocyclic group B may be an unsubstituted or substituted, saturated or unsaturated,-5- or 6-membered N-containing ring.
  • Suitable substituents include oxo, halogen, hydroxyl, CF 3 , CC1 3 , C,-C 4 alkyl such as methyl or ethyl, C,-C 4 alkoxy such as methoxy or ethoxy, -NA',, -CO 2 A' and -NH-CO-A' in which A' is as defined above.
  • Preferred substituents include methyl, ethyl, methoxy, ethoxy, hydroxy, amino, dimethylamino and -NH-CO-CH 3 .
  • the ring may optionally include one or two more heteroatoms selected from N, O and S.
  • Suitable rings include pyridyl, piperidyl, pyrrolidinyl, piperazinyl, imidazolyl and imidazolinyl.
  • the N-containing heterocyclic group may therefore be a 2-pyridyl, 3-piperidyl, 2-pyrrolidinyl, 1-pyrrolidinyl, 4-piperazinyl or 2-imidazolyl group.
  • a ring may be substituted on a N-atom as appropriate by a C,-C 4 alkyl group such as a methyl group.
  • the N-containing heterocyclic group B may be a fused ring system such as a said unsubstituted or substituted, saturated or unsaturated, 5- or 6- membered N-containing ring fused to an aryl group such as a benzene ring.
  • the benzene ring may itself be substituted or unsubstituted.
  • Suitable substituents for the benzene ring include halogen, hydroxyl, C,-C 4 alkyl such as methyl or ethyl, C,-C 4 alkoxy such as methoxy or ethoxy, -NA' 2 , -CO,A' and NH-CO-A' in which A' is as defined above.
  • a suitable such N-containing heterocyclic group fused to a benzene ring is a benzimidazolyl group such as a benzimidazol-2-yl group.
  • the benzimidazolyl group is typically substituted at any position on the benzene ring by halogen.
  • the number of carbon atoms in the alkylene group W and the position at which the group B is attached to the - W- group are such that the N atom of the N- containing heterocyclic group B is spaced from the group Y by from 3 to 5 atoms, preferably by 3 or 4 atoms.
  • the 5- or 6- membered N-containing heterocyclic ring formed by Zdon Z 2 and the nitrogen atom to which Z, and Z 2 are attached may be a saturated or unsaturated such ring.
  • Suitable substituents include oxo, halogen, hydroxyl, nitro, cyano, CF 3 , CC1 3 , C,-C 4 alkyl such as methyl or ethyl, C,-C 4 alkoxy such as methoxy or ethoxy,
  • C,-C 4 alkylthio such as methylthio or ethylthio, -NA' 2 , -CO 2 A' or -NH-CO-A 1 in which A' is as defined above and -CO A" wherein A" is as defined above.
  • Preferred substituents include methyl, ethyl, methoxy, ethoxy, hydroxy, amino, dimethylamino and -NH-CO-CH 3 .
  • the ring may optionally contain one or two more heteroatoms selected from N, O and S. Suitable rings include N-morpholino, N-piperazino and
  • Y is -O-.
  • Each A' is preferably hydrogen, methyl or phenyl and each A" is preferably methyl or phenyl.
  • R [ is a C,-C 4 alkyl group or a group -(C,-C 4 alkyl)-R, it is typically unsubstituted at the position or substituted at the position other than by a methyl group.
  • R is an aryl group or a -(C,-C 4 alkyl)-aryl group
  • the aryl group or moiety is typically a phenyl group or moiety or a phenyl group or moiety fused to a 3- to 6- membered heterocyclic group such as a 1 ,4-dioxolane group.
  • Preferred substituents on the aryl group or moiety include aryl such as phenyl, halogen, C,-C 4 alkoxy, C,-C 4 haloalkoxy, C,-C 4 alkyl, C,-C 4 haloalkyl, nitro and cyano.
  • R is a heteroaryl group or a -(C,-C 4 alkyl)-heteroaryl group
  • the heteroaryl group or moiety is typically an imidazolyl, thiazolyl, thienyl, pyrrolyl or furyl group or moiety.
  • Preferred substituents on the heteroaryl group or moiety include aryl such as phenyl, -(C,-C 4 alkyl)-aryl such as benzyl or chlorobenzyl, halogen, C,-C 4 alkoxy, C,-C 4 haloalkoxy, C,-C 4 alkyl and C,-C 4 haloalkyl.
  • R is hydrogen; aryl, for example phenyl, heteroaryl, -(linear C,- C 4 alkyl)-R in which the alkyl moiety is unsubstituted at the ⁇ position and R is aryl, for example phenyl, or heteroaryl, for example imidazolyl or thienyl, or R, is linear C,-C 4 alkyl optionally substituted other than at the a position with hydroxy, halogen, -CF 3 , -CC1 3 , -NA' 2 , -CO 2 A' or -NH-CO-(C,-C 4 alkyl), or R, is -CONA * 2 ; -COA" or
  • R is hydrogen, -(CH 2 )-aryl, for example benzyl, -(CH 2 )- heteroaryl, for example -CH 2 -imidazolyl or -CH 2 -thienyl, aryl, for example phenyl, 3-hydroxy-n-propyl, 3-dimethylamino-n-propyl, 2-phenylethyl, 2-(CO 2 Me)-ethyl, -CONMe 2 , -COMe, -COPh or -SO 2 Me.
  • aryl for example phenyl, 3-hydroxy-n-propyl, 3-dimethylamino-n-propyl, 2-phenylethyl, 2-(CO 2 Me)-ethyl, -CONMe 2 , -COMe, -COPh or -SO 2 Me.
  • R is hydrogen, phenyl, benzyl, -(CH 2 )-R wherein R is imidazolyl or thienyl, or -CO-phenyl.
  • R 2 is preferably -XNMe 2 wherein X is an alkylene group having 3 or 4 carbon atoms or R 2 is -WB wherein W is an-alkylene group having 1, 2, 3, 4 or 5 carbon atoms and B is (a) a pyridyl, piperidyl, pyrrolidinyl, piperazinyl or imidazolyl group optionally substituted where appropriate on the nitrogen atom with a methyl group or (b) a benzimidazolyl group optionally substituted on the benzene ring with halogen. More preferably R, is -(CH 2 ) 3 NMe 2 or -(CH 2 ) 4 NMe 2 .
  • Z, and Z 2 are the same or different and represent aryl, heteroaryl, 3- to 6- membered heterocycyl, hydrogen, C,-C 4 alkyl, -(C,-C 4 alkyl)-aryl, -(C,-C 4 alkyl)-heteroaryl or -(C,-C 4 alkyl)-(3- to 6- membered heterocyclyl), or Z, and Z 2 , together with the N atom to which they are attached, form a said 5- or 6- membered
  • the aryl group or moiety is typically a phenyl group or moiety or a phenyl group or moiety fused to a heteroaryl group such as a pyrrole or thiadiazole group or to a 3- to 6- membered heterocyclic group, such as a 1 ,4-dioxolane group, a tetrahydrofuran group or a pyrrolidine group, in particular a 2,5-dioxopyrrolidine group.
  • a heteroaryl group such as a pyrrole or thiadiazole group
  • a 3- to 6- membered heterocyclic group such as a 1 ,4-dioxolane group, a tetrahydrofuran group or a pyrrolidine group, in particular a 2,5-dioxopyrrolidine group.
  • Preferred substituents on the aryl group or moiety include aryl such as phenyl, heteroaryl, 3- to 6- membered heterocyclyl, halogen, C,-C 4 alkoxy, C,-C 4 haloalkoxy, C,-C 4 alkyl, C,-C 4 haloalkyl, nitro, cyano, and, when the aryl group or moiety is fused to a heterocyclyl group, oxo.
  • Said heteroaryl and heterocyclic substituents are typically 5- or 6- membered heteroaryl or heterocyclic groups containing 1,2 or 3 heteroatoms selected from N, O and S, for example a thiadiazolyl, thiazole, imidazole, isoxazole, isothiazole, furan, pyrazole, pyrrole or thiophene group.
  • Thiadiazole and furan substituents are preferred heteroaryl substituents.
  • the heteroaryl group or moiety is typically a pyridyl, thiazolyl, thienyl or imidazolyl group or moiety or a pyridyl, thiazolyl, thienyl or imidazolyl group or moiety fused to a phenyl or cyclohexyl group.
  • Preferred substituents on the heteroaryl group or moiety include aryl such as phenyl, heteroaryl, C 3 -C 6 carbocyclyl, 3- to 6- membered heterocyclyl, halogen, C,-C 4 alkoxy, C,-C 4 haloalkoxy, C,-C 4 alkyl, C,-C 4 haloalkyl, nitro, cyano, and, when the heteroaryl group or moiety is fused to a heterocyclyl or carbocyclyl group, oxo.
  • Z is H, C,-C 4 alkyl, for example methyl or i-propyl or phenyl and
  • Z 2 is H, C,-C 4 alkyl, such as methyl or i-propyl, aryl, for example phenyl, heteroaryl, for example quinoline, -(C,-C 4 alkyl)-aryl, such as benzyl or -(C,-C 4 alkyl)- heteroaryl, or Z, and Z 2 together form a said heterocyclic group.
  • R 3 is hydrogen, C,-C 4 alkyl, aryl or -(C,-C 4 alkyl)-aryl. More preferably, R-, is hydrogen, phenyl or benzyl, most preferably hydrogen.
  • R 4 is -CO 2 A' wherein A 7 is as defined above, -CONZ,Z, wherein Z, and Z, are as defined above, C r C 4 alkyl, -CF 3 , -CC1 3 , halogen, C,-C 4 alkoxy, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, furanyl or pyridyl, -(C,-C alkyl)-aryl such as benzyl or -(C,-C 4 alkyl)-heteroaryl.
  • a 7 is as defined above, -CONZ,Z, wherein Z, and Z, are as defined above, C r C 4 alkyl, -CF 3 , -CC1 3 , halogen, C,-C 4 alkoxy, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, furanyl or pyridyl, -(C,-C
  • R 4 is -CO,H, -CO,Me, phenyl, oxadiazolyl, furanyl, pyridyl, C,-C 4 alkyl, -(C,-C, alkyl)-phenyl or -CONZ.Z, wherein Z, and Z, are as defined above.
  • Preferred compounds of the invention are compounds of formula (la) or (lb), as defined above, in which:
  • R is hydrogen; aryl for example phenyl, heteroaryl, -(linear C,-C 4 alkyl)-R in which the alkyl moiety is unsubstituted at the a position and R is aryl, for example phenyl, or heteroaryl, for example imidazolyl or thienyl, or R, is linear C,-C 4 alkyl optionally substituted other than at the position with hydroxy, halogen, -CF 3 , -CCl j , -NA' 2 , -CO 2 A' or -NH-CO-(C,-C 4 alkyl); or R, is -CONA' 2 ; -CON * or -SO 2 A"; wherein A' and A" are as defined above;
  • R 2 is -X ⁇ Me 2 wherein X is an alkylene group having 3 or 4 carbon atoms or R 2 is -WB wherein W is an alkylene group having 1, 2, 3, 4 or 5 carbon atoms and B is (a) a pyridyl, piperidyl, pyrrolidinyl, piperazinyl or imidazolyl group optionally substituted where appropriate on the nitrogen atom with a methyl group or (b) a benzimidazolyl group optionally substituted on the benzene ring with halogen;
  • - R 3 is hydrogen, C,-C 4 alkyl, aryl or -(C,-C 4 alkyl)-aryl; and - R 4 is -CO 2 A ; wherein A 1 is as defined above, -CONZ,Z 2 wherein Z, and Z 2 are as defined above, C,-C 4 alkyl, -CF 3 , -CC1 3 , halogen, C,-C 4 alkoxy, aryl, for example phenyl, heteroaryl, for example oxadiazolyl, furanyl or pyridyl, -(C,-C 4 alkyl)-aryl such as benzyl, or (C,-C 4 alkyl)-heteroaryl, and pharmaceutically acceptable salts thereof.
  • Further preferred compounds of the invention are compounds of formula (la) or (lb), as defined above, in which:
  • - Y is -O-;
  • - R is hydrogen, -(CH,)-aryl for example benzyl, -(CH 2 )-heteroaryl for example -CH,-imidazolyl or -CH,-thienyl, aryl for example phenyl, 3-hydroxy-n- propyl, 3-dimethylamino-n-propyl, 2-phenylethyl, 2-(CO 2 Me)-ethyl, -CONMe 2 , -COMe, -COPh or -SO 2 Me;
  • - R 2 is -(CH 2 ) 3 NMe 2 or -(CH 2 ) 4 NMe 2 ;
  • R 3 is hydrogen, phenyl or benzyl
  • R 4 is -C0 2 H, -CO,Me, phenyl, oxadiazolyl, furanyl, pyridyl, -C,-C 4 alkyl, -(C,-C, alkyl)-phenyl or -CONZ,Z, wherein Z, and Z, are as defined above, and pharmaceutically acceptable salts thereof.
  • Preferred compounds of formula (lb) are those in which Y is -O-, R, is aryl or
  • R is aryl or heteroaryl
  • R 2 is -XNMe 2 or -XNHMe wherein X is as defined above
  • R 3 is hydrogen and R 4 is aryl, for example phenyl, or -(C,-C 4 alkyl)-aryl, for example benzyl, and pharmaceutically acceptable salts thereof.
  • R in the formula (lb) is -(C,-C 4 alkyl)-R
  • R is typically phenyl, phenyl fused to 1 ,4-dioxolane or thienyl.
  • R 3 and R 4 form the divalent group -(CH) 4 -.
  • This group is optionally substituted, i.e. each hydrogen atom in the group can be replaced by a suitable substituent.
  • Suitable substituents include one or more, preferably one or two, substituents selected from aryl such as phenyl, heteroaryl, -(C,-C 4 alkyl)-R wherein R is aryl or heteroaryl, C,-C 4 alkyl such as methyl or ethyl, C,-C 4 haloalkyl, halogen such as chlorine, hydroxy, nitro, cyano, C r C 4 alkoxy such as methoxy or ethoxy, C,-C 4 haloalkoxy, C,-C 4 alkylthio, -NA' 2 , -CO 2 A' and -NH-CO-A' wherein A' is as defined above.
  • Preferred substituents include methyl, ethyl
  • Further preferred compounds of the invention are compounds of formula (la), or pharmaceutically acceptable salts thereof in which R 3 and R 4 together form the said divalent group -(CH) 4 -.
  • These compounds are indazoles and have the formula (Ic) as set out below.
  • Z denotes one or more, preferably one or two, selected from hydrogen, aryl such as phenyl, heteroaryl, -(C,- C 4 alkyl)-R wherein R is aryl or heteroaryl, C,-C 4 alkyl such as methyl or ethyl, C,- C 4 haloalkyl, halogen such as chlorine, hydroxy, nitro, cyano, C,-C 4 alkoxy such as methoxy or ethoxy, C,-C 4 haloalkoxy, C,-C 4 alkylthio, -NA' 2 , -CO 2 A' and -NH-CO- A' wherein A' is as defined above.
  • Z is one or two selected from hydrogen, methyl, ethyl, hydroxy, chlorine, dimethylamino or -NH-acetyl.
  • R 2 in the formula (lc) is -XNMe, or -XNHMe wherein X is defined above or -WB wherein W and B are as defined above.
  • Preferred compounds of formula (lc) are those in which Y is -O-, R, is hydrogen, aryl, for example phenyl, heteroaryl, -(linear C,-C 4 alkyl)-R in which the alkyl moiety is unsubstituted at the oc position and R is aryl, for example phenyl, or heteroaryl, for example imidazolyl or thienyl, or R, is linear C,-C 4 alkyl optionally substituted other than at the oc position with hydroxy, halogen, -CF 3 , -CC1 3 , -NA' 2 ,
  • -CO 2 A' or -NH-CO-(C,-C 4 alkyl) or R is -CONA' 2 , -COA" or -SO 2 A" wherein A' and A" are as defined above, and R 2 is -XNMe 2 wherein X is an alkylene group having 3 or 4 carbon atoms or R 2 is -WB wherein W is an alkylene group having 1 , 2, 3, 4 or 5 carbon atoms and B is (a) a pyridyl, piperidyl, pyrrolidinyl, piperazinyl or imidazolyl group optionally substituted where appropriate on the nitrogen atom with a methyl group or (b) a benzimidazolyl group optionally substituted on the benzene ring with halogen, or pharmaceutically acceptable salts thereof.
  • More preferred compounds of formula (lc) are those in which Y is -O-, R, is hydrogen, -(CH 2 )-aryl, for example benzyl, -(CH 2 )-heteroaryl, for example -CH 2 - imidazolyl or -CH 2 -thienyl, aryl for example phenyl, 3-hydroxy-n-propyl, 3- dimethylamino-n-propyl, 2-phenylethyl, 2-(CO 2 Me)-ethyl, -CONMe 2 , -COMe, -COPh or -SO 2 Me and R 2 is -(CH 2 ) 3 NMe 2 or -(CH 2 ) 4 NMe 2 , or pharmaceutically acceptable salts thereof.
  • 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.
  • inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid
  • 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.
  • 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.
  • Particularly preferred compounds of the invention are : l-Benzyl-3-(3-dimethylaminopropyloxy)-lH-pyrazole-5-carboxylic acid; l-Benzyl-3-(3-dimethylaminopropyloxy)-5-methylaminocarbonyl-lH- pyrazole; 3 -(3 -Dimethylaminopropyloxy)-5 -phenyl- 1 H-pyrazole;
  • the present invention also provides a compound of the formula (la) or (lb), or a pharmaceutically acceptable salt thereof, in which R, to R 4 are as defined above except for:
  • the compounds of the present invention in which Y is -O- may be prepared by a process comprising reacting a compound of formula (Ila) or (lib):
  • the reaction proceeds via a Mitsunobu reaction.
  • this reaction takes place in the presence of an azodicarboxylate coupling agent such as 1 , l'-(azodicarbonyl)dipiperidine or 1,1-azobisdimethylformamide and a trialkylphosphine such as tri-n-butylphosphine.
  • the reaction typically takes place in a hydrocarbon solvent such as toluene or tetrahydrofuran at a temperature of from 0 to 100°C, preferably from 20 to 80°C.
  • X is a leaving group
  • it is preferably a halide such as a chloride, bromide or iodide.
  • the reaction proceeds via nucleophilic attack on the compound of formula (III).
  • the reaction takes place in the presence of a base in a solvent such as tetrahydrofuran at a temperature of from 0 to 100°C.
  • a base in a solvent such as tetrahydrofuran at a temperature of from 0 to 100°C.
  • the base is typically sodium hydride.
  • the base is typically potassium tertiary butoxide or potassium carbonate.
  • a compound of formula (la) or (lb) in which R, is a hydrogen atom may be converted into another compound of formula (la) or (lb) by a reaction with a compound of formula:
  • R is as defined above with the exception of a hydrogen atom or an aryl group and X is OH or a leaving group.
  • R is a linear C,-C 4 alkyl group or a -(linear C,-C 4 alkyl)-aryl group
  • X is OH or a leaving group.
  • the reaction conditions are typically the same as for the reaction between the compounds of formulae (II) and (III).
  • R is -CONA' 2 , -COA" or -SO 2 A" wherein A' and A" are as defined above
  • X is typically a leaving group such as chlorine or bromine.
  • a compound of formula (la) or (lb) in which R, is a hydrogen atom may also be converted into a compound of formula (la) or (lb) in which R, is an aryl or heteroaryl group by reaction with a compound of formula:
  • R is an aryl or heteroaryl group.
  • the reaction typically takes place in the presence of cupric acetate and a base such as pyridine in a solvent such as dichloromethane and at a temperature of from 0 to 50°C.
  • a base such as pyridine
  • a solvent such as dichloromethane
  • n is from 0 to 4 and Z and R, are as defined above.
  • a diazotisation reagent such as sodium nitrite
  • an acidic aqueous medium such as aqueous HC1.
  • a reducing agent such as sodium hydrosulfite.
  • Ar is an aryl group, such as a phenyl group.
  • the compound of formula (XI) can be prepared from the corresponding acyl chloride by known methods.
  • This reaction is typically conducted in a polar solvent such as ethanol at a temperature of from 0 to 100°C. Similar such reactions are described in Hamper et al, J Org. Chem., 57, 5680 (1992).
  • compounds of formula (Ila) or (lib) in which R 3 and R 4 do not form an optionally substituted group -(CH) 4 - can be prepared by reacting a compound of formula (XXI):
  • the reaction is typically conducted in a polar solvent such as ethanol at a temperature of from 0 to 100°C.
  • a polar solvent such as ethanol
  • OR 5 is methoxy or ethoxy.
  • the compounds of formulae (XIX) and (XX) are known compounds or may be prepared by analogy with known processes.
  • the compounds of formula (XXI), in which R 3 is hydrogen, can be prepared by reaction of an acid halide of formula (XXIII) with a compound of formula (XXIV):
  • R 4 is as defined above and X is a halogen such as chlorine.
  • the reaction is typically conducted in two steps, the first step involving reaction of the two compounds in the presence of a base such as pyridine in an inert solvent such as CC1 4 or dichloromethane at a temperature of from 0 to 100°C.
  • the second step typically involves treatment of the crude isolate from the first step with an alcohol such as ethanol at a temperature of from 0 to 100°C.
  • R 3 and OR 5 are as defined above, with a hydrazine of formula (XX) as defined above.
  • a hydrazine of formula (XX) as defined above.
  • the reaction takes place in a polar solvent such as ethanol at from 0 to 100°C.
  • the compounds of formula (XXII) can also be used to prepare compounds of formula (XXI) as defined above, in which R 4 is hydrogen. To this end, they can be reacted with an acid, such as hydrochloric acid, in a solvent such as water at from 0 to 50°C.
  • the compounds of formula (XXII) can be prepared by reacting an ester of formula (XXV):
  • the reaction is typically conducted in a polar aprotic solvent such as dimethylformamide at a temperature of from 0 to 150°C.
  • a polar aprotic solvent such as dimethylformamide
  • the compounds of formulae (XXV) and (XXVI) are known compounds or may be prepared by analogy with known processes.
  • Compounds of formula (la) or (lb) in which R 2 is -XNMe 2 wherein X is as defined above can be prepared from corresponding compounds having an -XNH 2 group at the R 2 position by reductive amination of formaldehyde, typically in the presence of a reducing agent such as sodium cyanoborohydride and in the presence of an acid such as acetic acid.
  • the reaction is typically conducted in a solvent such as methanol at from 0 to 100°C, preferably at room temperature.
  • Compounds of formula (la) or (lb) in which R 4 is a carboxylic acid group can be formed from an ester precursor by saponification with, for example, aqueous sodium hydroxide, using standard techniques.
  • the compounds of formula (la) and (lb) in which R 4 is a carboxylic acid group are typically treated with an activating agent such as O-(1H- benzotriazol-l-yl)-NN,N',N-tetramethylammonium tetrafluorob ⁇ rate or O-(7- azabenzotriazol- 1 -yl)-N,N,N,N-tetramethyluroniumhexafluorophosphate (HATU), and are then coupled with the amines of formula (XVIII), typically in the presence of a base, such as diisopropylethylamine, in a solvent such as acetonitrile ⁇ -methyl- pyrrolidine or dimethylformamide at 0 to 100°C.
  • an activating agent such as O-(1H- benzotriazol-l-yl)-NN,N',N-tetramethylammonium tetrafluorob ⁇ rate or O-(7- azabenzo
  • the work up of compounds thereby prepared typically involves the use of a sequestration enabling reagent, for example tetrafluorophthalic anhydride, and polymer bound scavenger resins to remove unwanted starting material.
  • a sequestration enabling reagent for example tetrafluorophthalic anhydride
  • polymer bound scavenger resins to remove unwanted starting material.
  • R 1 , R 3 and R 4 are as defined above, Y is -CH 2 - or -NH-, X' is an alkylene group having 2 to 4 carbon atoms and R is -NMe 2 or -NHMe. X' may be substituted or unsubstituted in the same way as the group X.
  • a compound of formula (IVa) or (IVb) is typically reacted with a hydride reducing agent in an ether solvent such as dioxane, tetrahydrofuran or diethyl ether, at a temperature of from 0 to 100°C.
  • a hydride reducing agent such as dioxane, tetrahydrofuran or diethyl ether
  • the reaction takes place in dioxane, with lithium aluminium hydride as the reducing agent at a temperature of from 70 to 80 °C.
  • a compound of formula (la) or (lb) is thereby obtained.
  • reaction typically takes place by preparation of an intermediate acid chloride, followed by quenching of this intermediate with NHMe 2 or NH 2 Me.
  • acid chloride is prepared by reaction with thionyl chloride and the reaction with NHMe 2 or NH 2 Me takes place in an etheral solvent such as tetrahydrofuran or diethyl ether, at a temperature of from -50 to 50°C.
  • Compounds of formula (Va) and (Vb) are typically prepared from a diketone precursor of formula (VI) by reaction with a hydrazine of formula (VII.) in a polar solvent such as ethanol.
  • R,, R 3 and R 4 are as defined above and Y is -CH 2 -.
  • R wherein R protest R 3 and R 4 are as described above and R is -NHMe or -NMe 2 .
  • the compound of formula (X) may, if desired, be substituted on the double bond to prepare compounds of formula (IVa) and (IVb) in which the X' moiety is substituted.
  • Compounds of formula (Villa) and (VHIb) are either commercially available or may be prepared by analogy with known processes.
  • 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. Conditions attributable to down regulation of sGC can thus be alleviated.
  • the compounds of the invention are particularly effective in the treatment or prevention of glaucoma.
  • 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, carboxymefhylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • 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.
  • Diphenyl carbamoylazide was prepared by the following method. A solution of carbamoyl chloride (lOg, 43.2 mmol) in acetone (20 mL) was added dropwise to an ice-cold solution of sodium azide (4.2g, 64.6 mmol) in water (14 mL). The resultant solution was allowed to stir at room temperature (rt) overnight. The layers were separated and the aqueous layer extracted twice with ethyl acetate. The combined organic material was dried (MgSO 4 ) and concentrated under reduced pressure. A crude yield of 8.84g (86%>) was obtained and no further purification was attempted.
  • the diphenylcarbamoylazide was then dissolved in xylene and treated as described by Koga et al. Tetrahedron 1972, 28, 4515 to give the title compound (34%) as a white solid.
  • reaction mixture was heated to 100 °C and kept at this temperature for 8 h.
  • the reaction mixture was cooled to rt and water (20 mL) was added.
  • the mixture was extracted with diethyl ether (3 x 50 mL), combined organic extracts were dried over magnesium sulfate, and concentrated under reduced pressure.
  • the crude product was purified by flash chromatography using cyclohexane/EtOAc (80:20) to give the title compound as a pale yellow solid (280 mg, 35%). Mp 78-79 °C.
  • Example 8 3-(3-Dimethylaminopropyloxy)-lH-indazole.
  • 3-indazolinone (10.0 g, 74.6 mmol)
  • 3-dimethylamino-l-propanol (9.0 mL, 76.1 mmol)
  • tributylphosphine (18.5 mL, 75.0 mmol) in toluene (600 mL)
  • l,l'-(azodicarbonyl) dipiperidine (19.0 g, 75.3 mmol) portionwise.
  • the resultant mixture was heated at 80 °C for 15 h.
  • the cooled mixture was filtered and the residue washed with toluene.
  • the combined filtrate was washed with three 100 mL portions of 10%> aq HCl and the combined acidic washings were basified by addition of 10%) aq NaOH.
  • the basified material was extracted with CH 2 C1 2 and the combined organic phase was dried (MgSO 4 ) and concentrated under reduced pressure.
  • the crude material was flash chromatographed using 0.88 ammonia/EtOH/EtOAc (2: 10:88) to give the title compound, which was recrystallised from MeOH/CH 2 Cl 2 /petroleum ether.
  • Example 10 3-(3-Dimethylaminopropyloxy)-l-phenyl-l/ -pyrazole. From l-phenyl-3-hydroxy-lH-pyrazole (Harries et al. Ber. 1896, 29, 513) as the starting material, using same process as in Example 8. The work up employed involved the addition of MeOH (20 mL) and DOWEX 50W X8 (4 g) to the mixture which was then swirled at rt for 1 h. The mixture was filtered and the resin washed with MeOH (50 mL). The resin was suspended in 0.88 ammonia/MeOH (15:85) (20 mL) and swirled for 30 min. Then filtered and washed with the same mixture (20 mL). The ammonia/MeOH washings were combined and concentrated under reduced pressure. The products were purified by flash chromatography using 0.88 ammonia/MeOH/CHClj (2: 10:88).
  • Example 11 3-(3-Dimethylaminopropyloxy)-5-trifluoromethyl-l /-pyrazole. From the compound of Preparation Example 12 using same process as in Example 8.
  • Example 14 3-(l-Methyl-3-piperidinyI)methyloxy-5-phenyl-lH-pyrazole. From intermediate 3-hydroxy-5-phenyl-lH-pyrazole and 1 -methyl-Shy droxymethylpiperidine using same process as in Example 8. Reaction carried out in T ⁇ F at 70 °C for 3.5 h. After a Dowex resin work-up as in Example 10, the crude compound was purified by flash chromatography using 0.88 "" ammonia/MeO ⁇ /C ⁇ Cl 3 (1:5:94) followed by recrystallisation from cyclohexane/EtOAc. Example 15 5-PhenyI-3-(4-pyridinylmethyloxy)-lH-pyrazole.
  • Example 17 3-(3-Dimethylaminopropyloxy)-l-methyl-l /-indazole.
  • Example 19 l-Benzyl-3-(3-dimethylaminopropyloxy)-5-methyIaminocarbonyl-l/ -pyrazole.
  • To the compound of Example 18 ( 1 M solution in DMF, 0.5 mL, 0.5 mmol), 40%> aq methylamine (0.5 mL) and DIPEA (2 M solution in DMF, 2 mL, 2 mmol) was added TBTU (1 M solution in DMF, 0.7 mL, 0.7 mmol) and the reaction mixture stirred at rt overnight.
  • the DMF was removed under reduced pressure ( ⁇ 1 mmHg) and the residue taken up in saturated brine and made basic with 0.88 ammonia and extracted with THF.
  • the crude THF extracts were dried (Na 2 SO 4 ) and flash columned using 0.88 ammonia/EtOH/CHCl 3 (2:14:84) as solvent.
  • Example 18 From the compound of Example 18, using same process as in Example 19 and morpholine as the amine. The work up followed that described in Example 20.
  • Example 18 From the compound of Example 18, using same process as in Example- 19 with dime hylamine as the amine using NMP as solvent at 100 °C. Purification by flash chromatography using 0.88 ammonia/MeOH/CHCl ⁇ 1 :5:94).
  • Example 8 To a solution of the indazole of Example 8 (185 mg, 0.84 mmol) in THF (3.5 mL) was added t-BuOK (142 mg, 1.27 mmol) followed by methyl bromopropionate (0.1 1 mL, 1.00 mmol). The resultant mixture was heated to reflux for 4 h, then allowed to cool and concentrated under reduced pressure. The crude material was purified by flash chromatography using 10% MeOH/CHCl 3 .
  • Example 25 3-(3-DimethylaminopropyIoxy)-l-(3-hydroxypropyl)-l//-indazole.
  • Example 8 From the compound of Example 8 and 3-bromopropanol, using same process as in Example 24. Purified by flash chromatography using 0.88 ammonia/MeOH/CHCl 3 (1:5:94).
  • Example 8 From the compound of Example 8 and 1 -bromo-2-phenylethane using same process as in Example 24. Purified by flash chromatography using 5% MeOH/CHCl 3 .
  • Example 27 l-(3-DimethyIaminopropyl)-3-(3-dimethylaminopropyloxy)-li/-indazole. From the compound of Example 8 and l-chloro-3-dimethylaminopropane hydrochloride using same proces of Example 24 with 2.2 equivalents of t-BuOK.
  • Example 28 l-Acetyl-3-(3-dimethylaminopropyloxy)-l /-indazole.
  • acetic anhydride 0.1 1 mL, 1.12 mmol
  • the solvent was then removed under reduced pressure and the residue was purified by flash chromatography using 0.88 ammonia/MeOH/CHCl 3 (1 :3:96).
  • Example 31 3-(4-DimethylaminobutvD-5-phenyl-l/- r -pyrazole
  • a solution of lithium di-isopropylamide (2.0M in THF, 25 mL) in THF (50 mL) was cooled to -70°C.
  • a solution of acetophenone (6g, 50 mmol) in THF (50 mL) was added dropwise and the mixture maintained at -70°C for 30 min.
  • the title compound was prepared from 3-(3-dimethylaminocarbonylpropylamino)-5- pheny 1-1 H-pyrazole using the same process as in Example 31. Purification was by flash chromatography using C ⁇ Cl 3 /MeO ⁇ /0.88 ammonia (95:5: 1). The resulting oil was converted to its hydrochloride salt with HCl (1.0 M in diethyl ether).
  • Example 35 3-(3-Dimethylaminopropyloxy)-5-(3-furyl)-lH-pyrazole l, l'-(Azodicarbonyl)dipiperidine (0.45 g, 1.78 mmol) was added to a solution of 3- hydroxy-5-(3-furyl)-lH-pyrazole (Preparation Example 16) (0.18 g, 1.20 mmol), 3- dimethylaminopropanol (0.22 mL, 1.86 mmol) and tributylphosphine (0.45 mL, 1.82 mmol) in toluene (12 mL) at room temperature. The resultant mixture was heated to 80 °C overnight.
  • the reaction mixture was allowed to cool to room temperature and then filtered.
  • the residue was washed with two lots of toluene and then the combined filtrate was extracted three times with 10%> aqueous ⁇ C1 solution.
  • the aqueous extracts were combined, basified by the addition of 10%> aqueous NaO ⁇ solution and re-extracted three times with C ⁇ 2 C1 2 .
  • the CH 2 C1 2 extracts were combined, dried (MgSO 4 ) and concentrated under reduced pressure.
  • the residue was purified by flash chromatography using 0.88 ammonia/MeOH/CHCl 3 (1 : 10:89) to give the product as a white solid (0.11 g, 39 %) which was recrystallised (hexane/CH 2 Cl 2 ).
  • the residue was washed with two lots of toluene and then the combined filtrates were extracted three times with 10%> aqueous ⁇ C1 solution.
  • the aqueous extracts were combined, basified by the addition of 10% aqueous NaOH solution and re-extracted three times with CH 2 C1 2 .
  • the CH 2 C1 2 extracts were combined, dried (MgSO 4 ) and concentrated under reduced pressure.
  • the residue was purified by flash chromatography using 0.88 ammonia MeOH/CHCl j (1 : 10:89) to give the product as a white solid (0.39 g, 64 %) which was recrystallised (hexane/CH 2 Cl 2 ) to produce off-white prisms.
  • Example 37 l,5-Diphenyl-3-(3-dimethylaminopropyloxy)-lH-pyrazole 1,1 '-(Azodicarbonyl)dipiperidine (0.32 g, 1.27 mmol) was added to a solution of 1 ,5- diphenyl-3-hydroxy-lH-pyrazole (Preparation Example 18) (0.20 g, 0.85 mmol), 3- dimethylaminopropanol (0.15 mL, 1.27 mmol) and tributylphosphine (0.32 mL, 1.30 mmol) in toluene (10 mL) at room temperature. The resultant mixture was heated to 80 °C overnight.
  • the reaction mixture was allowed to cool to room temperature and then filtered.
  • the residue was washed with two lots of toluene and then the combined filtrates were extracted three times with 10%> aqueous ⁇ C1 solution.
  • the aqueous extracts were combined, basified by the addition of 10%> aqueous NaO ⁇ solution and re-extracted three times with C ⁇ 2 C1 2 .
  • the CH 2 C1 2 extracts were combined, dried (MgSO 4 ) and concentrated under reduced pressure.
  • the residue was purified by flash chromatography using 0.88 ammonia/EtOH/ethyl acetate (1 :5:94) to give the product as a clear colourless oil (0.39 g, 64 %>).
  • Example 38 3-(3-Dimethylaminopropyloxy)-4-benzyl-lH-pyrazole 1,1 '-(Azodicarbonyl)dipiperidine (0.44 g, 1.74 mmol) was added to a solution of 3- hydroxy-4-benzyl-l H-pyrazole (Preparation Example 19) (0.20 g, 1.15 mmol), 3- dimethylaminopropanol (0.20 mL, 1.69 mmol) and tributylphosphine (0.43 mL, 1.74 mmol) in toluene (12 mL) at room temperature. The resultant mixture was heated to 80 °C overnight. The reaction mixture was allowed to cool to room temperature and then filtered.
  • the reaction mixture was allowed to cool to room temperature and then filtered.
  • the residue was washed with two lots of toluene and then the combined filtrates were extracted three times with 10%> aqueous ⁇ C1 solution.
  • the aqueous extracts were combined, basified by the addition of 10%> aqueous NaO ⁇ solution and re-extracted three times with C ⁇ 2 C1 2 .
  • the CH 2 C1 2 extracts were combined, dried (MgSO 4 ) and concentrated under reduced pressure.
  • the residue was purified by flash chromatography 0.88 ammonia/MeOH/CHCl 3 (1: 10:89) to give the product as a white solid which was recrystallised from hexane (yield 46 %>).
  • the reaction was then cooled to room temperature, filtered and washed with toluene.
  • the toluene extracts were acidified with 10% ⁇ C1 (3 x 50 mL).
  • the acidic layers were combined and basified with 10%) NaOH solution ( 100 mL).
  • the product was then extracted from the aqueous phase with dichloromethane (3 x 50 mL) and the organic extracts combined, dried over MgSO 4 , and concentrated under reduced pressure.
  • the product was purified by flash chromatography using ethyl acetate/EtOH/0.88 ammonia (94:5: 1) as eluent, followed by recrystallisation from cyclohexane/ethyl acetate to give 440 mg, 52 % of the title compound as a white crystals.
  • the aryl amine (different for each reaction), (0.1 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (86.0 mg, 0.3 mmol, loading 3.5 mmol/g) and O-(7- azabenzotriazol-l-yl)-N,N,N,N-tetramethyluronium hexafluoro phosphate ( ⁇ ATU) (38.0 mg, 0.1 mmol) were added and the whole reaction mixture was shaken under nitrogen in anhydrous acetonitrile (4 mL) and heated to 50 °C for 5 hours. After this time the reaction mixture was cooled to room temperature.
  • PS-DIEA N,N-(diisopropyl)amino-methylpolystyrene resin
  • ⁇ ATU O-(7- azabenzotriazol-l-yl)-N,N,N,N-tetramethyluronium
  • the sequestration enabling reagent -tetrafluorophthalic anhydride (65.0 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 analysis was carried out by LC-MS.
  • Example 76 l-Benzyl-3-(3-dimethylamino-propoxy)-lH-pyrazole-5-carboxyIic acid (3- chloro-4-methoxy-phenyl)-amide l-Benzyl-3-(3-dimethylaminopropoxy)-lH-pyrazole-5-carboxylic acid (Example 18) (0.5 g, 1.65 mmol) was dissolved in anhydrous acetonitrile (20 mL).
  • N.NNN-tetramethyluronium hexafluorophosphate (0.63 g, 1.65 mmol) were added and the whole reaction mixture was stirred under nitrogen and heated to 50 °C for 8 hours. After this time the reaction mixture was cooled to room temperature. Tetrafluorophthalic anhydride (1.09 g, 4.95 mmol) was then added and the reaction mixture was stirred under nitrogen for 18 hours. Macroporous triethylammonium methylpolystyrene carbonate resin (MP-carbonate), (10.4 g, 0.33 mol, loading 3.18 mmol/g) was then added and the reaction mixture was stirred under nitrogen for a further 48 hours. The reaction mixture was then filtered, washed with methanol and concentrated. The resulting residue was purified by flash chromatography using ethyl acetate/ethanol/0.88 ammonia (94:5:1) to give 0.39 g, 53
  • Example 77 l-Benzyl-3-(3-dimethylamino-propoxy)-lH-pyrazole-5-carboxylic acid (4- bromo-phenyl)-amide l-Benzyl-3-(3-dimethylaminopropoxy)-lH-pyrazole-5-carboxylic acid (Example 18) (bis-hydrochloride salt) (1.5 g, 3.98 mmol), N, N-(diisopropyl)amino- methylpolystyrene resin (PS-DIEA), (4.46 g, 15.95 mmol), and O-(7- azabenzotriazol- 1 -yl)-N,N,N,N-tetramethyluronium hexafluorophosphate ( ⁇ ATU) (1.51 g, 3.98 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes.
  • PS-DIEA N
  • Example 79 l-BenzyI-3-(3-dimethyIamino-propoxy)-lH-pyrazoIe-5-carboxyIic acid (4- methoxy-biphenyl-3-yl)-amide l-Benzyl-3-(3-dimethylaminopropoxy)-lH-pyrazole-5-carboxylic acid (Example 18) (bis-hydrochloride salt) (1.5 g, 3.98 mmol), N,N-(diisopropyl)amino- methylpolystyrene resin (PS-DIEA), (4.46 g, 15.95 mmol), and O-(7- azabenzotriazol- 1 -yl)-N,NN,N-tetramethyluronium hexafluorophosphate ( ⁇ ATU) (1.51 g, 3.98 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes.
  • Example 18 This was prepared using the method of Example 76 from l-benzyl-3-(3- dimethylaminopropoxy)-lH-pyrazole-5-carboxylic acid (Example 18) (0.5 g, 1.65 mmol), 1-aminoisoquinoline (0.24 g, 1.65 mmol), N,N-(diisopropyl)amino- methylpolystyrene resin (PS-DIEA), (1.41 g, 4.95 mmol, loading 3.5 mmol/g) and O-(7-azabenzotriazol- 1 -yl)-NNN,N-tetramethyluronium hexafluorophosphate ( ⁇ ATU) (0.63 g, 1.65 mmol). After the work-up the resulting residue was purified by flash chromatography using ethyl acetate/ethanol/0.88 ammonia (94:5: 1) to give
  • Example 81 l,5-Dibenzyl-3-(3'-dimethyIamino-l'-propoxy)-5-benzyI-lH-pyrazole 3-(3'-Dimefhylamino- 1 '-propoxy)-5 -benzyl- 1 H-pyrazole (Example 39) (50 mg, 0.20 mmol) and potassium t-butoxide (27 mg, 0.25 mmol) were dissolved in freshly distilled T ⁇ F (5 mL) under a nitrogen atmosphere and stirred for 0.5 h.
  • MeO ⁇ /C ⁇ Cl 3 (7:93) as eluent afforded the product as a red oil, yield 23 mg, 34 %.
  • the resin was then filtered off, washed with methanol, and the resin suspended in 20% piperidine/MeOH solution, and stirred for 2 h.
  • the resin was filtered off, washed with 20%> piperidine/MeOH, and the resulting organic extracts concentrated under reduced pressure.
  • the resulting residue was purified by flash chromatography using MeOH/CHCl 3 (8:92) on silica gel to provide the desired products.
  • Example 86 l-(3'-(Trifluoromethoxy)benzyI)-3-(3'-dimethylamino-l'-propoxy)-5-benzyl-l//- pyrazole Prepared according to Reference Example 1 using 3-(trifluoromethoxy)benzyl alcohol (122 mg, 0.64 mmol) to yield 19 mg, 8 %>.
  • Example 87 l-(4'-Bromobenzyl)-3-(3'-dimethylamino-l'-propoxy)-5-benzyl-lH-pyrazole
  • Example 94 2-Piperonyl-3-(3'-dimethylamino-l'-propoxy)-5-benzyl-2H-pyrazoIe Prepared according to Reference Example 1 using piperonyl alcohol (97 mg, 0.64 mmol) to yield 51 mg, 22 %.
  • reaction mixture was then filtered through celite and washed with methanol, and the organic filtrate concentrated under reduced pressure.
  • the product was then isolated by flash chromatography using MeO ⁇ /C ⁇ Cl 3 (8:92) as eluent to afford the resulting product.
  • Example 109 l-(3'-Thiophen)-3-(3'-dimethylamino-l'-propoxy)-5-benzyl-lH-pyrazole Prepared according to Reference Example 2 using thiophene-3-boronic acid (81 mg, 0.64 mmol); Yield 6 mg, 3 %.
  • Example 116 l-(3'-Acetylphenyl)-3-(3'-dimethylamino-r-propoxy)-5-benzyI-lH-pyrazoIe Prepared according to Reference Example 2 using 3-acetylphenylboronic acid (70 mg, 0.43 mmol); Yield 76 mg, 52 %.
  • Example 118 l-(2'-ChIorophenyl)-3-(3'-dimethylamino-l'-propoxy)-5-benzyl-lH-pyrazole Prepared according to Reference Example 2 using 2-chlorobenzeneboronic acid (67 mg, 0.43 mmol); Yield 7 mg, 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.
  • Activity Example 2 The ability of the compounds of the inventions to inhibit platelet aggregation was also determined. 1C 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 aggregation was monitored using either a Chrono-Log model 560-CA dual channel ormodel 570-4S four channel aggregometer (Chrono-Log Corp., 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 de dérivés de pyrazoles et d'indazoles en tant qu'activateurs de guanylate cyclase soluble. Certains composés décrits sont nouveaux. Tous les activateurs sont des vasodilatateurs et/ou ils inhibent l'agrégation plaquettaire et sont par conséquent utiles dans le traitement de troubles vasculaires périphériques tels que l'hypertension, l'angine de poitrine ou l'athérosclérose, ou dans le traitement ou la prévention du glaucome, de la prééclampsie, de la maladie de Raynaud, de l'ictus ou de dysfonctionnements érectiles.
PCT/GB1999/003663 1998-11-05 1999-11-05 Activateurs de guanylate cyclase soluble WO2000027394A1 (fr)

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Cited By (81)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001032604A1 (fr) * 1999-11-05 2001-05-10 University College London Activateurs de la guanylate cyclase soluble
WO2003031435A1 (fr) * 2001-10-06 2003-04-17 Merck Patent Gmbh Derives pyrazole inhibiteurs de transport de glycine
WO2003035625A1 (fr) * 2001-09-19 2003-05-01 Pharmacia Corporation Composes d'indazole substitues destines au traitement de l'inflammation
WO2003076408A2 (fr) * 2002-03-08 2003-09-18 Abbott Laboratories Derives d'indazole qui sont des activateurs de guanylate cyclase soluble
WO2003086407A1 (fr) * 2002-04-12 2003-10-23 Bayer Healthcare Ag Utilisation de stimulateurs de la guanylate cyclase soluble pour traiter le glaucome
WO2004050634A1 (fr) * 2002-12-02 2004-06-17 F. Hoffmann-La Roche Ag Derives d'indazole utilises en tant qu'antagonistes de crf
US6858592B2 (en) 2001-06-29 2005-02-22 Genzyme Corporation Aryl boronic acids for treating obesity
WO2006021462A1 (fr) * 2004-08-27 2006-03-02 Laboratorios Del Dr. Esteve, S.A. Inhibiteurs de récepteur sigma
US7041280B2 (en) 2001-06-29 2006-05-09 Genzyme Corporation Aryl boronate functionalized polymers for treating obesity
WO2007009589A2 (fr) * 2005-07-16 2007-01-25 Bayer Healthcare Ag Utilisation d'activateurs de la guanylate cyclase soluble pour traiter les phenomenes de raynaud
US7338956B2 (en) 2002-08-07 2008-03-04 Sanofi-Aventis Deutschland Gmbh Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals
EP1940397A2 (fr) * 2005-08-03 2008-07-09 Tap Pharmaceutical Products, Inc. Methodes de traitement de l'hypertension
US7423054B2 (en) 2004-11-29 2008-09-09 Warner Lambert Company Llc Therapeutic pyrazolo[3,4-b]pyridines and indazoles
WO2008124505A2 (fr) * 2007-04-05 2008-10-16 Ironwood Pharmaceuticals,Inc. Modulateurs de la guanylate soluble (scg) pour le traitement de troubles liés aux lipides
JP2008543970A (ja) * 2005-06-27 2008-12-04 エグゼリクシス， インコーポレイテッド ピラゾールベースのｌｘｒモジュレーター
DE102007026392A1 (de) 2007-06-06 2008-12-11 Bayer Healthcare Ag Lösungen für die Perfusion und Konservierung von Organen und Geweben
WO2009032249A1 (fr) * 2007-09-06 2009-03-12 Merck & Co., Inc. Activateurs de la guanylate cyclase soluble
WO2009068652A1 (fr) * 2007-11-30 2009-06-04 Smithkline Beecham Corporation Pyridines 2, 6-disubstituées et pyrimidines 2, 4-disubstituées en tant qu'activateurs de guanylate cyclase soluble
WO2009071504A1 (fr) * 2007-12-03 2009-06-11 Smithkline Beecham Corporation Pyridines 2,6-disubstituées comme activateurs de la guanylate cyclase soluble
JP2009528317A (ja) * 2006-03-02 2009-08-06 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ シグマ受容体阻害剤
US7592363B2 (en) 2004-08-03 2009-09-22 Wyeth Indazoles
WO2009123316A1 (fr) * 2008-04-04 2009-10-08 武田薬品工業株式会社 Dérivé hétérocyclique et son utilisation
EP2113501A1 (fr) 2008-04-25 2009-11-04 Laboratorios Del. Dr. Esteve, S.A. Pyrazoles de 5-Methyl-1-(naphthalen-2-YL)-1H- utiles en tant qu'inhibiteurs de récepteur sigma
WO2010015653A1 (fr) * 2008-08-07 2010-02-11 Smithkline Beecham Corporation Dérivés de pyrimidine comme activateurs de guanylate cyclase soluble
US7728029B2 (en) 2006-03-22 2010-06-01 Hoffmann-La Roche Inc. Adamantyl-pyrazole carboxamides as inhibitors of 11β-hdroxysteroid dehydrogenase
US20100216764A1 (en) * 2009-02-26 2010-08-26 Kim Ronald M Soluble Guanylate Cyclase Activators
JP2011507916A (ja) * 2007-12-26 2011-03-10 サノフィ−アベンティス Ｐ２ｙ１２拮抗薬としてのピラゾール−カルボキサミド誘導体
WO2011115804A1 (fr) 2010-03-17 2011-09-22 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
WO2012003405A1 (fr) 2010-06-30 2012-01-05 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
US8138186B2 (en) * 2006-03-02 2012-03-20 Laboratorios Del Dr. Esteve, S.A. Pyrazole derivatives as sigma receptors antagonists
WO2012064559A1 (fr) 2010-11-09 2012-05-18 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
US8293740B2 (en) 2004-08-27 2012-10-23 Laboratories Del Dr. Esteve, S.A. Sigma receptor inhibitors
EP2524694A1 (fr) * 2011-05-19 2012-11-21 Laboratorios Del. Dr. Esteve, S.A. Utilisation de ligands sigma dans la douleur liée au diabète de type 2
WO2012165399A1 (fr) 2011-05-30 2012-12-06 アステラス製薬株式会社 Composé imidazopyridine
WO2013101830A1 (fr) 2011-12-27 2013-07-04 Ironwood Pharmaceuticals, Inc. Pyrazoles 2-benzyle, 3-(pyrimidin-2-yle)-substitués utiles comme stimulateurs de scg
CN101010302B (zh) * 2004-08-27 2013-11-06 埃斯蒂维实验室股份有限公司 σ受体抑制剂
WO2014047111A1 (fr) 2012-09-18 2014-03-27 Ironwood Pharmaceuticals, Inc. Stimulateurs de la sgc
WO2014047325A1 (fr) 2012-09-19 2014-03-27 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
WO2014031928A3 (fr) * 2012-08-24 2014-05-22 Philip Jones Modulateurs hétérocycliques de l'activité du facteur hif utilisés pour le traitement de maladies
WO2014031936A3 (fr) * 2012-08-24 2014-05-22 Philip Jones Modulateurs hétérocycliques de l'activité du facteur hif utilisés pour le traitement de maladies
WO2014084312A1 (fr) 2012-11-30 2014-06-05 アステラス製薬株式会社 Composé imidazopyridine
WO2014100620A3 (fr) * 2012-12-21 2014-08-21 Plexxikon Inc. Composés et procédés pour la modulation de kinase, et indications associées
WO2014144100A2 (fr) 2013-03-15 2014-09-18 Takashi Nakai Stimulateurs de sgc
US8841333B2 (en) 2005-05-09 2014-09-23 Takeda Pharmaceuticals U.S.A., Inc. Methods for treating nephrolithiasis
WO2015089182A1 (fr) 2013-12-11 2015-06-18 Ironwood Pharmaceuticals, Inc. Stimulateurs de la sgc
WO2015106268A1 (fr) 2014-01-13 2015-07-16 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement de troubles neuromusculaires
US9107912B2 (en) 2010-09-10 2015-08-18 Takeda Pharmaceuticals U.S.A., Inc. Methods for concomitant treatment of theophylline and febuxostat
EP2929883A1 (fr) * 2014-04-08 2015-10-14 Institut Pasteur Dérivés du pyrazole en tant qu'inhibiteurs de la dihydrooratate déhydrogénase (DHODH)
WO2016044447A1 (fr) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. Dérivés de pyrazole utilisés comme stimulateurs de sgc
WO2016044446A2 (fr) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
WO2016044445A2 (fr) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
US9365574B2 (en) 2010-05-27 2016-06-14 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
MD4425C1 (ro) * 2012-09-07 2017-01-31 Boehringer Ingelheim International Gmbh Alcoxipirazoli în calitate de activatori ai guanilat-ciclazei solubile
US9663504B2 (en) 2014-02-25 2017-05-30 Board Of Regents, The University Of Texas System Salts of heterocyclic modulators of HIF activity for treatment of disease
WO2017106175A2 (fr) 2015-12-14 2017-06-22 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'un dysfonctionnement du sphincter gastro-intestinal
WO2017103319A1 (fr) * 2015-12-18 2017-06-22 Consejo Superior De Investigaciones Científicas (Csic)) Nouvelle famille de dérivés carbonyliques de 1-indazolyl avec des propriétés cannabinoïdes et/ou colinergiques et/ou régulatrices du peptide bêta-amyloïde
US9757358B2 (en) 2010-02-04 2017-09-12 Laboratorios Del Dr. Esteve, S.A. Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof
US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
US9789115B2 (en) 2010-08-03 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in opioid-induced hyperalgesia
US9844516B2 (en) 2010-02-04 2017-12-19 Laboratorios De Dr. Esteve Sigma ligands for use in the prevention and/or treatment of post-operative pain
WO2018009596A1 (fr) 2016-07-07 2018-01-11 Ironwood Pharmaceuticals, Inc. Promédicaments à base de phosphore de stimulateurs de sgc
WO2018009609A1 (fr) 2016-07-07 2018-01-11 Ironwood Pharmaceuticals, Inc. Formes solides d'un stimulateur de la gcs
WO2018045276A1 (fr) 2016-09-02 2018-03-08 Ironwood Pharmaceuticals, Inc. Stimulateurs sgc bicycliques fusionnés
US9914705B2 (en) 2008-04-25 2018-03-13 Laboratorios Del Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof
US9931346B2 (en) 2013-12-17 2018-04-03 Laboratorios Del Dr. Esteve S.A. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations
WO2018089330A2 (fr) 2016-11-08 2018-05-17 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
WO2018089328A1 (fr) 2016-11-08 2018-05-17 Ironwood Pharmaceuticals, Inc. Traitement de maladies du snc au moyen de stimulateurs de gcs
WO2018111795A2 (fr) 2016-12-13 2018-06-21 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité œsophagienne
KR20180124149A (ko) * 2016-04-07 2018-11-20 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 단백질 조정제로서 유용한 헤테로시클릭 아미드
WO2019126354A1 (fr) 2017-12-19 2019-06-27 Cyclerion Therapeutics, Inc. Stimulateurs de sgc
WO2019173551A1 (fr) 2018-03-07 2019-09-12 Cyclerion Therapeutics, Inc. Formes cristallines d'un stimulateur de sgc
WO2020014504A1 (fr) 2018-07-11 2020-01-16 Cyclerion Therapeutics, Inc. Utilisation de stimulateurs gcs pour le traitement de maladies mitochondriales
WO2020109354A1 (fr) 2018-11-28 2020-06-04 Topadur Pharma Ag Nouveaux activateurs de la guanylate cyclase solubles à double mode d'action, inhibiteurs de phosphodiestérase et leurs utilisations
WO2021195403A1 (fr) 2020-03-26 2021-09-30 Cyclerion Therapeutics, Inc. Stimulateurs de sgc deutérés
WO2021202546A1 (fr) 2020-03-31 2021-10-07 Cyclerion Therapeutics, Inc. Interventions médicamenteuses précoces pour réduire la détresse respiratoire, la nécessité d'assistance respiratoire et la mort liées à la covid-19
WO2022225902A1 (fr) 2021-04-20 2022-10-27 Cyclerion Therapeutics, Inc. Traitement de maladies du snc avec des stimulateurs de sgc
WO2022225903A1 (fr) 2021-04-20 2022-10-27 Cyclerion Therapeutics, Inc. Stimulateurs de sgc
WO2022265984A1 (fr) 2021-06-14 2022-12-22 Curtails Llc Utilisation d'inhibiteurs de nep pour le traitement de troubles du sphincter gastro-intestinal
WO2023018795A1 (fr) 2021-08-11 2023-02-16 Curtails Llc Inhibiteurs de nep pour le traitement de la fourbure
WO2024086182A1 (fr) 2022-10-18 2024-04-25 Tisento Therapeutics Inc. Traitement de maladies mitochondriales avec stimulateurs de sgc
WO2024086179A1 (fr) 2022-10-18 2024-04-25 Tisento Therapeutics, Inc. Stimulateurs de la sgc pyrimidiques

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS497279A (fr) * 1972-05-27 1974-01-22
FR2301250A1 (fr) * 1975-02-21 1976-09-17 Bellon Labor Sa Roger Nouveaux diaryl-1, 4o-aminoalcoxy-3 pyrazoles et leurs sels
JPS61129124A (ja) * 1984-11-28 1986-06-17 Kureha Chem Ind Co Ltd 抗腫瘍剤
US5500230A (en) * 1987-01-23 1996-03-19 The General Hospital Corporation Method for treatment of glaucoma with nitrogen containing guanylate cyclase activators
WO1998016507A2 (fr) * 1996-10-14 1998-04-23 Bayer Aktiengesellschaft Nouveaux derives de pyrazol heterocyclylmethyle-substitues
DE19649460A1 (de) * 1996-11-26 1998-05-28 Bayer Ag Neue substituierte Pyrazolderivate
WO1998058633A2 (fr) * 1997-06-23 1998-12-30 Queen's University At Kingston Traitement par administration de microdoses

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS497279A (fr) * 1972-05-27 1974-01-22
FR2301250A1 (fr) * 1975-02-21 1976-09-17 Bellon Labor Sa Roger Nouveaux diaryl-1, 4o-aminoalcoxy-3 pyrazoles et leurs sels
JPS61129124A (ja) * 1984-11-28 1986-06-17 Kureha Chem Ind Co Ltd 抗腫瘍剤
US5500230A (en) * 1987-01-23 1996-03-19 The General Hospital Corporation Method for treatment of glaucoma with nitrogen containing guanylate cyclase activators
WO1998016507A2 (fr) * 1996-10-14 1998-04-23 Bayer Aktiengesellschaft Nouveaux derives de pyrazol heterocyclylmethyle-substitues
DE19649460A1 (de) * 1996-11-26 1998-05-28 Bayer Ag Neue substituierte Pyrazolderivate
WO1998058633A2 (fr) * 1997-06-23 1998-12-30 Queen's University At Kingston Traitement par administration de microdoses

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
BARBAZ ET AL.: "1-substituted 3-aminoalkoxy-4,5-cycloalkylparazoles with central nervous system depressant activity", J. MED. CHEM., vol. 15, no. 10, 1972, pages 1027 - 1029, XP000876634 *
CATANESE ET AL.: "Effects of benzydamine and other non-steroidal antiinflammatory drugs on platelet aggregation induceds by; arachidonic acid, ADP and collagen", BOLL. CHIM. FARM., vol. 125, no. 7, 1986, pages 228 - 233, XP000879042 *
CORSI: "Preparazione di possbili metaboliti della benzidamina", BOLL. CHIM. FARM.-, vol. 111, no. 9, 1972, pages 566 - 572, XP000879068 *
DATABASE WPI Week 197412, Derwent World Patents Index; AN 1974-21885v, XP002133681 *
DATABASE WPI Week 198630, Derwent World Patents Index; AN 1986-194723, XP002133682 *
JANSEN ET AL.: "Antithrombotische Wirkung von Benzydamin", ARZNEI. FORSCHUNG, vol. 37, no. 5a, 1987, pages 626 - 628, XP000876724 *
KO ET AL.: "YC-1, anovel activator of platelet guanylate cyclase", BLOOD, vol. 84, no. 12, 15 December 1994 (1994-12-15), pages 4226 - 4233, XP000878904 *
NAGASAKI ET AL.: "Metabolism of Benzydamine hydrochloride", CHEM. PHARM. BULL., vol. 19, no. 7, 1971, pages 1511 - 1513, XP000879139 *
SCHMIDT ET AL.: "Potentiation of NO and Endothelium-independent relaxation through a long-lasting soluble guanylyl cyclase stimulation by YC-1 (3-(5-hydroxymethyl-2'-furyl)-1-benzyl-indazol)", BR. J. PHARMACOL., vol. 123, no. proc. suppl., March 1998 (1998-03-01), pages 299p, XP000878914 *
SOGA ET AL.: "Synthesis of 1-substitutd 3-(dialkylaminoalkoxy)-4,5,6,7-tetrahydro-1H-indazoles", BULL. CHEM. SOC. JPN, vol. 53, 1980, pages 825 - 826, XP000876596 *
SUGRUE: "New approaches to antiglaucoma therapy", J. MED. CHEM., vol. 40, no. 18, 1997, pages 2793 - 2809, XP000878913 *
TENG ET AL.: "YC-1, a nitric oxide-independent activator of soluble guanylate cyclase, inhibits platelet-rich thrombosis in mice", EUR. J. PHARMACOL., vol. 320, no. 2-3, 12 February 1997 (1997-02-12), pages 161 - 166, XP000878912 *
WEGENER ET AL.: "Activation of soluble guanylyl cyclase by YC-1 in aortic smooth muscle but not in ventricular myocardium from the rat", BR. J. PHARMACOL., vol. 122, no. 7, December 1997 (1997-12-01), pages 1523 - 1529, XP000878915 *
ZONI ET AL.: "Proprieta' farmacologiche di alchil-derivati dell'1-(m-trifluorometilfenil)-3-idrossi-1H-indazolo", FARMACO, vol. 25, no. 5, 1970, pages 386 - 405, XP000876729 *
ZONI ET AL.: "Sintesi di alchil-derivati dell'1-(m-trifluorometilfenil)-3-idrossi-1H-indazolo", BOLL. CHIM. FARM., vol. 107, no. 10, 1968, pages 598 - 605, XP000879272 *

Cited By (165)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001032604A1 (fr) * 1999-11-05 2001-05-10 University College London Activateurs de la guanylate cyclase soluble
US7049304B2 (en) 2001-06-29 2006-05-23 Genzyme Corporation Aryl boronic acids for treating obesity
US6858592B2 (en) 2001-06-29 2005-02-22 Genzyme Corporation Aryl boronic acids for treating obesity
US7456156B2 (en) 2001-06-29 2008-11-25 Genzyme Corporation Aryl boronic acids for treating obesity
US7041280B2 (en) 2001-06-29 2006-05-09 Genzyme Corporation Aryl boronate functionalized polymers for treating obesity
WO2003035625A1 (fr) * 2001-09-19 2003-05-01 Pharmacia Corporation Composes d'indazole substitues destines au traitement de l'inflammation
WO2003031435A1 (fr) * 2001-10-06 2003-04-17 Merck Patent Gmbh Derives pyrazole inhibiteurs de transport de glycine
WO2003076408A2 (fr) * 2002-03-08 2003-09-18 Abbott Laboratories Derives d'indazole qui sont des activateurs de guanylate cyclase soluble
WO2003076408A3 (fr) * 2002-03-08 2004-04-01 Abbott Lab Derives d'indazole qui sont des activateurs de guanylate cyclase soluble
WO2003086407A1 (fr) * 2002-04-12 2003-10-23 Bayer Healthcare Ag Utilisation de stimulateurs de la guanylate cyclase soluble pour traiter le glaucome
US7338956B2 (en) 2002-08-07 2008-03-04 Sanofi-Aventis Deutschland Gmbh Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals
US7214699B2 (en) 2002-12-02 2007-05-08 Roche Palo Alto Llc Indazole derivatives as CRF antagonists
WO2004050634A1 (fr) * 2002-12-02 2004-06-17 F. Hoffmann-La Roche Ag Derives d'indazole utilises en tant qu'antagonistes de crf
US7592363B2 (en) 2004-08-03 2009-09-22 Wyeth Indazoles
WO2006021462A1 (fr) * 2004-08-27 2006-03-02 Laboratorios Del Dr. Esteve, S.A. Inhibiteurs de récepteur sigma
US8470867B2 (en) 2004-08-27 2013-06-25 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
EP2325174A1 (fr) * 2004-08-27 2011-05-25 Laboratorios Del. Dr. Esteve, S.A. Inhibiteurs de recepteur sigma
US8314096B2 (en) 2004-08-27 2012-11-20 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
AU2005276590B2 (en) * 2004-08-27 2011-05-19 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
US8293740B2 (en) 2004-08-27 2012-10-23 Laboratories Del Dr. Esteve, S.A. Sigma receptor inhibitors
KR101352012B1 (ko) * 2004-08-27 2014-01-15 라보라토리오스 델 드라. 에스테브.에스.에이. 시그마 수용체 저해제
JP2008510767A (ja) * 2004-08-27 2008-04-10 ラボラトリオス デル ドクトール エステベ エセ．ア． シグマ受容体阻害剤
CN101010302B (zh) * 2004-08-27 2013-11-06 埃斯蒂维实验室股份有限公司 σ受体抑制剂
US7696199B2 (en) 2004-08-27 2010-04-13 Laboratorios Del Dr. Esteve, S.A. Sigma receptor inhibitors
US20100190780A1 (en) * 2004-08-27 2010-07-29 Christian Laggner Sigma receptor inhibitors
US7485636B2 (en) 2004-11-29 2009-02-03 Pfizer Inc. Therapeutic pyrazolo[3,4-b]pyridines and indazoles
US7423054B2 (en) 2004-11-29 2008-09-09 Warner Lambert Company Llc Therapeutic pyrazolo[3,4-b]pyridines and indazoles
US8841333B2 (en) 2005-05-09 2014-09-23 Takeda Pharmaceuticals U.S.A., Inc. Methods for treating nephrolithiasis
JP2008543970A (ja) * 2005-06-27 2008-12-04 エグゼリクシス， インコーポレイテッド ピラゾールベースのｌｘｒモジュレーター
WO2007009589A2 (fr) * 2005-07-16 2007-01-25 Bayer Healthcare Ag Utilisation d'activateurs de la guanylate cyclase soluble pour traiter les phenomenes de raynaud
WO2007009589A3 (fr) * 2005-07-16 2007-08-16 Bayer Healthcare Ag Utilisation d'activateurs de la guanylate cyclase soluble pour traiter les phenomenes de raynaud
JP2009501737A (ja) * 2005-07-16 2009-01-22 バイエル・ヘルスケア・アクチェンゲゼルシャフト レイノー現象の処置のための可溶性グアニル酸シクラーゼ活性化剤の使用
EP1940397A4 (fr) * 2005-08-03 2010-01-20 Takeda Pharmaceuticals North A Methodes de traitement de l'hypertension
EP1940397A2 (fr) * 2005-08-03 2008-07-09 Tap Pharmaceutical Products, Inc. Methodes de traitement de l'hypertension
JP2009528317A (ja) * 2006-03-02 2009-08-06 ラボラトリオス・デル・ドクトル・エステベ・ソシエダッド・アノニマ シグマ受容体阻害剤
US8138186B2 (en) * 2006-03-02 2012-03-20 Laboratorios Del Dr. Esteve, S.A. Pyrazole derivatives as sigma receptors antagonists
US7728029B2 (en) 2006-03-22 2010-06-01 Hoffmann-La Roche Inc. Adamantyl-pyrazole carboxamides as inhibitors of 11β-hdroxysteroid dehydrogenase
WO2008124505A2 (fr) * 2007-04-05 2008-10-16 Ironwood Pharmaceuticals,Inc. Modulateurs de la guanylate soluble (scg) pour le traitement de troubles liés aux lipides
WO2008124505A3 (fr) * 2007-04-05 2009-08-20 Ironwood Pharmaceuticals Inc Modulateurs de la guanylate soluble (scg) pour le traitement de troubles liés aux lipides
DE102007026392A1 (de) 2007-06-06 2008-12-11 Bayer Healthcare Ag Lösungen für die Perfusion und Konservierung von Organen und Geweben
JP2010538065A (ja) * 2007-09-06 2010-12-09 メルク・シャープ・エンド・ドーム・コーポレイション 可溶性グアニレートシクラーゼ活性化因子
WO2009032249A1 (fr) * 2007-09-06 2009-03-12 Merck & Co., Inc. Activateurs de la guanylate cyclase soluble
US8455638B2 (en) 2007-09-06 2013-06-04 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
WO2009068652A1 (fr) * 2007-11-30 2009-06-04 Smithkline Beecham Corporation Pyridines 2, 6-disubstituées et pyrimidines 2, 4-disubstituées en tant qu'activateurs de guanylate cyclase soluble
WO2009071504A1 (fr) * 2007-12-03 2009-06-11 Smithkline Beecham Corporation Pyridines 2,6-disubstituées comme activateurs de la guanylate cyclase soluble
JP2011507916A (ja) * 2007-12-26 2011-03-10 サノフィ−アベンティス Ｐ２ｙ１２拮抗薬としてのピラゾール−カルボキサミド誘導体
US8461348B2 (en) 2008-04-04 2013-06-11 Takeda Pharmaceutical Company Limited Heterocyclic derivative and use thereof
WO2009123316A1 (fr) * 2008-04-04 2009-10-08 武田薬品工業株式会社 Dérivé hétérocyclique et son utilisation
EP2113501A1 (fr) 2008-04-25 2009-11-04 Laboratorios Del. Dr. Esteve, S.A. Pyrazoles de 5-Methyl-1-(naphthalen-2-YL)-1H- utiles en tant qu'inhibiteurs de récepteur sigma
US9914705B2 (en) 2008-04-25 2018-03-13 Laboratorios Del Dr. Esteve, S.A. 1-aryl-3-aminoalkoxy pyrazoles as sigma ligands enhancing analgesic effect of opioids and attenuating the dependency thereof
WO2010015653A1 (fr) * 2008-08-07 2010-02-11 Smithkline Beecham Corporation Dérivés de pyrimidine comme activateurs de guanylate cyclase soluble
AU2010218224B2 (en) * 2009-02-26 2013-06-27 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
JP2012519169A (ja) * 2009-02-26 2012-08-23 メルク・シャープ・エンド・ドーム・コーポレイション 可溶性グアニレートシクラーゼ活性化剤
CN102414194A (zh) * 2009-02-26 2012-04-11 默沙东公司 可溶性鸟苷酸环化酶激活剂
US20100216764A1 (en) * 2009-02-26 2010-08-26 Kim Ronald M Soluble Guanylate Cyclase Activators
US8507512B2 (en) 2009-02-26 2013-08-13 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
WO2010099054A3 (fr) * 2009-02-26 2010-10-21 Merck Sharp & Dohme Corp. Activateurs solubles de guanylate cyclase
US9757358B2 (en) 2010-02-04 2017-09-12 Laboratorios Del Dr. Esteve, S.A. Sigma ligands for potentiating the analgesic effect of opioids and opiates in post-operative pain and attenuating the dependency thereof
US9844516B2 (en) 2010-02-04 2017-12-19 Laboratorios De Dr. Esteve Sigma ligands for use in the prevention and/or treatment of post-operative pain
WO2011115804A1 (fr) 2010-03-17 2011-09-22 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
US9782483B2 (en) 2010-05-21 2017-10-10 Laboratories Del Dr. Esteve, S.A. Sigma ligands for the prevention and/or treatment of emesis induced by chemotherapy or radiotherapy
US9365574B2 (en) 2010-05-27 2016-06-14 Merck Sharp & Dohme Corp. Soluble guanylate cyclase activators
AU2011272800B2 (en) * 2010-06-30 2016-11-03 Cyclerion Therapeutics, Inc. sGC stimulators
US10189809B2 (en) 2010-06-30 2019-01-29 Ironwood Pharmaceuticals, Inc. SGC stimulators
WO2012003405A1 (fr) 2010-06-30 2012-01-05 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
CN107021951A (zh) * 2010-06-30 2017-08-08 铁木医药有限公司 sGC刺激物
EP3173407A1 (fr) 2010-06-30 2017-05-31 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
EA026692B1 (ru) * 2010-06-30 2017-05-31 Айронвуд Фармасьютикелз, Инк. Стимуляторы sgc
TWI582091B (zh) * 2010-06-30 2017-05-11 艾諾屋製藥公司 可溶性鳥苷酸環化酶（ｓＧＣ）刺激物
KR101813931B1 (ko) 2010-06-30 2018-01-02 아이언우드 파마슈티컬스, 인코포레이티드 Sgc 자극제
CN107021951B (zh) * 2010-06-30 2020-10-20 赛克里翁治疗有限公司 sGC刺激物
CN103313976A (zh) * 2010-06-30 2013-09-18 铁木医药有限公司 sGC刺激物
US9789115B2 (en) 2010-08-03 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in opioid-induced hyperalgesia
US9107912B2 (en) 2010-09-10 2015-08-18 Takeda Pharmaceuticals U.S.A., Inc. Methods for concomitant treatment of theophylline and febuxostat
WO2012064559A1 (fr) 2010-11-09 2012-05-18 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
US9061030B2 (en) 2010-11-09 2015-06-23 Ironwood Pharmaceuticals, Inc. sGC stimulators
CN107266433A (zh) * 2010-11-09 2017-10-20 铁木医药有限公司 sGC刺激剂
JP2013542253A (ja) * 2010-11-09 2013-11-21 アイロンウッド ファーマシューティカルズ， インコーポレイテッド ｓＧＣ刺激剤
US9789117B2 (en) 2011-05-18 2017-10-17 Laboratorios Del Dr. Esteve, S.A. Use of sigma ligands in diabetes type-2 associated pain
KR101937255B1 (ko) 2011-05-19 2019-01-11 에스테베 파마슈티칼스 에스에이 제 2형 당뇨병 관련 통증에서 시그마 리간드의 이용
EP2524694A1 (fr) * 2011-05-19 2012-11-21 Laboratorios Del. Dr. Esteve, S.A. Utilisation de ligands sigma dans la douleur liée au diabète de type 2
WO2012156497A1 (fr) * 2011-05-19 2012-11-22 Laboratorios Del Dr. Esteve, S.A. Utilisation de ligands sigma dans une douleur associée au diabète de type 2
US9447090B2 (en) 2011-05-30 2016-09-20 Astellas Pharma Inc. Imidazopyridine compounds
WO2012165399A1 (fr) 2011-05-30 2012-12-06 アステラス製薬株式会社 Composé imidazopyridine
WO2013101830A1 (fr) 2011-12-27 2013-07-04 Ironwood Pharmaceuticals, Inc. Pyrazoles 2-benzyle, 3-(pyrimidin-2-yle)-substitués utiles comme stimulateurs de scg
CN106117194A (zh) * 2011-12-27 2016-11-16 铁木医药有限公司 可用作sgc刺激剂的2‑苄基、3‑(嘧啶‑2‑基)取代的吡唑类
US9139564B2 (en) 2011-12-27 2015-09-22 Ironwood Pharmaceuticals, Inc. 2-benzyl, 3-(pyrimidin-2-yl) substituted pyrazoles useful as sGC stimulators
EP3112363A1 (fr) 2011-12-27 2017-01-04 Ironwood Pharmaceuticals, Inc. Dérivés de pyrimidine 2-[1-[(2-fluorophényl)méthyl]-5-(3-isoxazolyl)-1h-pyrazol-3-yl] et composés similaires en tant que stimulateurs de la cyclase soluble du guanylate (csg) pour le traitement de l'hypertension pulmonaire
CN104066731A (zh) * 2011-12-27 2014-09-24 铁木医药有限公司 可用作sgc刺激剂的2-苄基、3-(嘧啶-2-基)取代的吡唑类
US9481692B2 (en) 2012-08-24 2016-11-01 Board Of Regents, The University Of Texas System Heterocyclic modulators of HIF activity for treatment of disease
CN104736535A (zh) * 2012-08-24 2015-06-24 德州大学系统董事会 用于治疗疾病的hif活性的杂环调节剂
US9018380B2 (en) 2012-08-24 2015-04-28 Boar of Regents, The University of Texas System Heterocyclic modulators of HIF activity for treatment of disease
US10208059B2 (en) 2012-08-24 2019-02-19 Board Of Regents, The University Of Texas System Heterocyclic modulators of HIF activity for treatment of disease
US11001594B2 (en) 2012-08-24 2021-05-11 Board Of Regents, The University Of Texas System Heterocyclic modulators of HIF activity for treatment of disease
WO2014031928A3 (fr) * 2012-08-24 2014-05-22 Philip Jones Modulateurs hétérocycliques de l'activité du facteur hif utilisés pour le traitement de maladies
WO2014031936A3 (fr) * 2012-08-24 2014-05-22 Philip Jones Modulateurs hétérocycliques de l'activité du facteur hif utilisés pour le traitement de maladies
MD4425C1 (ro) * 2012-09-07 2017-01-31 Boehringer Ingelheim International Gmbh Alcoxipirazoli în calitate de activatori ai guanilat-ciclazei solubile
WO2014047111A1 (fr) 2012-09-18 2014-03-27 Ironwood Pharmaceuticals, Inc. Stimulateurs de la sgc
US9487508B2 (en) 2012-09-19 2016-11-08 Ironwood Pharmaceuticals, Inc. SGC stimulators
WO2014047325A1 (fr) 2012-09-19 2014-03-27 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
JPWO2014084312A1 (ja) * 2012-11-30 2017-01-05 アステラス製薬株式会社 イミダゾピリジン化合物
EA027909B1 (ru) * 2012-11-30 2017-09-29 Астеллас Фарма Инк. Имидазопиридиновые соединения
WO2014084312A1 (fr) 2012-11-30 2014-06-05 アステラス製薬株式会社 Composé imidazopyridine
KR20150090157A (ko) 2012-11-30 2015-08-05 아스테라스 세이야쿠 가부시키가이샤 이미다조피리딘 화합물
CN105308036B (zh) * 2012-12-21 2019-06-21 普莱希科公司 用于激酶调节的化合物和方法及其适应症
US10301280B2 (en) 2012-12-21 2019-05-28 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
CN105308036A (zh) * 2012-12-21 2016-02-03 普莱希科公司 用于激酶调节的化合物和方法及其适应症
US9676748B2 (en) 2012-12-21 2017-06-13 Plexxikon Inc. Compounds and methods for kinase modulation, and indications therefor
WO2014100620A3 (fr) * 2012-12-21 2014-08-21 Plexxikon Inc. Composés et procédés pour la modulation de kinase, et indications associées
CN105408328A (zh) * 2013-03-15 2016-03-16 铁木医药有限公司 sGC刺激剂
CN108912111B (zh) * 2013-03-15 2021-09-14 赛克里翁治疗有限公司 化合物及药用组合物
EP3998260A1 (fr) 2013-03-15 2022-05-18 Cyclerion Therapeutics, Inc. Stimulateurs sgc
US11207323B2 (en) 2013-03-15 2021-12-28 Cyclerion Therapeutics, Inc. sGC stimulators
US9586937B2 (en) 2013-03-15 2017-03-07 Ironwood Pharmaceuticals, Inc. sGC stimulators
US10183021B2 (en) 2013-03-15 2019-01-22 Ironwood Pharmaceuticals, Inc. sGC stimulators
US9481689B2 (en) 2013-03-15 2016-11-01 Ironwood Pharmaceuticals, Inc. sGC stimulators
CN108912111A (zh) * 2013-03-15 2018-11-30 铁木医药有限公司 化合物及药用组合物
WO2014144100A2 (fr) 2013-03-15 2014-09-18 Takashi Nakai Stimulateurs de sgc
JP2019034952A (ja) * 2013-03-15 2019-03-07 アイアンウッド ファーマシューティカルズ インコーポレイテッド ｓＧＣ刺激薬
EP3660013A1 (fr) 2013-03-15 2020-06-03 Cyclerion Therapeutics, Inc. Stimulateurs sgc
US10639308B2 (en) 2013-03-15 2020-05-05 Cyclerion Therapeutics, Inc. sGC stimulators
US10517874B2 (en) 2013-03-15 2019-12-31 Cyclerion Therapeutics, Inc. sGC stimulators
WO2015089182A1 (fr) 2013-12-11 2015-06-18 Ironwood Pharmaceuticals, Inc. Stimulateurs de la sgc
JP2016540017A (ja) * 2013-12-11 2016-12-22 アイアンウッド ファーマシューティカルズ インコーポレイテッド ｓＧＣ刺激物質
US9931346B2 (en) 2013-12-17 2018-04-03 Laboratorios Del Dr. Esteve S.A. Serotonin-norepinephrine reuptake inhibitors (SNRIs) and Sigma receptor ligands combinations
WO2015106268A1 (fr) 2014-01-13 2015-07-16 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement de troubles neuromusculaires
US10363248B2 (en) 2014-02-25 2019-07-30 Board Of Regents, The University Of Texas System Salts of heterocyclic modulators of HIF activity for treatment of disease
US9663504B2 (en) 2014-02-25 2017-05-30 Board Of Regents, The University Of Texas System Salts of heterocyclic modulators of HIF activity for treatment of disease
US10888554B2 (en) 2014-02-25 2021-01-12 Board Of Regents, The University Of Texas System Salts of heterocyclic modulators of HIF activity for treatment of disease
WO2015155680A3 (fr) * 2014-04-08 2016-04-21 Institut Pasteur Dérivés de pyrazole en tant qu'inhibiteurs de la dihydroorotate déshydrogénase (dhodh)
EP2929883A1 (fr) * 2014-04-08 2015-10-14 Institut Pasteur Dérivés du pyrazole en tant qu'inhibiteurs de la dihydrooratate déhydrogénase (DHODH)
WO2016044445A2 (fr) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
WO2016044446A2 (fr) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
WO2016044447A1 (fr) 2014-09-17 2016-03-24 Ironwood Pharmaceuticals, Inc. Dérivés de pyrazole utilisés comme stimulateurs de sgc
WO2017106175A2 (fr) 2015-12-14 2017-06-22 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de la sgc pour le traitement d'un dysfonctionnement du sphincter gastro-intestinal
WO2017103319A1 (fr) * 2015-12-18 2017-06-22 Consejo Superior De Investigaciones Científicas (Csic)) Nouvelle famille de dérivés carbonyliques de 1-indazolyl avec des propriétés cannabinoïdes et/ou colinergiques et/ou régulatrices du peptide bêta-amyloïde
JP7466596B2 (ja) 2016-04-07 2024-04-12 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド タンパク質調節因子として有用な複素環式アミド
KR102527784B1 (ko) 2016-04-07 2023-04-28 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 단백질 조정제로서 유용한 헤테로시클릭 아미드
KR20180132806A (ko) * 2016-04-07 2018-12-12 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 단백질 조정제로서 유용한 헤테로시클릭 아미드
KR20180124149A (ko) * 2016-04-07 2018-11-20 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 단백질 조정제로서 유용한 헤테로시클릭 아미드
JP7119158B2 (ja) 2016-04-07 2022-08-16 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド タンパク質調節因子として有用な複素環式アミド
JP2019510796A (ja) * 2016-04-07 2019-04-18 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ タンパク質調節因子として有用な複素環式アミド
KR102527786B1 (ko) 2016-04-07 2023-04-28 글락소스미스클라인 인털렉츄얼 프로퍼티 디벨로프먼트 리미티드 단백질 조정제로서 유용한 헤테로시클릭 아미드
JP2022166060A (ja) * 2016-04-07 2022-11-01 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド タンパク質調節因子として有用な複素環式アミド
US11970480B2 (en) 2016-04-07 2024-04-30 Glaxosmithkline Intellectual Property Development Limited Heterocyclic amides useful as protein modulators
JP2021105013A (ja) * 2016-04-07 2021-07-26 グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッドＧｌａｘｏｓｍｉｔｈｋｌｉｎｅ Ｉｎｔｅｌｌｅｃｔｕａｌ Ｐｒｏｐｅｒｔｙ Ｄｅｖｅｌｏｐｍｅｎｔ Ｌｉｍｉｔｅｄ タンパク質調節因子として有用な複素環式アミド
WO2018009609A1 (fr) 2016-07-07 2018-01-11 Ironwood Pharmaceuticals, Inc. Formes solides d'un stimulateur de la gcs
WO2018009596A1 (fr) 2016-07-07 2018-01-11 Ironwood Pharmaceuticals, Inc. Promédicaments à base de phosphore de stimulateurs de sgc
EP3872080A1 (fr) 2016-09-02 2021-09-01 Cyclerion Therapeutics, Inc. Stimulateurs de la sgc bicycliques fusionnés
WO2018045276A1 (fr) 2016-09-02 2018-03-08 Ironwood Pharmaceuticals, Inc. Stimulateurs sgc bicycliques fusionnés
WO2018089328A1 (fr) 2016-11-08 2018-05-17 Ironwood Pharmaceuticals, Inc. Traitement de maladies du snc au moyen de stimulateurs de gcs
WO2018089330A2 (fr) 2016-11-08 2018-05-17 Ironwood Pharmaceuticals, Inc. Stimulateurs de sgc
WO2018111795A2 (fr) 2016-12-13 2018-06-21 Ironwood Pharmaceuticals, Inc. Utilisation de stimulateurs de sgc pour le traitement de la motilité œsophagienne
WO2019126354A1 (fr) 2017-12-19 2019-06-27 Cyclerion Therapeutics, Inc. Stimulateurs de sgc
WO2019173551A1 (fr) 2018-03-07 2019-09-12 Cyclerion Therapeutics, Inc. Formes cristallines d'un stimulateur de sgc
WO2020014504A1 (fr) 2018-07-11 2020-01-16 Cyclerion Therapeutics, Inc. Utilisation de stimulateurs gcs pour le traitement de maladies mitochondriales
WO2020109354A1 (fr) 2018-11-28 2020-06-04 Topadur Pharma Ag Nouveaux activateurs de la guanylate cyclase solubles à double mode d'action, inhibiteurs de phosphodiestérase et leurs utilisations
WO2021195403A1 (fr) 2020-03-26 2021-09-30 Cyclerion Therapeutics, Inc. Stimulateurs de sgc deutérés
WO2021202546A1 (fr) 2020-03-31 2021-10-07 Cyclerion Therapeutics, Inc. Interventions médicamenteuses précoces pour réduire la détresse respiratoire, la nécessité d'assistance respiratoire et la mort liées à la covid-19
WO2022225902A1 (fr) 2021-04-20 2022-10-27 Cyclerion Therapeutics, Inc. Traitement de maladies du snc avec des stimulateurs de sgc
WO2022225903A1 (fr) 2021-04-20 2022-10-27 Cyclerion Therapeutics, Inc. Stimulateurs de sgc
WO2022265984A1 (fr) 2021-06-14 2022-12-22 Curtails Llc Utilisation d'inhibiteurs de nep pour le traitement de troubles du sphincter gastro-intestinal
WO2023018795A1 (fr) 2021-08-11 2023-02-16 Curtails Llc Inhibiteurs de nep pour le traitement de la fourbure
WO2024086182A1 (fr) 2022-10-18 2024-04-25 Tisento Therapeutics Inc. Traitement de maladies mitochondriales avec stimulateurs de sgc
WO2024086179A1 (fr) 2022-10-18 2024-04-25 Tisento Therapeutics, Inc. Stimulateurs de la sgc pyrimidiques

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