WO2000027394A1 - Activateurs de guanylate cyclase soluble - Google Patents
Activateurs de guanylate cyclase soluble Download PDFInfo
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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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- pyrazole
- benzyl
- dimethylamino
- propoxy
- phenyl
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- 0 *c1c(*=C)[n](*)nc1* Chemical compound *c1c(*=C)[n](*)nc1* 0.000 description 2
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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
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- A61K31/4164—1,3-Diazoles
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- A61K31/4164—1,3-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
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- 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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- C07D401/04—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
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