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1. (WO2001032604) ACTIVATORS OF SOLUBLE GUANYLATE CYCLASE
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

ACTIVATORS OF SOLUBLE GUANYLATE CYCLASE

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).

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, December 1997, Vol 18, p.484). Activators of sGC can therefore be expected to have valuable therapeutic properties.

As explained above, NO is known as an activator of sGC. However, 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)-1-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.

Accordingly, the present invention provides the use of a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the activation of soluble guanylate cyclase


wherein:

- R1 and R2 are the same or different and each represent a C1-C6 alkyl group, or R1 and R2 together form a C3-C6 alkylene group;

- Z is a C1-C4 alkylene group;

- P is a direct bond or a moiety -X-, -Y-, -W-, -XY-, -YW- or -XYW-, wherein:

W is -O-, -S-, or -NR3, wherein R3 is hydrogen or C1-C6 alkyl;

Y is a moiety -U-V- wherein V is a direct bond or a C1-C6 alkylene group and U is -CS-, -CO-, -S(O)2- or -C(=NR)- wherein R is hydrogen, hydroxy or C1-C6 alkyl;

X is -O- or -NR6- wherein R6 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; and

R4is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, a group -R-A wherein R is -(C1-C6 alkyl)-, -(C2-C6 alkenyl)- or -(C2-C6 alkynyl)- and A is aryl, heteroaryl, carbocycyl or heterocyclyl, or R4 is a group -COR//, -CO2R//, -S(O)2R// or -CONR/R// wherein R/ is hydrogen, C1-C6 alkyl, C2-C6 alkenyl or

C2-C6 alkynyl and R// is is aryl, heteroaryl, carbocyclyl or heterocyclyl.

In the moiety P, the moiety -X-, when present, is attached to R4 and the moiety W, when present, is attached to Z. In the moiety Y, the moiety V is attached to W or, if W is not present, to Z, and the moiety U is attached to X or, if X is not present, to R4.

As used herein, a C1-C6 alkyl group or moiety is a linear or branched alkyl group or moiety. Suitable alkyl groups and moieties include C1-C4 alkyl groups and moieties, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl and t-butyl. Methyl, ethyl, n-propyl and t-butyl are preferred.

A C1-C6 alkyl group or moiety can be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries 1, 2 or 3 substituents. Suitable substituents include C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy,

heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, oxo, -NR/R// wherein R/ and R// are the same or different and are hydrogen or C1-C6 alkyl, =NR, -COR, -CONR/R, -CO2R, -NR/COR, -NR/CO2R, -NR/CONR/R, -S(O)2R and -S(O)2NR/R wherein each R/ can be the same or different and represents hydrogen or C1-C6 alkyl and each R can be the same or different and represents C1-C6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(C1-C6 alkyl)-R///and -O-(C1-C6 alkyl)-R/// wherein each R/// can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group.

Preferred substituents include oxo, halogen, C1-C6 alkyl, aryl, arylthio, aryloxy, heteroaryl, heteroarylthio, heteroaryloxy and -NR/R//, =N-R, -CONHR and -NHCO2R wherein R, R/ and R// are as defined above. Further, two preferred substituents on the same carbon atom may, together with the atom to which they are attached, form a carbocyclyl group, preferably a C3-C6 cycloalkyl group.

More preferred substituents are oxo, halogen, for example chlorine and fluorine, C1-C4 alkyl, for example methyl, ethyl or t-butyl, aryl, for example phenyl, -CONH-aryl, for example -CONH-phenyl, =N-aryl, for example =N-phenyl, -NH-CO2-(C1-C4 alkyl), heteroarylthio, for example pyrimidinethio and -CO-aryl, for example -CO-phenyl. It is also preferred that two substituents on the same carbon atom may, together with the atom to which they are attached, form a C3-C6 cycloalkyl group.

As used herein, a C2-C6 alkenyl group or moiety is a linear or branched alkenyl group or moiety. Suitable alkenyl groups and moieties include C2-C4 alkenyl groups and moieties such as ethenyl, propenyl and butenyl groups and moieties. Ethenyl and propenyl are preferred. A C2-C6 alkenyl group or moiety may be substituted or unsubstituted at any position.

A C2-C6 alkenyl group is typically unsubstituted or carries 1, 2, 3 or 4 substituents. Preferably, it carries at least two substituents. Suitable substituents include oxo, C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy,

heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR/R// wherein R/ and R// are the same or different and are hydrogen or C1-C6 alkyl, =N-R, -COR, -CONR/R, -CO2R, -NR/COR, -NR/CO2R, -NR/CONR/R, -S(O)2R and -S(O)2NR/R wherein each R/ can be the same or different and represents hydrogen or C1-C6 alkyl and each R can be the same or different and represents C1-C6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(C1-C6 alkyl)-R/// and -O-(C1-C6 alkyl)-R/// wherein each R/// can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group.

Preferred substituents include oxo, halogen, C1-C6 alkyl, aryl, arylthio, aryloxy, heteroaryl, heteroarylthio, heteroaryloxy and -NR/R//, =N-R, -CONHR and -NHCO2R wherein R, R/ and R// are as defined above. Further, two preferred substituents on the same carbon atom may, together with the atom to which they are attached, form a carbocyclyl group, preferably a C3-C8 cycloalkyl group.

More preferred substituents are halogen, for example chlorine and fluorine, C1-C4 alkyl, for example methyl, ethyl or t-butyl, aryl, for example phenyl, heteroaryl, for example furanyl, -CONH-aryl, for example -CONH-phenyl, -NH-CO2-(C1-C4 alkyl), -NH-CO-(C1-C4 alkyl), -NH-CO-aryl, for example -NH-CO-phenyl, heteroarylthio, for example pyrimidinethio and -CO-aryl, for example -CO-phenyl. It is also preferred that two substituents on the same carbon atom may, together with the atom to which they are attached, form a C3-C8 cycloalkyl group.

A C2-C6 alkynyl group or moiety is typically an ethynyl, propynyl or butynyl group or moiety. It may be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries 1 or 2 substituents. Suitable substituents include C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR/R// wherein R/ and R// are the same or different and are hydrogen or C1-C6 alkyl, - COR, -CONR/R, -CO2R, -NR/COR, -NR/CO2R, -NR/CONR/R, -S(O)2R and

-S(O)2NR/R wherein each R/ can be the same or different and represents hydrogen or C1-C6 alkyl and each R can be the same or different and represents C1-C6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(C1-C6 alkyl)-R/// and

-O-(C1-C6 alkyl)-R/// wherein each R/// can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group.

Preferred substituents include halogen, C1-C6 alkyl, aryl, arylthio, aryloxy, heteroaryl, heteroarylthio, heteroaryloxy and -CONHR and -NHCO2R wherein R is as defined above. Further, two preferred substituents on the same carbon atom may, together with the atom to which they are attached, form a carbocyclyl group, preferably a C3-C6 cycloalkyl group.

More preferred substituents are halogen, for example chlorine and fluorine, C1-C4 alkyl, for example methyl, ethyl or t-butyl, aryl, for example phenyl,

-CONH-aryl, for example -CONH-phenyl, -NH-CO2-(C1-C4 alkyl), heteroarylthio, for example pyrimidinethio and -CO-aryl, for example -CO-phenyl. It is also preferred that two substituents on the same carbon atom may, together with the atom to which they are attached, form a C3-C6 cycloalkyl group.

A C1-C6 alkoxy group is typically a said C1-C6 alkyl group attached to an oxygen atom. A C1-C6 alkylthio group is typically a said C1-C6 alkyl group attached to a sulphur atom.

As used herein, a said alkylene group is a divalent alkyl moiety. It may be unsubstituted or substituted at any position. Typically, it is unsubstituted or monosubstituted. Suitable substituents include halogen, for example chlorine and flourine, hydroxy, C1-C4 alkyl such as methyl and ethyl, C1-C4 alkoxy, for example methoxy, C1-C4 haloalkyl, for example -CF3 and -CCl3 and C1-C4 haloalkoxy, for example -OCF3 and -OCCl3. These substituents are typically themselves

unsubstituted.

A halogen is typically chlorine, fluorine, bromine or iodine. It is preferably chlorine.

A haloalkyl or haloalkoxy group is typically a said alkyl or alkoxy group substituted by one or more said halogen atoms. Typically, it is substituted by 1, 2 or 3 said halogen atoms. Preferred haloalkyl and haloalkoxy groups include

perhaloalkyl and perhaloalkoxy groups such as -CX3 and -OCX3 wherein X is a said halogen atom. Particularly preferred haloalkyl groups are CF3 and CCl3. Particularly preferred haloalkoxy groups are -OCF3 and -OCCl3.

As used herein, an aryl group or moiety is typically a C6-C20 aryl group or moiety. Suitable such aryl groups and moieties include phenyl, naphthyl and pyrenyl. Phenyl and pyrenyl are preferred.

An aryl group or moiety may be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries 1, 2, 3 or 4 substituents. Suitable substituents include C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, cyano, hydroxy, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR/R// wherein R/ and R// are the same or different and are hydrogen or C1-C6 alkyl, -COR, -CONR/R, -CO2R, -NR/COR, -NR/CO2R,

-NR/CONR/ R, -S(O)2R and -S(O)2NR/R wherein each R/ can be the same or different and represents hydrogen or C1-C6 alkyl and each R can be the same or different and represents C1-C6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(C1-C6 alkyl)-R/// and -O-(C1-C6 alkyl)-R/// wherein each R/// can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl.

Preferred substituents include C1-C6 alkyl, for example methyl and ethyl, C1-C6 alkoxy, for example methoxy, C1-C6 alkylthio, for example methylthio, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, for example chlorine and fluorine, nitro, cyano, aryl, for example phenyl, aryloxy, for example phenyloxy, arylthio, for example phenylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, -NR/R// wherein R/ and R// are the same or different and are hydrogen or C1-C6 alkyl, -CONH-(C1-C6 alkyl),

-NHCONH-R wherein R is aryl, for example phenyl, or heteroaryl, -S(O)2NHR/ wherein R/ is aryl, for example phenyl, or heteroaryl, -S-(C1-C6 alkyl)-R// wherein R// is aryl, for example phenyl, or heteroaryl and -COR/// wherein R/// is heterocycyl, heteroaryl or aryl.

Particularly preferred substituents are phenyl, in particular 4-phenyl, phenoxy, in particular 2-phenoxy, phenylthio, halogen, -CF3, -CCl3, nitro, cyano, -OCF3, -OCCl3, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, -CONH-(C1-C4 alkyl),

-CO-phenyl, -S(O)2NH-phenyl, -S-(C1-C4 alkyl)-phenyl, -S-(C1-C4 alkyl)-pyrazole,

-S-(C1-C4 alkyl)-pyrimidine, -(C1-C4 alkyl)-NH-CO2-(C1-C4 alkyl), thiazole, -COR wherein R is benzothiophenyl or β-carbolinyl and -NH-(CH2)nNR/R// wherein n is from 2 to 4 and R/ and R// are the same or different and are C1-C4 alkyl.

An aryl group or moiety may be fused to a further said aryl group or to a carbocyclic, heterocyclic or heteroaryl group. For example, an aryl group may be fused to a pyridine ring to form a quinoline or isoquinoline group, or to a furan ring. It may also, for example, be fused to a cyclopropyl or cyclohexyl group or to a tetrahydro furyl group, a 1,4-dioxolane group or a pyrimidone ring, for example a 4-pyrimidone ring.

As used herein, a carbocyclic group or moiety is a non-aromatic, saturated or unsaturated carbocyclic group or moiety. Typically, it has from 3 to 10, for example from 3 to 8, carbon atoms. Preferably, it has from 3 to 8, for example 3 to 6, carbon atoms. Examples of suitable carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopetadienyl, cyclohexyl, cyclohexenyl and cyclooctanyl groups. Preferred carbocyclic groups include cyclohexyl, cyclooctanyl and cyclohexenyl groups.

A carbocyclic group or moiety may be unsubstituted or substituted at any position. Typically, it carries up to 3 substituents. Suitable substituents include oxo, C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR/R// wherein R/ and R// are the same or different and are hydrogen or C1-C6 alkyl, =NR, -COR, -CONR/R, -CO2R, -NR/COR, -NR/CO2R,

-NR/CONR/R, -S(O)2R and -S(O)2NR/R wherein each R/ can be the same or different and represents hydrogen or C1-C6 alkyl and each R can be the same or different and represents C1-C6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and

-S-(C1-C6 alkyl)-R///and -O-(C1-C6 alkyl)-R/// wherein each R/// can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group.

Preferred substituents include oxo, C1-C6 alkyl, for example methyl and ethyl, C1-C6 alkoxy, for example methoxy, C1-C6 alkylthio, for example methylthio, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, for example chlorine and fluorine, nitro, cyano, aryl, for example phenyl, aryloxy, for example phenyloxy, arylthio, for example phenythio, heteroaryl, heteroarylthio, heterocyclyl, -CONH-(C1-C6 alkyl), -NHCONH-R wherein R is aryl, for example phenyl, or heteroaryl, =NR/ wherein R/ is aryl, for example phenyl, or heteroaryl, -S(O)2NHR// wherein R// is aryl, for example phenyl, or heteroaryl, -S-(C1-C6 alkyl)-R/// wherein R/// is aryl, for example phenyl, or heteroaryl, and -COR//// wherein R//// is heterocyclyl, heteroaryl or aryl.

Particularly preferred substituents are oxo, =N-aryl, for example =N-phenyl, aryl, for example phenyl, and -CO-aryl, for example -CO-phenyl.

A carbocyclic group or moiety may be fused to a further carbocyclic group or to an aryl, heteroaryl or heterocyclic group.

A heteroaryl group or moiety is typically a 5- to 10- membered aryl ring containing at least one heteroatom, for example 1, 2 or 3 heteroatoms, selected from

O, S and N. Preferably, the heteroaryl group or moiety is a 5- or 6- membered ring.

Suitable heteroaryl groups and moieties include pyridyl, pyranyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, imidazolyl, pyrazolyl, iso thiazolyl, isoxazolyl, furazanyl, triazolyl and thiadiazolyl groups. Pyridyl, pyrrolyl, thienyl, thiazolyl, furanyl, pyrazinyl and

1, 2, 3-thiadiazolyl groups are preferred.

A heteroaryl group or moiety may be unsubstituted or substituted at any position. Typically, it is unsubstituted or carries up to three substituents. Suitable substituents include C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy,

heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR/R// wherein R/ and R// are the same or different and are hydrogen or C1-C6 alkyl, -COR, -CONR/R, -CO2R, -NR/COR, -NR/CO2R,

-NR/CONR/R, -S(O)2R and -S(O)2NR/R wherein each R/ can be the same or different

and represents hydrogen or C1-C6 alkyl and each R can be the same or different and represents C1-C6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and

-S-(C1-C6 alkyl)-R///and -O-(C1-C6alkyl)-R/// wherein each R/// can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl.

Preferred substituents include C1-C6 alkyl, for example methyl and ethyl, C1-C6 alkoxy, for example methoxy, C1-C6 alkylthio, for example methylthio, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, for example chlorine, cyano, nitro, aryl, for example phenyl, aryloxy, for example phenoxy, arylthio, for example phenylthio and

-O-(C1-C6 alkyl)-R, -S-(C1-C6 alkyl)-R, -S-(C1-C6 alkyl)-CONH-R, -CO-R and

-CO-NH-R, wherein R is an aryl group, for example a phenyl group.

Particularly preferred substituents include phenyl, halogen, for example chlorine, C1-C4 alkyl, for example methyl, -CF3, -CCl3, -OCF3, -OCCl3, phenylthio, phenoxy, -S-(C1-C4 alkyl)-CONH-phenyl, -S-(C1-C4alkyl)-phenyl,

-O-(C1-C4 alkyl)-phenyl, -CO-phenyl, cyano, C1-C4 alkylthio, nitro,

2,3-dihydrobenzafuranyl and -CO-NH-(1, 2, 3, 4-tetrahydranaphthalen-8-yl).

A heteroaryl group may be fused to a said aryl or carbocyclic group or to a further heteroaryl group or to a heterocyclic group. Examples of such fused heteroaryl groups include quinolyl, indolyl, isoindolyl, benzothiophenyl,

imidazo[1,2-α]pyridyl and β-carbolinyl groups.

As used herein, a heterocyclic group or moiety is a non-aromatic, saturated or unsaturated cyclic group or moiety containing at least one, for example, one, two or three, heteroatoms selected from N, O and S. Typically, it is a 3- to 6- membered ring. Preferably, it is a 5- or 6- membered ring containing, as heteroatoms, one or two nitrogen atoms.

Suitable heterocyclic groups and moieties include pyrazolidinyl, piperidyl, piperazinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolinyl, 3,4-dihydro-2H-pyranyl, tetrahydropyrimidinyl (for example 1,2,3,4- or 1,4,5,6-tetrahydrapyrimidinyl), 2-hydropyridinyl, 2-hydrothiazolyl, tetrahydropyridinyl (for example 1,2,5,6- or 2,3,4,5-tetrahydropyridinyl) and tetrahydropyridazinyl, for example 3 ,4,5 ,6-tetrahydropyridazinyl.

A heterocyclic group or moiety may be substituted or unsubstituted at any position. Typically, it is unsubstituted or carries 1, 2, 3, 4 or 5 substituents. Suitable substituents include oxo, C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy, heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR/R// wherein R/ and R// are the same or different and are hydrogen or C1-C6 alkyl, -NR, -COR, -CONR/R, -CO2R, -NR/COR,

-NR/CO2R, -NR/CONR/R, -S(O)2R and -S(O)2NR/R wherein each R/ can be the same or different and represents hydrogen or C1-C6 alkyl and each R can be the same or different and represents C1-C6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(C1-C6 alkyl)-R///and -O-(C1-C6 alkyl)-R/// wherein each R/// can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group.

Preferred substituents include oxo, C1-C6 alkyl, for example methyl and ethyl, C1-C6 alkoxy, for example methoxy, C1-C6 alkylthio, for example methylthio, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, for example chlorine and fluorine, nitro, cyano, aryl, for example phenyl, aryloxy, for example phenyloxy, arylthio, for example phenythio, heteroaryl, heteroarylthio, heterocyclyl, -CONH-(C1-C6 alkyl), -NHCONH-R wherein R is aryl, for example phenyl, or heteroaryl, =NR/ wherein R/ is aryl, for example phenyl, or heteroaryl, -S(O)2NHR// wherein R// is aryl, for example phenyl, or heteroaryl, -S-(C1-C6 alkyl)-R/// wherein R/// is aryl, for example phenyl, or heteroaryl, and -COR//// wherein R//// is heterocyclyl, heteroaryl or aryl.

Particularly preferred substituents are oxo, =N-aryl, for example =N-Ph, aryl, for example phenyl, halogen, C1-C4 alkyl, for example methyl and ethyl, C1-C4 alkoxy, for example methoxy and ethoxy, C1-C4 haloalkyl, for example -CF3 and -CCl3 and C1-C4 haloalkoxy, for example -OCF3 and -OCCl3.

Heterocyclic groups carrying one oxo substituent and up to 2, for example 0,

1 or 2, further substituents are particularly prefered.

A heterocyclic group or moiety may be fused to a further said heterocyclic group or to a said carbocyclic, aryl or heteroaryl group. Typically, it is non- fused or is fused to a benzene ring or to an iodole group. Examples of such fused heterocyclic groups include chromanyl and chromonyl groups.

An aryloxy, heteroaryloxy, heterocyclyloxy or carbocyclyloxy group is typically a said aryl, heteroaryl, heterocyclyl or carbocyclyl group attached to an oxygen atom. An arylthio, heteroarylthio, heterocyclylthio or carbocyclylthio group is typically a said aryl, heteroaryl, heterocyclyl or carbocyclyl group attached to a sulphur atom.

Typically, R1 and R2 are the same or different and represent methyl, ethyl, propyl, n-butyl or t-butyl. Preferably the groups represented by R1 and R2 are unsubstituted or carry one or two substituents. Preferred substituents for R1 and R2 include C1-C4 alkyl, for example methyl and ethyl, C1-C4 alkoxy, for example methoxy and ethoxy, halogen, for example chlorine, C1-C4 haloalkyl, for example -CF3 and -CCl3 and C1-C4 haloalkoxy, for example -OCF3 and -OCCl3 Typically, these substituents are themselves unsubstituted.

More preferably, R1 and R2 are methyl or R1 and R2 together form a n-butylene group.

Z is methylene, ethylene, propylene or butylene and is preferably propylene. Preferably Z is unsubstituted, monosubstituted or disubstituted. Preferred substituents for Z include C1-C4 alkyl, for example methyl and ethyl, C1-C4 alkoxy, for example methoxy and ethoxy, halogen, for example chlorine, C1-C4 haloalkyl, for example -CF3 and -CCl3 and C1-C4 haloalkoxy, for example -OCF3 and -OCCl3. Typically, these substituents are themselves unsubstituted. Particularly preferred substituents for Z are C1-C4 alkyl groups, in particular methyl groups. A preferred substituted alkylene group is 2,2-dimethylpropylene.

Typically, the moiety P is -Y-, -XY-, -YW- or -XYW-. Preferably, the moiety P is -XYW- or -YW-. When P is -W- or is a direct bond, R4 is typically an aryl, heteroaryl or heterocyclyl moiety and/or is typically substituted by an aryl, heteroaryl, heterocyclyl or carbocyclyl substituent.

Typically, W is -O- or -NR3. Typically, R3 is hydrogen or is methyl, ethyl,

propyl, n-butyl or t-butyl. Preferably, R3 is unsubstituted or carries one or two substituents. Preferred substituents for R3 include C1-C4 alkyl, for example methyl and ethyl, C1-C4 alkoxy, for example methoxy and ethoxy, halogen, for example chlorine, C1-C4 haloalkyl, for example -CF3 and -CCl3 and C1-C4 haloalkoxy, for example -OCF3 and -OCCl3. Typically, these substituents are themselves unsubstituted.

More preferably, R3 is hydrogen or methyl, most preferably hydrogen.

V is preferably a direct bond. U is preferably -CO-, -S(O)2-, -C(=NH)- or -C(=NOH)-, more preferably -CO-.

X is typically -NR6-. When X is a group -NR6-, R6 is typically C1-C4 alkyl, for example methyl, ethyl, propyl, n-butyl and t-butyl, aryl, for example phenyl, or heteroaryl, for example pyridyl. Preferably, R6 is unsubstituted or carries 1, 2 or 3 substituents. Preferred substituents for R6 include C1-C4 alkyl, for example methyl and ethyl, C1-C4 alkoxy such as methoxy or ethoxy, halogen, for example fluorine or chlorine, C1-C4 haloalkyl, for example -CF3 and -CCl3, C1-C4 haloalkoxy, for example -OCF3 and -OCCl3, cyano, nitro and -NR/R// wherein R/ and R// are the same or different and are hydrogen or C1-C4 alkyl. Typically, these substituents are themselves unsubstituted.

Preferably, X is -NH-.

Typically, the group R4 has up to 30 carbon atoms and up to 10 heteroatoms selected from N, O and S. Preferably, it has up to 25 carbon atoms and up to 7 heteroatoms. Typically, the group R4 contains at least one, preferably at least two, aryl or heteroaryl rings.

Preferably, R4 is C1-C6 alkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, -(C1-C6 alkyl)-aryl, -(C1-C6 alkyl)-heteroaryl or -COR//, -CO2R// or -CONR/R// wherein R/ is hydrogen or C1-C6 alkyl and R// is an aryl, heteroaryl, carbocyclyl or heteroaryl group.

Suitable substituents for the group R4 are oxo, C1-C6 alkyl, C1-C6 alkylthio, C1-C6 alkoxy, C1-C6 haloalkyl, for example -CF3 and -CCl3, C1-C6 haloalkoxy, for example -OCF3 and -OCCl3, halogen, hydroxy, cyano, nitro, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy, heteroarylthio, heterocyclyl, heterocyclyloxy,

heterocyclythio, carbocyclyl, carbocyclyloxy, carbocyclylthio, -NR/R// wherein R/ and R// are the same or different and are hydrogen or C1-C6 alkyl, =NR, -COR, -CONR/R, -CO2R, -NR/COR, -NR/CO2R, -NR/CONR/R, -S(O)2R and -S(O)2NR/R wherein each R/ can be the same or different and represents hydrogen or C1-C6 alkyl and each R can be the same or different and represents C1-C6 alkyl, aryl, heteroaryl, heterocyclyl or carbocyclyl, and -S-(C1-C6 alkyl)-R/// and -O-(C1-C6 alkyl)-R/// wherein each R/// can be the same or different and represents aryl, heteroaryl, heterocyclyl or carbocyclyl. Further, two substituents on the same atom can, together with the atom to which they are attached, form a carbocyclyl or heterocyclyl group. Substituents on the group R4 may be further substituted.

Typically, when P is a direct bond, -O- or -NH-, R4 is not a moiety (A) or (B).


wherein:

R'1 is: hydrogen, aryl, heteroaryl, 3- to 6- membered heterocyclyl, -(C1-C4 alkyl)-R wherein R is aryl, heteroaryl or 3- to 6- membered heterocyclyl, C1-C4 alkyl, -CONA'2, -COA" or -SO2A" wherein each A' is the same or different and is selected from H, C1-C4 alkyl and aryl and each A" is the same or different and is selected from C1-C4 alkyl and aryl; and

R'3 and R'4 are either:

(a) the same or different and selected from -CO2 A' wherein A' is as

defined above, -CF3, -CCl3, halogen, C1-C4 alkoxy, -(C1-C4 alkyl)- aryl, -(C1-C4 alkyl)-heteroaryl, hydrogen, C1-C4 alkyl, C3-C6 carbocyclyl, 3- to 6- membered heterocyclyl, -SO2NA'2 wherein A' is

as defined above, and -CONZ1Z2 wherein Z1 and Z2, which are the same or different, represent H, C1-C4 alkyl, aryl, heteroaryl, C3-C6 carbocyclyl, 3- to 6- membered heterocyclyl or -(C1-C6 alkyl)-R wherein R is aryl, heteroaryl, 3- to 6- membered heterocyclyl or C3-C6 carbocyclyl, or Z1 and Z2, together with the nitrogen atom to which they are attached, denote a 5- or 6- membered N-containing heterocyclic group; or

(b) different, one of R'3 and R'4 being aryl or heteroaryl and the other being as defined above

or R'1 is as defined above and R'3 and R'4 together form the divalent group,

-(CH)4-, which group is optionally substituted.

Preferably, R4 is not a 3- or 5- pyrazole or a 3- indazole group when P is a direct bond, -O- or -NH-. More preferably R4 is not a pyrazole or indazole group when P is a direct bond, -O- or -NH-. More typically, R4 is not a 3- or 5- pyrazole or a 3- indazole group or, more preferably, a pyrazole or indazole group when P does not contain the moiety U.

More preferably, when P is a direct bond, -O- or -NH- and R4 is a heteroaryl group, R4 is a pyridyl, pyrimidyl, thiazolyl or thienyl group. R4 is typically also a pyridyl, pyrimidyl, thiazolyl or thienyl group when P does not contain the moiety U and R4 is a heteroaryl group. Suitable pyridyl, pyrimidyl, thiazolyl and thienyl groups include groups fused to a said aryl or said carbocyclic group or to a said heteroaryl or said heterocyclic group. In such compounds, R4 may be substituted by one or more of the groups mentioned above as appropriate substituents for R4.

Preferred compounds of the invention are those in which X is -NR6- wherein R6 is as defined above, and R4 is aryl or heteroaryl. In these preferred compounds, P is typically -XYW-. Y is typically -CO-. W is typically -NR3- wherein R3 is as defined above. X is preferably -NH- and/or R4 is preferably phenyl, thienyl or pyrazolyl.

In the above preferred compounds, when R4 is phenyl it is typically substituted by a phenoxy group or by a phenylthio group, in particular a 2-phenoxy or 2-phenylthio group, or by a further phenyl group, in particular a 4-phenyl group. When R4 is thienyl or pyrazolyl, it is typically substituted by a phenyl or phenylthio group. These substituents may be unsubstituted or may be further substituted at any position. Typically, they are unsubstituted or carry one, two or three further

substituents. Preferred further substituents include halogen, for example chlorine and fluorine, C1-C4 alkyl, for example methyl and ethyl, C1-C4 alkoxy, for example methoxy and ethoxy, C1-C4 haloalkyl, for example -CF3 and -CCl3, and

-S(O)2NH-phenyl. These further substituents are typically themselves unsubstituted.

In the above preferred compounds of the invention, R4 is preferably

2-phenoxyphenyl, 2-fluoro-diphen-4-yl, 5-(4-chlorophenylthio)rthien-3-yl,

4-(4-fluorophenyl)-thien-2-yl, 5-(4-chlorophenyl)-1-(3,4-dichlorophenyl)-pyrazol-3-yl or -(C6H4)-S-(C6H4)-S(O)2-NH-(C6H4).

Further preferred compounds of the invention are those in which P is -YW-and R4 is an aryl, heterocyclyl or heteroaryl group. In these further preferred compounds, Y is typically -CO-. W is typically -NR3- wherein R3 is as defined above. Further, R4 is preferably an oxo-substituted heterocyclic group such as a chromonyl group or is a pyrazolyl, thienyl, phenyl or indolyl group.

In the above further preferred compounds, R4 is typically unsubstituted or substituted by one or more, for example, one, two or three substituents selected from C1-C6 alkyl, for example t-butyl, phenyl, thiazolyl, phenylthio, cyano, nitro, C1-C6 alkylthio, for example i-propylthio, C1-C6 alkoxy, halogen such as chlorine and -S-(C1-C4 alkyl)-phenyl. These substituents may be unsubstituted or may be substituted at any position. Typically, they are unsubstituted or carry one, two or three further substituents. Preferred further substituents include halogen, for example chlorine, C1-C4 haloalkyl, for example -CF3, phenyl and -S(O)2-NH-phenyl. These further substituents are typically themselves unsubstituted.

Additional preferred compounds of the invention are those in which P is -W-or -YW- wherein Y is -CO- and W is -O-.

Particularly preferred compounds of the invention are compounds of formula

(I/) and pharmaceutically acceptable salts thereof,


wherein:

R1 and R2 are the same or different and each represent a C1-C6 alkyl group, or R1 and R2 together form an alkylene group having from 3 to . 6 carbon atoms;

Z is an alkylene group having from 2 to 4 carbon atoms; R3 is hydrogen or C1-C6 alkyl;

Y is -CO- or -S(O)2-;

X is a direct bond or -NR6- wherein R6 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or heteroaryl; and

R4is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, a group -R-A wherein R is -(C1-C6 alkyl)-, -(C2-C6 alkenyl)- or -(C2-C6 alkynyl)- and A is aryl, heteroaryl, carbocycyl or heterocyclyl, or R4 is a group -COR/ or -CO2R/ wherein R/ is aryl, heteroaryl, carbocyclyl or heterocyclyl.

Further particularly preferred compounds of the invention are compounds of formula (I//), and pharmaceutically acceptable salts thereof


wherein R1 and R2 are methyl or together form a n-butylene group, R3 is hydrogen or methyl, R4 is as defined in the formula (I) or in the formula (I/) and X is a direct bond or is -NR6- wherein R6 is as defined above. Preferably, when X in the formula (I//) is -NR6-, R4 is as defined as in the above preferred compounds of the invention. Preferably, when X in the formula (I//) is a direct bond, R4 is as defined in the above further preferred compounds of the invention.

The present invention includes pharmaceutically acceptable salts of the compounds of the invention. Suitable salts include salts with pharmaceutically

acceptable acids, both inorganic acids such as hydrochloric, sulphuric, phosphoric, diphosphoric, hydrobromic or nitric acid and organic acids such as citric, fumaric, maleic, malic, ascorbic, succininc, tartaric, benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic or p-toluenesulphonic acid. Salts may also be formed with pharmaceutically acceptable bases such as alkali metal (eg sodium or potassium) and alkali earth metal (eg calcium or magnesium) hydroxides and organic bases such as alkyl amines, aralkyl amines or heterocyclic amines.

Particularly preferred compounds of the invention are:

1-(3-Dimethylamino-propyl)-3-(2-phenoxy-phenyl)-urea

1-[2-(4-Chloro-phenoxy)-pyridin-3-yl]-3-(3-dimethylaminopropyl)-urea

1-(3-Dimethylamino-propyl)-3-pyren-1-ylmethyl-urea

1-(3-Dimethylamino-propyl)-3-[(lR,2R)-5-phenyl-2-(1-phenyl-methanoyl)- cyclohexyl]-urea

1-(3-Dimethylamino-propyl)-3-[2-(4-phenoxy-phenyl)-ethyl]-urea

1-(3-Dimethylamino-propyl)-3-[3-methyl-5-(4-methyl-[1,2,3]thiadiazol-5- yl)-1-(4-trifluoromethoxy-phenyl)-1H-pyrazol-4-yl]-urea

2'-[3-(3-Dimethylamino-propyl)-ureido]-biphenyl-2-carboxylic acid (4- fluoro-phenyl)-amide

N-(3-Chloro-4-methyl-phenyl)-4-[3-(3-dimethylamino-propyl)-ureido]-3- phenyl-butyramide

1-[4-(4-Chloro-phenylsulfanyl)-thiophen-3-yl]-3-(3-dimethylamino-propyl)- urea

1-[2-(3,4-Dimethoxy-phenyl)-6-methyl-quinolin-4-yl]-3-(4-dimethylamino- propyl)-urea

1 -(6-Bromo-2-thiophen-3-yl-quinolin-4-yl)-3 -(3-dimethylamino-propyl)-urea

1-[3-(4-Chloro-phenyl)-4-cyano-5-isobutylsulfanyl-thiophen-2-yl]-3-(3- dimethylamino-propyl)-urea

1-[6-(2,4-Dichloro-phenyl)-cyclohex-3-enyl]-3-(3-dimethylamino-propyl)- urea

1-(2-Benzylsulfanyl-phenyl)-3-(3-dimethylamino-propyl)-urea

2-{2-[3-(3-Dimethylamino-propyl)-ureido]-phenylsulfanyl}-N-phenyl-

benzenesulfonamide

1-(3-Dimethylamino-propyl)-3-(2'-fluoro-biphenyl-4-yl)-urea

N-(3,5-Dichloro-phenyl)-2-{3-[3-(3-dimethylamino-propyl)-ureido]-pyridin- 2-ylsulfanyl}-acetamide

1-(3-Dimethylamino-propyl)-3-{2-[1-(1-trifluoromethyl-1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanoyl]-phenyl}-urea

8-{2-[3-(3-Dimethylamino-propyl)-ureido]-phenylsulfanyl}-naphthalene-1-carboxylic acid methylamide

1-[1-(3,4-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridin-3-yl]-3-(3-dimethylamino-propyl)-urea

1-(3-Dimethylamino-propyl)-3-(3-oxo-1 ,2,3-triphenyl-propyl)-urea

1-[5-(4-Chloro-phenyl)-1-(3,4-dichloro-phenyl)-1H-pyrazol-3-yl]-3-(3-dimethylamino-propyl)-urea

1-{4-[4-(4-Chloro-phenyl)-thiazol-2-yl]-phenyl}-3-(3-dimethylamino-propyl)-urea

1-(3-Dimethylamino-propyl)-3-[5-(4-fluoro-phenyl)-thiophen-2-yl]-urea

1-[3-(4-tert-Butyl-benzyloxy)-thiophen-2-yl]-3-(3-dimethylamino-propyl)-urea

1-(3-Dimethylamino-propyl)-3-[4-(4-phenyl-thiazol-2-yl)-phenyl]-urea

1-[3-(3,4-Dichloro-benzylsulfanyl)-thiophen-2-yl]-3-(3-dimethylamino-propyl)-urea

1-[2-(5-Chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfanyl)-phenyl]- 3-(3-dimethylamino-propyl)-urea

1-[2-(4-Chloro-benzylsulfanyl)-3-methyl-4-oxo-3,4-dihydro-quinazolin-7-yl]-3-(3-dimethylamino-propyl)-urea

1-(3-Dimethylamino-propyl)-3-{4-[4-(4-methoxy-phenyl)-pyrimidin-2-ylsulfanylmethyl]-phenyl}-urea

1-(4-Bromophenyl)-3-(3-(1-pyrrolidinyl) propyl) urea

1-(4-Bromophenyl)-3-(3-dimethylamino propyl) urea

3-(4-Bromophenyl)-1-methyl-1-(3-dimethylamino propyl) urea

1-(3-Phenyl-5-methoxy phenyl)-3-(3-dimethylamino propyl) urea

3-(4-Chlorophenyl)-1-methyl-1-(3-dimethylamino propyl) urea

1-(3-Nitrophenyl)-1-benzyl-3-(3-dimethylamino propyl) urea

1-Benzyl-1-(4-methyl-3-pyridinyl)-3-(3-dimethylamino propyl) urea 1-Methyl-1-(3,5-bistrifluoromethylphenyl)-3-(3-dimethylaminopropyl)urea 1-(2-Phenacyl-4-chorophenyl)-1-methyl-3-(3-dimethylamino propyl) urea 1-(2-Chloro-4-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea 1 -(3-Fluoro-5-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea 1-(3-N-tert-butoxycarbonyl-benzylamino)-3-(3-dimethylaminopropyl) urea N-(3-Dimethylamino-propyl)-2-[1-(4-fluorobenzoyl]-benzamide

2-[1-(4-Chlorobenzoyl]-N-(3-dimethylamino-propyl)-benzamide

5-(4-Chloro-phenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid (3-dimethylamino-propyl)-amide

5-Chloro-3-phenyl-1H-indole-2-carboxylic acid (3-dimethylamino-propyl)-amide

N-(3-Dimethylamino-propyl)-2-(2-phenylsulfamoyl-phenylsulfanyl)-benzamide

2-Benzylsulfanyl-N-(3-dimethylamino-propyl)-benzamide

6,8-Di-tert-butyl-4-oxo-4H-chromene-2-carboxylic acid (3-dimethylamino -propyl)-amide

3-(4-Chloro-phenyl)-4-cyano-5-isobutylsulfanyl-thiophene-2-carboxylic acid

(3 -dimethylamino-propyl)-amide

4-(4-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-3-nitro-benzamide N-(3-Dimethylamino-propyl)-4-(4-phenyl-thiazol-2-yl)-benzamide

1 -(3 -Dimethylamino-propyl)-3 -(2-phenoxyphenyl)-urea

1-[4-(4-Chloro-phenylsulfanyl)-thiophen-3-yl]-3-(3-dimethylamino-propyl)

-urea

1-(3-Dimethylamino-propyl)-3-(2'-fluoro-biphenyl-4-yl)-urea

N-(3-Dimethylamino-propyl)-2-[1-(4-fluorobenzoyl]-benzamide

N-(3-Dimethylamino-propyl)-3-phenoxy-benzamide

N-(3-Dimethylamino-propyl)-2-phenoxy-benzamide

2-(4-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-nicotinamide

4'-n-Propyl-biphenyl-4-carboxylic acid (3-dimethylamino-propyl)-amide

2-[1-(4-Bromo-phenyl)-methanoyl]-cyclohexanecarboxylic acid (3-dimethylamino-propyl)-amide

5-(3-Trifluoromethyl-phenyl)-furan-2-carboxylic acid (3-dimethylamino-propyl)-amide

2-[1-(4-Chlorobenzoyl]-N-(3-dimethylamino-propyl)-benzamide

2-Phenyl-quinoline-4-carboxylic acid (3-dimethylamino-propyl)-amide

2-[1-(4-Chloro-3-nitrobenzoyl)]-N-(3-dimethylamino-propyl)-benzamide

N-(3-Dimethylamino-propyl)-2-pyren-1-yl-acetamide

N-(3-Dimethylamino-propyl)-2-[1-(3-methyl-benzo[b]thiophen-2-yl)-methanoyl]-benzamide

4-Chloro-N-(3-dimethylamino-propyl)-2-phenoxy-benzamide

N-(3-Dimethylamino-propyl)-3-(4-phenoxy-phenyl)-propionamide

N-(3 -Dimethylamino-propyl)-2-[1-(1-trifluoromethyl-1,3,4,9-tetrahydro-b-carbolin-2-yl)-methanoyl]-benzamide

1-(4-Chloro-phenyl)-2,5-dimethyl-1-pyrrole-3-carboxylic acid (3-dimethylamino-propyl)-amide

2-{1-[(3-Dimethylamino-propylcarbamoyl)-methyl]-cyclopentyl}-N-(4-trifluoromethoxy-phenyl)-acetamide

8-[2-(3-Dimethylamino-propylcarbamoyl)-phenylsulfanyl]-naphthalene-1-carboxylic acid methylamide

3-Methyl-5-(4-methyl-[1,2,3]thiadiazol-5-yl)-1-(4-trifluoromethoxy-phenyl)-1H-pyrazole-4-carboxylic acid (3-dimethylamino-propyl)-amide

6,8-Di-tert-butyl-4-oxo-4H-chromene-2-carboxylic acid (3-dimethylamino-propyl)-amide

2-(Furan-2-yl)-quinoline-4-carboxylic acid (3-dimethylamino-propyl)-amide

Biphenyl-2,2'-dicarboxylic acid 2'-[(3-dimethylamino-propyl)-amide]-2-[(4-fluoro-phenyl)-amide]

3-Phenyl-pentanedioic acid (3-chloro-4-methyl-phenyl)-amide (3-dimethylamino-propyl)-amide

2-(3,4-Dimethoxy-phenyl)-6-methyl-quinoline-4-carboxylic acid (3-

dimethylamino-propyl)-amide

6-Bromo-(2-thiophen-3-yl)-quinoline-4-carboxylic acid (3-dimethylamino-propyl)-amide

3-(4-Chloro-phenyl)-4-cyano-5-isobutylsulfanyl-thiophene-2-carboxylic acid (3-dimethylamino-propyl)-amide

4-(4-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-3-nitro-benzamide

6-(2,4-Dichloro-phenyl)-cyclohex-3-ene carboxylic acid (3-dimethylamino-propyl)-amide

N-(3-Dimethylamino-propyl)-2-(2-phenylsulfamoyl-phenylsulfanyl)-benzamide

2'-Fluoro-[1,1'-biphenyl]-4-carboxylic acid (3-dimethylamino-propyl)-amide

2-Benzylsulfanyl-N-(3-dimethylamino-propyl)-benzamide

Pyrazine-2,3-dicarboxylic acid 2-[(3-dimethylamino-propyl)-amide] 3- [(5,6,7,8-tetrahydro-naphthalen-1-yl)-amide]

2-[(3,5-Dichloro-phenylcarbamoyl)-methylsulfanyl]-N-(3-dimethylamino-propyl)-nicotinamide

2-(3-Trifluoromethyl-phenyl)-thiazole-4-carboxylic acid (3-dimethylamino-propyl)-amide

2-(4-Chloro-phenyl)-thiazole-4-carboxylic acid (3-dimethylamino-propyl)-amide

5-Chloro-1-(2,4-dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (3 -dimethylamino-propyl)-amide

1-(2,4-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (3-dimethylamino-propyl)-amide

5-Chloro-1-(3,4-dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3 -carboxylic acid (3 -dimethylamino-propyl)-amide

1-(3,4-Dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (3-dimethylamino-propyl)-amide

5-Chloro-1-(2,6-dichloro-benzyl)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (3-dimethylamino-propyl)-amide

1,1-Dimethyl-indan-4-carboxylic acid (3-dimethylamino-propyl)-amide

N-(3-Dimethylamino-propyl)-2-[1-(4-ethyl-phenyl)-methanoyl]-benzamide

N-(3-Dimethylamino-propyl)-3-(2,4,5-trimethyl-phenyl)-butyr amide

2-[3-(3,4-Dichloro-phenyl)-ureido]-N-(3-dimethylamino-propyl)-benzamide

N-(3-Dimethylamino-propyl)-4-oxo-2,3,4-triphenyl-butyramide

5-(4-Chloro-phenylsulfanyl)-[1,2,3]thiadiazole-4-carboxylic acid (3-dimethylamino-propyl)-amide

2-(3-Chloro-5-trifluoromethyl-pyridin-2-ylsulfanyl)-3-methyl-3H-imidazole- 4-carboxylic acid (3-dimethylamino-propyl)-amide

2-(2-Chloro-4-trifluoromethyl-phenyl)-[1,3]-thiazole-4-carboxylic acid (3-dimethylamino-propyl)-amide

2-(2,3-Dihydro-1-benzofuran-5-yl)-1,3-thiazole-4-carboxylic acid (3-dimethylamino-propyl)-amide

2-(2,3-Dichloro-phenyl)-1,3-thiazole-4-carboxylic acid (3-dimethylamino-propyl)-amide

4-[4-(4-Chloro-phenyl)-thiazol-2-yl]-N-(3-dimethylamino-propyl)-benzamide

5-(4-Fluoro-phenyl)-thiophene-2-carboxylic acid (3-dimethylamino-propyl)-amide

4-Methyl-2-(3-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid (3-dimethylamino-propyl)-amide

3-(4-tert-Butyl-benzyloxy)-thiophene-2-carboxylic acid (3-dimethylamino-propyl)-amide

4-Oxo-3-(3-trifluoromethyl-phenyl)-3,4-dihydro-phthalazine-1-carboxylic acid (3-dimethylamino-propyl)-amide

2-(4-Chloro-phenyl)-N-(3-dimethylamino-propyl)-4-oxo-4-phenyl-butyramide

5-(4-Chloro-phenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid (3-dimethylamino-propyl)-amide

N-(3-Dimethylamino-propyl)-4-(4-phenyl-thiazol-2-yl)-benzamide

1-(2,4,5-Trichloro-phenylsulfonyl)-pyrrolidine-2-carboxylic acid (3-dimethylamino-propyl)-amide

3-(3,4-Dichloro-benzylsulfanyl)-thiophene-2-carboxylic acid (3-

dimethylamino-propyl)-amide

5-Chloro-3-phenyl-1H-indole-2-carboxylic acid (3-dimethylamino-propyl)-amide

N-(3-Dimethylamino-propyl)-2-[1-(4-fluoro-benzyl)-1H-indol-3-yl]-acetamide

2-Phenyl-imidazo[1,2-a]pyridine-3-carboxylic acid (3-dimethylamino-propyl)-amide

N-(3-Dimethylamino-propyl)-2-(7-ethyl-1H-indol-3-yl)-4-oxo-4-phenyl-butyramide

Phenyl-trifluoromethyl-thieno[3,2-b]pyridine-2-carboxylic acid (3-dimethylamino-propyl)-amide

3-(4-Nitro-3-trifluoromethyl-phenoxy)-thiophene-2-carboxylic acid (3-dimethylamino-propyl)-amide

2-(5-Chloro-1-methyl-3-phenyl-1H-pyrazol-4-ylmethylsulfanyl)-N-(3-dimethylamino-propyl)-benzamide

2-(4-Chloro-benzylsulfanyl)-3-methyl-4-oxo-3,4-dihydro-quinazoline-7

-carboxylic acid (3-dimethylamino-propyl)-amide

N-(3 -Dimethylamino-propyl)-4- [4-(4-methoxy-phenyl)-pyrimidin-2

-ylsulfanylmethyl]-benzamide

1 -(4-chlorobenzyl)-3-(2-N,N-dimethylethylamido)-6-pyridone

1-(2,6-dichlorobenzyl)-3-(3-N,N-dimethylpropylamido)-6-pyridone

1 -(3 -trifluoromethylbenzyl)-3 -(2-N,N-dimethylethylamido)-2-pyridone 1-(2,6-dichlorobenzyl)-3-(2-N,N-dimethylethylamido)-2-pyridone

1-(3,4-dichlorobenzyl)-3-(N-[2,N,N-dimethylaminoethylamido])-2-pyridone 1-(2,6-dichlorobenzyl)-3-(N-[2-N,N-dimethylaminoethylamido])-6-pyridone

5-chloro-1-(3,4-dichlorobenzyl)-3-(2-N,N-dimethylaminoethylamido)-6

-pyridone

5-chloro-3-(2-N,N-dimethylaminoethylamido)-1-(3-trifluoromethylbenzyl)-6-pyridone

5-chloro-1-(3,4-dichlorobenzyl)-3-N-(2-[N',N'-dimethylaminoethylamido])-2-pyridone

5-chloro-1-(4-chlorobenzyl)-3-N-(2-(N',N'-dimethylamino)ethyl)amido-2-pyridone

5-chloro-1-(3-trifluoromethylbenzyl)-3-N-(2-(N',N'-dimethylamino)ethyl) amido-2-pyridone

1-benzyl-5-chloro-3-N-(2-[N',N'-dimethylamino]ethyl)carboxamido-6-pyridone

5-chloro-1-(4-chlorobenzyl)-3-N-(2-[N',N,-dimethylamino]ethyl)carboxamido

-6-pyridone

4-(2,4-dichlorobenzoyl)pyrrole-2-N-dimethylaminopropylcarboxamide 4-[(N-[3-(N',N'-dimethylaminopropyl)]carboxamido]-2-phenylthiazole

4-(N-(3-N,,N'-dimethylaminopropyl)carboxamido)-2-(4-pyridinyl)thiazole

2-[4-(N-[3-N',N'-dimethylaminopropyl]carboxamido)phenyl-4- (3-trifluoromethylphenyl)]thiazole

4-(4-chlorophenyl)-2-(4-[3-N',N'-dimethylaminopropyl]carboxamido)phenyl) thiazole

1-(3,5-bis(trifluoromethyl)benzyl)-3-[N-(2-dimethylaminoethyl)

carboxamido]-2[1H]-pyridone

N-(3-dimethylaminopropyl)-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy) phenylsulfonamide

N 1-[3-(dimethylamino)propyl]-3-[3-chloro-5-(trifluoromethyl)-2-pyridyl] propanamide

3-(N-(2-dimethylaminoethyl)carboxamido]-1-(4-trifluoromethylbenzyl))-2

[1H]-pyridone

1-ethyl-3-(3-dimethylaminopropyl)urea

1-(3-(dimethylamino)-propyl)-3-phenylurea

N 1-[2-(2,4-dichlorophenoxy)phenyl]-N2-[3-(dimethylamino)propyl] ethanediamide

N4-[3-(dimethylamino)propyl]-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-c arboxamide

N-[[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbonyl]-N'-[3-(dimethyla mino)propyl]urea

N-(4-chlorophenyl)-N'-[3-dimethylaminopropyl]urea

N-(3,5-Dichloro-phenyl)-3-(3-dimethylamino-propylamino)-propionamide [3-(2-Ethyl-6-methyl-pyridin-3-yloxy)-propyl]-dimethyl-amine

8-(3-Dimethylamino-propoxy)-1,3,7-trimethyl-3,7-dihydro-purine-2,6-dione 2-(3 -Dimethylamino-propylamino)-isophthalonitrile

Dimethylamino-(3-methyl-benzo[b]thiophen-2-yl)-propan-1-one (HCl) N-Benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-propane-1,3-diamine

N,N-Dimethyl-N-(5-nitro-quinolin-8-yl)-propane-1,3-diamine

1-(4-Chloro-phenyl)-3-(3-dimethylamino-propyl)-urea

2- Amino-N-(3-dimethylamino-propyl)-benzamide

3-Phenyl-acrylic acid 3-dimethylamino-propyl ester

3,5-Dinitro-benzoic acid 2-dimethylamino-ethyl ester

[4-(4-Bromo-phenyl)-3-(3-dimethylamino-propyl)-3H-thiazol-2-ylidene]-phenyl-amine

3-Methyl-benzofuran-2-carboxylic acid dimethylamino-dimethyl-propyl ester

N'-(2-Chloro-4-nitro-phenyl)-N,N-dimethyl-propane-1,3-diamine

[3-(3-Dimethylamino-propyl)-5-(4-nitro-phenyl)-3H-thiazol-2-ylidene]-phenyl-amine

[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-dimethyl-amine

2,3-Dimethyl-1H-indole-5-carboxylic acid 2-dimethylamino-ethyl ester

N'-(3,4-Dinitro-5-pyridin-2-yl-thiophen-2-yl)-N,N-dimethyl-propane-1,3-diamine

Cyclooctyl-dithiocarbamic acid 2-dimethylamino-ethyl ester (HCl)

N-(2,6-Difluoro-phenyl)-C-dimethylamino-acetamide

2-Acetylamino-3-(4-chloro-phenyl)-N-(3-dimethylamino-propyl)-acrylamide N-[2-[5-(4-Bromo-phenyl)-furan-2-yl]-1-(3-dimethylamino-propyl carbamoyl)-vinyl]-4-methyl-benzamide

2,6-Bis-(3-dimethylamino-propylamino)-3-nitro-benzonitrile

N-[2-(2,4-Dichloro-phenoxy)-phenyl]-N'-(3-dimethylamino-propyl)-oxalamide

3,5-Dichloro-N-(3-dimethylamino-propyl)-2,6-dimethoxy-benzamide

2-Dimethylaminomethyl-3,4-dihydro-2H-naphthalen-1-one (HCl)

2-({1-[N-(3-Dimethylamino-propyl)-3-trifluoromethyl-phenyl]- methanimidoyl}-amino)-6-fluoro-benzoic acid

2,4-Dichloro-N-(3-dimethylamino-propyl)-N'-hydroxy-benzamidine

3-(3-Methyl-ureido)-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid

(3 -dimethylamino-propyl)-amide

5-Bromo-N-(3-dimethylamino-propyl)-2-hydroxy-benzamide

N-(2,4-Dichloro-phenyl)-6-(2-dimethylamino-ethylsulfanyl)-4- trifluoromethyl-nicotinamide

1-(2,6-Dichloro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid

(2-dimethylamino-ethyl)-amide

3-Amino-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid

(3-dimethylamino-propyl)-amide

Certain compounds of the invention are novel. Thus, the present invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, in which R1, R2, Z, R3, Y, X and R4 are as defined above except for:

2-Benzylsulfanyl-N-(3-dimethylamino-propyl)-benzamide

N-(3-Dimethylamino-propyl)-3-phenoxy-benzamide

1-(4-chlorobenzyl)-3-(2-N,N-dimethylethylamido)-6-pyridone

1-(2,6-dichlorobenzyl)-3-(3-N,N-dimethylpropylamido)-6-pyridone

1-(3-trifluoromethylbenzyl)-3-(2-N,N-dimethylethylamido)-2-pyridone 1-(2,6-dichlorobenzyl)-3-(2-N,N-dimethylethylamido)-2-pyridone

1-(3,4-dichlorobenzyl)-3-(N-[2,N,N-dimethylaminoethylamido])-2-pyridone 1-(2,6-dichlorobenzyl)-3-(N-[2-N,N-dimethylaminoethylamido])-6-pyridone

5-chloro-1-(3,4-dichlorobenzyl)-3-(2-N,N-dimethylaminoethylamido)-6- pyridone

5-chloro-3-(2-N,N-dimethylaminoethylamido)-1-(3-trifluoromethylbenzyl)-6- pyridone

5-chloro-1-(3,4-dichlorobenzyl)-3-N-(2-[N',N'-dimethylaminoethylamido])-2- pyridone

5-chloro-1-(4-chlorobenzyl)-3-N-(2-(N',N'-dimethylamino)ethyl)amido-2-pyridone

5-chloro-1-(3-trifluoromethylbenzyl)-3-N-(2-(N',N'-dimethylamino)ethyl) amido-2-pyridone

1-benzyl-5-chloro-3-N-(2-[N',N'-dimethylamino]ethyl)carboxamido-6-pyridone

5-chloro-1-(4-chlorobenzyl)-3-N-(2-[N',N'-dimethylamino]ethyl)

carboxamido-6-pyridone

4-(2,4-dichlorobenzoyl)pyrrole-2-N-dimethylaminopropylcarboxamide 4-[(N-[3-(N',N'-dimethylaminopropyl)]carboxamido]-2-phenylthiazole

4-(N-(3-N',N'-dimethylaminopropyl)carboxamido)-2-(4-pyridinyl)thiazole

2-[4-(N-[3-N',N'-dimethylaminopropyl]carboxamido)phenyl-4- (3-trifluoromethylphenyl]thiazole

4-(4-chlorophenyl)-2-(4-[3-N',N'-dimethylaminopropyl]carboxamido)phenyl) thiazole

1-(3,5-bis(trofluoromethyl)benzyl)-3-[N-(2-dimethylaminoethyl)

carboxamido]-2[1H]-pyridone

N-(3-dimethylaminopropyl)-4-(3-chloro-5-trifluoromethyl-2-pyridyloxy) phenylsulfonamide

N 1-[3-(dimethylamino)propyl]-3-[3-chloro-5-(trifluoromethyl)-2-pyridyl] propanamide

3-(N-(2-dimethylaminoethyl)carboxamido]-1-(4-trifluoromethylbenzyl))-2

[1H]-pyridone

1-ethyl-3-(3-dimethylaminopropyl)urea

1-(3-(dimethylamino)-propyl)-3-phenylurea

N 1-[2-(2,4-dichlorophenoxy)phenyl]-N2-[3-(dimethylamino)propyl] ethanediamide

N4-[3-(dimethylamino)propyl]-3-(2,6-dichlorophenyl)-5-methylisoxazole-4-c arboxamide

N-[[3-(2,6-dichlorophenyl)-5-methylisoxazol-4-yl]carbonyl]-N'-[3- (dimethylamino)propyl]urea

N-(4-chlorophenyl)-N'-[3-dimethylaminopropyl]urea

N-(3,5-Dichloro-phenyl)-3-(3-dimethylamino-propylamino)-propionamide [3-(2-Ethyl-6-methyl-pyridin-3-yloxy)-propyl]-dimethyl-amine

8-(3-Dimethylamino-propoxy)-1,3,7-trimethyl-3,7-dihydro-purine-2,6-dione 2-(3-Dimethylamino-propylamino)-isophthalonitrile

Dimethylamino-(3-methyl-benzo[b]thiophen-2-yl)-propan-1-one (HCl) N-Benzo[1,3]dioxol-5-ylmethyl-N,N-dimethyl-propane-1,3-diamine

N,N-Dimethyl-N-(5-nitro-quinolin-8-yl)-propane-1,3-diamine

1-(4-Chloro-phenyl)-3-(3-dimethylamino-propyl)-urea

2-Amino-N-(3-dimethylamino-propyl)-benzamide

3 -Phenyl-acrylic acid 3-dimethylamino-propyl ester

3,5-Dinitro-benzoic acid 2-dimethylamino-ethyl ester

[4-(4-Bromo-phenyl)-3-(3-dimethylamino-propyl)-3H-thiazol-2-ylidene]-phenyl-amine

3-Methyl-benzofuran-2-carboxylic acid dimethylamino-dimethyl-propyl ester

N'-(2-Chloro-4-nitro-phenyl)-N,N-dimethyl-propane-1,3-diamine

[3-(3-Dimethylamino-propyl)-5-(4-nitro-phenyl)-3H-thiazol-2-ylidene]-phenyl-amine

[3-(10,11-Dihydro-dibenzo[a,d]cyclohepten-5-ylidene)-propyl]-dimethyl-amine

2,3-Dimethyl-1H-indole-5-carboxylic acid 2-dimethylamino-ethyl ester

N'-(3,4-Dinitro-5-pyridin-2-yl-thiophen-2-yl)-N,N-dimethyl-propane-1,3-diamine

Cyclooctyl-dithiocarbamic acid 2-dimethylamino-ethyl ester (HCl)

N-(2,6-Difluoro-phenyl)-C-dimethylamino-acetamide

2-Acetylamino-3-(4-chloro-phenyl)-N-(3-dimethylamino-propyl)-acrylamide N-[2-[5-(4-Bromo-phenyl)-furan-2-yl]-1-(3-dimethylamino-propylcarbamoyl)-vinyl]-4-methyl-benzamide

2,6-Bis-(3-dimethylamino-propylamino)-3-nitro-benzonitrile

N-[2-(2,4-Dichloro-phenoxy)-phenyl]-N'-(3-dimethylamino-propyl)-oxalamide

3,5-Dichloro-N-(3-dimethylamino-propyl)-2,6-dimethoxy-benzamide

2-Dimethylaminomethyl-3,4-dihydro-2H-naphthalen-1-one (HCl)

2-({1-[N-(3-Dimethylamino-propyl)-3-trifluoromethyl-phenyl]- methanimidoyl}-amino)-6-fluoro-benzoic acid

2,4-Dichloro-N-(3-dimethylamino-propyl)-N'-hydroxy-benzamidine

3-(3-Methyl-ureido)-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid

(3 -dimethylamino-propyl)-amide

5-Bromo-N-(3-dimethylamino-propyl)-2-hydroxy-benzamide

N-(2,4-Dichloro-phenyl)-6-(2-dimethylamino-ethylsulfanyl)-4- trifluoromethyl-nicotinamide

1-(2,6-Dichloro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid

(2-dimethylamino-ethyl)-amide

3-Amino-4-oxo-3,4-dihydro-quinazoline-2-carboxylic acid

(3-dimethylamino-propyl)-amide

Compounds of the invention in which P is -U-W- may be prepared by reacting a compound of formula (II)


wherein Z, R1 and R2 are as defined above and W/ is a group WH wherein W is as defined above, with a compound of formula (III)


wherein R4 is as defined above and U/ is a group -UL wherein U is as defined above and L is a hydroxy group or a leaving group such as a halogen atom.

Compounds of formulae (II) and (III) are known compounds, or may be prepared by analogy with known methods.

Typically, the reaction takes place in the presence of a base such as diisopropylethylamine or the equivalent polymer bound resin N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), and a coupling agent such as O-(7-azabenzotriazol-1-yl)-N,N, N, N-tetramethyluronium hexafluorophosphate (HATU). The reaction typically takes place in a solvent such as acetonitrile at a temperature of from 0 to 100 °C, preferably from 20 to 80 °C. The work-up typically involves the use of a sequestration enabling reagent such as tetrafluorophthalic anhydride and polymer bound scavenger resins to remove unwanted starting materials. Such techniques are described in Parlow et al Tetrahedron Lett., 1997, 38, 7959.

Compounds of the invention wherein P is -ΝH-CO-W- can be prepared by reacting a compound of formula (II) above with a compound of formula (IV)


wherein R4 is as defined above.

Typically, the reaction takes place in a hydrocarbon solvent such as toluene at a temperature of from 0 to 100 °C. The work-up typically involves the use of a sequestration enabling reagent such as tetrafluorophthalic anhydride and polymer bound scavenger resins to remove unwanted starting materials. The amides thereby prepared may be converted to the corresponding amidines by standard methods.

The compounds of formula (IV) may be prepared by techniques known in the art. For example, they may be prepared by reacting a compound of formula (V)


wherein R4 is as defined above, with diphenylphosphoryl azide (DPP A), in the presence of a base such as triethylamine. Typically, the reaction takes place under reflux, in a solvent such as toluene. Compounds of formula (V) are known compounds or may be prepared by analogy with known methods.

Compounds of the invention wherein P is -X-U-W- wherein X, U and W are as defined above can be prepared by reacting a compound of formula (II) above with a compound of formula (VI)


wherein R4, X and U are as defined above and L is a hydroxy group or leaving group such as a 4-nitro-phenoxy group. Typically, the reaction takes place in a hydrocarbon solvent such as tetrahydrofuran at a temperature of from 60 to 70 °C. The work-up typically involves the use of a sequestration enabling reagent such as tetrafluorophthalic anhydride and polymer bound scavenger resins to remove unwanted starting material.

The compounds of formula (VI) are known compounds or may be prepared by analogy with known methods. For example, compounds of formula (VI) in which U is -CO- can be prepared by reacting a compound of formula (VII)


wherein R4 and X are as defined above, with a chloroformate, for example an aromatic chloroformate such as 4-nitrophenyl chloroformate. Typically, the reaction takes place under reflux, in a solvent such as anhydrous THF. Further, compounds of formula (VI) in which U is -C-(=ΝH)- can, for example, be prepared from the corresponding nitrile of formula R4-X-C≡N, for example by reaction with

hydrochloric acid.

Compounds of the invention in which P is -X-Y- or -X-Y-W- and R4 is other than -COR//, -CO2R//, -S(O)2R// and -CONR/R// can be made by standard techniques, for example by reacting a compound of formula (VIII)


wherein R4 is other than -COR//, -CO2R//, S(O)2R// and -CONR/R// and X is as defined above, with a compound of formula (IX)


wherein Y, Z, R1 and R2 are as defined above and L represents a hydroxy group or a leaving group such as a halogen. The reaction is typically conducted in the presence of a base at from -78°C to the reflux temperature of the solvent.

The compounds of formulae (VIII) and (IX) are known compounds or may be prepared by analogy with known methods.

Compounds of the invention in which P is -X-U-W- and R4 is -COR//, -CO2R//, -S(O)2R// or -CONR/R// can be made in an analogous fashion by reacting a compound of formula (X)


wherein R4, X and U are as defined above and L represents a hydroxy group or a leaving group such as a halogen, with a compound of formula (XI)


wherein W, Z, R1 and R2 are as defined above.

The compounds of formula (X) and (XI) are known compounds or may be prepared by analogy with known methods.

Compounds in which P is X or W and R4 is other than -COR//, -CO2R//, -S(O)2R// and -CONR/R// can be prepared, for example, by reacting a compound of formula (XII)


wherein A is -X- or -W-, wherein X and W are as defined above and R4 is other than -COR//, -CO2R//, -S(O)2R// and -CONR/R//, with a compound of formula (XIII)


wherein Z, R1 and R2 are as defined above and L is a leaving group such as a triflate group or a halogen atom. The reaction can be conducted under standard conditions. Typically, it takes place in the presence of a base in a solvent such as

DMF.

The compounds of formula (XII) are known compounds or may be prepared by analogy with known methods. The compounds of formula (XIII) are also known compounds or may be prepared by analogy with known methods. For example, they can be prepared from a corresponding compound of formula HO-Z-NR1R2 by reaction with triflic anhydride or with PCl5.

Compounds of the invention in which P is X or W and R4 is -COR//, -CO2R//, -S(O)2R// or CONR/R// can be prepared by reacting a compound of formula (IXV)


wherein A, Z, R1 and R2 are as defined above, with R4-L, wherein R4 is as defined above and L is a hydroxy group or a leaving group, for example a halogen. The reaction can be conducted under standard conditions, such as those given above for the reaction of compounds of formulae (VIII) and (IX).

Compounds of formula (IXV) and compounds of formula R4-L are known compounds or may be prepared by analogy with known methods.

Compounds of the invention in which P is Y, Y is -CO- and R4 is aryl or heteroaryl may be prepared, for example, by a Friedel-Crafts reaction between a compound of formula (XV)


wherein R4 is aryl or heteroaryl, and a compound of formula (XVI)


wherein L is a hydroxy group, a group OR wherein R is alkyl, or a halogen, for example chlorine, and Z, V, R1 and R2 are as defined above. The reaction can be performed under conventional conditions, in the presence of a catalyst such as AlCl3.

Examples of such reactions are described in section 1-15 of "Advanced Organic

Chemistry", 3rd Edition, by Jerry March.

The compounds of formulae (XV) and (XVI) are known compounds or may be prepared by analogy with known methods.

Compounds in which P is -Y- or -XY- and in which X, Y and R4 are as defined above may be prepared, for example, by reacting a compound of formula

(XVII)


wherein R4 is as defined above, Y/ is -U- or -X-U-, and L is a hydroxy group or a leaving group, for example a halogen atom, with an organometallic compound of formula (XVIII)


wherein B is -V-Z- wherein V and Z are as defined above, R1 and R2 are as defined above and M is a metal-containing moiety such as Li or -MgX wherein X is a halogen atom such as bromine.

The reaction can be carried out under conventional conditions. Preferably, M in the formula (XVIII) is Li. When M in the formula (XVIII) is -MgX, it may be necessary to conduct the reaction at around -78 °C and to use a large excess of the compound of formula (XVII).

The compounds of formula (XVII) are known compounds or may be prepared by analogy with known methods. The compounds of formula (XVIII) are also known compounds or may be prepared by analogy with known methods. For example, compounds of formula (XVIII) in which M is Li can be prepared by reacting a corresponding compound of formula Br-B-NR1R2 with lithium or with magnesium.

In some cases, it may be necessary to protect the -NR1R2 group during the synthesis of the compounds of formula (XVIII) or during the reaction between the compounds of formulae (XVIII) and (XVII). This can be done by standard techniques.

Compounds of the invention in which P is -Y-W- or -XYW-, wherein Y is -UV- and -V- is -(C1-C6 alkyl)-, can be made, for example, by reacting a compound of formula (IXX)


wherein R4 and P are as defined above and L is a leaving group such as a halogen atom or a triflate group, with a compound of formula (XX)


wherein W, Z, R1 and R2 are as defined above. The reaction can be conducted under conventional conditions. Typically, it is conducted in the presence of a base. If necessary, the NR1R2 group can be protected during the reaction by conventional means.

The compounds of formulae (IXX) and (XX) are knowN compounds, or may be prepared by analogy with known methods. For example, the compounds of formula (IXX) can be prepared by reacting a corresponding compound of formula R4-P-OH with triflic anhydride or PCl5.

Compounds in which P is a direct bond can be prepared by conventional synthetic techniques.

A compound of the invention can, of course, be converted to a different compound of the invention by standard functional group intercon versions known to those of skill in the art. For example, a compound of the invention in which U is -CO- can be converted to a compound of the invention in which U is -C(=NR)- by reaction with a compound of formula RNH2. Suitable such reactions are described in section 6-14 of "Advanced Organic Chemistry" 3rd Edition, by Jerry March.

Pharmaceutically acceptable salts of the compounds of formula (I) may be prepared by salifying a compound of formula (I) with an appropriate acid or base.

The compounds of the invention are activators of sGC. They can be used as selective sGC activators. A compound of the invention can therefore be used as a vasodilator or to inhibit platelet aggregation. It can be used for the treatment or prevention of peripheral vascular diseases such as hypertension, angina pectoris, arteriosclerosis, or for the treatment or prevention of glaucoma, preeclampsia, Raynaud's Syndrome, stroke or erectile dysfunction. Further, the compounds of the invention are effective in improving ocular blood flow. They can therefore be used in the treatment and prevention of age-related macular degeneration (AMD). For example, they can be used in the treatment and prevention of non-exudative or exudative AMD. They can also be used in the treatment and prevention of neo vascular or non-neovascular AMD.

Conditions attributable to down regulation of sGC can thus be alleviated.

Accordingly, the present invention also provides a compound of formula (I), as defined above, or a pharmaceutically acceptable salt thereof, for use in the treatment of the human or animal body, wherein R1, R2, Z, R3, Y, X and R4 are as defined above.

The compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules. The compounds of the invention may also be administered parenterally, either

subcutaneously, intravenously, intramuscularly, intrasternally, transdermally or by infusion techniques. The compounds may also be administered as suppositories.

A compound of the invention is typically formulated for administration with a pharmaceutically acceptable carrier or diluent. For example, solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations. Such pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film coating processes.

Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.

Suspensions and emulsions may contain as carrier, for example a natural

gum, agar, sodium alginte, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol. The suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.

Solutions for intravenous or infusions may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.

A therapeutically effective amount of a compound of the invention is administered to a patient. A typical daily dose is from about 0.1 to 50 mg per kg of body weight, according to the activity of the specific compound, the age, weight and conditions of the subject to be treated , the type and severity of the disease and the frequency and route of administration. Preferably, daily dosage levels are from 5 mg to 2 g.

The Examples which follow illustrate the invention.

EXAMPLES

The synthesis of some of the compounds of the invention is detailed below.

Examples 1 to 69

The aryl acid (different for each reaction) (0.1 mmol), 3-(dimethylamino)-propylamine (10 mg, 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-1-yI)-N, N, N, N-tetramethyluronium hexafluorophosphate (HATU) (38 mg, 0.1 mmol) were 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.

Tetrafluorophthalic anhydride (65 mg, 0.3 mmol) was then added and the reaction mixture was shaken under nitrogen for 18 hours. Macroporous

triethylammonium methylpolystyrene carbonate resin (MP-carbonate), (610 mg, 1.96 mmol, loading 3.18 mmol/g) was then added and the reaction mixture was shaken under nitrogen for a further 48 hours. The reactions were then filtered through filter syringes into vials and washed with methanol. The solvent was removed on a vacuum concentrator and each product was weighed and analysed by LC-MS.

This method was used to synthesise the following compounds. The molecular weight, purity and yield of the compounds synthesised is shown in Table 1.

Examples 70 to 99

The aryl acid (different for each reaction) (0.1 mmol) was stirred under nitrogen in anhydrous toluene (2 mL) and heated to 50 °C. Triethylamine (10 mg, 0.1 mmol) dissolved in 1 mL of anhydrous toluene was then added. The temperature was raised to 80 °C and diphenylphosphorylazide (DPP A), (27.0 mg, 0.1 mmol) was added.

The reaction was kept at this temperature for 1 hour then cooled to room temperature while still stirring under nitrogen.

3-(Dimethylamino)-propylamine (10 mg, 0.1 mmol) was added and the whole mixture was stirred at room temperature overnight. Tetrafluorophthalic anhydride (64.7 mg, 0.3 mmol) was added and the reaction stirred for a further 18 hours.

Following this 20 equivalents of macroporous triethylammonium methylpolystyrene carbonate resin (MP-carbonate), (610 mg, 1.96 mmol) was added and the reactions were stirred for another 24 hours. Each reaction was then filtered through filter syringes into vials and washed with methanol. The solvent was removed using a vacuum concentrator and each product was weighed and analysed by LC-MS.

This method was used to synthesise the following compounds. The molecular weight, purity and yield of the compounds synthesised is shown in Table 2.

Example 100

1-(4-Bromophenyl)-3-(3-(1-pyrrolidinyl) propyl) urea (CFM2138)

4-Nitrophenyl chloroformate (87.0 mg, 0.436 mmol), 4-bromoaniline (50.0 mg, 0.29 mmol) and triethylamine (44.0 mg, 0.436 mmol) were refluxed under nitrogen in anhydrous THF (20 mL) for 18 hours. After this time 1-(3-aminopropyl) pyrrolidine (55.0 mg, 0.436 mmol) was added and the whole reaction mixture was refluxed for a further 2 hours.

The reaction mixture was cooled to room temperature and tetrafluorophthalic anhydride (191.0 mg, 0.87 mmol) was added. The reaction was stirred at room temperature under nitrogen for 1 hour, then 6 equivalents of tris-(2-aminoethyl)amine polystyrene resin (PS-trisamine), (500 mg, 1.74 mmol, loading 3.5 mmol/g) was added and the reaction stirred for 2 hours. Following this 20 equivalents of Dowex AG1 resin (OH- form) (1.68 g, 5.8 mmol, loading 3.45 mmol/g) was added and the mixture was stirred for 18 hours at room temperature.

It should be noted that the Cl- form of the resin was converted to the OH- form by washing with 20 volumes of 1M NaOH solution, followed by distilled water until the washings are neutral. Another 20 equivalents of the resin was added after this time and the reaction was stirred for a further 2 hours. The reaction mixture was then filtered and the solvent removed using a vacuum concentrator.

Example 101

1-(4-Bromophenyl)-3-(3-dimethylamino propyl) urea (CFM2134)

Prepared as in Example 100 using 4-nitrophenyl chloroformate (77.2 mg, 0.38 mmol), 4-bromoaniline (30.0 mg, 0.174 mmol) and triethylamine (38.8 mg, 0.38 mmol) to form the intermediate followed by 3-(dimethylamino)propylamine (26.6 mg, 0.26 mmol) to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using MeOH/CHCl3 (40:60).

Example 102

3-(4-Bromophenyl)-1-methyl-1-(3-dimethylamino propyl) urea (CFM2139)

Prepared as in Example 100 using 4-nitrophenyl chloroformate (87.0 mg, 0.436 mmol), 4-bromoaniline (50.0 mg, 0.29 mmol) and triethylamine (44.0 mg, 0.436 mmol) refluxed for 5 hours in anhydrous THF (20mL) to form the intermediate. Then N,N,N-trimethyl-1,3-propanediamine (50.5 mg, 0.436 mmol) was added and

the reaction mixture refluxed for 18 hours to form the title compound. Work-up as in Example 100.

Example 103

1-(3-Phenyl-5-methoxy phenyl)-3-(3-dimethylamino propyl) urea (CFM2148)

Prepared as in Example 100 using 4-nitrophenyl chloroformate (45.5 mg, 0.226 mmol), 5-phenyl-o-anisidine (30.0 mg, 0.151 mmol) and triethylamine (22.8 mg, 0.226 mmol) refluxed in anhydrous THF (20 mL) for 18 hours to form the intermediate followed by 3-(dimethylamino)-propylamine (23.1 mg, 0.226 mmol) and refluxed for a further 5 hours to form the title compound. Work-up as in

Example 100.

Example 104

3-(4-Chlorophenyl)-1-methyl-1-(3-dimethylamino propyl) urea (CFM2200) Prepared as in Example 100 using 4-nitrophenyl chloroformate (830 mg, 4.12 mmol),

4-chloroaniline (350 mg, 2.75 mmol) and triethylamine (416 mg, 4.12 mmol) refluxed for 7 hours in anhydrous THF (30mL) to form the intermediate. Then NNN'-trimethyl-1,3-propanediamine (478 mg, 4.12 mmol) was added and the reaction mixture refluxed for 18 hours to form the title compound. Work-up as in Example 100.

Example 105

1-(3-Νitrophenyl)-1-benzyl-3-(3-dimethylamino propyl) urea (CFM2270) Prepared as in Example 100 using 4-nitrophenyl chloroformate (66.0 mg, 0.328 mmol), N-benzyl-3-nitroaniline (50.0 mg, 0.219 mmol) and triethylamine (33.0 mg,

0.328 mmol) refluxed in anhydrous THF (20 mL) for 6 hours to form the

intermediate followed by 3-(dimethylamino)propylamine (44.6 mg, 0.438 mmol) and refluxed for a further 36 hours to form the title compound. Work-up as in Example 100.

Example 106

1-Benzyl-1-(4-methyI-3-pyridinyl)-3-(3-dimethylamino propyl) urea (CFM2271) Prepared as in Example 100 using 4-nitrophenyl chloroformate (76.0 mg, 0.378 mmol), 2-benzylamino-4-methyl-pyridine (50.0 mg, 0.25 mmol) and triethylamine (38.0 mg, 0.378 mmol) refluxed in anhydrous THF (20 mL) for 5 hours to form the intermediate followed by 3-(dimethylamino)propylamine (38.0 mg, 0.378 mmol) and refluxed for a further 18 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 to 50 % MeOH (in CHCl3) to give the title compound.

Example 107

1-Methyl-1-(3,5-bistrifluoromethylphenyl)-3-(3-dimethylaminopropyl)urea (CFM2311)

Prepared as in Example 100 using 4-nitrophenyl chloroformate (62.0 mg, 0.308 mmol), N-methyl-3,5-bis(trifluoromethyl)aniline (50.0 mg, 0.206 mmol) and triethylamine (31.0 mg, 0.308 mmol) refluxed in anhydrous THF (20 mL) for 5 hours to form the intermediate followed by 3-(dimethylamino)propylamine (31.5 mg, 0.308 mmol) and refluxed for a further 18 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 to 40 % MeOH (in CHCl3) to give the title compound.

Example 108

1-(2-Phenacyl-4-chorophenyl)-1-methyl-3-(3-dimethylamino propyl) urea

(CFM2310)

4-Nitrophenyl chloroformate (61.5 mg, 0.31 mmol), 5-chloro-2-(methylamino)-benzophenone (50.0 mg, 0.20 mmol) and triethylamine (30.80 mg, 0.31 mmol) were refluxed for 5 hours in anhydrous THF (20 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)-propylamine (32.0 mg, 0.31 mmol) was added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash

chromatography using a gradient from 10 - 40% MeOH (in CHCl3) to give the title compound.

Example 109

1-(2-Chloro-4-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea

(CFM2421)

4-Nitrophenyl chloroformate (77.0 mg, 0.39 mmol), 4-amino-3-chloro-benzotrifluoride (50.0 mg, 0.26 mmol) and triethylamine (38.0 mg, 0.39 mmol) were refluxed for 18 hours in anhydrous THF (20 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)-propylamine (38.0 mg, 0.39 mmol) was added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash

chromatography using a gradient from 10 - 40% MeOH (in CHCl3) to give the title compound.

Example 110

1-(3-Fluoro-5-trifluoromethylphenyl)-3-(3-dimethylaminopropyl) urea

(CFM2422)

4-Nitrophenyl chloroformate (84.0 mg, 4.19 mmol), 3-amino-5-fluorobenzotrifluoride (50.0 mg, 0.28 mmol) and triethylamine (42.0 mg, 4.19 mmol) were refluxed for 18 hours in anhydrous THF (20 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)-propylamine (42.0 mg, 4.19 mmol) was added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 - 40% MeOH (in CHCl3) to give the title compound.

Example 111

1-(3-N-tert-butoxycarbonyl-benzylamino)-3-(3-dimethylaminopropyl) urea CFM2374

4-Nitrophenyl chloroformate (3.13 g, 15.54 mmol), 3-amino-1-(N-tert-butoxy-carbonyl)benzylamine (2.30 g, 10.36 mmol) and triethylamine (1.56 g, 15.54 mmol) was refluxed for 18 hours in anhydrous THF (100 mL) as in Example 100 to form the intermediate. Then 3-(dimethylamino)propylamine (1.58 g, 15.54 mmol) was

added and the mixture was refluxed for a further 5 hours to form the desired product. Work-up same as in Example 100. The crude product was purified by flash chromatography using a gradient from 10 - 40% MeOH (in CHCl3) to give the title compound.

Example 112

N-(3-Dimethylamino-propyl)-2-[1-(4-fluorobenzoyl]-benzamide (CFM2262) 2-(4-Fluorobenzoyl)benzoic acid (1.25 g, 5.12 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (4.30 g, 15.36 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (1.95 g, 5.12 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.52 g, 5.12 mmol) was added and the temperature was taken up to 50 °C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (3.40 g, 15.36 mmol) was added and the mixture was allowed to stir for 5 hours. To the mixture was added water (5 mL) and the solvent was removed on a vacuum concentrator. The crude product was purified by flash chromatography using a gradient from 5 to 10% MeOH (in CHCl3) and the title compound was isolated as a white solid 0.36 g, 22 % yield (mp 84 - 85 °C).

Example 113

2-[1-(4-Chlorobenzoyl]-Ν-(3-dimethylamino-propyl)-benzamide (CFM 2269)

2-(4-Chlorobenzoyl)-benzoic acid (1.25 g, 4.80 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (4.00 g, 14.38 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (1.82 g, 4.80 mmol) was stirred in anhydrous acetonitrile (50 mL) at room

temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.50 g, 4.80 mmol) was added and the temperature was taken up to 50 °C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (3.20 g, 14.40 mmol) was added and the mixture was left to stir for 5 hours. The workup and purification was the same as

described in Example 112. The title compound was isolated as a white solid 0.68g, 41 % yield (mp 108-110 °C).

Example 114

5-(4-Chloro-phenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2404)

5-(4-Chlorophenyl)-1-phenyl-1H-pyrazole-3-carboxylic acid (1.10 g, 4.09 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (3.40g, 12.27 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (ΗATU) (1.56 g, 4.09 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.42 g, 4.09 mmol) was added and the temperature was taken up to 50 °C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (2.70 g, 12.27 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a white solid 0.62g, 44 % yield (mp 165 °C).

Example 115

5-Chloro-3-phenyl-1H-indole-2-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2408)

5-Chloro-3-phenyl-1H-indole-2-carboxylic acid (1.00 g, 3.68 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (3.00 g, 11.04 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (ΗATU) (1.49 g, 3.68 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.38 g, 3.68 mmol) was added and the temperature was taken up to 50 °C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (2.43 g, 11.00 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a white solid 0.24 g, 18.5 % yield (mp 143-144 °C).

Example 116

N-(3-Dimethylamino-propyl)-2-(2-phenylsulfamoyl-phenylsulfanyl)-benzamide(CFM2349)

2-(2-Phenylsulfamoyl-phenylsulfanyl)-benzoic acid (1.10 g, 2.60 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (2.18g, 7.78 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (0.98 g, 2.6 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.26 g, 2.60 mmol) was added and the temperature was taken up to 50 °C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (1.70 g, 7.78 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a white solid (0.1 g, 9 %), (mp 75-76 °C).

Example 117

2-Benzylsulfanyl-Ν-(3-dimethylamino-propyl)-benzamide (CFM2351)

2-Benzylsulfanyl-benzoic acid (1.00 g, 4.09 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (3.40 g, 12.27 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (1.55 g, 4.09 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine

(0.42 g, 4.09 mmol) was added and the temperature was taken up to 50 °C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (2.60 g, 12.27 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a white solid 0.41g, 30.5 % yield (mp 85-86 °C).

Example 118

6,8-Di-tert-butyI-4-oxo-4H-chromene-2-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2339)

6,8-Di-tert-butyl-4-oxo-4H-chromene-2-carboxylic acid (1.00 g, 3.31 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (2.78 g, 9.93 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (ΗATU) (1.25 g, 3.31 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.34 g, 3.31 mmol) was added and the temperature was taken up to 50 °C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (2.18 g, 9.93 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a white solid (0.26g) in 20 % yield (mp 135-136 °C).

Example 119

3-(4-Chloro-phenyl)-4-cyano-5-isobutylsulfanyl-thiophene-2-carboxylic acid (3-dimethylamino-propyl)-amide (CFM2346)

3-(4-Chlorophenyl)-4-cyano-5-isobutylsulfanyl-thiophene-2-carboxylic acid (1.00 g, 2.84 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (2.37 g, 8.53 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-teframethyluronium

hexafluorophosphate (ΗATU) (1.08g, 2.84 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.3 g, 2.84 mmol) was added and the temperature was taken up to 50 °C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (1.87 g, 8.52 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a white oil/solid 0.3 g, 24 % yield.

Example 120

4-(4-Chloro-phenoxy)-N-(3-dimethylamino-propyl)-3-nitro-benzamide

(CFM2347)

4~(4-Chlorophenoxy)-3-nitro-benzoic acid (1.00 g, 3.40 mmol), N, N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (2.84 g, 10.20 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (1.29 g, 3.40 mmol) was stirred in anhydrous acetonitrile (50 mL) at room temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine (0.35 g, 3.40 mmol) was added and the temperature was taken up to 50 °C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (2.24 g, 10.20 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a yellow solid (0.6 g) in 46.5% yield (mp 165-167 °C.

Example 121

Ν-(3-Dimethylamino-propyI)-4-(4-phenyl-thiazol-2-yl)-benzamide (CFM2405)

4-(4-Phenyl-thiazol-2-yl)-benzoic acid (1.38 g, 4.91 mmol), N,N-(diisopropyl)amino-methylpolystyrene resin (PS-DIEA), (3.84 g, 14.70 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (HATU) (1.87 g, 4.91 mmol) was stirred in anhydrous acetonitrile (50 mL) at room

temperature under nitrogen for 5 minutes. Then 3-(dimethylamino)propylamine

(0.50 g, 4.91 mmol) was added and the temperature was taken up to 50 °C and the mixture was left to stir at this temperature for 18 hours. The mixture was allowed to cool and tetrafluorophthalic anhydride (3.24 g, 14.70 mmol) was added and the mixture was allowed to stir for 5 hours. The workup and purification was the same as described in Example 112. The title compound was isolated as a white solid (1.18 g) in 66% yield (mp 204-205 °C).

Example 122

1-(3-Dimethylamino-propyl)-3-(2-phenoxyphenyl)-urea (CFM2260)

2-Phenoxybenzoic acid (1.50 g, 7.00 mmol) was stirred in anhydrous toluene (50 mL) at 50 °C under nitrogen. To this mixture was added triethylamine (0.71 g, 7.00 mmol) and the temperature was increased to 80 °C at which stage

diphenylphosphorylazide (DPP A) (1.92 g, 7.00 mmol) was added and the mixture was left to stir at this temperature for 5 hours. After this period 3-(dimethylamino)propylamine (0.71 g, 7.00 mmol) was added and the mixture was left to stir at 80 °C overnight under nitrogen. The solvent was removed on a vacuum concentrator The residue was taken up in chloroform (100 mL) and washed with 1M sodium hydroxide (2 × 50 mL). The organic fraction was washed with saturated sodium chloride solution and then dried (Na2SO4). The solvent was removed on a vacuum concentrator. The crude product was purified by flash chromatography using a gradient from 5 to 10% MeOH (in CHCl3) and the title compound was isolated as a white solid (1.00 g ) in 46% yield (mp 126- 128 °C).

Example 123

1-[4-(4-Chloro-phenylsulfanyl)-thiophen-3-yl]-3-(3-dimethylamino-propyl)-urea (CFM2356)

4-(4-Chlorophenylsulfanyl)-thiophene-3-carboxylic acid (1.30 g, 4.80 mmol) was stirred in anhydrous toluene (50 mL) at 50 °C under nitrogen. To this mixture was added triethylamine (0.48 g, 4.80 mmol) and the temperature was increased to 80 °C at which stage diphenylphosphorylazide (DPP A) (1.32 g, 4.80 mmol) was added and the mixture was left to stir at this temperature for 5 hours. After this period 3- (dimethylamino)propylamine (0.48 g, 4.80 mmol) was added and the mixture was left to stir at 80 °C overnight under nitrogen. The solvent was removed on a vacuum concentrator. The residue was taken up in chloroform (100 mL) and washed with 1M sodium hydroxide (2 × 50 mL). The organic fraction was washed with saturated sodium chloride solution and then dried (Na2SO4). The solvent was removed on a vacuum concentrator. The crude product was purified by flash chromatography using a gradient from 5 to 10% MeOH (in CHCl3) and the title compound was isolated as a white solid (0.50 g ) in 28% yield (mp 125-126 °C).

Example 124

1-(3-Dimethylamino-propyI)-3-(2'-fluoro-biphenyl-4-yl)-urea (CFM2363)

2-Fluoro-biphenyl-4-carboxylic acid (1.00 g, 4.63 mmol) was stirred in anhydrous toluene (50 mL) at 50 °C under nitrogen. To this mixture was added triethylamine (0.47 g, 4.63 mmol) and the temperature was increased to 80 °C at which stage diphenylphosphorylazide (DPP A) (1.27 g, 4.63 mmol) was added and the mixture was left to stir at this temperature for 5 hours. After this period 3-(dimethylamino)propylamine (0.48 g, 4.63 mmol) was added and the mixture was left to stir at 80 °C overnight under nitrogen. The solvent was removed on a vacuum concentrator. The residue was taken up in chloroform (100 mL) and washed with 1M sodium hydroxide (2 × 50 mL). The organic fraction was washed with saturated sodium chloride solution and then dried (Na2SO4). The solvent was removed on a vacuum concentrator. The crude product was purified by flash chromatography using a gradient from 5 to 10% MeOH (in CHCl3) and the title compound was isolated as a orange oil (0.50 g ) in 34% yield.

Physical data for some of the compounds synthesised in the Examples is given in Table 3.

Activity Example 1

Compounds of the invention were assayed to determine their ability to activate sGC. The assay employed was an enzyme immunoassay to measure changes in cGMP. To perform the assay recombinant soluble Guanylate cyclase was added to 1.1 mg/ml IBMX, 2.6 mg/ml GTP, 667 nM DeaNO and the test compound (10μM). The mixture was then incubated at room temperature for 10 minutes. Compounds were formulated in DMSO diluted in Tris HCl (pH 7.4) buffer and with a final DMSO concentration of <0.5%.

To determine the amount of cGMP produced, the Biotrak™ cGMP enzyme immunoassay system commercially available from Amersham™ 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.

The results are shown in Tables 4 to 7. The results shown in Tables 6 and 7 relate to commercially available compounds.

Activity Example 2

The ability of the compounds of the invention to inhibit platelet aggregation was also determined. IC50 values were measured as set out below.

Materials

Prostacyclin (PGI2 ; ICN Pharmaceuticals, Oxford) in Tris (0.05M, pH 9), Sodium citrate solution, Tyrodes solution without calcium (140mM NaCl; 3mM KCl; 12mM NaHCO3; 0.4mM NaH2PO4.H2O; 2mM MgCl2.6H2O; 0.1% Glucose) contains 0.05M Hepes, pH7.4. Collagen (collagenreagent Horm, Nycomed

Arzneimittel GmbH, Munchen).

PGI2 dissolved in Tris buffer (0.05M, pH9). Test compounds dissolved in DMSO (at 10mM) and subsequent dilutions made in Tyrodes; final assay

concentration of DMSO did not exceed 0.1% (which is without effect on platelet reactivity).

Platelet Preparation

Platelets prepared according to Vagas, J.R., Radomski, M. and Moncada, S. The use oƒ prostacyclin in the separation ƒrom plasma and washing oƒ human platelets. PROSTAGLANDINS 1982; 23:6:929-945.

Briefly, fresh human blood was collected into tubes containing 1 :9 sodium citrate (3.15%) and centrifuged immediately at 260g for 20 minutes to separate the red cells from the platelet rich plasma (PRP). The PRP was decanted and PGI2 (0.3μg/ml) was added. The PRP was then centrifuged at 180g for 10mins to sediment the remaining red and white cells. The resulting PRP was decanted into new tubes,

PGI2 (0.15μg/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 10mins 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/μl using Tyrodes. The resultant suspension was placed on ice for approximately 1 hour until use.

Platelet Assays

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.

For each sample, baseline reading was established for a 3 min period, followed by addition of test compound or buffer. An EC50 dose of collagen was added 1 min later and the response measured 3 min after addition of collagen.

Data Analysis

The amplitude of each aggregatory response, normalised to the collagen control, was used to plot dose-response curves. The concentration of drug that inhibited collagen-induced platelet aggregation by 50% (IC50) was calculated from the dose-response curves.

The results are shown in Tables 4 to 7. The results shown in Tables 6 and 7 relate to commercially available compounds.