WO1999059584A1 - Combination of phentolamine and cyclic gmp phosphodiesterase inhibitors for the treatment of sexual dysfunction - Google Patents

Abstract

A method of treating sexual dysfunction comprising administering a therapeutically effective amount of a combination of phentolamine and cGMP PDE inhibitor such as sildenafil, as well as pharmaceutical compositions and kits useful in those methods, are disclosed.

Description

COMBINATION OF PHENTOLAMINE AND CYCLIC GMP

PHOSPHODIESTERASE INHIBITORS FOR THE TREATMENT

OF SEXUAL DYSFUNCTION

BACKGROUND

The present invention relates to pharmaceutical compositions comprising a combination of phentoiamine and cyclic guanosine 3',5^'-monophosphate phosphodiesterase (cGMP PDE) inhibitors and to methods of treating sexual dysfunction, especially erectile dysfunction, comprising administering an effective amount of a combination of phentoiamine and cGMP PDE inhibitors.

The use of the pharmaceutical compositions and methods of this invention results in an unexpected potentiation of human sexual response.

SUMMARY OF THE INVENTION

Tne present invention is directed to the use of phentoiamine in combination with cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE) inhibitors for the treatment of human sexual dysfunction. Preferably, the invention contemplates the use of Type V cGMP PDE inhibitor in combination with phentoiamine with sildenafil being the preferred Type V cGMP PDE inhibitor.

More particularly, the present invention relates to a method of treating sexual dysfunction, especially erectile dysfunction, comprising administering to a human in need of such treatment an effective amount of a combination of phentoiamine, or a pharmaceutically acceptable salt, solvate or ester thereof, and a cGMP PDE inhibitor, or a pharmaceutically acceptable salt or solvate thereof. Preferably, the invention contemplates the use of Type V cGMP PDE inhibitor in combination with phentoiamine, with sildenafil being the preferred Type V cGMP PDE inhibitor. Phentolamine mesylate and sildenafil citrate are the most preferred active ingredients for use in the methods of this invention.

In a second aspect, the invention relates to a pharmaceutical composition comprising an effective amount of phentoiamine, or a pharmaceutically acceptable salt, solvate or ester thereof, and a cGMP PDE inhibitor, or a pharmaceutically acceptable salt solvate thereof. Preferably, the pharmaceutical compositions envisioned by the present invention comprise phentoiamine, or a pharmaceutically acceptable salt, solvate or ester thereof, and a Type V cGMP PDE inhibitor, or a pharmaceutically acceptable salt solvate thereof, with sildenafil being the preferred Type V cGMP PDE inhibitor. Phentoiamine mesylate and sildenafil citrate are the most preferred active ingredients of the pharmaceutical compositions of this invention.

In a third aspect, the invention relates to a kit comprising in one container an effective amount of phentoiamine, or a pharmaceutically acceptable salt, solvate or ester thereof in a pharmaceutically acceptable carrier, and in a separate container, an effective amount of a cGMP PDE inhibitor, or a pharmaceutically acceptable salt, solvate thereof in a pharmaceutically acceptable carrier, with sildenafil being the preferred Type V cGMP PDE inhibitor. Phentoiamine mesylate and sildenafil citrate are the most preferred active ingredients for use in the kits of this invention.

In a fourth aspect, the invention relates to a pharmaceutical composition for the treatment of human sexual dysfunction comprising a therapeutically effective amount of a first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof, a therapeutically effective amount of a second vasodilating agent or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. Preferably, the first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is an adrenergic blocker. More preferably, the adrenergic blocker is an alpha-adrenergic blocker. Also preferred is that the alpha adrenergic blocker is selected from the group consisting of an alphal -adrenergic blocker, an alpha2-adrenergic blocker or both an alphal -adrenergic blocker and an alpha2-adrenergic blocker. Preferably, the second vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is a cGMP PDE inhibitor. Also preferrred is that the first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is an adrenergic blocker and the second vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is a cGMP

PDE inhibitor. The adrenergic blocker can be selected from the group consisting of phentoiamine, phentoiamine mesylate, phentoiamine hydrochloride, phenoxybenazmine, tolazoline, dibenamine, yohimbine, terazosin, doxazosin, prazosin and the like. The cGMP PDE inhibitor can a cGMP PDE V inhibitor. Preferably, the cGMP PDE V inhibitor is selected from the group consisting of: sildenafil,

(6R, 12aR)-2,3,6,7, 12,12a-hexahydro-2-methyl-6-(3,4- methylenedioxyphenyl)-pyrizino[2',1 ':6,1]pyrido[3,4-b]indole-1 ,4-dione

(Compound A), and

(3S.6R, 12aR)-2,3,6,7,12, 12a-hexahydro-2,3-dimethyl-6-(3,4- methyienedioxyphenyl)-pyrazino[2',1 ':6,1]pyrido[3,4-b]indole-1 ,4-dione

(Compound B) or a pharmaceutically acceptable salt or solvate thereof.

In a fifth aspect, the invention relates to a method of treating human sexual dysfunction comprising the simultaneous or sequential administration of a therapeutically effective amount of a therapeutically effective amount of a first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof, a therapeutically effective amount of a second vasodilating agent or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier. The classes and types of compounds which can be used in the method are described in the fourth aspect, above.

DETAILED DESCRIPTION

Humans include, of course, males and females. Although the pharmaceutical compositions of the present invention are envisaged primarily for the treatment of erectile dysfunction or male sexual dysfunction, they may also be useful for the treatment of female sexual dysfunction. Such female sexual dysfunction may include orgasmic dysfunction due to clitoral irregularities or disturbances.

Phentoiamine, 3-[[(4,5-dihydro-1 H-imidazol-2-yl)methyl](4- methylphenyl)amino]phenol, and pharmaceutically acceptable salts, solvates, hydrates, crystalline polymorph forms and the free base thereof, are useful in the treatment of sexual dysfunction. A rapidly disintegrating tablet and method of use to treat sexual dysfunction is disclosed in United States Patent No. 5,731 ,339, also incorporated herein by reference. Representative formulations comprising phentoiamine are disclosed in U.S. 5,731 ,339. Phentoiamine can exist in unsolvated as well as solvated forms, including hydrated forms, e.g. hemi-hydrate. In general, the solvated forms, with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to the unsolvated forms for purposes of the invention. Phentoiamine can form pharmaceutically acceptable salts with organic and inorganic acids. Examples of suitable acids for salt formation are hydrohalic acids such as hydrochloric and hydrobromic; as well as other acids such as sulfuric, phosphoric,- acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic, toluenesulfonic and other mineral and carboxylic acids known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the salts are otherwise equivalent to their respective free base form for purposes of this invention. Phentoiamine can also form crystalline polymorph forms or crystalline forms thereof using suitable or conventional crystallization procedures.

The present invention is directed to the use of cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE) inhibitors in combination with the salts or esters of phentoiamine, preferably, with phentoiamine mesylate for the treatment of human sexual dysfunction, preferably erectial dysfunction Examples of cGMP PDE inhibitors contemplated in this invention are as follows and are described in the following documents, as indicated. The disclosure of each of the below-referred to document is incoφorated herein by reference. European published application number 0201188, which discloses compounds of the formula

and the pharmaceutically acceptable salts thereof, in which:

R, is a lower afkyl of from one to six carbon atoms, a lower alkenyl of from one to six carbon atoms, a lower hydroxyalkyl of from one to six carbon atoms, a lower hydroxyalkenyl of from two to six carbon atoms, a lower aminoalkyl of from one to six carbon atoms, or a lower aminoalkenyi of from two to six carbon atoms; n is 0 or an integer of from 1 to 4; and

Ar is a radical of the following general formula (R₂)

or 2, 3, or 4-pyridyl, in which X, Y, and Z are. independently, (1) hydrogen; (2) lower alkyl of from one to six carbon atoms; (3) halogen, (4) hydroxyl;

(5) lower alkoxy of from one to six carbon atoms; -

(6) nitro; (7) amino; (8) NR'FT wherein R' and R" are each, independently, (a) hydrogen or (b) lower alkyl of from one to six carbon atoms optionally substituted by (i) amino, (ii) morpholino or (iii) cycloalkyl of from, five to seven carbon atoms; (9) sulfonyl; or

(10)-SO,NR^*R" wherein R' and R" are as defined above; with the proviso that not all of X, Y, and Z can be nitro, amino, or NR'R" at once. Preferred compounds include:

1-ethyl-3-methyl-5-phenylpyrazolo[4,3-dJ- pyrimidiπe-7-one;

1.3-dim^θthyl-5-ph^θnylpyrazolof4,3-d]pyrlmidine-7- one;

1 ,3-dimethy l-5-(4-c loropheny l)pyrazolo[43-dl- pyrimldine-7-one;

1,3-dlm³thyf-5-(4-methylphenyl)pyr_Szolo[4₁3-d]- pyrimidiπe-7-one;

1,3-dimethyl-5-(4-nitrophenyl)pyra2olo-[4,3-dμ pyrimidine-7-one;

1.3-dim_ethyl-S-(4-trif^| _l ^joromethylphenyl)pyr_a2Dlo- l4,3-d]-pyrimidine;

1.3-dimethyl-5-(4-aminophenyl)pyrazolo{43-dl- pyrimidiπe-7-one;

1,3-dimethyl-5-(3-aminophenyl)pyrazolo[43-d]- pyrimidtne-7-one;

1,3-dimethyl-5-{3-nitrophenyl)pyra2olo[4,3-d]- pyrimidine-7-one;

1,3-dimethyf-5^2-methoxypheny pyra2olo(4,3-d pyrιmιdine-7-one; t.3-dimethyl-5-(3.4-dichl₀rophenyl)pyrazolo[4,3-dJ- ρyrimιdιne-7-one; ^J

1.3-dimethyl-5-(3.4-dimeihox_yphenyl)pyra₂olo[4.3- dtpyrimidiπe-7-one;

European published application number 0214708, which discloses compounds of the formula

in which:

A represents a group of formula:

NHR¹²

or ( e )

R^* and R-" are the same or different and each represents a hydrogen atom, a halogen atom or a group of formula -OR';

R' and R' are the same or different and each represents a carbamoyl group or a carboxy group:

R' and R' both represent hydrogen atoms or together they represent an extra carbon-carbon bond between the carbon atoms to which they are attached; R' represents a hydrogen atom, a halogen atom or a group of formula -OR'. -NR"R^*' or -SR';

R* represents a halogen atom or a group of formula -OR', -NR'^R" or -SR';

R^* represents a hydrogen atom, a C,-C» alkyl group, an alkylsulphonyl group, a haloalkylsul- phonyl group, an arylsulphonyl group or a hydroxy- protechπg group;

R" and R" are the same or different and each

represents a hydrogen atom, a hydroxy group, a C,-C, alkyl group, a C-C« hydroxyalky! group, a C- C, aminoalkyl group, an aralkyl group, an^" aryl group, a C,-C, alkoxy group, an aralkyloxy group, an amino group, a C,-C» aliphatic acyl group or an aromatic acyl group; or R" and R." together represent a substituted methylene group, or R^*** and R", together with the nitrogen atom to which they are attached, represent a heterocyclic group having 5 or 6 ring atoms, of which, in addition to the nitrogen atom shown, 0 or 1 are additional oxygen, nitrogen or sulphur heterc-atoms, said heterocyclic group being unsubstituted or having from 1 to 3 C- C alkyl and/or C,-C« alkoxy subsβtuents;

R" represents a C,-C« alkyl group;

Z represents a hydrogen atom, a hydroxy group or a substituted hydroxy group; and

W represents an alkoxy group or an aralkoxy group; provided that, when A represents said group of formula (e), R* and R^* both represent hydrogen atoms; and pharmaceutically acceptable salts and esters thereof. Preferred compounds include:

2-Amino-6-desamino-6-hydroxygriseolic acid and pharmaceutically acceptable salts and esters thereof.

2-Amino-6-desamino-6-hydroxygriseolic acid 7'-amide and pharmaceutically acceptable salts and esters thereof.

, 2-Aminogrisθolic acid and pharmaceutically acceptable salts and esters thereof.

Bis(pivaloyloxymethyl) 2-εmino-6- desaminσ-6-hydroxygriseolate and pharmaceutically acceptable salts thereof.

2-Amino-N '- ethoxygriseolic acid and pharmaceutically acceptable salts and esters thereof.

2-Amino-N^,-benzyloxygriseolic acid and pharmaceutically acceptable salts and esters thereof.

2-Fiuorogriseoiic acid and pharmaceutically acceptable salts and esters thereof.

2-Chiorogrisβolic acid and pharmaceutically acceptable salts and esters thereof.

— . 2-Amino-6-desamino-6-hydroxy-7'-desoxyg- riseoiic acid and pharmaceutically acceptable salts and esters thereof.

2-Amino-7^*-desoxygriseolic acid and pharmaceutically acceptable salts and esters thereof.

2-Chloro- -desoxygrisθolic acid and pharmaceutically acceptable salts and esters thereof.

2-Amino-β-desamino-6-hydroxy-2'-chloro- 2'-desoxygrisθolic acid and pharmaceutically acceptable salts and esters thereof.

^" f . 2-Amino-6-desamino-6-hydroxy-2'-desoxyg- riseαlic acid and pharmaceutically acceptable salts and esters thereof.

2-Arnino-2^*-chloro-2'-dβsαxygrisθolic acid and pharmaceutically acceptable salts and esters thereof.

. 2-Amino-2'-de$oxygriseoFic acid and pharmaceutically acceptable salts and esters thereof.

2-Chloro-2'-desoxygriseoIic acid and pharmaceutically acceptable salts and esters thereof.

Griseolic add ^*-oxide and pharmaceutically acceptable salts thereof.

2-Acetylamino-6-desamino-6-hydroxy-4'.5'- dffiydrogriseolic add and pharmaceutically acceptable salts and esters thereof.

2-Amino-6-desamino-B-hydroxy-4^,.5'- dihydrogrisθofic add and pharmaceutically acceptable salts and esters thereof.

2-Acetylamino-6-desamino-6-hydroxy-4^,,5'- dihydro-7'-desαxygrisθolic add and pharmaceutically acceptable salts and esters thereof.

2-Amlno-6-desamino-fr4ιydroxy4',5'- dihydi^*o-7'-desoxygriseolic add and pharmaceutically acceptable salts and esters thereof.

2_I6-Dj<^oro-6-deεarnino-4^,,5'-dihyαrog- riseotic add and pharmaceutically acceptable salts and esters thereof.

2-Chloro-4\5^*-dihyα^*rogriseolic add and pharmaceutically acceptable salts and esters thereof. 99/59584

-10-

European published application number 0319050, which discloses compounds of the formula

in which:

A represents a group of formula:

R¹ and R² are the same or different and each represents a hydrogen atom, a halogen atom or a group of formula -OR⁹;

R³ and R' are the same or different and each* represents a artiamoyl-group'or a carboxy group;

R^s and R⁶ both represent hydrogen atojns

R³ represents a hydrogen atδrr a Ci -Cβ alkyl group, an alkylsulphonyi group, a haloalkylsulphoπyl group, an arylsulp oπy! group or a hydroxy-protectiπg group;

R^1Z represents a Cι-C« alkyl group; and pharmaceutically acceptable salts and esters thereof. 59584

-11-

European published application number 0293063, which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein R¹ is Ci.s3lkyl.or C₂,jalkenyl. and R² is hydrogen or hydroxy.

2-(2-propoxyphenyl)-6-purinone,

Preferred compounds include: 2-(2-ethoxyphβnyl)-6-purinone.

2-(2-butoxyphenyl)-6-purinone,

2-(2-isobutoxyphenyl)-6-purinono.

2-(2-propoxyphenyi)purine-6,8-dione,

2-(2-methoxyρhenyl)purine-S,8-dione,

2-{2-offtoxyρhenyl)purinθ-6,8-dione,

2-(2-butoxyphenyl)purine-6.8-dione,

2-(2-isobutoxyρheny)puriπe-e,8-dione. or

2-(2-allylo^* yphenyl)purine-6-8-dione or a pharmaceutically acceptable salt thereof.

European published application number 0347027, which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein

X Is 0 or S;

R' is C.-salkyl, C_-<^*alkenyl. C -scycloalkylCi -talkyi. or Cι-*.al yl substituted by 1 to 6 fluoro groups:

R^*- is hydrogen, -CN, -CONR⁵R⁶, -COzR', 5-tatrazolyl, -N0₂, -NHj or -NHCOR⁸ wherein R⁵, R^E, B? and

R⁸ are Independently hydrogen or Ci-ialkyl;

R³ is hydrogen or Ci -♦alkyl; and

R* is hydrogen or C< -«alkyl: wfth the proviso that R^! is not methyl when R² is -CO.H, -COzCH_zCH₃ or -CN. X is 0, R³ Is hydrogen and

R* is hydrogen or methyl. Preferred compounds include:

3-cyano-8-<2-propoxyphenyl)-2(l H)-pyridiπoπe,

6-(2-propoxyphenyl)-l .2-dihydro-2-oxopyridine-3-carboxamide.

6-(2-propoxyphenyl)-1 ,2-dihydro-2-oxopyridine-3-carboxylic acid. methyl 6-(2-ρropoxyphenyl)-1 ,2-dihydro-2-oxopyridine-3-carbo^χylate.

6-(2-propoxyphenyl)-3-{1H-tetrazol-5-yl)-2(i H)-pyridinone.

6-(2-proρoxyphenyl)-2{l H)-pyridinone,

3-nitro-6-(2-propoxyphenyl)-2(1 H)-pyridinone,

3-cyano-6-(2-θthoxypheπyl)-2f1 H)-pyridinone ,

3-amino-6-(2-propoxypheπyl)-2(1 H)-pyrid^*πoπe,

3-cyano-4-methyl-6-(2-propoxyphenyl)-2(1 H)-pyridinone,

3-cyano-5-methyl-6-(2-propθxyphonyl)-2(1 H)-pyridinone,

3-cyano-6-(2-(l ,1.2,3.3.3-hexafluoropropoxy)phenyl-2(1 H)-pyridinone,

3-cyano-6-(2-propoxyphenyl)-2(l H)-pyridinethione,

1.2-dihydro-4-methyl-2-oxo-6-(2-propoxyphenyl^'pyridine-3-carboxylic acid, methyl l ,2-dιhydro-4-methyl-2-oxo-6-(2-propoxyphenyl)-pyridin -3-carboxylate.

1 ,2-dihydro-4-methyI 2-oxo-e-{2-propoxyphenyl)pyridinθ-3-carboxamide,

3-cyano-6-(2-cyclopropylmethoxyphenyl)-2(1H)-pyri inone,

6-(2-butoxyphenyl)-3-cyano-2( 1 H)-pyridiπonβ,

6-(2-allyioxyphenyl)-3-cyano-2(1 H)-pyridinone.

3-cyano-6-[2-(2-methylpropoxy)phei^*iy l]-2( 1 H)-pyridinone,

6-(2-ethoxyphenyl - 1 ,2-dihydro-2-oxopyridine-3-carboxamide,

6-(2-cyclopropylmethoxyphenyl^'-" .2-dihydro-2-oxopyridine-3-carboxarrttde.

6-(2-butoxyphenyl)-l ,2-dihydro-2-oxopyridine-3-carboxarnido.

6-{2-allyloxyρhenyl)-1 ,2-dihydro-2-oxopyridine-3-carboxamide, or

6-[2-(2-methy!propoxyphenylM ,2-dihydro-2-oxopyridιne-3-carboxamide, or a pharmaceutically acceptable salt thereof.

European published application number 0347146, which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein

is a ring of sub-formula (a), (b). (c), (d). (e). {f) or (g) :

(a) (b) (c) (d)

R¹ is C -εalkyl, Cs-ealkeπyl, C₃-scycloalkylCι -«alkyl, or Ci -salkyl substituted by 1 to 6 fluoro groups; R^z is Ci -ςalkylt io, Ci -salkylsulphonyl, Ci -ςalkoxy, hydroxy, hydrogen, hydrazino, Ci-salkyl, phenyl, -NHCOR³ wherein FI³ is hydrogen or d-βalkyl, or - R^*-R^S wherein R* and R⁵ together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, hexahydroazepiπo. morpholino or piperaziπo ring, or R⁺ and R^s are independently hydrogen, Cj-s cycloalkyl or Ct-s alkyl which is optionally substituted by -CF₃, phenyl, -S(0)_ftCι -< alkyl wherein n is 0, 1 or 2, -OR⁵, -C0₂R^? or -NR^βR³ wherein R⁵ to R³ are independently hydrogen or Ci-ealkyl, provided that the carbon atom adjacent to the nitrogen atom is not substituted by said -S(0)„Cι -« alkyl, -OR⁵ OF--NR⁸R⁹ groups; and R is hydrogen and can also be hydroxy when R² is hydroxy.

Preferred compounds include:

2-(2-ρropoxyphenyl)pyrido[2,3-d]pyrimld-4<3H)-one.

2-{2-propoxyρhenyt)ρyrido[3,4-d]ρyrlmld-4(3H)-one_<

2-{2-propoxyphenyRpyrido[4,3-d]ρyrimid-4<3H)-one,

2-{2-ρropoxyphenyl)pyrido[3,2-d]ρyrimid-4(3H)-one,

2-(2-propoxyphenyl)pteridin-4(3H)-one,

2-(2-propoxyphenyl)pteridin-4,6(3H,5H)-dione,

2-<2-propoxyρhenyl)pteridin-4.6,7(3H.5H,8H)-trione,

5,β-dihydro-3-methylthio-5-oxo-7-(2-propoxyphenyl)ρyrimido(5,4-e] [1 ,2.43triazine.

3-amirκ 5,6-dihydro-5-oxo-7-(2-proρoxyphenyl)pyrimido[5,4-eIt,2,4]triazine,

3-methylamino-S,6-dihydro-5-oxo-7-(2-propoxyphenyl)pyrimido[5.4-e3t1.2.4]triazine.

3-niethoxy-5.6-dihydro-5-oxo-7-)2-propoxyphenyl)pyrimiclo[5,4-el[1-2,4Jtria2ine,

3-methylthio-8-oxo-6-{2-propoxyphenyl)-7,8-dlhydropyrimlc ι[4.5-θ][1^.4]triazine,

3-amino-8-o^*<o-6* 2-r opoxyphenyl)-7,8-cfihydropyrimldo[4.5-e][l,2.4]triazine.

3-methytamino-8-oxo-6-<2-ρroρoxyrj4renylb7,8^

3-rrtθthoxy-8^xo-&-(2-propoxyphenyl)-7.8-dihydroρyrimido[4^-el[1-2,4ltriazine_t

3,8<lkwc>-β-<2-prc>poxyphenyl)-3Λ7,8-tθtrahydropyrimido[4,5-eϊ1,2,4Jtria2tne,

3-dimethylaminr 8^xo-β^2-r c»poxyphθnyl)-7.8siihydropyrimioto

3-me^*thyMio-8-oxo-6-(2-allytoxyphenyl .8-dihydrr^

3-methylthio-8-oxo-β-(2-tεobutoxγphβny1)-7.8^

3-methytøio-8-oxo-6-(2-cyclopropylmetrια:<yphβnyl)-7,8d^

3-methylthio-8-oxo-6-(2-methoxyphenyl)-7,8-dihydropyrimtdo[45-e][1-2.4]triazlng or a pharmaceutically acceptable salt thereof. European published application number 0349239, which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein

is a ring of sub-formula (a), (b) or (c):

(a) (h) (c) ,

X is oxygen or sulphur, and

R¹ is Ci -ςalkyl, C₂-€alkenyl, Ca-scycloalkylCj -*alkyl, or Cι -«.alkyi substituted by 1 to θ fiuoro groups,

Preferred compounds include:

6-(2-proρoxypheπyl)ρyra2oio(3,4-d]pyrimidirι-4{5Hhoπe, 2-{2-propoxyphenyi tnieno[2,3-d3pyrimldin-4{3H)«one, 2-<2-propoxypheπyl)t1 ,2^]oxadia^**ok^3,4-d]pyrlm!cfin_*4<3H)-orre , or 2^2-prcfloxyph^nyl) l,2,5ithia a2oto[3,4-d]i5yrimidln-4{3H)-one, or a pharmaceutically acceptable salt thereof. European published application number 0351058, which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein

R^* is Ci -εalkyl, C2-_Ealk9nyl, C3-scyc^[oalkylC,-salkyl, or Ci -εaikyI substituted by 1 to 6 fiuoro groups; R² is Ci -εaikylthio, Ci -s alkylsulphonyi, Cι-βaikoxy, hydroxy, hydrogen, hydrazino, Ci -εalkyl, phenyl, ^•NHCOR³ wherein R³ is hydrogen or Ci -salkyl, or -NR'-R^*-, wherein R^*- and R⁵ together with the nitrogen atom to which they are attached form a pyrroiidino, piperidino, hexahydroazeptno, morpholino or piperazino ring, or R* and R⁵ are independently hydrogen, Ca -5 cycloalkyl or Ct -βalkyl which is optionally substituted by -CFj, phenyl, -S(0)₀Ct-_ alkyl wherein n is 0, 1 or 2, -OR^ε, -CO₂R⁷ or -NR⁸R³ wherein R^s to R³ are independently hydrogen or Ci -j alkyl, provided that the carbon atom adjacent to the nitrogen atom is not substituted by said -S(0)„Cj -s alkyl, -OR⁶ or -NR^BR³ groups; and

is a ring of sub-formula (a) or (b) :

(a) (b) .

Preferred compounds include:

7-ri^thylthlo-4-oxc>-2-(2-prc>poxyphenyl)-3,4-dihydropyrimido[4.5-dIpyrimidine, 7-methylthfo-2-(2-ethoxyphenyl}-4-oxo-3₁4-dlhydropyrtmido[4₁S-d3pyrimidine, 7-rrrøfJιylthio-2-{2-mθthoxyphθnyι 4-oxo-3,4-dihydropyrtmido[4,5-d]pyrirn5dlne, 7-mefnylthio-2-^sobutox^*yphenylM-ox^

7-me^*myltMo-2-{2-cycloρroρylm^βthoxyphenylH"'^oxo^>^^

7-methylthio-2-(2-ailyloxyphriiiyl)-4-oxo-3,4-dihydropyrimido[4₁5-dlpyrimcdjne,

7-amiπr 4-oxo-2-(2-propoxyprrenyl)-3,4<lihydropyrimk^*lo[4,5-d]ρyrimidiπe,

7-methylaminr 4-oj<o-2-{2-propoxypheny0-3,4 iihydrr^yrimido{4,5-d]pyrimidine,

7- fime lamirκ 4-oxo-2-(2-propoxypheπyl)-3₁4-dihydropyrimido[4₁5-d]ρyτimidinθ,

7-hydraztno-4-oxo-2-(2-pror xyph9riyl>3.4-dihydropyrimidoC4,5-d3pyrimidine,

4-oxo-2-(2-p_fopoxyphenyl)-3,4-dlhydropyrimido[4,5-d]pyrimidine,

7-ethylamino*4-oxo-2-{2-i3rcpoxypheny0-3,4-dihydropyrimido[4,5-d]pyrimidιne₁

7-(2-hydroxyetjιyiamino)-4-oxo-2-(2-ρrofX)xyphenyl)-3,4Hdihydropyrimido[4,5-d]pyrtmidirte_I

7-efiiyl-4-oxo-2-{2-propoxyphenyl)-3,4-dihydrppyrimido[4,5-dlpyrimidine

7-me1hylajnlnr 2-(2-methoi<yphenyl)-4^xo-3,4^hydropyrimtdof4,5-d]pyrimidine,

7-ρrrenyl-4-αxo-2-(2-pro x>xyphenyl)-3,4-dlhyo^ 7-morpholino-4.-oxo-2-(2-propoxyphenyl)-3,4-dihydroρyrimido[4,5-d]pyrimidine,

7-cyclopropylam!no-4-oxo-2-(2-propoxyphenyl)-3.4-dihydropyrimido[4_<5-d]pyrimidine,

7-acetamido-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine,

7-proρylamino-4-αxo-2-{2-ρropoxyphenyl)-3,4-dihydropyrimido[4,S-d]ρyrimidine,

7-(3-hydroxypropylamino)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,S-d]pyrimidine,

7-(2-methoxyethylamino)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine,

7-(2-dimethylaminoethylamino)-4-oxo-2-{2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine,

7-(2-hydroxypropylamino)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimtdo[4,5-d]pyrimidine₁

7-{3-methylthiopropylamino)-4-oxo-2-{2-propoxyph9/-yl)-3₁4-dihydropyrimido[4,5-d]pyrimidine,

7-(2-aminoethylamino)-4-oxo-2-(2-propoxypheny -3,4-dlhydropyrimido[4,5-d]pyrimidine hydrochloride,

7-{3-methylsulphinylpropylamino)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrlmldlne,

7-(3-mefhylsulphonylpropylamiπo)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine,

4,7-dioxo-2-{2-propoxyphenyl)-3,4,7,8-tetrahydropyrimido{4,5-d]pyrlmldine,

7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine,

7-c3ethylamino-4-oxo-2-{2-propoxyphenyl)-3,4-dihydropyrimido{4,5-d]pyrirnidine,

7-(2-ethoxycarbonyiethylamino)-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidtne,

7-{ethoxycarbonylmethylamino>-4-oxo-2-(2-propoxyphenyi)-3,4-dihydropyrimido[4,5-d]pyrimidine,

7-(2-carboxyethylamino)-4-oxo-2-{2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine,

7-(carboxymethy!amino)-4-oxo-2-{2-propoxyphenyl)-3,4-dlhydropyrimido(4,5-d]pyrimidine,

7-ethoxy-4-oxo-2-(2-ρroρoxyρhenyl)-3,4-dihydropyrimidot4_l5-d]pyrimid!ne,

7-methoxy-4-oxo-2-(2-propoxypheπyl)-3.4-dihydropyrimido[4₁5-d3pyrlmidlne,

7-(2,2,2-bι'fluoroθthylamino)-4-oxo-2-(2-propoxyphθnyl)-3,4-dihydropyrimido(4,5-d]pyrimidinθ,

7-propoxy-4-oxo-2-{2-propoxyphenyl)-3,4-dihydropyrimido[4_>5-d]pyrimidine,

7-{N-ethyl-N-hydroxv'ethylamiπoH-oxo-2-{2-ρropαxyphθπyl)-3,4-dihydropyrimido[4,5-d]ρyrimidine,

7-dlpropylamlno-4-oxo-2-{2-propoxyphenyl)-3_t4-dihydroρyrimido[4₍5 l]ρyrimidine,

7-(2-phenethylamirro}-4-oxo-2-<2-prorx)xyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine₁ or

4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimldo[5,4-d)pyrimidine, or a pharmaceutically acceptable salt thereof.

European published application number 0352960, which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein ¹ is C^halky!. Ca-^βalk^βnyl, C--₅cycloalkylCι ~*alkyl, phenylC, -,alky| or C,- alkyi substituted by t to 6 fiuoro groups; -

R² is hydrogen, hydroxy, Cι-*aJkyl, phenyl, mercapto, C,-,alkylthio, CF, or amino; R³ is hydrogen, nitro, amino, Ci - alkanoyiamino, C_t -+-alkoxy, Cι -+alkyl. halo,' SOa R^R* CONR*RS cyano or Cι-₄alkyIS{0)π; '

R* and R⁵ are independently hydrogen or d-_HaJkyf; and Preferred compounds include:

2-{2-l2.2.2-trifIuoroethoxy]phenyl)purin-6-one,

2-(2-cyclopropy(methoxyphenyl)purfn-6-one,

2-{2-cyclapropylmethoxyphenyl)purin-e,8-dione,

2-(2-benzyloxyphenyl)purin-6,8-dione,

2-(2-propoxyphenyl>-8-trifluorome(hyipurin-8-one,

2-{2-propoxyphenyl)-8-phenylpurin-e-one,

2-{2-propoxyphenyl)-8-metriylpurin-6-one,

2-(2-propoxyphenyl>-8-mercaptopurin-6-one,

2-{2-propoxyphenyl>-8-methylthiopurin-6-one₁

2-(2-propoxyphenyl>-8-aminopurin-6-one,

2-{2-propoxy-5-nitrophenyl)purin-6-one,

2-(2-propoxy-5-aminophenyl)purin-6-one,

2-{2-propoxy-5-acetamidophenyl)purin-6-one,

2-{2-propoxy-4-methoxyphenyl)purin-6-one,

2-(2-propoxy-5-methoxyphenyl)purin-8-one,

2-{2-propoxy-5-chlorophenyl)purin-6-one,

2-{2-proρoxy-4-mθthy[phenyθpurin-6-one,

2-(2-propoxy-5-fluoropheπyl)puriπ-6-oπe,

2-{2-propoxy-5-dimethylsulphamoyiphenyl)purin-6-one,

2-(2-propoxy-5-methylsulphamoylphenyl)purin-8-one,

2-{2-propoxy-5-sulphamoylpherryl)purin-8-one,

2-(2-propoxy-4-methylthropheny|)purin-e-one,

2-{2-propoxy-5-cyanophenyl)purln-6-one, or

Σ^-propoxy-δ-carbamoylphenylJpuriπ-β-onθ, or a pharmaceutically acceptable salt thereof.

European published application number 0371731 , which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein ¹ is Oi-^βalkyl, Ca-^galkenyl, C₃-_scydoalkylCι -♦alkyl, phθnylC, -*alkyl or Ci -_♦alkyl substituted by 1 to 6 fiuoro groups;

R² is hydrogen, Ci-talkyJ, Ci-salkyfthio, Ct -.alkoxy. nftr o or - RW; and

R³ and R* are independently hydrogen or Ct -♦alkyl optionally substituted by hydroxy provided that the carbon atom adjacent to the nitrogen atom is not substituted by hydroxy; with the proviso that R¹ is not methyl or ethyl when R² Is hydrogen. /59584

-18-

Preferred compounds include:

2-(2-propoxyρhenyl)quinazolin-4(3H)-one_r 7-methylthio-2-(2-ρropoxyphenyl)quiπa2olin-4(3H)-one, 7-nitro-2-(2-propoxyphenyl)-4(3H -qulna2olinone₍ 7-amino-2-(2-propoxyphenylh4{3H)-quinazolinone, or 7-me{hylamino-2-{2-propoxyphenyl)-4{3H)-quina20linone or a pharmaceutically acceptable salt thereof.

European published application number 0395328, which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein

R" is Ci -εaJkyl, C₂-₆alkenyI, C₃-scycloalkylCt -βalkyl, phenylCi -εalkyl or Ci -.alkyl substituted by 1 to 6 fiuoro groups; and

R² is C, -.alkyl, phenyl, hydroxy, C, -₆alkoxy, halo. -NHCOR³. -NHCONHR^*- . S-tetrazolyl, -C0₂R^s. cyano,

•CONR⁶R⁷, or -NR⁸R³ wherein R³ to R⁷ are independently hydrogen or Ci -salkyl and R⁸ and R³ are independently hydrogen or Ci -sallcyl optionaily substituted by hydroxy provided that the carbon atom adjacent to the nitrogen atom is not substituted by hydroxy;

Preferred compounds include: e-amlno-2-(2-propoxyphønyl)pyrimidin-4{3H]-one,

6-acetamio^2-{2-ρropoxyphθnyl)pyrimidin-4[3H]-onβ, fj-propionamido-2-(2-ρroρoxyphenyl)pyrimidtn-4{3H}-one,

8-butyramido-2-(2-propoxyphenyl)pyrimidin-4(3H]-one,

6-N'-methylureldo-2-(2-propoxyρhenyl)pyrimidin-4[3H]-one,

4,6-dihydroxy-2-(2-propoxyphenyl)pyrimldiπe,

4-chloro-6-hydroxy-2-<2-propoxyphenyl)pyrlmidine,

6-ethylaminc^2-(2- opoxyphenyl)pyrfmidin-4{3H]-one, ^β-propylamino-2-(2*i,ropoxyprιeπyl)pyrimld)n-4[3H3-one.

6-{2-hydroxyethylamiπo)-2-{2-propoxyphenyl)pyrimlcliπ-4t3H]- ιne₁

6-<3-hydrc^^ropy!amino)-2-{2-propoxyphenyl)pyrimidin-4[3H]-o ne ,

4-hydroxy6-methyl-2-(2-propoxyphenyl)pyrimidine.

6-hydroxy-2-{2-prowxyphenyl)pyrimidine-4-carboxylic acid, ethyl 5 ιydroxy--2^*<2-propoxyρheπyl)pyrimidine-4-carboxylate.

6-hydroxy-2-(2-propo^χyρheπy0pyrimidlnβ-4-carboxamide.

4-cyano-8-hydroxy-2-{2-propoxyphenyl)pyrimId}ne.

2-{2-prcipoxyphef)yl)-6-{fH-tetra2ol*^*5-yl>pyrimidin-4<3H)-one,

4-etftyl-6-hydroxy-2-<2-propoxyphenyl)pyrimidine.

4-hydroxy-6-ρhenyl-2-{2-ρropoxyρhenyl)ρ^* rimidine.

N-methyl 6-hydro>ry-2-(2-propoxyphenyl)pyrimidine-4-carboxam/de,

N-ethyl 6-hydroxy-2-(2-propoxyρhenyl)pyrimioSne-4-(»rboxamkiθ.

N-propyl 6-hyaVoxy-2-(2-propoxyphenyl)pyrimidine-4-carboxamide.

6-ethoxy-2-(2-^rox⁾xyphenyl)pyrimidin-4(3H)-one, or

6-N,N-bis-(2-hydroxyethyl)amlnc>-2-(2-ρropc^ or a pharmaceutically acceptable salt thereof. European published application number 0400583, which discloses compounds of the formula

wherein -

A is N or CH;

B is N CRs;

D is N or CR₂;

R, R_I , are the same or independently hydrogen, hydroxy, loweralkyl, lower alkoxy, phenyloxy, R_GS(0)_n-, W-

ALK-Q-,

R∑ is hydrogen, lower alkyl, phenyl which may be substituted by up to three methoxy groups, lower alkyl substituted by phenyl which may be substituted by up to three methoxy groups, - lower alkyl -N(R_B)2,

loweralkyl— N j

-lower alkyl -N X . -lower alkyl -N^N ,

pyridiπyl or lower-alkyl pyridinyl;

R3 is hydrogen, lower alkyl, phenyl, lower alkylphenyl, pyridinyl or loweralkyl pyridiπyl;

R*., Rs are the same or independently hydrogen or lower alkyl;

Hs is lower alkyl, phenyl, lower alkylphenyl or pyridinyl;

R7 are the same or independently hydrogen, loweralkyl, phenyl. pyridinyl.

Ra are the same or independently lower alkyl, phenyl or pyridinyl; Q is -0-, -N-, -CHjO- or -CH_jN- R, R,

W is hydroxy, loweralkoxy, phenoxy, -N(R_w)_j. — J — N x

ALK is a Ci-Ct straight or branched chain alkyl;

Rs is hydrogen, lower alkyl or phenyl;

Rio are the same or independently hydrogen, loweralkyl or phenyl;

R1 are the same or independently hydrogen or lower alkyl;

X is -CH2-. -0-. S(0)_n, -NR,₀; n is tlie integer 0. 1 or 2 and p is the integer 0 or 1. with the provisos that: a) one and only one of B or D must be N; b) when A is CH, when D is N, when B Is CR where R₃ is H, when ₂ is hydrogen, lower alkyl or phenyl then R and or Ri must be ^**-

or W-ALK-Q-; and the pharmaceutically acceptable salts thereof.

Preferred compounds include:

pyriclc{2^e]pyrazirw 5H)-ons. or 2-(1H-imidaz -1-yDimidazo[1^-a]pyrido[3^-el_*)yτazin-6(5H)-one. 584

-21-

European published application number 0400799, which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein

R¹ is C»-«alkyl. C2-ealkenyl, C3-scycloa!kylCι -_Balkyl. phenylCi -e alkyl or Cι ~εalkyl substituted by 1 to 6 fiuoro groups; and

P? Is hydrogen, amino. -NHCOR^*-. αr -C0NR⁴R⁵, wherein R³ is d-ealkyl, R* is Ci -ealkyl and R^b is hydrogen or Ci -ς alkyl-

Preferred compounds include:

1,6- hydrr €-cιxo-2-(2-r opoxypheny)ρyrirrιkiine-5-carboxam^

N-methyl f ,6- ffhydrc 6-oxo-2-(2-rxoκ>χyphenyf)pyrim

N.N-dimøthyl 1 ,6-dihydrr>^-oxc^2-(2-pror^{χ χ}yphenyl)pyrimirf!ne-5-c»u-tκιxamϊde,

5-amino-2-{2-propoxypheπyl)ρyrimicfin-4^H}-one,

5-acetamido-2-(2-propoxyphenyl)pyrimidin-4{3H)-one, or

2-(2-proρoxyρheπyl)ρyrinrιJd(n-4(3H)-one, or a pharmaceutically acceptable εalt thereof.

/59584

-22-

European published application number 0428268, which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein

X is O or S;

R¹ is Ci -.alkyl, Cj-salkenyl, C--scycloalkylC, -«alkyl, or C alkyl substituted by 1 to 3 fiuoro groups;

R² is hydrogen, -CN, -CONR'-R⁶, -Cθ2R⁷,5-tetrazolyl. -N0₂, -NH₂ or -NHCOR⁸ wherein R⁵ to R^B are independently hydrogen or Ct -+alkyi;

RF³ is hydrogen or Cι-*alkyl;

R^*1 is hydrogen or Ci -<aJkyl; and

R is halo, Cι -*alkyl. C,-*alkoκy, cyano, -CONR⁹R'°, -C0₂R", -S(0)_nCι-<all<yr. -N0₂, -NH₂, -NHCOR¹². or

-SC *NR*³R wherein n is 0, 1 or 2 and R¹ to R^,+ are independently hydrogen or Cι- alkyl; with the proviso that R¹ is not methyl when R-^* is -C0₂H, -Cθ2CH>CH„ or -CN, X is 0, R³ is hydrogen, R⁴ is hydrogen or methyl and R is 6-methoxy.

Preferred compounds include:

3-cyano-6-(2-methoxy-4-methylthiophenyl)-2{1H)-pyridinone,

3-cyano-6-(4-mθthylthlo-2-propoxyphσnyl)-2(1H)-pyridlnone.

1 ,2-dihydro-6-<4-rnethylBi(θ-2-propoxypheπyl)-2-oxo-3-pyridine carboxamtde,

3-cyano-6-(2-methoxy-4-meti^*ιylsulphiπylphenyl)-2(1H)-pyrIdinone_l

3-cyano-6-<4-methylsuIphinyI-2-ρropoxyphenyl)-2(1H)-pyridiπone,

3-cyano-6-(4-methylsulphonyl-2-propoxyphenyl)-2(lH)-pyridinone,

3-cyano-6-(2-rrtcthoxy-4-mefhylsulphonyiphenyl)-2(1H}-pyridinone,

3-cyano-6-(5-fluoro-2-propoxyphenyl)-2(1r^*i pyridinone,

1 ,2-dihydro-6-(5-fiuorσ-2-propoxyphenyl)-2-oxo-3-pyridiπe carboxamide,

3-cyarw-6-(4-mefhoxy-2-propoxyphenyl)-2(1H>-pyridinone,

1 ^-dihydro-6-(4-methoxy-2-propoxyphenyl)-2-oxo-3-pyridlne carboxamide,

3-cyaπo-6-(5-methoxy-2-proρoxyphenylJ-2(1H)-pyridinone,

1 ,2-dihydro-6-{5-methoxy-2-propoxyρhenyl)-2-oxo-3-pyridine carboxamide,

3-cyano-6-(5-cyano-2-propoxyphonyl)-2(lH)-pyridinone, θ-tS-can oxa i o-l^- ihydro^-oxc-θ- yήdin lJ-^pror jxyirøriia ide, methyl 3-(3-cyano-1 ,2-dihydro-{2-oxo-e-pyridinyl)-4-propoxyben2oato,

3-(3-cyaπo-1,2-dihydro-'2-oxo-6-ρyridinyl)-4-propoxyben2amlde₍

N-mothyl-3-(3-<^arκ)-1^-dihydrcκ2-oxc>-6-pyri nyl)-4^ropoxybenzamide,

N-methyl 3-(3- arboxamido-1 -2-dihyciro-2-oxo-6^yridinyl)-4-propoxybenzamide,

N, N-dimβthyl-3-(3-cyano-1 ,2-dihydro-2-oxo-6-pyridinylH-proρoxybenzamide.

N,N-dimethyl 3-(3-carboxarnido-1 ,2-dihydro-2-oxo-e-pyridiπyl)-4-ρropoxybenzamide,

4-(3-cyarιo-1.2-dihydro-2-oxo-6-pyrfdinyl)-3-pro^

4-(3-raιtιoxamido-1^-dihydro-2-oxo-6-ρyridinyl)-3-propoxybeπzamirJe, 3-cyano-B-(5-methy)thio-2-propoxypheny -2(1H)pyricfinone,

3-(3-cyano- l _<2-d!hydrr 2-oxo-6-pyridιnyl)-4-propoxy-N_<N-dimethylbenzenesulphonamidθ,

3-{3-carboxamido-1,2-dihydro-2-oxo-6-pyridinyl)-4-propoxy-N,N-dimethy1ben2βπesulphonamide,

6-(2-cyclopropylmethoxy-5-flourophenyl)-1.2-dihydro-2-oxoρyridine-3-carboxamide,

6-(5-fluoro-2-{2-methylpropoxy)pheny|)-1,2-dihydro-2-oxopyridine-3-cart)Oxamide,

3-cyaπo-6-(5-nitro-2-propoxyphenyl)-2(1H)-pyridιnone,

1 ,2-dihydro-6-(5-πitro-2-propoxypheny l)-2-oxo-3-pyridinone carboxamide,

3-cyano-6-(5-amino-2-propoxyphenyl)-2(1H)-pyridinone,

1,2-dihydro-6-(5-amino-2-propoxyphenyl)-2-oxo-3-pyridinone carboxamide,

3-cyano-6-(5-acetamido-2-propoxyphenyl)-2(1 H)-pyridinone or

1 ,2-dihydro-6-{5-acetamido-2-proρoxypheπyl'-2-oxo-3-pyridine carboxamide, or a pharmaceuticaJly acceptable salt thereof.

European published application number 0442204, which discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein

vided that the carbon atom adjacent to the nitrogen atom Is not substituted by tsakl -S(0)_nC₁--₈aJkyl, -OR⁸ or -NR»R^S groups ;

R is halo. C_MaIkyt. d^alkoxy, cyano, -CONR¹⁰R", COj ⁱ*, C,^ alkylS(0}_π. -NOj, -NH* -NHCOR« or SO_jNR R^,s wherein n Is 0. 1 or 2 and R¹⁰ to R« are independently hydrogen or C_M alkyl ; and

£> ' is a ring αf sub-formula (a) or (b)

(a) (b) European published application number 0579496, which discloses compounds of the formula

wherein — represents a single or double bond;

R¹ is hydrogen or C,_» alkyl;

Y is a single bond or C _e alkylene;

A is

(ii) -0-R» or-S{0)_p-R», or

(iii) -NR'«R¹⁷; in which R° is hydrogen, C_1-t alkyl, hydroxy-C,^ alkyl or -CyA-(R²)),^* R^1β and R¹⁷ independently are hydrogen or C^ alkyl; p is 0-2; CyAis

(1) a 3-7 membered, saturated or uπεafurated carbocycle,

(2) a 4-7 membered, unsaturated or partially saturated heterocy e containing one nitrogen atom,

(3) a 4-7 membered, unsaturated or partially saturated hefβrocycle containing one nitrogen atom and one oxygen atom,

(4) a 4-7 membered, unsaturated or partially saturated heterocyde containing one nitrogen atom and two oxygen atoms.

(5) a 4-7 membered, unsaturated or partially saturated heterocyde containing two nitrogen atoms and one oxygen atom,

(6) a 4-7 membered, unsaturated or partially saturated heterocyde containing one or two sulfur atoms,

(7) a 4-7 membered, unsaturated, partially saturated or fully saturated heterocyde containing one or two oxygen atoms;

R² is (1) hydrogen, (2) C_1-4 alkyl, (3) C_1-4 alkoxy, (4) -COOR⁶, in which R⁶ is hydrogen or C^ alkyl, (5) -NR^βR⁷, in which R^β and R⁷ Independently are hydrogen or C,_, alkyl, (6) -S0₂NR⁸R⁷, in which R* and R⁷ are as hereinbefore defined, (7) halogen, (8) frifluoromethyl, (9) nitro or (10) trifluoromethoxy; Z is a single bond, methyleπe, ethylene, viπyleπe or ethyπyleπe; CyB is

(1) a 4-7 membered, unsaturated or partially saturated heterocyde containing one nitrogen atom,

(2) a 4-7 membered, unsaturated or partially saturated heterocyde containing two nitrogen atoms,

(3) a 4-7 membered, unsaturated or partially saturated heterocyde containing three nitrogen atoms,

(4) a 4-7 membered, unsaturated or partially saturated heterocycle containing one ortwo oxygen atoms,

(5) a 4-7 membered, unsaturated or partially saturated heterocyde containing one or two sulfur atoms, R* is hydrogen, C^ alkyl, C,_« alkoxy, halogen or trifluoromethyl; *^•

R-* is (1) hydrogen, (2) C,_« alkyl, (3) C^ alkoxy, (4) -COOR⁸, in which R^s is hydrogen or C_1-4 alkyl, (5) -NR^BR¹⁰, in which R^fl is hydrogen. C alkyl or ρheπyl(Cι_₄ alkyl) and R¹⁰ is hydrogen or C^ alkyl, (6) -NHCOR1¹, In which R« is C_M alkyl, (7) -NHSO_jR¹¹, in which R« Is as hereinbefore defined, (8) SOj RW in which R^B and R¹⁰ are as hereinbefore defined, (9) -OCOR¹¹, in which R¹¹ is as hereinbefore defined, (10) halogen, (11) frifluoromethyl, (12) hydroxy, (13) nttro, (14) cyano, (15) -Sθ₂N=CHNR«R<³ in which R^,z is hydrogen or C_M alkyl and R¹¹ is ά,^ alkyl. (16) -CONR'*R^ls in which R-⁴ is hydrogen or C,.* alkyl or phenyl(C₁^ alkyl) and R'δ is C,_^, alkyl or (17) C^ alkylthto. (18) C^ alkylsulfinyl, (19) Ci.* alkyisutfoπyl. (20) ethynyl, (21) hydroxymethyl, (22) tri(C,_* alkyl)sllylethynyl or (23) acetyl; and I, m and n independently are 1 or 2; with the proviso that

(1) CyA-fR )_! does not represent cydopentyl or frif luoromethylphenyl when Y is a single bond,

(2) CyB does not bond to Z through a nitrogen atom when Z Is vinylene or ethyπyiene,

(3) CyB is not pyridine or thiophene when CyA is a 4-7 membered unsaturated, partially saturated or fully saturated heterocyde containing one ortwo oxygen atoms, and

(4) Y Is not a single bond when A is (ϊ) -0-R» or -S(0)_p-R° or (iii) -NR<«R"; or a pharmaceutically acceptable salt thereof, or a hydrate thereof. Preferred compounds include:

4-pheπylmefhylamino-2-(3-pyridyl)quinazoline, 4-(3-methylpheπylmethyl)amiπo-2-(3-pyridyl)quinazoliπe, 4-(3,4-dιmethoxyphsnylmethyl)amlπo-2-(3-pyridyl)quiπazoliπe, 4-(4-carboxyphenylmethyl)amino-2-(3-ρyridyl)quιnazoline, 4-(3-mefhoxycarboπylpheπylmethyl)amiπo-2-{3-pyτidyl)quιnazolιπe, 4-(4-{N,N-dimethylamino)ρhenylmethyl)amino-2-(3-ρyridyl)quinazoline, 4-(4-sulfamoylpheπylmefhyl)amino-2-(3-pyridyl)quiπazoline, 4-(3-chlorophenylmethyl)amino-2-(3-ρyridyl)quinazoline, 4-(3-lrifluoromethylphenylmethyl)amiπo-2-(3-pyridyl)quinazoline, 4-(3-nifrophenylmethyl)amino-2-(3-pyridyl)quinazoline, 4-phenylmethylamino-2-(6-methyl-3-pyridyl)quinazdine, 4-phenylmefhylamino-2-(6-mefhoxy-3-pyridyl)quinazoline, 4-phenylmethylamino-2-(6-chloro-3-pyridyr)quinazoliπe, 4-phenylmethylamino-2-(6-trifluoromethyl-3-pyridyl)quinazoline, 4-phenylmethylamino-6-methyl-2-(3-ρyridyl)quinazdine, 4-phenylmef hylamino-6-mefhoxy-2-(3-pyridyl)quinazoline, 4-phenylmethylamino-6,7-dimethoxy-2-(3-ρyrtøyi)quinazoline, 4-phenylmethylamlπo-6-carboxy-2-(3-pyridyl)quinazoline, 4-ρhenylmethylamino-6-methoxycarbonyl-2-(3-ρyridyl)quinazoline, 4-phenylmethylamiπo-6-amiπo-2-(3-pyridyl quinazolιne, 4-phenylmethylamino-6-(N,N-dimethylamino)-2-(3-ρyridyl)quiπazoline, 4-phenylmethylamiπo-6-acetylamiπo-2-{3-pyridyl)quinazoliπe, 4-ρhenylmethylamino-6-methanesulfonylamino-2-(3-ρyridy0quinazoliπe, 4-phenylmethylamiπo-B-sulfamoyl-2-(3-pyridyl)quinazoline, 4-pheπylmefhylamino-6-acefoxy-2-(3-pyridyl)quinazoline, 4-pheπylmethylamiπo-6-chlo^*O-2-(3-pyridyl)quiπazoline, 4-pheπylmethylamino-6-bromo-2-(3-pyridyl)qulπazoliπe, 4-pheπylmethylamiπo-7-fluoro-2-(3-pyridyl)quiπazoline, 4-phenylmef hylamino-6-frifluoramefhyl-2-(3-pyridyl)quinazo(iπe, 4-ρhenylmethylamino-6-trifluorømethoxy-2-(3-ρyridyl)quinazoline, 4-phenylmefhylamino-6-hydroxy-2-(3-pyridyl)quinazoline_l 4-phenylmethylamino-6-nitro-2-(3-pyridyl)quinazoline, 4-phenylmethylamiπo-6-cyano-2-(3-pyridyl)quinazoline, 4-phenylmet hylamino-6-met hyl-2-(4-ρyridyl)quinazoline, 4-phenylmethylamino-6-methoxy-2-(4-pyridyi)quinazoline, 4-phenylmef hylamino-β,7-dimθthoxy-2-(4-pyridyl)quinazoline, 4-phenylmethylamino-6-carboxy-2-(4-pyridyl)quinazoline, 4-phenylmethylamino-6-methoxyr^rbonyl-2-(4-pyridyl)quinazoline, 4-phenylmethylamino-6-amiπo-2-(4-pyridyl)qulnazoline, 4-phenylmet hyfamino-6-(N,N-dlmethylamlno)-2-(4-pyridvl)quinazoliπe₁ 4-ρhenylmethylaminc--6-a⁽»lylamino-2-(4-rjyridyl)quiήazdine. , 4-phenylmethylamino-6-methanesulfonylamino-2-(4-pyridyl)quiπazoliπe,

4-phenylmethylamino-6-sulfamoyl-2-(4-pyridyl)quiπazoliπe.

4-ρheπylmethylamino-6-aceloxy-2-(4-ρyridyl)quinazoline,

4-phenylmethylamiπo-6-chloro-2-(4-pyridyl)quinazoline,

4-phenylmethylamincι-6-brorno-2-(4-pyridyl)quinazoline,

4-pheπyimethylamiπo-7-fluoro-2-(4-pyridyl)quinazoliπe,

4-phenylmethyiamino-6-frifluoromefhyl-2-(4-pyridyl)quiπazdine,

4-pheπylmethylamiπo-6-trifluoromethoxy-2-(4-pyridyl)quiπazoIiπe,

4-phenylmethylamino-6-hydroxy-2-(4-pyridyl)quinazoliπe_l

4-phenylmethylamiπo-6-πltro-2-(4-pyridyl)quiπazoliπe.

4-phenylmef hylamino-6-cyano-2-(4-pyridyl)quinazoline,

4-phenylamino-2-(3-pyridy quinazoline.

4-(3-methoxycarDorιylpheπyl)arnino-2-(3-pyrMyl)quinazoline,

4-ρhenylethylamino-2-(3-ρyridyl)quina2θline. 4-phenylmefhylamino-2-(2-pyridyl)quiπazoline,

4-phenylmefhylamino-2-(4-pyridyl)quinazoline,

4-phenylmethylamino-2-(2-(3-pyridyl)ethyl)quinazdine,

4-phenylmefhylamino-2-(2-(3-pyridyl)vinyl)quinazoline,

6-iodo-4-phenyimethylamino-2-(3-pyridyl)quinazoline,

4-(3-carboxyphenyl)amino-2-(4-pyridyl)quinazoline,

6-fluoro-4-ρhenylmethylamino-2-(3-ρyridyl)quinazoline,

4-(cydopropylmethyl)amino-2-(3-pyridyI)quinazoline,

4-(cydohexylmethyl)amino-2-(3-pyridyl)quinazoline,

4-(2-azepiπylmethyl)amiπo-2-(3-pyridyl)quinazoline,

4-(3-ρyridylmethyl)arninc-2-(3-ρyridyi)quinazoline,

4-((1-mefhyf-2-pyrrolyl)methyl)amiπo-2-(3-pyridyl)quinazoline,

4-(3-isoxazoiyl)amino-2-(3-pyridyl)quinazoline,

4-(3-isoxazolylmethyl)amiπo-2-(3-pyridyl)quinazoliπe,

4-(2-thienyimethyl)amino-2-{3-ρyridyl)quiπazoline.

4-(2-furylmethyl amiπo-2-(1 -imidazolyljquiπazoliπe,

4-(2-tetrahydrofuranylmethyl)amino-2-(1 -imidazolyl)quinazoline,

4-(4-tetrahdyropyranylmethyl)amino-2-(1 -imidazσlyl)quinazoliπe,

6-methoxy-4-(4-fefrahydropyranylmethyl)amino-2-(1-imidazdyl)quinazoline,

6-chloro-4-(4-tetrahydropyraπylmethyl)amiπo-2-(1-imidazolyl)quiπazoliπe,

4-(2-phenoxyefhyl)amino-2-(1-i idazolyl)quinazoliπe,

4-(2-thieπylmethyl)amiπo-2-(1 -imidazolyl)quinazoliπe,

4-(2-mefhoxyethyl)amino-2-(1-i idazolyl)quinazoline,

4-(1,1-dimethyl-2-rnethoxyethyl)amino-2-(1-imidazolyl)quinazoline,

6-methoxy-4-(2-methoxyefhyf)amino-2-(1-imidazdyl)quinazoliπe,

6-chloro-4-(2-methoxyethyl)amino-2-(1-imidazolyl)quinazoline,

4-(3-ethoxypropyl)amino-2-(1-imidazolyl)quinazoline,

6-nifro-4-(2-methoxyefhyl)arnino-2-(1-imidazolyl)quinazoline,

6-chloro-4-(2-ethoxyethyl)amino-2-(3-pyridy()quiπazoline,

6,7-dimethoxy-4-(2-methoxyefhyl)amino-2-{1-imidazolyl)quinazoline,

6-chloro-4-(2-{2-hydroxyethoxy)ethyl)amino-2-{1-imidazdyl)quinazdine, e-chloro-4-(2-dimethylaminoefhyl)amino-2-(1-imidazolyl)quinazoline,

6-methoxy-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(1-imidazolyl)quinazdiπe,

4-(2-mefhoxyefhyl)amino-6-iodo-2-(1-imidazdyl)quinazoline,

4-(2-methoxyethyl)amirκ)-6-methoxy-2-{2-methyl-1-irnidazolyl)quirιazoline,

4-(2-hydroxyethyl)amino-6-rnefhoxy-2-(1-imidazqlyi)quinazoIiπe,

4-(2 nethαxyethyl)amino-6,8-diiodo-2-{1-itτιidazolyl)quinazolirιe,

4-(2-(2-hydroxyethoxy)ethyl amino-6-iodo-2-(1-imidazolyl)quiπa2θline,

4-(2-rnetlιoxyethy amino-6-rnethylthiCH2-(1-imidazo|yl)quinazolirιe,

4-(2-metr )xyethyl)amino-6-methylsutfinyl-2-(1-imldazolyl)quirιazoline,

4-(2-methoxyethyl)amino-6-methylsulfonyl-2-(1-imidazoly1)quinazoline,

4-(2-(2-hydroxyethoxy)ethyl)amino-S-methylsulfiπyl-2-(1-imidazolyl)-quinazdine,

2-(1-ιmidazoι )-4-(2-mefhoxyethy0amino-6-{2-lriefhylsifylefhynyl)quinazoline,

6-acetyl-4-{2-methoxyethyl)amiπo-2-(3-pyridyl)quiπazoline,

6-ethynyl-4-(2-rrιethoxyethyl)-tmi o-2-(3-pyndyl)quina2αline_l

4-[2-(2-hydroxyetrtoxy)ethyf]amino-6-acetyl-2-(1-lmida20lyl)quinazoline,

4-(2-metlrlthioethy0ιamirκ^-methoxy-2-(1-imidazolyl)quinazoline,

4-(2-*nethylsulfiπytethyl)amiπo-6-rrιethoxy-2-(1-lmida2θlyl)cμιπazoliπe₍

4-(2-rneth^sulfonyletlvl)amino-6-methoxy-2-(1-imidazolyl)quinazoline,

4-[2-(2-hydroxy^*eihoχγ)ethyl]amlπo-6-methoxyc3τb^^

4-p-(2-hydraxy rthoxy)ethyl]amino-6-hydroxymethyl-2-(1-irnidazdyl)-quinazoliπe₁

4-(2-methoxyethy^*^mlno-β-hydroxymethy(-2-(1-imida^*zoιyl)αulπazoline,

4-(2-ιnefrιoxyefhyl)amlno-G-methoxycarbony^2-(1-imidazdyl)quinazoline,

4-(3-methoxypro|>y0amino-β-rnethoxy-2-(1-lmidazdyl)quinazoliπe,

4-(2-(2-hydroxyethoxy)ethyl)amlno-6-mefhylthio-2-(1-imidazolyl)quinazoline,

2-(1-imιyazolyO-4-P-{2-l^*ιydroxyethoxy)ethv^

2-(1-imWazolyl)-4-[2-(2-hydroxyethoxy)ethyι n^rκ)-6-ethyn^* quιrιazoliπe,

4-ρhenylmethytemino-e-methy1-2-{1-imidazdy0quinazoline,

4-pheπylmethylamiπo-6-methoxy-2-(1-lmldazdyl)quiπazoliπe₎

4-phθnyimefhylamin ι-β,7-dimθtιτoxy-2-(1-imidazolyl)quirιazoliπθ,

4-phenylmethylamlno-β-caιtoxy-2-(1-lmldazol^*/l)qulπazoliπe,

4-pheπyimethylamirκ>-β-mθthoxyrøι )oπyl-2-(1-imιdazσlyl)quinazolinθ, 4-pheπylmethylamino-6-amino-2-(1-imidazolyl)quinazoliπe,

4-phenylmef hylamino-6-(N,N-dιmθthylamιno)-2-(1-imidazolyl)quiπazolιπθ,

4-ρhenylmethylamino-6-acetylamino-2-(1-imidazolyl)quιnazoline,

4-phenylmethylamino-6-methanesulfonylamiπo-2-(1-imidazolyl)quinazoline,

4-phenylmethylamino-6-sulfamoyl-2-(1-imidazolyl)quinazoline,

4-pheπylmethylamino-6-acetoxy-2-(1-imidazolyl)quinazoline,

4-phenylmethylamino-6-chloiO-2-{1-imidazolyl)quinazoline,

4-pheπylmethylamino-6-bromo-2-(1-imidazolyl)quιnazdine,

4-phenylmet hylamino-7-fluoro-2-(1-imidazolyl)quinazoline,

4-phenylmethylamiπo-6-trιfluoromethyl-2-(1-imidazolyl)quιnazoline,

4-phenylmethylamino-^β-tπfluoromethoxy-2-(1-imidazolyl)quinazoline,

4-phenylmethylamino-6-hydroxy-2-(1-ιmιdazolyl)quiπazolιne,

4-phenylmethylamino-^β-nitro-2-(1-ιmidazolyl)quinazoline,

4-pheπylmet hylamiπo-6-cyaπo-2-(1 -imidazolyl)quiπazoliπe ,

4-phenylmet hyiamino-2-(1-imidazolyl)quinazolιπe,

4-pheπylmethyfamiπα-2-((1-imidazolyl)rnethyl)quiπazoliπe,

4-phenylmethylamiπo-2-(2-mefhyl-1 -imidazoly1)quinazolιne,

6-bromo-4-pheπylmethylamino-2-(1-imidazolyl)quiπazoliπe,

7-chloro-4-pheπylmethylamiπo-2-{1-imidazolyl)quinazolιπe,

6-chioro-4-ρhenylamιno-2-(1-imidazolylrnethyl)quiπazolιne,

6-nitro-4-phenylmethylamιno-2-(1-ιmidazolyl)quinazoline,

6-methoxy-4-phenylmethylamιno-2-(1-imidazolyl)quinazoline,

6-chloro-4-phenylmefhylamino-2-{1-imidazoly1methyl)quinazoIιπe,

6-chloro-4-(3-carboxyρhenyl)amino-2-(1 -imidazolylmethyl)quinazoline,

6-dimethylaminosulfbnyl-4-ρhenylmethylamino-2-(1-imidazolyl)quiπazoliπe,

6,7-dimethoxy-4-phenylmethylamino-2-(lH^'midazolyl)quinazdine,

4-(3,4-dimethoxyphenylmethyl)amiπo-2-(1-imidazolyl)quinazoline,

6-dimethylaminomethylideneaminosulfonyl-4-phenylmethylamino-2-(1-imidazolyl)quinazoline,

6-(phenylmethylaminosulfonyl)-4-ρhenylmethylamino-2-(1-imidazolyl)quinazoline,

4-(2-phenylethyl)amino-2-(1 -imidazolyl)quiπazoliπe,

4-cydohexylmethylamino-2-(1 -imidazolyl)quinazoline,

6-carboxy-4-phenylmethylamino-2-(1-imidazolyl)quinazoline,

6-ρhenylmethyIaminocarbonyl-4-ρhenylmethylamino-2-(1-imidazolyl)quinazoline,

6-iodo-4-phenylmethylamino-2-(1-imidazolyl)quiπazoliπe,

6-ethoxycarbonyI-4-phenylmethylamino-2-(1-imidazolyl)quinazoline,

6-hydroxy-4-pheπyimethylamino-2-(1-imidazolyl)quiπazoline,

4-(4-trifulorornethoxyρhenylmethyl)amino-2-(lH^'midazolyl)quinazdine,

4-phenylmethylamiπo-2-(2-azepiπyl)quinazdine₁

4-phenylmet hylamino-2-(1,5-diazepiπ-2-yl)quinazoline,

4-pheπylmethylamiπo-2-(2-pyrimidinyl)quinazoliπe,

4-phenylmet hylamino-2-(2-friazinyl)quinazoline,

4-phenylmethylamino-2-(2-pyrrdyl)quiπazoline.

4-phenylmethylamino-2-(1-triazdyl)quinazoline,

6-hydι^*oxy-4-phenylmethylamiπo-2-(1-imldazoIyl)quinazoline,

4-(3-tn^'fluoιomethoxypheπylmethyl)amino-2-(1-^'ιmidazolyOquiπazoline

4-pheπylmelhylamino-6,8-diiodo-2-(1-lmldazolyl)quiπazoline,

4-(2-phenoxyethyl)amino-6-methoxy-2-(1-imidazolyl)quiπazoline,

6-hydroxyτnethyl-4-phenylrrιethylamlπo-2-(3-pyrldyI)quiπazoliπe

6-methylthlo-4-pheπylmefhylamiπo-2-(3-pyridyl)quinazoliπe₁

6-metrrylsulfiπyl-4-phefiylιτιethylanιirιo-2-(3-pyridyl)quiπazoliπe,

6-methylsιiflnyl-4-pherιylmethylarnino-2-(3-pyridyl)quinazoline,

4-phenylmethylamino-2-(2-thienyl)quιnazoline₁

4-phenylmethylamlno-2-(2-furyl)quiπazdine,

4-phenylmethyla irκ)-2-(1-inϊdaz yl)-5.6,7,8-tetrahydroquinaύ.oline,

6-c_tfbco /-4-phenylmethylamino-2-(1-imldazolyl)-5,6_l7,8-tetrahydroquinazollne, e-etrKJxyOTrbonyM-phenylmefl-rylaminc-^-O-imida^

6^thyIaminocarboπyl-4-pheπylπ^*ιethylamlno-2-(1-imldaz^

4-(2-metl yβthyl)amino-2-(1-imtøazolyl)-5,β_t7,8-tβta

4-(2-(2-hydroxyetiιoxy)ethyl)amlno-2-{1-lnτlcla2dyl)-5,6.7,8-tetrahydroquI^ European published application number 0636626, which discloses compounds of the formula

and salts and solvates (e.g. hydrates) thereof, in which.^*

R¹ represents arylmethyl or C, -<, alkyl optionally substituted by one or more fluorine atoms;

R² represents methyl;

R^? represents C? -.alkyl;

R-¹ represents nitro, cyano, C, -_Ealkoxy. C( = X)NR⁵ R⁷. NR^SR⁹ , (CH₂)_mNR¹°C( = Y)R¹¹ or a 5-membered heterocyclic ring selected from thieπyl, thiazolyl and 1 ,2,4-triazolyl each ring optionally substituted by a

Cι -₄a⁽kyl or aryl group; or when R¹ is arylmelhyi or Ci -εalkyl substituted by one or more fluorine atoms then R* may also represent hydrogen;

R⁵ represents hydrogen or Cι -«alky(;

R^c represents hydrogen or Cι -6alkyl;

R⁷ represents hydrogen, amino, hydroxyl, Ci -₆alkyl, aryl or arylCi - <ι alkyl;

R⁸ represents hydrogen or Cι -« alkyl;

R⁹ represents hydrogen, C, -.alkyl, S0₂R¹², CO2R¹², C( = NCN)SR¹² or C( = NCN)NR¹³R^1<*;

R¹⁰ represents hydrogen or Ci -salkyl;

R¹¹ represents Ci -salkyl optionally substituted by one or more halogen atoms, or Rⁿ represents aryl, arylCi -.alkyl, thienyl, NR^{ls ,ε}, CH₂NR^,7R¹⁸ or R'° and R" together represent -A(CH_Z)„-;

R¹² represents Cj -. alkyl, aryl or arylCi -.alkyl;

R'³ represents hydrogen or & -c alkyl; R" represents hydrogen, C, --, alkyl. aryl. arylC, -.alkyl or R» and R" together with the nitrogen atom to which they are attached form a morpholine. piperazine or N-C-.alkylpiperaz.ne ring; R« represents hydrogen or C, -<*alky! or R'° and R¹⁵ together represent -A(CH,)_n- R" represents hydrog n, C -.alkyl. aryl. arylCi -.alkyl. CCfeR". CH.CO R- or - and R- together with the nitrogen atom to which they aro attached form a morpholine, piporaan^β or N-d - .alkyl- piperazine ring;

R¹⁷ represents hydrogen or Ci -βalkyl: ...

R* represents hydrogen, C, -.alkyl. aryl. arylC, -.alkyl. CO or R'⁷ and Rⁱ together with the nitrogen atom to which they are attached form a morpholine, piperazine or N-d -. alky Ipⁱperazme nng; A represents CH2 or C = 0; m represents zero or 1; n represents 12. or 3;

X represents S or NH, or when R⁷ represents amino then X may also represent O; Y represents O or S; for use in therapy.

Preferred compounds include:

1 ,3-DinrothyI-S-(2-propoxy-5-acetamidopheny -1.5-dihydropyrazoIo[3,4-d]pyrimidin-4-one-

1-ettιyl-3^ethyl-6-[2-propoxy-5-(4-melfιyl-2-miazolyl)phenyl]-1^dihydropyrazoio[3.4-d]pyrimidi(i-4-cxιe^* 1-etrryl-3-rnethyl-6-[2-prorjoxy-5^^

1 -ethyl-3-methy l-6-f2-propoχy-5-(2-(3-pyridyl)-4-thiazolyl)phenylH .5-dihydropyrazolo[3.4-d]pyrimidin-4- ' one;

1.3-dimethyl^-[2-propoxy-5-(2-methyl-4-thiazolyl)phenylh1.5-dihydiOpyrazolo[3.4-dJpyrlmldin-4-one^* 1.3-d.methyl-6-[2-propoxy-5-(3-phenyM ,2,4-triazo)-5-yl)phenyl]-ι ,5-dihydrop_yrazolo[3.4-d]pyrimidin-4- ι ,3-dimethyl^-(2-prorxι^*<y-5-methanesulfonamidophenylhl,5<lihydro-pyrazoι^3,4^]pyrimidin-4τθne^* and physiologically acceptable salts and solvates (e.g. hydrates) thereof. European published application number 0640599, which discloses compounds of the formula

wherein A is a bond, C1-4 alkylene or C1-4 oxyalkyiene; is a bond, C1-4 alkylene, C1-4 alkyleneoxy, C1-4 alkoxyphenylene or pheπyl(C1-4)alkyleπe;

Z is a bond or vinyleπe;

R1 Is 4-15 membered heterocyclic ring containing one ortwo nitrogen atoms optionally substituted by one or two groups chosen from C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl and πitro;

R2 is (i) 4-15 membered heterocydic ring containing one ortwo hetero atoms chosen from nitrogen, oxygen, and sulphur, not more than one hetero atom being sulphur, optionally substituted by one or two groups chosen from C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, πitro and groups of formula:

-COOR10 wherein R10 is hydrogen or C1-4 alkyl, (ii) C4-15 carbocydic ring, (iii) C1-4 alkoxy, (iv) hydroxy(C1-4 alkoxy) or (v) hydroxy;

R3 is (i) 4-15 membered heterocydic ring containing one ortwo hetero atoms chosen from nitrogen, oxygen and sulphur, not more than one hetero atom being oxgen or sulphur, optionally substituted by one or two groups chosen from C1-4 alkyl, C1-4 alkoxy, halogen, trifluoromethyl, nitro, cyano, ethynyl and groups of formula;

-SONR7R8 wherein R7 and R8 are independently hydrogen or C1-4 alkyl. (ii) C4-15 carbocydic ring, (iii) a group of formula:

CH2=CH(X)- wherein X is halogen, or (iv) hydrogen, and I is 1 or 2, provided that R2 Is not hydroxy when Y is a bond; R1 is not bonded through its nitrogen atom when Z is viπylene; and exduding compounds of the formula:

wherein R*-^*- is methyl or n-propyl;

R⁶⁶ is cydopentyl, cyc ihexyl, 2-hydroxyethyl, methoxyethyl, 2-(1-piperWinyl)ethyl, or phenyl or benzyl which may be substituted by 1 or 2 of methyl, methoxy, chloro, nitro and trifluoromethyl;

R⁰⁰ is hydrogen or methyl;

R°° is methyl or n-propyl, isopropyl or benzyl; and ^ is hydrogen or methyl; and th

and Its

Preferred compounds include:

-imidazolyl)-4-[2-(2-hydroxyethoxy)ethyl]amino-5-(3-methoxyphenyl>-methylpyrimidine,

-lmidazolyl)-4-ρhenylmethyiaminopyrimidine,

-lmidazolyl}-4-(2-methoxyethyl)aminopyrimidine,

-lmidazolyl}-5-ethyl-4-phenylmethylaminoρyrimidine,

-lmidazolyl)-5-phenylmethyl-4-phenylmethylaminopyrimidine

-lmidazolyl)-5-methyl-4-phenyl methylaminopyrimidine,

•lmidazolyl)-5,6-dimethyl-4-pheπylmethylamiπopyrimidiπe

2-(1-lmidazolyl)-5-(3-methoxyphenyl)methyl-4-(2-methoxyethyl)amino-pyrimidine.

2-(1-lmidazolyl)-5-(4-nιethoxyphenyl)methyl-4-t2-(2-hydroxyethoxy)ethyQ-aiTiirκ)pynmidine,

2-(1-lmidazolyl)-5-(4-methoxyphenvl)methyl-4-(2-methoxyethyl)amino-pyrimidine,

2-(1-lmidazolyl)-5-(4-methoxyρhenyl)methyl-4-ρhenylmethylamino-ρyrimidine.

2-(1-lmidazαlyl)-5-pheπoxymethyl-4-phenylmethylamiπopyrimidiπe,

2-(1-lmidazolyl)-5-(1-imidazolyl)mefhyl-4-phenylmefhylaminopyrimidine,

2-(1-lmidazolyl)-5-(1-chloroviπyl)-4-phenylmethylaminopyrimidiπe,

2-(1-lmidazolyl)-5-(2-thienyl)-4-pheπylmethylaminopyrimidine,

2-(1 -lmidazolyl)-5-(2-thiazolyl)-4-pheπylmethylamlπopyrimidine,

2-(1-lmidazolyl'-5-(2-thienyl)-4-(1 ,3-dioxaindan-5-yl) methylaminopyrimidine,

2-(1-lmidazolyl)-5-(2-thienyl)-4-[2-(2-hydroxyethoxy)ethyl] amiπopyrimidine.

2-(1-lmidazolyl)-5-(2-fhienyl)-4-(1 -naphthyl) methylaminopyrimidine,

2-(1-lmidazolyl)-5-(2-thienyl)-4-(4-methoxyphenyl) methylaminopyrimidine,

2-(1-lmidaz yi}-5-(2-thienyl)-4-(3-methoxyphenyl) methylaminopyrimidine,

2-(1-lmidazolyi)-5-(2-thienyl)-4-(2-furyl) methylaminopyrimidine,

2-(1-lmidazolyl)-5-(2-thienyl)-4-(2-thlenyl) methylaminopyrimidine,

2-(1-lmidazolyl)-5-(2-fhienyl)-4-(3-pyridyl) methylaminopyrimidine,

2-(1 -lmidazolyl)-5-(2-thienyl)-4-(2-methoxyethyl) aminopyrimidine,

2-(1-lmidazolyl 5-(2-thienyl)-4-phenylmethoxyaminopyrimidine,

2-(1-lmidazolyl)-5-(2-thierryl)-4-(4-chIoroρhenyl) methylaminopyrimidine,

2-(1-lmidazolyl}-5-(2-thienyl)-4-(3-chlorophenyl) methylaminopyrimidine,

2-(1 -lmidazolyl)-5-(2-thieπyl)-4-(1 , 3-d ioxaindan-5-yl) methylaminopyrimidine,

2-(1-lmidazolyl)-5-(4-methylphenyl)-4-(1,3-dioxaiπdan-5-yl) methylamino-pyrimidiπe,

2-(1-lmidaiθlyl)-5-(4-methoxyρhenyl)^*-4-(1,3-dioxalndan-5-yl) methylamino-ρyrimidine,

2-(1-lmldazdyl)-5-(5-methyl-2-fhienyl)-4-(1,3-dioxaindan-5 -yl)methylamino-pyrimidine,

2-(1-lmidazolyl}-5-(2-thienyl)-4-[4-(1-inrιidazd:y h

2-(1-lmidazolyl)-5-(3-pyridyl)-4-(1 ,3-dioxalπdaπ-5-yl) methylaminopyrimidine,

2-(1-lmidazolyl)-5-(3-furyl)-4-(1,3-dioxaindan-5-yl) methylaminopyrimidine,

2-(1-lmidaz yl)-5-(3-pyridy1)-4-phenylmethylamiπopyrimi iπe,

2-(1-lmidazolyl]H5^(4-c^loraρhenyl)-4-(1,3-dioxaindan-5-yl) rrιethylamino-ρyrimidine,

2-(Beπzimldazd-1-yl)-δ-(2-thienyl)-4-(1,3-dioxaiπdan-5-yl) methylamino-pyrimidine,

2-(1 -lmidazolyl)-5-(2-fhieπyl)-4-(4-ethoxycarbonylphenyl) methylamino-pyrimidine,

2-(1-lmldazαlyl)-5-(2-πaphthyi)-4-{1,3-dioxaiπdaπ-5-yl) methylamino-pyrimidine,

2-(3-Pyridyl)-5-(2-thienyl)-4-(1 ,3-dioxaiπdaπ-5-yl) methylaminopyrimidine,

2-[2-(3-l^dy vir^*r/l]-5-(2-thieπyl)-4-(1,3- ιoxalπdatv5-yl) r^

2-(2-Mef hyl-1 -lmidazolyl)-5-(2-thienyl)-4-(1 ,3-dioxalndan-5-yl) methylamino-pyrimid ine or

2-y -lmidazolyl)-5-(2-thierryl)-4-(benzimidazd-5-yf) methylaminopyrimidine European published application number 0668280, which discloses compounds of the formula

wherein R¹ and R² are the same or different and represent hydrogen, lower alkyl (which is optionally substituted with one to three substrtuents which are the same or different and are cydoalkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-substituted ammo, nitro, halogen, alicyclic heterocyde group (which is optionally substituted with one to three substituents which are the same or different and are lower alkyl, aralkyl, aryl optionally substituted with one to three substituents which are the same or different and are lower alkoxy, or aromatic heterocyde group)), cycloalkyl, btcycloalkyl, benzocycloalkyl (which is optionally substituted with one to three substituents which are the same or different and are lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, ammo, monoalkyl-substituted amino, dialkyl-substituted amino, nitro, sulfonamide, halogen, or trifluoromethyl), lower alkenyl, aryl (which is optionally substituted with ono to three substituents which are the same or different and are lower alkyl, hydroxy, lower alkoxy, carboxy, tower alkoxycarbonyl, amino, monoalkyl-substitutod amino, dialkyl-substituted amino, nitro, sulfonamide, halogen, or trifluoromethyl), aromatic heterocyde group-substituted alkyl (which is optionally substituted with one to three substituents which are the same or different and are tower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted am o, dialkyl-substituted ammo, nitro, sulfonamide, halogen or trifluoromethyl and where said alkyl part is optionally substituted with aryl), aromatic heterocyde group (which is optionally substituted with one to three substituents which are the same or different and are lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl- substituted amino, dialkyl-substituted amino, πitro, sulfonamide, halogen, or trifluoromelhyl), or aralkyl (where the aryl part of said aralkyl is optionally substituted with one to three substituents whid^* are the same or different and are lower alkyl. lower alkoxy, dialkyl-substituted amino, halogen, or trifluoromethyl), or R¹ and R^z are taken together to represent heterocyde group containing nitrogen atom (which is optionally substituted with one to three substituents which are the same or different and are lower alkyl, aryl, or aralkyl), R³ represents hydrogen, lower alkyl (which is optionally substituted with one to three substituents which are the same or different and are cydoalkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-substituted amino, nitro, halogen, or alicyclic heterocyde group (which is optionally substituted with one to three substituents which are the same or different and are lower alkyl, aralkyl, aryl optionally substituted with one to three substituents which are the same or different and are lower alkoxy. or aromatic heterocyde group)), cycloalkyl, lower alkenyl, aryl (which is optionally substituted with one to three substrtuents which are the same or different and are lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted ammo, dialkyl-substituted amino, nitro. sulfonamide, halogen, or trifluoromethyl), aromatic heterocyde group-substituted alkyl (where said aromatic heterocyde group part is optionally substituted with one to three substituents which are the same or different and arc lower alkyl, hydroxy, lower alkoxy, carboxy. lower alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-substituted amino, nitro, sulfonamide, halogen or trifluoromethyl, and where the alkyl part is optionally substituted with aryl), aromatic heterocyde group (where said aromatic heterocyde group Is optionally substituted with one to three substrtuents which are the same or different and are lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, amino, monoalkyl-substituted amino, dialkyl-substituted amino, nitro, sulfonamide, halogen, or trifluoromethyl), or aralkyl (where the aryl part of said aralkyl is optionally substituted with one to three substrtuents which are the same or different and are lower alkyl, lower alkoxy, dialkyl-substituted amino, halogen, or trilluoromethyl), and X represents oxygen atom or sulfur atom, or pharmacologically acceptable salts thereof. 9584

-32-

European published application number 0669324, which discloses compounds of the formula

W^r

(wherein R\ R², R³, R* and R⁵ may be the same or different from each other and each represents a hydrogen atom, a haiogeπ atom, a lower alkyl group or a lower alkoxy group; and

R^ε and R⁷ may be the same or different from each other and each represents a hydrogen atom, a lower alkyl group, a hydroxyalkyl group, a lower alkoxyalkyl group, a cyanoalkyl group, a heteroarylalkyl group, a cycloalkyl group, a cydoalkylalkyl group or a carboxyl alkyl group which may be protected, or alternatively R-^* and R⁷ may form a ring together with the nitrogen atom to which they are bonded, this ring optionally having a substituent). or a pharmacologically acceptable salt thereof:

WO91/19717 discloses compounds of the formula

wherein

J is oxygen or sulfur,

R¹ is hydrogen, alkyl or alkyl substituted with aryl or hydroxy;

R² is hydrogen, aryl, heteroaiyl, cycloalkyl, alkyl or alkyl substituted with aryl, heieroaryf, hydroxy, alkoxy, amino, monoalkyl amino or dialkylamlno, or -(CH2)mTCOR²⁰ wherein m is an integer from 1 to 6, T is oxygen or-NH- and R²" is hydrogen, aryl, heteroaryf, alkyl or alkyl substituted with aryl or heterσaryl; R³ is hydrogen, halo, trifluoromethyl, alkoxy, alkylthio, alkyl, cycloalkyl, aryl, aminosulfonyl, amino, monoalkyiamiπo, dialkyiamino, hydroxyalkylamino, aminoalkyla ino, carboxy, alkoxycarbonyl or aminocarbonyl or alkyl substituted with aryl, hydroxy, alkoxy, amino, monoalkylamino or dialkyiamino;

Ra, R^b, e and R^d independently represent hydrogen, alkyl, cycloalkyl or aryl; or (R^a and R^b) or (R^c and R^d) or (Rb and R^c) can complete a saturated ring of 5- to 7- carbon atoms, or (Ra and R^b) taken together and (R^b and R^c) taken together, each complete a saturated ring of 5- to 7-carbon atoms, wherein each ring optionally can contain a sulfur or oxygen atom and whose carbon atoms may be optionally substituted with one or more or the following:. alkenyl, alkynyl, hydroxy, carboxy, alkoxycarbonyl, alkyl or alkyl substituted with hydroxy, carboxy or alkoxycarbonyl; or such saturated ring can have two adjacent carbon atoms which are shared with an adjoining aryl ring; and n is zero or one.

Preferred compounds include: cis-5,6a,7,8₇9,9a-Hexahydro-5-methyl-3-(phenylmethyl)- cyclopeπta[4,5]imidazo[2,1-b]purin-4-one; 7,8-Dihydro-5-methyl-3-(phenylmethyl)-3W-imidazo[2,1~b]purin-4(5r)- one; ds-6a,7_f8,9,10,10a-Hexahydro-5-methyl-3-(pheπylmethyi)-3H- beπzimidazo[2,1-b] purin-4(5 -/}-one; 5,7,8,9-Tetrahydro-5-methyi-3-(phenylmethyl)pyrimjdof2,1-b]purin-

4(3W)-one; 7,8-Dihydro-8-phenyl-5-methyl-3-(phenylmethyl)-3H-imidazo[2,1- bjpurin-4(5W)-one; 5^,,7^*-Dihydro-5'-methyl-3^,-(pheny1methyl)spiro[cyclohexane-1 ,8^,-(8fτ)- imidazo[2,1 -b]ρurin]-4^,(3'rV)-αne; cis-5,6a,11 ,11 a-Tetrahydro-5-methy!-3-

(phenylmethy indenofV^'^.δjimidazoIS.I-bjpurin^SHJ-one; ^ '-Dihydr_D-Z.S¹ dimethyl-3'-(phenylmethyl)splro{cyclohexane-

1 ^'(δ'idJ-imidazo^.l -blpurin}-4^,(3^,Jd}-σn.e; 7_f8-Dihydro-2,5,7,7,8(R,S)-pentamethyl-3Jd-imidazo[2,1-b]purin-4(5Jl)- one; cis-5,6a,7,11 b-Tetrahydro-5-methyl-3- (phenylmethyl)indenor2^,,r,:4,5]imidazo[2_f1-b]purin-4(3W}-one; cis-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3-(pheπylmethy!)- cyclopenf[4,5jimidazo[2, 1 -b]purin-4-(3rV)-one; 5'- ethyl-3'-(phenyimethyl)-spiro[cyclopentane-1 ,7^l(8'H)-(3'H )- imidazo[2,1-b]purin]-4'(5'/V)-one;

7₎8-Dihydro-2,5,7,7-tetramethyl-3-(phenylmethy^{)-3U-imidazo[2,1- b]purin-4(5'H)-one;

7,8-Dihydro-7(R)-ρhenyl-2,5-dimethyl-3-(phenylmethyl)-3H-imidazo[2,1- b]purin-4(5Jϋ)-one;

7_?8-Dihydro-2_T5-dimethyl-3₎7(R)-bis(phenylmethyl)-3Ji-imidazo[2₎1- b]purin-4(5ii)-one;

(±)-7_l8-Dihydro-2,5-drmethyl-7-ethyl-3-(phenyimethyl)-3£l-imidazo[2,1- b]purin-4(5Jti)-one ;

6a(S)-7,8,9,10,10a(R)-Hexhydro-2,5-dimethyl-3-(phenylmethyI)-3H- benzimidazo[2,1-b]purin-4(5Ji}-one;

6a(R)-7,8,9,10,10a(S)-hexahydro-2_f5-dimethyl-3-(pheny!methyl)-3u- benzimidazo[2,1-b]purin-4(5Jd)-one;

7,8-Dihydro-2,5-dimethyl-7(R}-isopropyl-3-(phenyimethyl)-3H- imidazo[2,1-b]purin-4(5H)-one; 7_I8-Dihydro-2,5,7(R)-trimethyl-3-(phenylmethyl)-3H-imidazo[2,1-b]purin-

4(5Jl)-one; cis-7,7a,8_t9,10,10a-Hexahydro-2,5-dimethyI-3-(pheπylmethyl)-3H- cyclopenta[5,6]pyrimido[2,1-b]purin-4(5H)-one;

7,8-Dihydro-2,5-dimethyl-7(S)-(1-methylpropyl)-3-(pheπylmethyl)-3li- imidazo[2,1-b]purin-4(5H}-one;

7,8-Dihydro-2,5-dimethyf-7(R)-(2-methylpropyl)-3-(phenyimethyl)-3H- imidazo[2,1 -b]purin-4(5H)-one ; 7,8-Dihydro-2,5-cfimethyl-7(R,S)-(methoxycarbonyJ)-3-(phenylmethyl)-

3H-imidazo[2,1-b)purin-4(5H}-one;

7,8-Dihydro-2,5-dimethyl-7(R,S)-(1-propyI}-3-(phenyJmethyl)-3il- imidazo[2, 1 «b]purin-4(5ϋ)-one; 7,8.Dihydro-2,5 fimethyl-7(S)-(1-methylethyf)-3-(phenylmethy^[)-3ll- imidazo[2,1-bJρurin-4(5H)-one; 7,8-Dihydro-2,5,7,7,8(R,S)-pentamethyl-3Jhi-imidazor2,1-bIpurin-4(5H)- one; 5,7,8,9-Tetrahydro-2_f5,7,9(R,S)-pentamethyl-a-(phenylmethyl)- pyrimido[2,1-b]puriπ-4(3M)-one,^r 5,6a( ^:j),7,8,9,9a(S)-Hexahydro-2,5-dimethyl-3-

(phenylmethyf)cyclopentf4.5JimIdazoI2,1-b3purin-4(3ry)-one; 5,6a(S),7,8,9,9a( ^: )-Hexahydro-2_I5-dimethyl-3-

(pheπylmethyl)cyclopent[4,5Jimidazof2,1-bJρurin- (3W)-one; cis-6a,7,8,9,10,1 Oa-Hexahydro.-2,5-dimethyl-3-(phenylmethyl)-3rV - benzimidazo[2,1-b]purin-4(5W)-one; 5',7'-Dihydro-2',5^,-dimethyl-3^,-(phenylmethy!)spiro[cyciohexane-l,8'-

(8r )-imidazo[2, 1 -b]purin]-4'{3'r7)-one; cis-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3-(phenylmethyl)- cyclohept[6,7Jimidazo[2,1-blpurin-4(3 τ)-one; cis-5,6a,7,8,9,9a-HexahydrO-5-methyl-2-ethyl-3-(phenyimethyl)- cyclopent[4,5]imidazo[2,1-b]purin-4(3rV)-one; cis-6a,7,8,9,10,10a-Hexahydro-5-methyf-2-ethyl-3-(phenylmethyf)-3rV- benzimidazo[2,1-b]purin-4-(5r)*one; cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-ethyl-3-(phenylmethyl)- cyclopent[4,5]imidazoI2,1-b]purin-4(3r )-one; cis-5,6a,7,8,9,9a-Hexahydro-5-methyl-2-pheny!-3-(phenylmethy[)- cyclopent[4,5Jimidazo[2,1-b}purin-4(3/V)-one; cis-6a,7,8,9,10,10a-Hexahydro-5-methyl-2-phenyl-3-(phenyimethyl)-3rV- benzimidazo[2,1-b]ρurin-4(5H)-one; cis-δ.ea^.δ.θ.θa-Hexahydro-δ-methylcyciopenta^.δjimidazo^.l- b]purin-4(3H)-one; cis-δ,6a_t7,8,9,9a-Hexahydro-2,δ-dimethylcyclopθntaf4,δjimidazo[2,1-bJ- purin-4(3 V)-one; cis-δ,6a(R),7,8_I9,9a(S)-Hexahydro-2.δ-di-me!hyl' cyciopent[4,δ]imidazo[2, 1 -b]purin-4(3W}-one;

2'-Methyr-3'-spiro{cyclopentaπe-1 ,7^,(8'il)-(3'l J-imidazo[2, 1 -bjpurin}- 4^*(5'H)-one;

7,8-Dihydro-2,δ-dimethyl-7(R)-(1-methylθfhyl)-3H-imidazof2,1-b]purin- 4(δϋ)>one;

7,8-Dihydro-2,5,7,7-tetramethyl-3il-imidazo[2₎1-b3purin-4(δlD-one;

7,8-Dihydro-2_Iδ-dimethyl-7(S)-(1-methyfethyi)-3H-imidazo[2_l1-b]purin- 4(δϋ)-one;

6a(R}_l7,8_f9,10,10a(S}-Hexahydro-2,δ-dimethyl-3M-benzimidazo[2,l- b]purin-4(δJl)-one; δ^,,7^,-Dihydro-2^,,δ^,-dimethylspiro{cyclohexaπθ-1 ,7^,(8^,iD-imidazo[2,1- bJpuri J-^fS'iD-one; α^'s-δ.ea^.^β^.θa-Hexahydro-δ-methyl-S-

(phenylmethyl)cyclopenta[4,53imidazo[2,1-b]purin-4(3ry)-thione; 5,6a(fl),7,8,9,9a(^-Hexahydro-2_f5-dimethyl-3-

(phenyfm^βthyl)cyclopent[4,δJimidazo[2_>1-b]ρurin-4(3rV)-thioπe; cis-δ,6a,7,8,9,9a-Hexahydro-δ-methyl-3-(4-chlorophenyl- methyi)cyciopenta[4,5Jimidaz^Q[2,1-b]purIn-4(3/ )-one; ds-5,6a,7,8,9,9a-Hexahydra-δ-methyl-3-(cyclohexylmethyI)-- cyclopent[4,δ]imidazoI2,1-b]puriπ-4(3rτ)-one; ds-δ,6a,7,8,9_I9a-Hexahydro-δ-methyl-3-(2-naphthyimethyl}- cyclopeπtE4,δ]imidazo[2,1-b]ρurin-4(3H)-one; bromophenylmethyl)cyclopent[4,δ]imidazo[2,1-b]puriπ-4(3H)-one; δ,6a(R)-7,8_r9,9a(S)-H_θxahydro-2,δ-dimθthyl-3-(4- methoxyphenylmethyl)-cyclopent[4,δ]imidazo[2,l-b]purin-4(3Ji}- one; cis-δ,6a,7,8,9,9a-Hexahydro-2,3,δ-trimethyIcyciopent[4_Iδ]imidazo[2_I1- b}purin-4(3H)-oπe; cis-δ,6a,7,8,9,9a-Hexahydro-2-(hydroxymethyl)-δ-methyr-3-

(p _βι^l _θthyl)cydopβnt[4_ιqimldazoI2,1-b]purin-4(3H)one; cis-δ,6a,7,8,9,9a-Hexahydro-2-m_θthylth_to-δ-methyl-3-(phenylmethyl)- cyclopent[4,δ]imidazo[2,1-b]ρurin-4(3H)-one; cis-3,4,δ,6a_t7,8,9,9a-Octahydro-δ-methyl-4-oxo-3-(phenylmθthyl)- cyclopent[4_,δ]imidazo[2,1-b]ρurin-2-carboxylic acid; cis-3,4,δ,6a,7,8,9,9a-Octahydro-δ-methyl-4-oxo-3-(ρhenylmethyl)- cydopent[4,δJimidazor2,1-b]ρurin-2-carboxylic acid, methyl ester; ds-δ,6a.7,8,9,9a-Hexahydro-2-bromo-δ-methyl-3-(phenylmethyl)- cydopent|;4_tδ]imidazo[2,1-b]purin-4(3H)onβ; cis-δ,6a,7,8_I9,9a-Hexahydro-2-(methylaminosulfonyl)-δ-methyl-3-

(phenylmethyl)cyclopant[4,δ]imidazσ[2,1-b]purin-4(3H)one; ds-1-- clopentyi-δ,6a,7_>8₍9,9a-hβxahydro-δ-methyl- cyclopent[4,δ}imidazo[2,1-b]puriπ-4-(1 W)one; ds-δ,6a,7,8,9_<9a-Hexahydro-3,δ-bis-(phθnylmethyl) cyciopent(4,5)imidazo(2,1-b)purin-4(3H)one; cis-6a,7,8,9,10_rl0a-Hexahydro-3,5-bis-(phenylmethyl)-3 V- benzimidazo[2,1 -b]puriπ-4(δW)one; ds-3-Cycloρentyl-δ,6a_I7_f8,9,9a-hexahydro-δ-methyl' cyclopentr4,5]imidazo(2,1-b)puriR-4(3H)one; δ-Methyl-S'-Jphenylmethy^spirolcyclopentanθ-I δ'f -fS'H)- imidazo[2,1 -b]purin]-4*(ff /)one; 2',5^,-Dimethyl-3^,-(phenyimethyl)-spiro[cydopentane-1 ,7^,(8^, V)-(3Η)-

cis-δ,6a,(R)7,8,9_I9a(S)-Hexahydro-5-methyl-3-

(phenylmethyl)cyciopent[4,δ]lmidazo(2,1-b)purin-4(3W)one; cis-3-CyclopentyI-δ,6a,7,8,9,9a-Hexahydro-2.δ- dimethylcyciopent[4,δJimidazof2,1-b]ρurin-4(3W)one;36 δ'-Methyl-2'-trifluoromethyl-3^,-(phenylmethyl)spiro{cyclα-peπtane-

1 ,7^,(8^,r ]L-(3^,r<iimidazo[2_f1 -b]p rin}-4'{5'H)-one;

7,8-Dihydro-5_l7,7-tf1methyl-24rifluoromelriyl-3-(phenylrriethyl)-3H- lmIdazo[2,1 -b]puriπ-4(δJ )-one; (₊/-)-cis-5,6a,7,8,9,9a-Hexahydro-δ-m_θthyl-2-trifluoromethyl-3-

(phenylmethy!)cyclopent[4,6]imidazo[2,1-b]purin-4(3H)-one; (₊/-)-6a,7,8,9,9a,10,11 ,11a-Octahydro-2,δ-dimethyl-3-( phenylmθthyl)-

3H-pentaleno[ 6aM':4,δ] imidazo 2,1-b] purin-4(δH)-one; (+)-6a,7,8,9,9a, 10,11 ,11 a-Octahydro-2,δ-dimetbyl-3-phenylmethyl-3H- pentalenol 6a',1':4,δJ imidazo[2,1-b] purin-4(δH)-one; (-)-6a,7,8,9,9a,10,11 ,11a-Odahydro-2,δ-dimethyl-3-phenylmethyl-3H- pentaleno[6a',1':4 ] lmidazo[2,1-b] purin-4(δH)-one;

(+/-) 6a,7,8,9,9a,lO_t11 ,11 a-Odahydro-2,5-dimethyF-3H-pentafeno[

6a',1':4,δ] imida o[2.1-b] purin-4(δH)-one;. (+)-6a,7,B,9,9a,10,11,11 a-OctahydrO-2,5-dimethyf-3H-peπtaleno[

6aM':4,δ] imidazα[2,1-b] purin-4(δH)-one; (-)-6a,7,8,9,9a,10,11 ,11 a-Octahydro-2,δ-dimethyl-3H- pentaieno[6aM^*:4,δ] imidazo[2,1-b] purin-4(δH)-one; 6a,7,8,9,10,10a,11 ,12,13,13a-Decahydro-2,δ-dimethyl-(3- phenylmethyl)napthp,8a-d]imidazo[2,1-b]purin-4(δH)one; 7(R)-Cyclohexyf-7,8-dihydro-2,δ-dϊmethyl-3-(phenylmethyl)-3H- imidazo[2,1 -b]purin-4(3H)-one;

7(R)-Cyclohexyl-7_t8-dihydro-2,δ-dimethyl-3H-imidazo 2,1-b]purin-4(δH)- one;

7(S)-Cyclohexyl-7,8-dihydro-2,δ-dimethyl-3-(phenylmethyl)-3H- imidazo[2,1-b]purin-4(3H)-one; 7(S)-Cyclohexyl-7,8-dihydro-2,δ-dimethyl-3H-imidazo[2,1-bJpuriπ-

4(δH)-one; δ,6a(R),7,8,9,9a(S)-Hexahydro-2,δ-dimethyl-3-[

(trimethyiacetoxy)methy^}J-cycloρent[4^jimidazo[2,1-b]ρurin-4(3H)- oπe; δ,6a(R),7,8,9,9a(S)-Hexahydro-2,δ-dimethyl-3-(4-pyridylmethyl)- cyciαpent[4,δ]imidazo[2,1-b]purin-4{3H)-one; δ,6a(R),7,8,9,9a(S)-Hexahydro-2,δ-dimethyl-3-[2-(1- morphoIinyl)ethyi]cyclopent 4,δ]imidazo 2_I1-b3purin-4(3H)-one; δ,6a(R),7,8,9,9a(S)-Hexahydro-2_fδ-dimethyl-3-

[acetoxymethyl]cyclopent|;4,δ3imidazot2,1 -bjpuri n-4(3H)-oπe; δ,6a_I7,8,9,9a-Hexahydro-2,δ,6a-trimethyl-3-

(phenyimethyl)cyclopent[4,δ]imidazo[2,1-b]purirr-4(3H)-one; δ,6a(f?),7(S),8_r9,9a-Hexahydro-2.δ,δa-trimethyl-3*-

(pheny^[methyl)cyciopent[4,δ]imidazo[2,1-b]purin-4(3H)-one; 5,6a(S),7(r?),8_f9,9a-Hexahydro-2_fδ,6a-trimethyl-3-

(phenylmethyl)cycloρent[4,δ]imidazo[2,1-b]purinh4(3H)-onel; cfe-6a,7,8,9, 10,10a-Hexahydro-2,δ,7-trimθthyl-3-(priθπylmethyI)-3H- benzimldazo[2,1 -b]puriπ-4(δH>oπeJ; ^^5,6a_f7,8,9,9a-Hexahydro-2,5_l6a-trimethylc dopent[4,GjimldazoI2_I1- b]purin-4(3H)-one]; or c/s-6a,7,8,9,10,10a-Hexahydro-2_lδ_I7-trimethyI-3H-benzimidazor2,1- b]purin-4(δH)-one].

WO 94/19351 discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein:

R , R₂ and R₃ are independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, halogeno, hydroxy, (di- lower atkyl)amino, 4-morphoIinyl, 1-pyrrolidinyl, 1-pyrrolyl, -CF₃, -OCF_3, phenyl and methoxyphenyl; or Ri and R₂ together are methylenedioxy; or Rt and R2 together with the carbon atoms to which they are attached form a benzene ring; and

R^a is hydrogen and R^b and R^c, together with the carbon atoms to which they are attached,. form a saturated ring of δ carbons; or R^a is lower alkyl, R is hydrogen or lower alkyl, and R^c is hydrogen; or R^a, R and the carbon atom to which they are attached form a saturated ring of δ- 7 carbons, and R^c is hydrogen; or R^a is hydrogen, and R^b, R^c and the carbon atoms to which they are attached form a tetrahydrofuran ring; or R^a and R , together with the carbon atom to which they are attached, and R and R^c, together with the carbon atoms to which they are attached, each form a saturated ring of δ-7 carbons.

Preferred compounds include:

2'-benzy!-spiro[cyc!opentane-1 ',7^* (8Η)-[3'H]-iππidazo[2,1- b]purin-4'-(5Η)-one;

2'-beπzyl-δ.7,7-trimethyI-3H-imidazo[2, 1-b]purin-4-(δH)-one;

(+)-2-benzyl-7, 8-dihydro-5-methyl-7-(1 -methytethyl)-1 H- imidazo[2, 1 -b]-purin-4(5H)-one;

(+.-)-6a, 7, 8, 9, 9a, 10, 11, 11a-octahydro-5-methyl-2-(3,4- methyiene-dioxyphenylmethyl)-3H-pentalen[6a, 1 :4,δ]imidazo[2, 1-b]purin- 4(δH)-one; and

(+)-cis-6a, 7, 9, 9a-tetrahydro-5-methyl-2-[4-(trifluoromethyi)- phenyimethyl]-3H-furor3', 4':4,δ]imidazo[2,1-b^"]puriπ-4(δH)-one.

WO 94/22855 discloses compounds of the formula

1. _A nitrogen-containing used-heterocyclic compound having the formula ( I ) or a pharmacologically acceptable salt thereof :

in which ring* A represents a benzene, pyridine or cyclohexane ring and B represents a pyridine, imidazole or pyrimidine ring, with the proviso that rings A and B are bonded to each other with two atoms _being shared by them, and the shared atoms may be any of carbon and nitrogen atoms;

R¹ represents a group represented by the formula: -NR⁴R⁵ (wherein R⁴ and R⁵ may be the same or different from each other and each represent a hydrogen atom, a lower alkyl or acyl group or a carboxyl group which may be protected, or alternatively R'^* and R^ may form a ring together with the nitrogen atom to which they are bonded, provided that the ring may be substituted), or a heteroaryl group which has one or two nitrogen atoms and may be substituted:

R-^* represents a hydrogen atom, a group represented by the formula:

(wherein R⁸ represents a carboxyl or tetrazolyl group which may be protected) , or a halogen atom; and

R³ represents a hydrogen atom or a group represented by the formula:

(wherein R^B and R⁷ each represent a hydrogen or halogen atom or a lower alkoxy group, or alternatively R^ε and R⁷ may together form a methylenedioxy or ethylenedioxy group ) . 84

- 1-

WO 95/19978 discloses compounds of the formula

and salts and solvates thereof, in which:

R° represents hydrogen, halogen or C-j-e ^a,ky

R represents hydrogen, C-j-βalkyl, C^s alkenyl, C₂* alkynyl, aloC-_j. ealkyl, C3_scycloalkyl, C3„βcycloalkylC₁..3alkyf, arylC^alkyl or heteroarylC-|_3alkyl;

R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiσphene, furan and pyridine or an optionally

substituted bicyciic ring

attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a δ- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and R³ represents hydrogen or C_M alkyl, or R^τ and R³ together represent a 3- or 4- membered alkyl or alkenyl chain.

Preferred compounds include:

Cis-2,3,6,7,12,12a4ιexahydro-2-(4-pyridylmethyl}-6-(3,4- methyienedioxyphenylHjyrazinoP', 1' : 6,1]pyrido[3,4-b]iπdole-1,4-dione; Ciε-2,3,6,7,12_l12a-hexahydro^-(2,3-dihydrobenzo[bJfuran-δ-yl)-2- methyl-pyrazino[2M ^«:6,1 lpyrido[3,4-b]indole -1 ,4-dione; Cis-2,3,6,7,12,12a-hexahydπ €-(δ-bromo-2-thienyl)-2-methyl- pyrazino[2\ 1*:6, 1 ]pyridof.3,4-b]indole -1 ,4-dione; Cis-2,3,6,7, 12,12a-hexahydro-2-butyl-6-(4-methylρhenyl)- pyrazino[2', 1 ':6, 1]pyτido[3,4-b]indole -1 ,4-dione;

(6R, 12aR)-2,3,6,7, 12,12a-Hexahydro-2-isopropyl-6-(3,4- methylenedioxyphenyl)-pyrazino[2'_l1':6,1]pyrido[3,4-b]indole -1 ,4-dione;

(6R, 12aR)-2,3,6,7, 12, 12a-Hexahydro-2-cyclopentyl-6-(3,4- methyienedioxyphenyl)-pyrazino[2',1^,:6,1]pyrido[3_>4-b]indoie -1,4-dione;

(6R, 12aR)-2,3,6,7, 12, l2a-Hexahydro-2-cyclopropylrnethyl-6-(4- methoxypheπyl)-ρyrazino[2\1^6,1]pyrido[3,4-b]indole -1 ,4-dione;

(6R, 12aR)-2,3,6,7, 12, 12a-Hexahydro-6-(3-chloro-4-methoxyphenyf)-2- methyl-pyraz)no[2',1':6,1]pyrido[3,4-b3indole -1 ,4-dione;

(6R,12aR)-2,3.6,7,12,12a-Hexahydro-2-methyl-6-(3,4- methylenedioxyphenyl)-pyrazino[2^,,1^,:6,1]pyrido[3,4-b]indole-1 ,4-dione;

(6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methylenedioxyphenyl)- pyrazinofZ, 1' : 6,1] pyrido [3,4-b] indole-1 ,4-dione;

(5aR, 12R, 14aS)-1 , 2,3,6,6,11,12,14a~Octahydro-12-(3,4- methyienedioxyphenyl)-pyrrolo[1",2" : ^.δ'J yrazino^l' : 6,1]pyrido[3,4- b]indoie-δ-1 ,4-dione; and physiologically acceptable salts and solvates thereof.

U.S. Patent No. 5,294,612 discloses compounds of the formula

wherein:

R¹ is hydrogen, alkyl, G« to C7 cycloalkyl, C-» to C₇ cycloalkyl substituted by C- to Cjo alkyl or hydroxyl, 2- or 3-tetraiydrofuraπyl, 3-tctιahydrothie- nyl 1,1, -dioxide, C4 to C7 cycloalkyl-Ci to Cjb alkyl, carboxy-C- to Cjo lkyL carbo-Ci to G» k>w- er-alkoxy-Cj to Cio alkyl, diallcylainino Cj to C1₀ •lkyl, phenyl-Ci to lower-alkyl, phenyl-Ci to C lower-alkyl in which the phenyl ring it substituted in the 2, 3, or -position by one or two substituents, the twine or different, selected from the group consisting of a ino, halogen, to Cioalkyl, carboxyl, carbo-Ci to C*lower-aIkoxy, carbamoyl, NHSOj- (quinoliπyl), nitro and cyano:

R³ is, Ci to Ci lo ei-alkyl, phenyl-C- to C« loweralkyl, kiwcr-alkoxyphenyl-Ci to lo er-alkyl, diCi to C* io er-alkoxy-phenyl-C] to C4. loweralkyl, pyridyl-Cj to C lowcr-alkyl, to C₇ cy- cloalkyl-C) to QIower-alky pπenylamiπo, diCj to Cioalky nuno, halogen, triflπoromethyl, Ci to C* lower-alky lthϊo, cyano or nitro- and

R^e is a nine or ten membered bicyclic .ring having carbon and from one to two nitrogen atoms, and -43-

thc heterocyde is made up of fused 5 or 6 membered rings or such ring substituted at any available carbon atom by one or two substituents, the same or different, selected from the group consisting of Ci to C₊ lower-alkyl, halogen, Ci to C lower- alkoxy, C to C7 cycloalkyloxy, -morpholiπyl, C_j to lower-alkoxy-C[ to C< lower-alkoxy, hy- droxy, imidazolyl, oxo and 4-morpholinyl-C* to C_J, lower-alkoxy, or at any available nitrogen atorn by Ci to C* lowcr-alkyl, C₂ to C4 lower-alkanoyl, or trifhioroacetyl; or a phaπnaceuticAlly acceptable acid-addition salt thereof.

U.S. Patent No. 5,405,847 discloses compounds of the formula

where the benzo ring can also contain a nitrogen atom instead of a CH group either in position 6, 7, 8 or 9 and the radicals R-, R₂, R3 and R₄ have the following meanings: R-: C2-Cβ-aIkenyl, Cz-Cts-alkynyl, hydroxy, Cj-Cβ- alkoxy, Cj-Cβ-alkenylσxy, C3-C«-alkynyloxy, Cz-Cfi-alkaaoyloxy, benzoyloxy, morphoUnocar- bonyioxy, Ci-Ce-alkyloxycarbonyloxy, Q-Cβ- al ylaminocarbonyloxy, Ci-C_fi-dialkylaminocar- bonyloxy or the group

-A!k-A where Alk: is -Cβ-alkyf, C_∑-Cβ-hydroxyalkyl or C-j-Cfi-cycloalkyl and the symbol A represents:

1) Hydrogen, halogen, hydroxy, Cι-C«-aIkoxy, C2-C«-alkanoyloxy, hen l

2) — NHRj, — N s fi, NRsRβRy, pyridylamiao, im- iάazolyl, pyrrolidiπ l, N— C[-^-aIkylpyrrolidi- nyi, piperidyiaπnπo, N-ζpheπyl-Ci-Ct-alkyl)- piperidylamino where Rf and R« may be the same or different and represent hydrogen, Cι-C«-fllkyϊ, Cj-C7-cy oalkyl, C₃-C₇-hydκraycycloaIkyi, mor- phoIino-Ci-Cs-alkyl, phenyl, phenyl-Ci-Ce-alkyl orphenyl-Cz-Ce-oxyalkvl, it also being possible for the phenyl radicals in R5 and Re to be substituted by halogen and R is hydrogen or Q-Cβ-alkyl; 3) The group:

-CO-D where D is phenyl, Ci-Cβ-alkyl, C₃-G -cycloalkyl, hydroxy, Ci-cValkαxy, Cj-C-T-pycloalkyloxy, . morpholino, pyrrolidino, piperidino, homopiperid o, piperazino, — NHRj or — NR5R0 and R5 and e have the meanings given herein- above; 4

-44-

4} The group:

(CMι)„

— N E

\ / where n can be the integers 1-3 and E represents CH_, oxygen, sulfur, NH, CHOH, CH— Ci-Cβ- alkyloxy, CH— Ci-Ce-alkaπoyloxy, CH Hj, CHCOA CH— CH₂QSH5, N— Cj-Cβ-alkyl, N— -Cό-hydroxyalkyl, N— CβHs,

N— CH2C6H5, N— CH(Q^*Hs)2, N—(CH2)2— OH, N— (CH₂)3— OH or NCOD and the phenyl radicals (Cells) may also be substituted by halogen, -Cβ-alkoxy, trifluoromethyl, Ci-Cfi-alkyL eth- ylenedioxy or cyan and D has the meanings given hereinabove; R₂ and R3, which may be the same or different- hydrogen, halogen, hydroxy, CH- alkyl, trifluoromethyl, — CN, Cι-C6-alkoxy, C₃- -alkenyloxy, Cs-Cβ-alkynyloxy, — NHR5, — NR5R& NRs «R7 (meanings R5, R5, R₇ as given hereinabove) or the group -G-Alk-A, where Alk and A have the meanings given hereinabove and G is oxygen, sulfur, NH or NR5 and R₂ can also be

/ \

^* Rs— N N— CH₂— CH— CH_j—O—

\ / OH

R- hydrogen or halogen, where Rj can also be hydrogen, when ₂ is the group

and R5 represents pheayL Ci-Cj-alkosyphenyl or diphenylmethyl and R₃ and Rj are hydrogen, and their physiologically acceptable acid addition salts and quaternary ammonium salts, with the exception of the compounds of Formula 1 where R_j is methyl, dimefhylaminopropyi, dimetrrylanώio- ethyl, orpholiπoethyl or pyπrolidinoethyl, R_& R3 and R* are hydrogen and the benzo ring does not contain a nitrogen atom instead of a CH group.

U.S. Patent No. 5,436,233 discloses compounds of the formula co

wherein R¹ is hydrogen or Cl- alkyh Y is single bond or Cl-6 alkylene; A is

(i) — QyA— ( ⁱ)ft

QΪ) — o— R° or S(O)_jr-R⁰, in which O is <" or R°*.

ROA is _CyA— (R2)J.

ROB is hydrogen or Cl-4 alkyl; p is 0-2; CyA is (1) 3-7 membered, saturated or unsaturated, mono- cyclic carbocyclic ring, (2) 7-membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, one nitrogen atom, one nitrogen and one oxygen atoms, two nitrogen and one oxygen atoms, or one nitrogen and two oxygen atoms,

(3) 6-membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, one nitrogen and one oxygen atoms, two nitrogen and one oxygen atoms, or one nitrogen and two oxygen atoms,

(4) 6-membered, unsaturated or partially saturated, monocyclic hetero ring containing as a hetero atom, one nitrogen atom,

(5) 4- or 5-membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, one nitrogen atom, one nitrogen and one oxygen atoms, two nitrogen and one oxygen atoms, or one nitrogen and two oxygen atoms,

(6) 4-7 membered, imsaturaied or partially saturated, monocyclic hetero ring containing as hetero atoms, one or two sulfur atoms or

(7) 4-7 membered, unsaturated or partially or fully saturated, monocyclic hetero ring containing as hetero atoms, one or two oxygen atom;

R2 iε " or R²B; -^ is (1) — NR«ARH in which R*^A and ™ independently are hydrogen or Cl-4 alkyl (with the proviso that R⁶-^** and R¹ are not hydrogen at same time),

in which R^ή and R⁷ independently are hydrogen or CJ-4 alkyl, (3) trifluoromethyl or (4) trifluoromethoxy; ^is (1) hydrogen, (2) Cl-4 alkyl, (3) Cl-4 alkoxy, (4) — COOR^s, in which S is hydrogen or Cl-4 alkyl (5) halogen, (6) nitro αr<7) — NRGBR , in which R^6fland R'^are hydrogen;

2 is 2λ or 2J>;

7 is methylene, ethylene, vinylene or ethyαylcnc

2P is single bond;

CyB is

(1) 7-membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, one, two or three nitrogen atoms,

(2) 6-membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, two or three nitrogen atoms,

(3) 6-membered, unsaturated or partially saturated, monocyclic hetero ring containing as a hetero atom, one nitrogen atom,

(4) 4- or 5-membcrcd, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, one, two or three nitrogen atoms, or

(5) 4-7 membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, one or two oxygen atoms, or one or two sulfur atoms;

R³ is hydrogen, Cl-4 alkyl, Cl-4 alkoxy, halogen or trifruoromethyl; ^ is R-t-Or R^*"; -" is (1) — NHSO2R", in which R« is Cl-4 alkyl, (2) SO2 R⁹ 1⁰, in which

R⁹ is hydrogen, Cl-4 alkyl or phenyl(CI-4 alkyl) and R¹⁰ is hydrogen or Cl-4 alkyl, (3) — OCORU, in which R" is as hereinbefore defined, (4) hydroxy, (5) — Sθ2N^*=CHNR^ι:ζ .-³ in which R" is hydrogen or Cl-4 alkyl and K" is Cl-4 alkyl (6) — CONR.H I⁵ in which R" is hydrogen or Cl-4 alkyl and R." is Cl-4 alkyl or pheπyI(Cl-4 alkyl), (7) ethynyl, (8) tri(CI-4 alkyl flylethynyt or (9) acetyl; R^is (1) hydrogen, (2) Cl-4 alkyl, (3) Cl-4 alkoxy, (4) —COOR⁸, in which R^s is hydrogen or Cl-4 alkyl, (5) — NR⁹R¹⁰, in which R' and R¹⁰ are as hereinbefore defined, (6) — NHCOR^{1 !}, in which Ri' is as hereinbefore defined, (7) halogen, (8) trifluoromethyl, (9) nitro, (10) cyano, (11) Cl-4 alkylth_to, (12) Cl^l- alkylsulfinyl, (13) Cl-4 alkylsnlfo- nyl, (14) hydroxymethyl, and 1, m and n independently are 1 or 2; with the proτiso that

(1) the group of the formula: — CyA— (R²)/ does not represent a cydopentyl and trifluoromethyl- phenyl group when Ϋ is a single bond, that

(2) a CyB ring does not bond to Z through a nitrogen atom in the CyB ring when Z is vinylene or ethynylene, that

(3) a CyB ring is not pyridine or thiophene when CyA is a ring of C A— (7) that

(4) Y is not a single bond, when A is (ii) — O— ° or — S(O)_/r-R⁰ aπ flιat

(5) A is not — CyA-^-(R²B)l and — OR^0B, when Z is Z^aπd R⁺is **⁵; or pharmaceutically acceptable acid addition salts thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.

Preferred compounds include:

4-phenyImethylamiπo-2-((l-unidazo]yI)methyl)- quinazαline, _

4-phenylnιethylanιino-2-((l -unidazolyI)methyl> quinazoline,

6-cWoro-4-phenylmethyIamino-2-(l-3midazoIylme- thyrjquinazoline,

6-c orc-4-phenylamino-2-(l-nnidazolylmethyl)- quiπazoline,

6-chIoro-4-(3 arboxyphenyl)ammo-2 l-hnidazolyl- methyl)quuiazoluιe or

4.phenylmethylaιniπo-2-(2-(3-pyridyl)viny^])quma2θ- line, and pharmaceutically acceptable acid addition salts thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.

4-(2-methylthιoethyl)amino-6-methoxy-2-{l- Lmid azolyl uiiiazoline,

4-(2-metliylsuirii*yle y1)aniiuc*_:6--metl*a*-y-2-(3 - imidazolyl)quinazoline, 4-(2-methylsulfoπylethyl)amino-6-methoxy-2-(l- imidazolyOquinazoline, 4-(3-trifluoromethylphenylmethyl)amino-2-(3- pyridyl)quinazoline, 4-(4^(N,N-dimethylamiDθ)phenylmethyl)amiπo-2-(3- pyridyl)qumazoIine, 4-(4-sulfamoylphenyImethyl)aπιino-2-(3-pyridyl)- quinazoline, 4-{4~trifuloromethoxyphenylmetlιyl)amino-2-( 1 - imida7o yl)qninaroltne, 4^3-trifiuororaethoxyρhenylmethyl)ammo-2-( 1 - i*3iidazolyl)quinazoline, 4-<2-ρhenoxyethyr)a-^*ainc-6-n-ι.ethoxy-2-(l- imidazolyl)quinazoline or 4-^2-phcΩθxycthyl)amino-2-(l-imidazolyI)quinazo- line, and phaπnaceutically acceptable acid addition salts

U.S. Patent No. 5,576,322 discloses compounds of the formula Q)

wherein RI, R3, and R4, each of which may be the same or different from each other, may each represent a hydiogcn atom, a halogen atom or a lower alkyl group or a lower alkoxy hydrogen atom, R2 is a halogen or cyan group RS is a group represented by the formula:

wherein u is 3 or 4 and R61 represents a carboxyl group which may be protected or a heteroaryl group; or R5 is a group rcprcscnted'by the formula;

^■* >- COOH

and R6 is a group represented by the formula

wherein X is hydrogen atom or a halogen atom or

or dⁱe pharraa ilogically acceptable salt thereof /59584

-48-

Preferred compounds include:

2-(4-carboxypiperidino)-4-(3,4-methylene-dtoxyben- zyl) amino-6-chloroquinazolinc- or a pharmaceutically acceptable salt thereof.

Sodium 2-(4-carboxypiperidino)-4-<3,4-meϋ-yIene- diσxybcπzyl) amino-β-chloroquinaroline.

WO 94/29277 discloses compounds of the formula

or a pharmaceutically acceptable salt thereof^ wherein

Ar is an optionally substituted aryl or heteroaryl ring selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridaziπyl, pyrazinyl, inridazolyl, thienyl, oxazolyl, ben2imidazolyl, benzoxazolyl, indolyl or thianaphthenyl, Xis CH orN;

R° is NR^ΪR² or hydrogen; and R¹ and R² are independently hydrogen or Ci.galkyL

Preferred compounds include:

3-amino-4-[4-(3-pyridyϊ)]aniIino-3-cyclobutene-l,2-c[ione,

3-aa3JΩθ-4-[3-(4^in3idazolyl)anuuιo]-3-cyclobutene- 1 ,2-dioπe,

3-πιe lam^*tøc>- -[3-(5-me^

3-<iimethylan-nπcMH3-(5-methyl-4~iπuα^ 1 ,2-dione.

3-aιnino-4-[3- 3-metby.-4-pyridyl)^^

3-an3mfr4-p-(2-^xazolyl)aniIiw⁾]-3- clob tene-l^-V^ione,

3-aπώo- -[3-<3-φyridyI)anffin^^^

3-anino-4-P-(2-thi∞yl)anilino]-3-cycIobutene-l^-dioπe, 3-amino-4-[3-(3-tMenyI)anuωo]-3-<yclobmene-l^-dioπe, 3-amino-4-P-⁽2-thianaphthenyl)aniiino]-3-cyclobutene- 1 ,2-dione,

3-a^tnino-4-t3-(2-benzoxazoyl)arώino]-3-cyclobutene-l,2-dione,

3-a ino-4H3-⁽2-benzinιidazolyl)anuωo3-3-cyclobutene-l,2-dione,

3-amino-4-p-(2-indolyl)aniIino]-3-cycIobutene-l,2-dione,

3-ammo-4-(3-phenyl)arιilino-3-cyclobutene-l,2-dione,

3-aπⁱino-4-P-(2-hydroxyphenyl)anu o]-3-^clobutenc-l,2-dione,

3-anrino- -P-(2-meώo ^henyl)aniliπo]-3-cyclobutene-l,2-dione,

3-annno-4-P-(3-hydroxy-2-pyrMyl)anmno]-3-^clobutene-l_t2-dione,

3-anύπo-4-P-(2-irnidazolyl)anilino]-3-cyclobutene- 1 ,2-dione,

3-an^*iiiK>- -f6-(4-pyridyI)-2-pyri^^

3-P-(4-pyrMyl)aniIino]-3-cyclobutene-l^-dione, or a pharmaceutically acceptable salt thereof.

WO 95/19978 discloses compounds of the formula

and salts and solvates thereof, in which:

R° represents hydrogen, halogen or C^ s'kyl;

R¹ represents hydrogen, Chalky!, C alkenyl, Cj alkynyl, haloC-|. eal yl, C3^cycloalkyl, C3_8CycloalkyrCl-3^alky-. arylC-|_3a!ky! or heteroarylC-_j_3alkyl;

R2 represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally

substituted bicyclic ring

attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and R³ represents hydrogen or C_M alkyl, or R¹ and R³ together represent a 3- or 4- membered alkyl or alkenyl chain. Preferred compounds include:

Cis-2,3,6,7,12,12a-hexahydro-2-{4-pyridylmethyl}-6-(3,4- methy1enedioxyphenyl)-pyrazino[2', V : 6,1]pyrido[3,4-b]iπdole-1,4-dione; Ciε-2,3,6,7.12, 12a-hexahydro-6-(2,3-dihydrobenzα[b]furan-5-yl}-2- memyl-pyrazinαp'.l'÷δ.llpyridoIS^-bjindote -1 ,4-dione; Cis-2,3,6,7,12,12a-hexahydro-€-(5-bromo-2-thienyl)-2-methyl- pyrazino[2', 1 ':6, 1 ]pyrido[3,4-bjindole -1 ,4-dione; Cis-2,3,6,7, 12, 12a-hexahydro-2-butyl-6-(4-methylpheπyl}- pyrazino[2\1':6,1]pyrido[3₍4-b]indole -1 ,4-dione; (6R, 12aR)-2_l3,6,7, 12, 12a-Hexahydro-2-isαpropyl-6-(3,4- methylenedioxypheπyl)-pyrazino[2' , 1 ':6, 1 ]pyrido[3,4-b]indole -1 ,4-dione; (6R, 12aR)-2,3,6,7, 12, 12a-Hexahydro-2-cyclopenty l-6-(3,4- methyienedioxyphanyl)-pyrazino[2',1':6,1]pyrido[3,4-bjindole -1 ,4-dione; (6R, 12aR)-2,3,6,7, 12, 12a-Hexahydro-2-cyclopropylmethyl-6-(4- methoxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-bjindoie -1 ,4-dione; (6R, 12aR)-2,3,6,7, 12, 12a-Hexahydro-6-(3-chloro-4-methoxypheny[)-2- methyl-pyrazino[2',1':6,1]pyrido[3,4-b]indoie -1 ,4-dione; (6R, 2aR)-2,3,6,7, 12,12a-Hexahydro-2-methy l-6-(3,4- methylenedioxypheπy^-pyrazinop'.l'^.IJpyridoIS^-bJindole-l ,4-dione; (6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(3,4-methyleπedioxyphenyl}- pyrazinα[2\ 1' : 6,1] pyrido [3,4-b] indole-1,4-dioπe; (5aR, 12R, 14aS)-1 ,2,3,5,6,11,12,14a-OcΛahydro-12-<3,4- methyienedioxyphenyl)-pyrrolo[1",2" : ^δ'JpyrazinoP'.l' : 6,1]pyrido[3,4- b]indole-5-1 ,4-dione; and physiologically acceptable salts and solvates thereof.

WO 96/28429 discloses compounds of the formula

wherein :

R¹ is tert-butyl, or cydopentyl;

R³ is methyl, ethyl, or phenylmethyl ; ,X is -CH2-, -0-, or -NH-; and

R⁶ is phenyl (or phenyl substituted by from one to three, the same or different, substituents selected from the group O 99/59584

-51-

consisting of lower-alkoxy, hydroxy, halogen, carboxylower-alkoxy, 4-morpholinyl-lσwer-alkoxy, 5-tetrazolyl-lower-alkoxy, dilower- alkylamino, trifluoromethyl, nitro, amino, lower- al y Is ulfonyl amino, di lower-alkyl amino- lowe -alkylphenyl carbonyloxy, and 1-imidazolyl ) ^• or when X is -CH2- R-*-^* is additionally 2-, 3-, or 4-pyridinyl, 1-pyrrolyl, 1-benzimidazolyl , 1,2,3,4 -te rahydro-2-isoquinolinyl , ,2,3,4-tetrahydro-l- quinolinyl, hydroxy, 1-imidazolyl, l-lower-alkyl-2 , 3 , 4 , or 5- pyrrolyl, 1-pyrazolyl, 3-/ -, or 5-isoxazolyl ( or 3,4, 01 5- isoxazolyl substituted on any available carbon atom thereof by lower-alkyl), 2-thienyl, or 3-thienyl; or a pharmaceutically acceptable acid-addition salt and/or hydrate thereof.

Preferred compounds include: l-cyclσpentyl-3-ethy -6-⁽4-methoxyphenylmethyl)pyrazolo C3,4-d]pyrimindin-4-one, l-cyclopentyl-3-ethyl-6- (4-hydroxyphenylmethyl)pyrazolo [3 , 4-d]pyrimindin-4-one, l-cyclopentyl-3-ethyl-6- (phenylmethyl)pyrazolo[3, 4-d] pyrimindin-4-one, and l-cyclopentyl-3-ethyl-6- (4-aminophenylmethyl)pyrazolo [3, 4-d]pyrimindin-4-one.

WO 96/28448 discloses compounds of the formula

wherein :

R¹ is tert-butyl, or cydopentyl ; R³ is lower-alkyl, or phenyl - lower-alkyl ,^• and R⁶ is phenyl, or phenyl substituted by from one to three, the same or different, substituents selected from the group consisting of lower-alkoxy, lower-alkyl, hydroxy, 1-imidazolyl, lower-alkenyloxy, dilower-alkylamino-lower-alkoxy , 4-m.orpholinyl - lower-alkoxy, lower-alkoxycarbonyl-lower-alkox , carboxylower- alkoxy, tri luoromethyl, 1 -piperidinyl - lower-alkoxy , 1- pyrrolidinyl-lower-alkox , nitro, halo, amino, -<CH₂)2θ-, lower- alkylεulf onylamino, lower-alkoxy-lower-alkoxy , lower-alkenyl , dilower-alkylaiπino, -OCH {CH3 ) CH2- , 4-morpholinyicarbonyl-lower- alkoxy, 4 -thiomorpholinyl -lower-alkoxy, pyridinyl-lower-alkoxy, 1- lower-alky 1-3 -hexahydroazepinyloxy , and 1 -lower- alkyl - 4 - piperidinyl oxy; or a pharmaceutically acceptable acid-addi t ion salt and/or hydrate thereof.

Preferred compounds include:

1- cydopentyl -3 -ethyl -6- (2-propoxyρhenyl ) pyrazolo [3 , 4 -d] pyrimindin- -one, l-cyclopentyl-3-ethyl-6- [4- (1-imidazolyl) phenyl] yrazolo [3 , 4-d]pyrimindin-4 -one, l-cyclopentyl-3-ethyl-6-[3- (2- (4-morpholinyl ! ethoxy) phenyl] pyrarrolo [3 , 4-d]pyrimindin-4-one,

1 -cydopentyl -3 -ethyl -6- [2 -ethoxy- 4- { 1-imidazolyl) phenyl ] pyrazolo [3 , -d]pyrimindin-4-one, and l-cyclopentyl-3-ethyl-6-t2-(CH2=CHCH2θ)phenyi]ρyrazolo

(3, 4-d] ρyrimindin-4-one. WO 96/32003 discloses compounds of the formula

and salts and soh/ates thereof, in which:

R° represents hydrogen, halogen or C-j_5 alkyl; R is selected from the group consisting of:

(a) hydrogen;

(b) C^alkyl optionally substituted by one or more substituents selected from phenyl, halogen, -C0₂R^a and -NR*R^b;

(c) C^cydoalkyl;

(d) phenyl; and

(e) a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from oxygen, nitrogen and sulphur, and being optionally substituted by one or more C^alkyl, and optionally linked to the nitrogen atom to which R¹ is attached via C^lkyl;

R² is selected from the group consisting of:

(f) C^cycioalkyl;

(g) phenyl optionally substituted by one or more substituents selected from -OR^a, -NR^aR^b, halogen, hydroxy, trifluoromethyl, cyano and nitro;

(h) a 5- or 6-membered heterocyclic ring containing at least one heteroatom selected from oxygen, nitrogen and sulphur; and

(1) a bicyclic ring

attached to the rest of the molecule via one of the benzene ring carbon atoms and A is a 5- or 6-membered heterocyclic ring as defined in point (h); and

R^a and R^b independently represent hydrogen or C_halky!. Preferred compounds include:

Cis-2-benzyl-5-(3,4-rnethylenedioxyphenyl)-5,6, 1 ,11 a-tetrahydro-1 H-imidazo [1\5':1,6]pyrido[3,4-b]indole-1,3(2H)-dione;

Trans-2-benzyl-5-<3,4-methylenedioxypheπyl)-5,6, 11,11 a-tetrahydro-1 H-imidazo [r,5^1.6]pyrido[3,4-b]indole-1,3(2H)-dione;

pyridor3,4-b]indole-1,3(2H)-dione;

Cis-2-ethyl-5-(4-methoxypheπyl)-5_I6, 11,11 a-tetrahydro-1 H-imidazo[1',5': 1 ,6] pyrido[3.4-b]indole-1 ,3(2H)-dione;

Trans^-ethyl-S^-methoxypheny -δ.^β, 11,11 a-tetrahydro-1 H-imidazo[1 ',5':1 ,6] ρyrido[3,4-bjindole-1 ,3(2H)-dione;

Trans-2-ethyl-5-(3,4-methylenedioxyphenyl)-5,6,11 ,11 a-tetrahydro-1 H-imidazo

[1 ',5': 1 ,6]pyrido[3,4-b]indoie-1 ,3(2H)-dione;

Trans-2-ethyl-5-(2-thienyl)-5,6, 11,11 a-tetrahydro-1 H-imidazo[1 ',5':1 ,6] pyrido

[3,4-b]indole-1 ,3(2H)-dione;

Trans-5-(4-dimethylaminoρhenyl)-2-ethyl-5,6, 11,11 a-tetrahydro-1 H-imidazo

[1 ',5': 1 ,6] pyrido[3,4-b]iπdole-1 ,3{2H)-dione;

Trans-2-butyl-9-methyl-5-phenyl-5,6, 11,11 a-tetrahydro-1 H-imidazo[1 ',5': 1 ,6] pyrido[3,4-bjindolβ- 1 ,3(2H)-dione;

Trans-θ-bromo^-butyl-δ-phenyl-δ.e.l 1,11 a-tetrahydro-1 H-imidazofl'.δ'rl ,6] pyrido[3,4-b]iπdole-1 ,3(2H)-dione;

Cis-2-butyl-5-(4-methoxyphenyl)-δ_I6, 11 ,11 a-tetrahydro-1 H-imidazo [1 \δ':^'l ,6} pyrido(3,4-b3indole-1 ,3(2H)-dione;

Trans-2-butyl-5-(4τmethoxyphenyl)-δ,6,11 ,11a-tetrahydro-1H-imidazo [1',δ':1 ,6] pyridoϊ3,4-b]indole-1 ,3(2H)-dione;

Cis-2-butyl-9-fluono-δ-(4-methoxyphenyl)-δ,6, 11,11 a-tetrahydro-1 H-imidazo

[1^,,δ^,:1,6J pyrido[3,4-b]indote-1,3(2H)-dione;

Traπs-2-buty!-9-fluoro-δ-<4-methoxypheπyl)-δ,6, 11,11 a-tetrahydro-1 H-imidazo

[r,δ':1,6] pyrido[3,4-b]indole-1,3(2H)-dione;

Trans-2-butyl-δ-<3,4-methylenedioxyphenyl)-5,6,11 ,11 a-tetrahydro-1 H-imidazo

(1 \5':1 ,6] pyrido[3,4-b]indole-1 ,3(2H)-dione;

Cis-2-butyJ-δ-(3-chlorophenyl 5,6, 11,11 a-tetrahydro-1 H-imϊdazo[1 5': 1 ,6]pyridσ

[3,4-b]iπdole-1 ,3{2H)-dione;

Trans-2-butyl-5-(3-chlorophenyl)-δ,6_t 11,11 a-tetrahyd ro-1 H-imidazo[1 ', 5':1 ,6] pyrido t3,4-b]indote-1,3(2H)-dione;

Cis-2-bιιtyl-5-{4-chfofθpheny1)-6,6_l11,11a-tetrahydro-1 H-imidazo [1',δ':1 ,6] pyrido [3.4-b]indote-1,3(2H>dioπe;

Trans-2-buty1-5^4 *ιlorophenyl -5_l6,11,11 a-tetrahydro-1 H-imidazo [I'.δ'rl.βJ pyridoϊ3,4-b]indole-1 ,3(2H)-dioπe;

Traπs-2-butyi-5-(4-fiuoropherιy1)-5,6,11,11a etrahydro-1H-imidazori^,,δ^,:1,6} pyrido [3,4-b]indole-1,3(2H)-dioπe; 584

-55-

Trans-2-butyl-5-(4-hydroxyphenyl)-5,6, 11,11 a-tetrahydro-1 H-imidazo[1 ',5': 1 ,6] pyrido f3,4-bjindole-1,3(2H)-dione;

Cis-2-butyl-δ-(4-trifluoromθthylphenyl)-δ,6, 11,11 a-tetrahydro-1 H-imidazo

[1^,,δ^,:1,6]pyridot3,4-b]indole-1,3(2H)-diαπe;

Cis-2-butyl-δ-(4-cyanσphenyl)-δ,6,11,11 a-tetrahydro-1 H-imidazo[1 ',5': 1 ,6] pyrido

[3,4-b]indole-1 ,3(2H)-dione;

Trans-2-butyl-δ-(4-cyanophenyl)-δ,6, 11,11 a-tetrahydro-1 H-imidazo[1 ',5': 1 ,6J pyrido[3,4-b]indole~1 ,3(2H)-dione;

Cis-2-butyl-5-{4-nitrophenyl)-δ,6, 11,11 a-tetrahydro-1 H-imidazo[1 ',δ': 1 ,6]pyrido

[3,4-bIindole-1 ,3(2H)-dione;

Trans-2-butyl-5-(4-nitrophenyι)-5,6,11 , 11 a-tetrahydro-1 H-imidazof 1 \δ': 1 ,6] pyrido[3,4-b]indole-1 ,3{2H)-dionβ;

Cis-2-butyl-5-(3-pvridy1)-5_I6,11,11 a-tetrahydro-1 H-tmidazoP'.δ'rl ,6]pyrido [3.4-b] indoie-1 ,3(2H)-dione;

Cis^-butyl-δ-CS-thieny -δ.e.H.lla-tetrahydro-IH-imidazofr.δ'r .βJpyrido p^- b]indole-1 ,3(2H}-dioπe;

Trans-2-butyi-6-(3-thienyl)-5,6, 11,11 a-tetrahydro-1 H-imidazo[1 ',5': 1 ,6]

Cis^-butyl-δ-CS-furyl^δ.β. l .lia-tetrahydro-IH-imidazotr.δ^l.δlpyrido p^ b]indoIe-1 ,3(2H)-d^ion€:

Trans-Σ-butyl-δ- S-fury -δ.e.ll.lla-tetrahydro-IH-imidazoπ'.δ^I.ei pyridofS - b]iπdole-1 ,3(2H)-dione;

Cιs-2-cyclohexy!-δ-<4-methoxyphenyl)-δ,6, 11,11 a-tetrahydro-1 H-imidazo f 1 ',δ':1 ,6] pyrido[3,4-b]indole-1 ,3(2H)-dione;

Trans-2-cyclohexyl-5-(4-methoxyphenyl)-δ,6, 11,11 a-tetrahydro-1 H-imidazo H'.δ'-.l ,6J pyrido[3,4-bJindole-1,3(2H)-dione;

Cis-2-cyclohexyl-9-fluoro-δ-(4-methoxyphenyl)-δ,6,11 ,11 a-tetrahydro-1 H- i idazofl \ ^1 ,6] pyrido[3,4-b)indole-1 ,3(2H)-dione;

Trans-2-cyclohexyf-9-fluoro-δ-(4-methoxyphenyl)-δ₁6, 11,11 a-tetrahydro-1 H- imidazo[1^*,δ^,:1,6] pyrido[3,4-b]indole-1,3(2H)-dione_l-

Traπs^-benzyl-δ-pheπyt-δ.β.ll.lla-tθtrahydro-IH-imidazorr.δ'.-I.ejpyrido rs^- b]iπdole-1 ,3(2H)-dione;

Cis-2-benzyf-5-{4-methoxyρheny -δ,6, 11,11 a4etrahydro-1 H-imidazo[1 \ δ': 1 ,6] pyrido [3,4~b]indote-1_f3(2H)-dione;

Trans-2-beπzyl-δ-(4-methoxyρhenyl)-δ,6,11₎11a-tetrahydro-1H-imidazo[1^,,δ^,:1_r6] pyrido

(5R,11aR)-2-bθnzyI-5-(3,4-methylenedioxypheπyl)-5,6,11 ,11 a-tetrahydro-1 H- iπ dazo [r,5^,:1_r63pyrido{3,4-b]indole-1 ,3(2H)-dione;

Trans-2-benzyI-5-<4-hydroxyphenyl -5,6,11,11a-tetrahydro-1H-imidazo [1\5':1,6J pyrido I3,4-bJindole-1,3(2H)-dione; Trans-2-(2-chlσroethyl)-δ-(4-methoxyphenyl)-δ,6, 11 ,1 1 a-tetrahy ro-1 H-imidazo [1^,,δ':1 ,6} pyrido[3,4-b]indole-1_>3(2H)-dione;

Cis^-beπzyf-δ-cyclohexyl-δ^.H .lla-tetrahydro-IH-imidazoπ'.δ^I.e] pyrido[3,4-b]indole-1,3(2H)-dione;

Trans^-benzyl-δ-cyclohexyl-δ.e.H.lla-tetrahydro-IH-imidazoir.S'rl.e] pyridoI3,4-b]indole-1,3(2H)-dione;

b]indole-1 ,3(2H)-dione;

Trans-2-cyclohexyi-δ-phenyl-δ,6.11,11a-tetrahydro-1H-imidazo[1'₍δ':1 ,6] pyrido [3,4-b)iπdole- ,3(2H)-dione;

Cis-2-cyclohexyl-δ-phenyl-δ,6,11 ,11 a-tetrahydro-1 H-imidazo[1 ',5': 1 ,6] pyrido [3,4-b]indole-1 ,3(2H)-dioπe;

Traπs-2-ethoxycarboπylmethyl-δ-(4-methoxyphenyl)-5,6,11 ,11 a-tetrahydro-1 H- imidazo[1',5':1,6] pyrido {3,4-bJindole-1 ,3(2H)-dione; Trans-δ-{4-methoxyphenyl)-2-[2-(2-pyridyl)-ethyt]-δ,6, 11 ,11 a-tetrahydro-1 H- imidazo[1^,,5':1,63pyrido[3,4-b]indole-1,3{2H)-dioπe; Traπs-2-cyclopropyl-5-phenyl-5,6,11,11 a-tetra ydro-1 H-imidazo[1 ',5': 1 ,6] ρyrido[3,4-b]indole-1,3(2H)-dione;

Trans

pyrido[3,4-b]indole-1 ,3{2H)-dione;

Trans-δ-phenyl-2-(2-pyridytmethy1)-5,6,11 ,11 a-tetrahydro-1 H-imidazo [1 '.δ': 1 ,6]pyrido[3.4-b)indole-1 ,3{2H)-dione;

Trans-δ-phenyl-2-(4-pyridylrnethyl)-δ,6,11,11 a-tetrahydro-1 H-imidazo [r,δ^,:1 ,6]pyrido[3,4-b}iπdole-1,3(2H)-dione;

Trans-5-{4-methoxyphenyl)-2-(3-pyridylmethyl)-δ,6,11 ,11 a-tetrahydro-1 H- imtdazo[1^,,δ^,:1,6]pyrido[3,4-b]indole-1,3(2H)-dione;

Trans-2-(2-dimethylaminα-ethyr)-δ-(4-methoxyphenyl)-5,6,11 ,11a-tetrahydro- 1

,6]pyrido [3,4-b]indole-1 ,3{2H)-dione; Trans-2-(3-dimethylamino-propyl)-δ-(4-methoxyphenyl)- 5,6,11 ,11a-tetrahydro - 1 H-imidazo[r,5':1 ,6] pyrido [3,4-b]iπdole-1 ,3(2H)-dione; Trans-2-(2-morpholin-4-yl-ethyl)-5-pheny1-5,6,11,11 a-tetrahydro-1 H- imidazo[1^,,5':1,6] pyrido [3,4-b]indole-1,3(2H)-dione;

Traπs-5-(4Hmethoxyphenyl)-2-[3-(4-methy1-piperazin-1-y1)-propyl]- 5.6.11 ,11a- tetrahydro-1H-imidazo[1'_t5':1,63 pyrido [3,4-b]indote-1,3(2H)-dione; Trans-5-<4-met oxyphenyl)-2-(2-pyrrolidin-1-yl-ethyl)-5,6_l 1,11 a-tetrahydro-1 H- imidazo[1\5':1,6] pyrido [3,4-b]indole-1,3(2H)-dion; Trans-5-(4-methoxyphenyI)-2-[2-(1-methy1-pyrrc)lidin-2-yl)-ethyl]-5,6,11 ,11a- tetrahydro -IH-imidazoir.δ'rtβ] pyrido [3,4-b]indole-1_f3(2H)-dioπe; Trans-5-(4-methoxyphenyl)-5,6, 11,11 a-tetrahydro-1 H-imidazo[1 ',&: 1 ,6] pyrido [3,4-bjindole-1,3 (2H)-dione;

Cis-5-(4-methoxyphenyl)-5_l6,11 ,11 a-tetrahydro-1 H-imidazoI1 \5*:1 ,6] pyrido [3,4- b]indole-1,3 (2H)-dione; and pharmaceutically acceptable salts and solvates thereof. WO 96/32379 discloses compounds of the formula

wherein

R¹ is hydrogen, halogen, nitro, carboxy, protected carboxy, acyl, cyano, hydroxy rnino (lower) alkyl, lower alkenyl optionally substituted with oxo, or lower alkyl optionally substituted with protected carboxy, carboxy or hydroxy;

R² is hydrogen, halogen, lower alkenyl, acyl, or lower alkyl optionally substituted with protected carboxy, carboxy, lower alkoxy or hydroxy;

R³ is lower alkenyl or lower alkyl, both of which are optionally substituted with one or more substituent (s) selected from the group consisting of

(1) oxo,

(2) aryl optionally substituted with one.or more substituent (s) selected from the group consisting of halogen, aryl, lower alkoxy, lower alkylenedioxy, cyano, nitro, carboxy, protected carboxy, acyl, and amino optionally substituted with acyl or protected carboxy, and

(3) a heterocyclic group optionally substituted with halogen; and R⁴ is carboxy, protected carboxy, acyl, cyano, halogen, a heterocyclic group, amino optionally substituted with acyl or protected carboxy, or lower alkyl optionally substituted with protected carboxy, carboxy or acyl; in addition to their significances above,

R¹ and R², together with the carbon atoms to which they are attached, represent a 4- to 7- me bered carbocydic ring optionally substituted with oxo, or its pharmaceutically acceptable salt.

WO 97/03070 discloses compounds of the formula

wherein R^* is a hydrogen atom or a halogen atom;

R² is a phenyl-lower alkyl group;

R³ is a heterocyclic group selected from the group consisting of an indolyl group, indolinyl group, IH-indazolyl group, 2(lH)-quinolinonyl group, 3,4- dihydro- ( 1H)-quinolinonyl group and 3 ,4-dihydro- l,4(2H)-benzoxazinyl group, said heterocyclic group may have 1 to 3 substituents selected from the group consisting of: a group of the formula -B-R*, (B, is a lower alkylene group; R* is a 5- to 11-membered saturated or unsaturated heterocyclic group of single ring or binary ring, having 1 to 4 hetero atoms selected from the group consisting of a nitrogen atom, oxygen atom and sulfur atom, (said heterocyclic group may have 1 to 3 substituents selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group and oxo group) or a group of the formula - ^R⁶ ( ⁵ and R⁶ are each the same or different, and a hydrogen atom, a lower alkyl group, a cycloalkyl group, a pyridyl- carbonyl group, an isoxazolylcarbonyl group which may have 1 to 3 lower alkyl groups as the substituents, a pyrrolylcarbonyl group, or an amino-substituted lower alkyl group which may have a lower alkyl group as the substituent; further R⁵ and R⁶ may form 5- to 6- membered saturated heterocyclic group by combining to each other, together with the adjacent nitrogen atom being bonded thereto, further with or without other nitrogen atom or oxygen atom; said heterocyclic group may have 1 to 3 substituents selected from the group consisting of a hydroxy group and a phenyl group)); a lower alkenyl group; a lower alkoxycarbonyl group; a phenoxy-lower alkyl group which may have cyano group as the substituents; a halogen-substituted lower alkyl group? and a lower alkoxycarbonyl-εubεtituted lower alkyl group;

A is a lower alkylene group; and n is 0 or 1 ,

Preferred compounds include: l-Benzyl-6-σhloro-2-{l-[3-(imidazαl-l- yl ) propyl ] indol~5-ylaminocarbonyl > be zimidazole , l-Benzyl-6-chloro-2-{l-[3-(N-cyclohexyl-N- methylamino ) propyl ] indol-5-ylami nocarbonyl > - benzimidazole . l-Benzyl-6-chloro-2-{i- [ 3- (pyrazσl-1- yl )propyl ]indol-5-ylaminocarbonyl }benzimidazole . l-Benzyl-6-chloro-2-{l- [ 3- ( 1 , 2 , -triazol-l- yl)propyl ]indol-5-ylaminocarbonyl }benzimidazole . l-Benzyl-6-chlσro-2-{l~[3-<3,5- dimethyliεoxazol-4-ylcarbonylamino)propyl ]indol-5- ylaminocarbonyl_/benzimidazole. l-Benzyl-6-chloro-2-{l-[3- (4-phenyl-4- hydroxypiperidin-1-yl )ρropylJ indol-5-ylaminocarbonyl - benzimidazole . l-Benzyl-6-chloro-2-{4-[ 3-(pyridin-2- ylcarbσnyla ino)propyl ]-3,4-dihydro-l , 4 { 2H) -benzoxazin- -ylaminocarbonyl}benzimidazole .

WO 97/03675 discloses compounds of the formula

and salts and solvates (e.g. hydrates) thereof, in which:

R° represents hydrogen, halogen or C-j-o alkyl;

R¹ represents hydrogen, Chalky), C₂-₆ alkenyl, C_z^ alkynyl, haloCi^al yl, C3_8cycloalkyI, C3_8cycioalkylC-|_3aIkyI, aryiC-|_3alky1 or heteroarylCι;_3alkyl;

R² represents an optionally substituted monocyclic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicyclic

ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionally one or two heteroatoms selected from oxygen, sulphur and nitrogen; and

R³ represents hydrogen or C,.₃ alkyl, or R¹ and R³ together represent a 3- or 4- membered alkyl or aikenyl chain; for the manufacture of a medicament for the curative or prophylactic treatment of erectile dysfunction in a male animal, including man.

Preferred compounds include:

Cis-2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methyleπedioxyphenyl}- pyrazino[2', V : 6,1]pyrido[3,4-b]indole-1,4-dione; Cis-2,3,6,7,12,12a-hexahydro-6-(2,3 lihydrobenzo[b]furan-5-yl)-2-methyl- pyrazino[2', 1 ':6, 1 ]pyrido[3,4-b]indole -1 ,4-dione; Cis-2₁3,6,7,12,12a ιexahydro-6-(5-bromo-2-thienyl)-2-methyl- pyraziπo[2',1':6,1jpyrϊdo 3,4-b]indo!e -1,4-dione;

Cis-2,3,6, 7, 12, 12a-hexahydro-2-butyl-6-(4-methyIphenyl>- pyrazino[2\ 1 ':6, 1 ]pyrido[3,4-b]indole -1 ,4-dione;

(6R_I12aR)-2,3,6,7,12,12a-Hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)- pyrazinop'.l're.ljpyri op^-blindole -l^ione;

(6R, 12aR)-2,3,6,7, 12,12a-Hexahydro-2-cyclopentyi-6-(3,4- methylenedioxypheny -pyrazino[2^,,1^,:6,1]pyridof3,4-b]iπdole -1 ,4-dione;

(6R, 12aR)-2,3_f 6,7.12, 12a-Hexahydro-2-cyclopropylmethyJ-6-{4-methoxyphenyl)- ρyrazino[2', 1 ':6, 1]pyrido[3,4-b3indole -1 ,4-dione;

(6R,12aR)-2,3,6,7_l12,l2a-Hexahydro-6-{3-chloro-4-methoxyphenyi)-2-methyl- pyrazinop', 1 ':6, 1]pyrido[3,4-bJiπdole -1 ,4-dione;

(6R,12aR)-2,3_>6,7,12,12a-Hexahydro-2-methyl-6-<3,4-methylenedioxyphenyl)- pyrazino{2\ 1 ':6, 1]pyrido[3,4-bjindole-1 ,4-dione;

(6R, laaRJ-a.S.e^.lΣ.^a-Hexahydro-e^S^- e hylene iσxypheπyl)- pyrazino[2', 1' : 6,1] pyrido [3,4-b] indole-1 ,4-dione;

(5aR, 12R, 14aS)-1, 2,3,5,6,11,12,14a-Octahydro-12-<3,4- methylenedioxypheny -pyrrolo[r-2" : 4^,,5'3pyraziπoE2^, _f1^, : 6,1]pyrido[3,4- b]indole-5-1 ,4-dione;

Cis-2,3,6,7,12,.12a-hexahydro-2Hyclopropyi-6-(3_<4-methyienedioxyphenyl)- pyrazino[2\ 1 ^,:6,1]pyrido[3,4-b3iπdole -1 ,4-dione;

<3S, 6R.12aR)-2,3,6,7,12,i2a-hexahydro-3-methyl-6-(3,4- methytenedioxypheny -pyrazinoP'.l'.-e.lJpyridop^-blindole -l^-dione; and physiologically acceptable salts and solvates (e.g. hydrates) thereof. WO 97/03985 discloses compounds of the formula

and solvates thereof, in which:

R° represents hydrogen, halogen or C-j_6 alkyl; R1 represents hydrogen or C-j_ealkyl; R² represents the bicyclic ring

which may be optionally substituted by one or more groups selected from halogen and C_1-3alkyl; and

R³ represents hydrogen or C^alkyl.

Preferred compounds include:

(6R, 12aR)-2,3,6,7, 12, 2a-Hexahydro-6-(5-benzofuraπyl)-2-methyl-pyrazino 2',1':6,1]pyrido[3,4-b]indofe-1 ,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzofuranyl)-pyrazino[2M^,:6,1] pyrido [3,4-b]indole-1 ,4-dione;

(3S, 6F 12aR)-2,3₍6,7,12,12a-Hexahydro-6-(5-benzόfuranyl)-3-rnefhyi- pyrazinoϊ2',1':6,1] pyrido [3,4-b]indote-1 ,4-dione;

(3S, 6R, 12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzofuranyl)-2_I3-dimethyl- ρyraziπo[2M':6,1] pyrido [3,4-b]indole-1 ,4-dione;

(6R,12aR)-2,3,6,7,12,12a-Hexahydro-6-(5-benzofuranyf)-2-isopropyl-pyrazino

[2',1':6,1] pyrido {3,4-b]indole-1 ,4-dione; and physiologically acceptable solvates thereof. WO 97/43287 discloses compounds of the formula

wherein

R represents -hydrogen or -halogen;

R¹ is selected from the group consisting of:

-hydrogen,

-N0_2l *

-trifluoromethyl,

-trifluoromethoxy,

-haiogen,

-cyano, a 5- or 6- membered heterocyclic group containing at least one heteroatom selected from oxygen, nitrogen and sulphur (optionally substituted by - C(=0)OR" or d_«a!kyi),

-Cεalkyl optionally substituted by -OR",

-Ci-salkoxy,

-C(=0)R\

-O-C(=0)R^»,

-C(-0)OR*.

-C^alkyleπe C(=0)OR*.

-O-C^alkyleπe -C^OJOR¹,

-Cι-₄alkylene-0-C,- alkyleπe-C(-=0)OR^, ₁

-C^OJNR'SO∑ ⁰,

-C(=0)C_t-₄alkylene Het. wherein Het represents 5- or 6-membered heterocyclic group as defined above,

-Cι-4alkylene NR ",

-C₂-ealkenyleneNR^*R^b,

-C(=0)NR*R^b,

-C(=0)NR^,R^e,

-C(=0)NR"C,- -lkylene OR^b

-C(=0)NR'C_t-₄alkylene Het. wherein Het represents a 5- or 6-membered O 99/59584 -64- heterαcyclic group as defined above,

-OR^*

-OC^alkylene NR^*R^b,

-OC,.<alkylene-CH(0R*)CH₂ NR'R^b.

-O-C₁ ^alkylene Het, wherein Het represents a 5- or 6- membered heterocyclic group as defined above,

-0-C₂- alkyiene-OR',

-O-C₂- alkylene-NR"-C(=0)-OR^b,

-NR'R",

-NR*C_<alkyleneNR'R^b,

-NR*C(=0)R^b,

-NR'C(=0)NR^*R^b,

-N(S0₂C_Ma!kyl)₂,

-NR^*(S0₂C,.4alkyl),

-S0₂NR*R^b, and

-OSO_ztrifluoromethyl;

R² is selected from the group consisting of:

-hydrogen,

-halogen,

-OR",

-Ci-β alkyl,

-NO₂, and

-NR'R⁶, or R¹ and R², together form a 3- or 4- membered alkylene or afkeπylene chain_, optiαπalfy containing at least one heteratom ;

R³ is selected from the group consisting of:

-hydrogen,

-halogen,

-NO_2l

-trifiuorαmethoxy,

-Ci-ealkyl, and

-C(=0)OR';

R⁴ is hydrogen, or R³ and R⁴ together form a 3- or 4- membered alkylene or alkenylene chain, optionally containing at least one heteratom;

R" and R", which may be the same or different, are independently selected from hydrogen and Chalky!.

R^e represents phenyl or C«cycloalkyl, which phenyl or C.w;cycloalkyf can be optionally substituted by one or more halogen atoms, one or more -C(=0)OR* or one or more -OR*; n is an integer selected from 1 , 2 and 3; m is an integer selected from 1 and 2; and pharmaceutically acceptable salts and solvates thereof.

U.S. Patent No. 5,393,755 discloses compounds of the formula

wberein

J is oxygen or sulfur,

R¹ is hydrogen, alkyl or alkyl substituted with aryl or hydroxy;

R² is hydrogen, aryl, heteroaryl, cycloalkyl, alkyl or alkyl substituted with aryl, heteroaryl; hydroxy, alkoxy, amino, monoalkyl amino or dialkyiamino, or — (CI mTCOR²⁰ wherein m is an integer from 1 to T is oxygen or — NH— aad R-^is hydrogen, aryl, heteroaryl, alkyl or alkyl substituted with aryl or heteroaryl;

R³ is hydrogen, halo, trifluoromethyl, alkoxy, alkyl- ihio, alkyl, cycloalkyl, aryl, aπώiosπlfbayl, amino, monoaU ylanώio, dialkyiamino, hydroxyalk- ylamino, aminoalkylamino, carboxy, alkoxycarbonyl or a iaocarbonyl or alkyl substituted with aryl, hydroxy, alkoxy, amino, mααoalkylaπtmo or dialkyUmino;

R^β, R*, R^cand R^iπdependently represent hydrogen, alkyl, cycloalkyl or aryl; or fR^Λa^*αd R*) or (R^eand R^) or (R*and R< can complete a saturated ring of 5- to 7-carbon atoms, or (R^Λ and R*) taken together aad R^b and R<) taken together, each complete a saturated ring of 5- to 7-carboπ atoms, wherein each ling optionally can contain a sulfur or oxygen atom and whose carbon atoms may be optionally substituted with one or more or the following: alkenyl, alkynyl, hydroxy, carboxy, alkoxycarbonyl, alkyl or alkyl substituted with hydroxy, carboxy or alkoxycarbonyl; or such saturated ring can have two adjacent carbon atoms which are shared with an adjoining aryl ring; and n is zero or one. Preferred compounds include: cis-5,6a,7,8,9,9a-Hexahy ro-5-meihyl-3-(ph-*πyl e- thyl)cyclopenta[4,5]imidazo[2,l-b]purin-4-o-te; 7,8-Dihydro-5-mettayl-3-(phenyl*^*net^*hy!>3H- imidazo [2, 1 -b]purin-4(5 H -oae; cis-6a,7,8,9, 10, 10a-Hcx hydro-5-methyl-3-(ph«nyIπιe- thyl)-3H-benzimidazo[2,l-b]ρurin-4{5H)-one; 5,7,8,9-Tetrahydro-5-metlιyl-3-(phenylmethyl)- pyr cddop, l-b]purin- (3H)-one; 7,8-Dihydro-8-phenyI-5-methyl-3-(phenylmethyl>3H- imidazo[2, 1 -b]purin-4(5H)-one;

5', 7'-Dihydro-5'-methyl-3'-(phenylmetbyl)sρiro[cy- clohexane- l,8^*-(8H)imidazo[2, l-b]purw]- '(3Η)-one' cis-5,6a, 11, 1 la-Tetrahydro-5-methyl-3-(ρhenylmethyl-

)indeno[ ,2':4,5]iπ^*ιidazo[2_f l-b]purift-4(3H)-θJ-ιe* 5',7'-Dihydro-2',5'dimethyl-3'-(phenylmetliyl)spiro{cy- clohexane-l,7'(8'H)-imlda2θ[2,l-b]purin}-4'-

(3Η)-one; 7,8-Pihydro-2,5,7,7,8(R,S)-peαtamethyl-3H- unidazo[2,l-b]purin-4(5IT>-one; cis-5,6a,7,llb-Tetrahydro-5-methyI-3-(phenylmethyl-

)indcno[2', ,:4,5]imidazo[2_Il-b]purin- (3H)-one; cis-5,6a,7,8,9,9a-Hexahydro-2,5-dimethyl-3-(phenylme- thyl)cyclopent[4,5]i idazo[2,l-b]purin-4-(3H)-one; 5'-Metiιyl-3'- pheπyIιnethyl)-spiro[cy clopentane- 1,7'-

(8Η)-(3'H)imidazo[2,!-b]purin]-4-<5'H)-one; 7,8-Dihydro-2,5,7,7-tetranιethyl-3-(phenylιπethyl)-3H- imidazo[2,l-bjpurin-4(5'H)-one; 7,8-Dihydro-7(R)-phenyl-2,5-dimethyl-3-(phenylme- thyr)-3H-imidazo[2, l-b]purin-4(5H)-ODe; 7,8-Dmydro-2,5-dimethyl-3,7(R)-bis(phenylπιethyl)-

SH-imtdazopil-blp rui-^SITi-one; (± 7,8-Dmydro-2,S^:Qimethyl-7-*thyl-3-(phenylrae- my -3H-iπudazo[2, l-b]purin-4(5H}-one; 6a(S 7,8,9,10,10a(R)-Hexhydro-2,5-dijπethyl-3-

(phenyImeώyl)-3H-beπ-!-u^*-idazo[2, 1 -b] purin-

4<5H)-one; 6a(R>7,8,9,10,10a(S)-hex-hydro-2,5-dimethyl-3-

(phenylmethyl)-3H-ben2imidazo[2,l-b]purin-

4(5H)-one; 7,8-I^ydro-2,5-diπιethyl-7(R)-isopropyl-3-(pheπylme- thyl>3H-irm'<iazot2,l-b]purh^5rI)-one; 7,8-I>mydrCH2,5,7(R) rimedτyI-3-{phenyknethyl)-3H- iπύάszo[2,lA3]pJi .-Ai51I)-oτie; cia-7,7a,8,9,10_rl0a-Hexahydro-2,5-dimethyl-3-<phenyl- methyl)-3H-cycIoρenta[5,6]pyώnido[2, l-b]ρuτin-

4(SH)-one 7,8-DihydrcH2,5-dimethyI-7(SKi-πιetlιylρropyi -3-

(phfiayln^*iethyl)-3H-imida2»[2, l-b]purin-4(5H)-one; 7,8-Dmydrch2,5-dimemyl-7(R)-( <nrfhylpropyl 3-

(phen lmethyl)-3H-mύda^2,l-b]purirHK5H)-one; 7,8-DmydrcH2,5-oimemyl-7(R,S>(memoxycarb nyl 3- i^enylrnethyl)-3H-Mda^2,l-b]purin-4(5H)-one; 7.8-Dmydrc-2,5-dimethyl-7(R,S>(l-propyI)-3-{phenyI-

^*methyl>3H-Jπύdazo^l-b]purin-4 5H)-one; 7,8-Dmydιx^2^-dimethyl-7(S)-(l-πιethylethyI 3- phenylme&yi 3H-unidazo[2 l-b]ρurm-4(5H)-onε; 7,8-Dmy4O-2^,7,7,8(R,SH>entamethyl-3H- imidazo[2, l-b]purin-4 5H)-one; 5,7,8,9-Tet)^ydro-2,5,7,9(R,S>ρentamethyl-3-<phenyl- ιncmy^yrmιidθ[2,l-b^urin-4{3H)-one; 5,6a(R).7,8,9,9 S He^*^ydr 2,5-dimethyl-3-<p jeιιyl- meΛ^*y3)cy^**-loper-^*rt[4,5]itttiά^ 5,6a(S),7,8,9,9a^ Hexahydro-2,5-dimethyl-3-^henyl- me&yl)cyotopent[4,5]lnudazo[2,l*lpurm-4^1=0-one; ct3-6a,7,8,9, 10,lOa-Hιixahj^o-2,5-d ethyl-3-rjphenyl- metnyl 3H -benzimMa∞[2,l-b]pmm-^5H)-c-ne; 5',7^*-Dihydro-2',5'-dϋnetlιyI-3'-(phcnylιrtethyl)spiro[cy- clohexane-l,8-(8H)-iimdazop₎I-b]purin]-4-(3'H)-one; s-5,6a,7,8,9,9a-Hexahydro-2,5-diιnetlιyl-3-(pheny]mc- thyl)cyclohept[6,7]itnidazoi2_l l-b]purin-4(3H -one; c^js-S,ώ,7₍8,9,9a-Hexahydro-5-mcthyl-2-ethyl-3-

(phenylmethyl)cyclopent[4,5]imidazo[2,l-b]ρurin-

4(3H)-one; cis-6a,7,8,9,10_r10a-Hexahydτo-5-met yI-2-ethyl-3-

{phenylmethyl)-3H-beπzimidazo[2, 1 -bJρurin-4-

(5H>one;

carboxylic acid, methyl ester; cis-5, 6a,7, 8,9,9a-Hcxahydro-2-bromo- 5-methyl- 3 -

(phenylmethyl)cyclopent[4,5]iniidaz:o[2,l-b]purin-

4(3H)one; cis*5,6a,7,8,9,9a-Hexahydro-2-(methylaι^*c nos^**dfoayl)-

5-methyl-3-{phenylιnethyl)cyclopent[4,-

5]imidazo[2, l-b]puriπ-4(3H)one cis-l-Cyclopentyl-S,6a,7,8,9,9a-hexahydro-5-methylcy- clopeπt[4,5Jimidazo[2, l-bIpurin-4-(lH)one; cis-5,6a,7,8,9,9a-Hexahydro-3,5-bis-(phenyhnethyl)cxy- cloρent(4,5 iπιidazo(2, l-b)purin-4 3H)one; cis-6a,7,8,9,10_r10a-Hexahydro-3,5-bis-(phcnylmethyl)-

3H-benzimidazo[2, I-b]purin-4(5H)one; cis-3-CycIopentyl-5,6a,7,8,9,9a-hexahydro-5-mcthylcy- opent[4,5Jιmidazo(2, l-b)purin- (3H)one; S'-MethyI-3'-føhcnylraethyl)spLro[cyclopentane-l,7-

(8ΗK3'H imidazo[2, l.b]purin]-4-(5H)one; 2',5'-Dimcthyl-3'-(ρhenylnιethyl)-spiro[cyclopcntane- l,7-(8ΗH3H)imidazo[2, l-b]purin]-4-(5'H)one; cis-5,6a,(R)7,8,9,9a(S)-Hexahydro-5^nethyl-3-(phcnyl- methyl)cyclopent[4^]imidazo(2,l-b)p^*urin-4(3H)one; cis-3-Cyclopentyl-5,6a,7,8,9,9a-Hexahydro^2,5-dime- thylcyclopentI4,5Jimidazo[2,l-b]ρurin-4(3H)one; 5'-Methyl-2'-trifluoromcthyl-3'-(ρhenylmethyl)spiro{ cyclo-pentane- l,7'(8'H)-(3'H)imidazo[2, 1 -b]purin}-4-

(5'H)-one; 7,8-Dihydro-5,7,7-trimethyl-2-trifIuoromethyl-3-

(phenylmethyO-3H-imidazo[2,l-b]ρurin-4{5H)-onc; (+/— cis-5,6a,7,89,9a-Hexahydro-5-methyI-2-tri- lluoromethyl-3- phenylmethyI)cyclopeπt[4,-

5]imidazo[2,l-b]purin-4(3H)-one (•+-/— )-€a,7,8,9,9a,10,π,l I a-0ctahydro-2,5-dimcthyl-

3-(phenylmethyl)-3H-peπtaleno{6a^*, :4,-

5]imidazo[2, 1 -b]purin-4(5H)-one; (+ 6a,7,8,9,9a,10,ll,lla-Ch5tahydro-2,5-dimethyl-3- phenyImcthyl-3H-pentalenof6a'₍ 1 ':4^]imidazo [2, 1 - b]ρurin-4(5H)-one; (— )-€a,7,8,9,9a,lO,π,πa-Ootahydro-2,5-dimethyl-3- ρhenylmethyl-3H-pentaleno[6a^*, l't4,3]Tτnidazo[2, 1- b]purin-4{5H)-oπc; (+/— ) 6a,7,8,9,9a,10,il,lla-Octahydro-2,5-dimethyl-

3H-pentaleno[6a', -4,5Jmidazo[2, l-b]purin-

4(5H)-one; (+)-€a,7,8,9,9ι^l0,π,lla-Octahydro-2^-dimethyI-3H- pent- eπo[6a^ -4 ]imida^*∑olϊl4)]p^*-τiα-4<5H)-oαe (-)-6a,7,8^,9a,10₎ll,Ua-Octahydro-2,5-dππcthyl-3H- pentaleno[6a', l^*:4^]imidazo 2, l-b]puriπ-4 5H>-one; 6a,7,8,9,10,10a,ll,lil3,I3a-Decahydro-2,5-dimethyl- ρhenylmethyr^apm[l,8a-d]irnidaa»[2,l-b]puιin-

4(5H)one; 7(R)-C^clohexyl-7^-dϊhydro-2,5-dimethyl-3-(pheny me yl -3H-iιnidazo 2,l-b]ρurin-4 3H)-one 70^)-Cyctohexyl-7,8-dihydrc-2,5-d-meΛyl-3H- imidazo 2, l-b]purin-4(5H)-one; 7(S Cydohexyl-7,8-dibydro-2,5-dunethyl-3-<phenyl- methyI)-3H-Jmida2o[2,l-blpurin-4<3H)-one; 7(S>^y ohexyl-7,8-dihydro-2,5-dimethyl-3H- imidazo[2, l-b]pαriπ- {5H)-one; 5,6^),7,8,9,9a(S Hexahyd^O-2,5-dimethyI-3- trmie- thylacetoxy)mcthyl]<yclopent{4^]uπidazo[2,l-b]ρu- rin-4(3H>one; 5,6a(R),7,8,9^a(Sr)-H^*aι-Λydr -2,5-dimethyl-3-(4- pyridylmethyl}oyclαpeπt[4_5]imidazQ[2₎ 1-bJρurin-

4(3H>-θtte;

5,6a S),7(R),8^,9a-Hexahydπ>-2,5,6a-trunethyl-3-

(phenylmemyI)cydopeπt[4,5]inridazo[2, 1 -b]pπrin-

4(3H)-one; cis-oa,7,8,9, 10, l0a-Hexahydro-2,5,7-trimethyl-3-

(phenyImerayl)-3H-r^ hnidazo[2, 1-blpurin-

4(5H)-one-, cis-5,6a,7,8,9,9a-Hexahydro-2^,6a-trimethylcy- clorjent[4,5]imkla2θ[2,l-b]purm-4(3H); or ds-6_ 7,8,9,10,10a-Hexahydπv2^,7-^*trimethyl-3H-ben- nmid-uoβ, l-b]p^*urin-4(5H)-one].

U.S. Patent No. 5,439,895 discloses compounds of the formula

wherein R¹ is hydrogen or Cl-4 alkyl; Y is Cl-6 alkylene; A is — O— R° or — S{0)p— O in which R° is Cl-4 alkyl-hydroxy; p is 0-2; Z is single bond, methylene, ethylene, vinylene or ethynylene CyB is

(1) 7-membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, one, two or three nitrogen atoms,

(2) 6-membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, two or three nitrogen atoms,

(3) 6-membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atom, one nitrogen atom,

(4) 4- or 5-membeτed, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, one, two or three nitrogen atoms, or

(5) 4-7 membered, unsaturated or partially saturated, monocyclic hetero ring containing as hetero atoms, one or two Oxygen atoms, or one or two sulfur atoms;

R3 is hydrogen, Cl-4 alkyl, Cl-4 alkoxy, halogen or trifluoromethyl; 4 is (1) hydrogen, (2) Cl-4 alkyl, (3) Cl-4 alkoxy, (4) —COOR⁸, in which R* is hydrogen or Cl-4 alkyl, (5) — R R^I0, in which * is hydrogen, C W alkyl or pheπyl(Cl-4 alkyl) and Wis hydrogen or Cl-4 aU yl, (6) —NHCOR' i, in which R» is Cl-4 alkyl, (7) — NHSQ-R", in which R¹' is as hereinbefore defined, (8) SChN S -⁰. in which R? and R^I0are as hereinbefore defined, (9) — OCOR". in which RU is as hereinbefore defined, (10) halogen, (11) trifluoromethyl, (12) hydroxy, (13) nitro, (14) cyano, (15) — SC N-^HNR^Rl* in which R¹² is hydrogen or Cl-4 alkyl and R¹³ is Cl-4 alkyl, (16) — CONR"R^lsin which R^1** is hydrogen or Cl-4 alkyl and R»is Cl^l alkyl or phenyl(Cl- alkyl), (17) C14 alkylthio, (18) Cl-4 alkylsulfinyl, (19) Cl-4 alkylsulfonyl, (20) ethynyl, (21) hy- droxymcthyl, (22) tri(CI-4 alkyl)silylethynyl or (23) acetyl; and m and n independently are 1 or 2; with the proviso that

(1) a CyB ring does not bond to Z through a nitro_¬ gen atom in the CyB ring when Z is vinylene or ethynylene; or pharmaceutically acceptable acid addition salts thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.

Preferred compounds include:

4-{2-(2-hydroxycthoxy)ethyl]amino-6-acetyl-2-(l- imidazolynquinazoline, 2-(l-imidazolyl)-4-[2-(2-hydroxyethoxy)ethynamino-

6-cthynylquinazoline, 2-(l-imidazolyl>4-[2-(2-hydroxyethoxy)ethyl]amino-

6-(2-trusopropyls2yIerhynyl)qumazoline, 4-[2-(2-hydroxyethoxy)ethyljanύno-6-hydroxymeth- yM- -imidazoly quinazσliπe, 4-(2-(2-hydroxyethoxy)ethyl)amino-6-methylsulfιnyl-

2-( l-imidazolyljquinazoline, 6-chIoro-4-(2-(2-hydroxyethoxy)ethyl)amino-2-( 1 - imidazolyQquinazoline, 4-[2-(2-hydroxyethoxy)ethyl]anuno-6-ιnethό xycar- bonyl-2^1-imidazolyl)φjinazoliπe_> 4-(2-(2-hydroxyetlMxy)ethyl)amino-6-methylthio-2-

(l-iι^*-idarolyl)quiπazoline, 4-(2-(2-hydroxyethoxy)ethyl)amino-6-iodo-2-(l - hnidazoly quinazoϊine, 4-(2-(2-hydroxyethoxy)etnyl)amino-2-(Hmidazolyl)-

5,6,7,8-tetrahydroquinazoline or 6-melhoxy-4-(2-(2-hydroxyethoxy)ethyl)amino-2-(I- imidazo!yI)quinazoHne, and phaππaceutically acceptable acid addition salts thereof, pharmaceutically acceptable salts thereof, or hydrates thereof.

584

-71-

U.S. Patent No. 5,488,055 discloses compounds of the formula

wherein: ¹ is lower-alkyl, pheπyl-lo er-alkyl, or cydoalkyl;

K² is hydrogen, or lower-alkyl;

R³ is hydrogen, lower-alkyl, or hydroxylower-alkyl;

R⁴ is cycloalkyl or cylcoalkyl substituted by from one to two, the xarat^* or different, substituents selected from the group consisting of lowcr-alkoxycarbonyl, carboxy, Iowcr-alkyllhio-lower-alkoxycarbonyl, hydroxylower- alkyl, hydroxy, oxo, lower-alkoxy, lowcr-alkyl, and halogen; and

R^s is from one to three, the same or different, substituents selected from the group consisting of hydrogen, lower- alkoxy, hydroxy, dilower-alkylarnino-lower-alkoxy, carboxylower-alkoxy, lowcr-alkoxycarbonyl-lowcr- alkoxy, nitro, polyhydroxylower-alkoxy, amino, epoxy- lower-alkoxy, carboxy, Iower-alkaπoylamino, lowcr- alkoxycarbonyl, pyridinyl, 4-morphoHπyl-lower- alkoxy, lowcf-alkylsulfonyl, cyano, ^' -imidazolyL, halogen, dϋower-alkylarainosπlfoπyl, oxadia2olyl (or oxadiazolyl substituted on any available carbon atom thereof by lower-alkyl), lowcr-alkylsulfinyl, 1-pyra- zόly] (or 1-pyrazolyl substituted on any available carbon atom thereof by lower-allyl), trifluorotncthylsul- fonyl, lowcr-alkcnyl, lowcr-alkyl, and lowcr-alkyπyl; or a pharmaceutically acceptable add-addition salt and/or hydrate and/or solvate thereof, or, where applicable, a steπ-oisomer or a racemic mixture (hereof.

Preferred compounds include

l-eaiyl-6-nitro-N-(S(+)-l-(cydohexyl) ^' ethyl]-lH-pyra- zolo 13,4-bJqtήπolm-4-amiπc, 1-ethyl -6-πiu^*o-N-[cydohexylmethyl]- IH-pyrazolo

[3,4-h]quiπolin-4-ι*πun*j, l-* l-6-cyano-N-rSf+ l-(cyclobcxyl)cthyl]-lH-pyra- zolo [3,4-b]quinolin-4-amine, 1 <thyl-6-bromo-N-[S(+)-l -(cyclohcxyl)ethyl]- 1 H-pyra- zolo [3,4-blquinolin-4-aminc, and l-e l-6^(l- razolyl N-^S •f (c ohcxyl)cthyl]- lH-pyrazolo {3 -b)qutoolin-4-amiπe. 584

-72-

U.S. Patent No. 5,525,064 discloses compounds of the formula

wherein Λ is a bond. C^ alkylene or C_M oxyalkylcnc;

Y is a bond, C,_, alkylene, C_1Jt alkyiencoxy. C„ alkox- ypticnylcno or phcnyl(C )alkylcuc;

/. is a bond or vinylene;

R¹ is u heterocydic ring selected from the group consi^βt- ine of pyn-ole, pyridine, a/cplne, imidazolc, pyrazo e, pyrimidine, pyrarfπe, pyridazine, bwwlmWa∞to, qt_iinolinc, isoquinoline anil partially or fully saturated rings ihcrcor;

R s

(i) a heterocyclic ring selected from the group consisting of pyrrole, pyridine, azcpinc, Imidazolc, pyra- zole, pyrimidine, pyraziπc, pyridazine, bcnzdmida- zole, quinoline, isoquinoline, furan, pyraπ, dioxolc, dioxine, benzofuraπ, bcnzopyian, benzodioxole, bcnzodioxiπe, thiophene, thioine, benxothiophenπ, betiλothionc and partially or fully saturated rings thereof, (ϋ) C«.ιs carbocydic ring, 'ii) C,.,, alkoxy, (iv) hydro^*cy(Cι_₄ alkoxy), or (v) hydroxy; with the proviso thai? when R¹ is pyridine or pyridine substituted by one or two of C,_ alkyl, C^ alkoxy, halogen, triflunromctliyl or nitro then R² is a member selected only from the group consisting of benzodioxole or benzodioxole substituted by one or two of C,_^, alkyl, C,_, alkoxy, halogen, trifluoromethyl, nitro or a group of (he formula:

—COOR"* wherein R^l" is hydrogen or C_t-, alkyl, and hydroxy(C_tJ, alkoxy); R^*» Ls

(i) a heterocydic ring selected from the group consisting of pyrrole, pyridine, azcpinc, imidazolc, py a- zole, pyrimidine, pyraziπc, pyridazine, benzimidazole, quinoline, Isoquinoline, furan, pyran, berαofαran, bcnzopyran, thiophene, thioine, bco- zothiophcac, bcπzolhione, Ihύtzule, isothiazule, flii- ojane, benzothiazoie, benzoisotbiazole, beozothiaz- ine and partially or folly saturated rings thereof,

(ii) .,., carbocydic ring,

(iii) a group of formula:

herein X is halogen, or

(iv) hydrogen, 1 is 1 or 2, with the proviso that the ring represented by R¹ may be substituted by one or two of C,_₄ alkyl, C_I-4 alkoxy, halogen, trifluoromethyl or nitro; tie ring represented by K²may be substituted by one or two of C,.₄ alkyl, C, alkoxy, halogen, trifluoromethyl. nitro or a group of the formula: — COOR¹⁰ wherein R¹⁰ is hydmgcn tir C_t^ alkyl, and the ring represented by R³ may be substituted by one or two of Cj_4 alkyl, .,, alkoxy, halogen, trifluoromethyl, nitro, cyano, ethynyl or a group of the formula:

— SONiΛ^*.' wherein R⁷ and R" are independently hydrogen or C_l_ alkyl, and with the proviso that R² is not hydroxy when Y is a bond; and

R¹ is not bonded through its nitrogen atom when Z is vinylene, or phaπnaceulically acceptable acid addition salts thereof or pharmace^utically acceptable salts thereof.

Preferred compounds include

2-( 1 -Imidazolyl>4-[2-(2-hydroxyothoxy)cthyl |nmmo-5-(3

-methoxy phcnyl)methyl pyrimidine, 2-(l-ImidazoIyl)-4-phcnylmcthylaminopyriratdirιc, 2-(l -lmidazolyl 4-(2-methoxyethyl)aminopyι^*i midinc, 2-(l-ImidazoIyl)-5-cthyl-4-phcnylmcthylaminopyrimuline, 2-(l-lmidaz»lyl 5-phenylιncll^*yl-4-))hcnylradhylaιniuopy- rimidine, 2-(l-Imidazoly] '5-mcthyl-4-phGnylmcthylamiιx>pyrimi- dinc, 2-(l-Imidιwolyl)-5,6-dimclhyl-4-phenylmclhylaminuρyri- midinc, 2-(l-Imidazolyl)-5-(3-mcthoxyphcnyl)mcthyl-4-(2-mcth- oχycthyl)amlnopyri midinc, 2-(l-Imidazolyl)-5-(4-mcthoxyphcnyl)mcthyl-4-r2-(2-hy- droxyelhoxy)cthyl]amiπopyrimldinc, 2-(l-Imida Λlyl)-5-(4-mcthoxyphcnyI)nιcthyI-4-(2-mc{h- oxycthyDarolnopyrimldlnc or 2-(l-Iιr da^dyl)-5-(4-raclhoxyphcnyl)mcUιyl-4-phcnylm- cdiylaminopyriniidinc. 2-(l-lmida/.olyl)-S-phenoxymcthyl-4-phcnylιr*cthylami- nopyrimidine, 2-(l-Inύda∞lyl)-5-(l-Imidazolyl)mcιhyl-4-phenylmethy- larrϋnopyrimidinc, 2-(l -ImidazolyI)-5-(l -chlc>roviπyl)-4-phcnylm lhylarai- nopyri midinc, 2-( I -lmida7Λlyl)-5-(2-thicny l)-4-phcnylmdhylaminopyri- midinc, 2-(l-rmida^*κ)lyl)-5-(2-thiazolyl)-4-phcnylmcthylaminuρyri- midine, 2 l-lmidazolyl)-5-C-thienyl)-4-{l,3-dioxaindan-5-yl)m- ethylaminopyrimidine, 2 l-Iιrdda/olyl)-5-(2-thienyl)-4-[2-(2-hydroxycthoxy-

)ethyl]aminopyrimidinc, 2-(l-IrradaTOlyl)-5-(2-thtenyl)-4-(l-naphthyl)tnclhylami- nopyri midinc, 2 l-lmiαazolyl>5-(2-lhlenyI)-4-(4-mcthoxyphcnyl)inclhy- iamiαopyri midinc, 2-(l-lmida^, olyl)-5-(2-thioayl)-'1-(3-mcthuxyphcnyl)mjcthy- laminopyrimidino, 2-(l-lmidazolyl)-5-(2-thlcnyl)-4-(2-furyl)mcthylam{nopyri- midinc, 2-(l-lmida/olyl)-5-(2-thicnyl)-4-(2-lhic«yl)mcthylatni- nopyrimidinc, 2-(l-Imidazolyl)-5-(2-thicιtyI)-4-(3-pyridyl)mcihylami- nυpyriπikliπc, 2-(l-ttnidazolyl)-5-(2-uιtctιyl)-4-(2-ιndhoxydhyl)atni- nopyri midinc, 2-(l-Imidazdlyl)-5-(2-thicnyl)-4-phcnylmctlιoxyamιnαp ιi- tnidine, 2-(l-Iraida/olyl)-5-(2-lhicnyl)-4-(4-chloraρhαιyl)mcιhy- laminυpyti midinc, 2-(l-imidazolyl)-5-(2-tlιicnyl)-4-(3-chloroplιcnyl)nιcll^*y- lanunopyrimklinc, 2-(l-lmida^*<olyl)-5-(2-thlcnyl)-4-(l ,3 -dioxaindau-5-y l)m- clhylaminopyri midinc, 2-(l-Imida/.olyl)-5-(4-mcthylphcnyl)-4-(l,3-dioxatndan-

5-yl)mcthylaminopyrimidinc, 2-(l-hnida^* oIyl)-5-(4-n\cthoxyphcuyl)4-(l,3-dioxaindan-

5-yl)mcthylaminopyrimidinc, 2-(l-Imlda/.olyl)-5-(5- cthyl-2-αιicιιyl)-4-( 1,3-dioxaiιι- dnn-S-ylJmcthylnmmopyrimidinc, 2-(l-lmidav»lyl)-5-(2-thicnyl)-4-[4-( l-imida^*Λolyl)phcnyl] methylaminopyrimidine, 2-(l-Imidtwolyl)-5-(3-pyridyl)-4-(l,3-dioxaindan- 5-yl)m- cthylaminopyriroldinc, 2-(l-Imidav:olyl)-5-(3-furyl)-4-(I,3-dioxaindan-5-yl)mcrtιy- laiiiinopyrimidinc, 2-(l-lmida* «lyl)-5-(3-ρyridyl)-4-phcnylmcιhylaminopyri ' midinc, 2-(l-ϊmidazolyl)-5-(4-cWotophcnyl -(l,3-dioxaindan-5- yl)nιc(lιylaminopyrimidinc, 2-(Hcnzimida/ol- 1 -yl)-S-(2-thionyl)-4-(l ,3-dioxaindan-S- y mclhylaminopyrimidinc, 2-(l-lmidazolyl)-5-(2-lhicπyl)-4-(4-dhoxycatb()nylphcnyl-

)mcihylamlnoρyrimklinc, 2-(l-Imldazolyl)-5-(2-naphlbyl)-4-(l,3-diuxairκlαn-5-yl)m- dhylαmlnopyrimidinc, 2-(3-Pyridyl)-5-(2-tWcnyl)-4-(t,3-(lioxaiπtlan-.S-yl)mcthy- laminopyrimidine, 2-r2-(3-Pyridyl)viπyl]-5-(2-thicπyl)-4-(l^-dioxaindan-5- yl)mcthylaminopyrimidine, 2-(2-Mdlιyl-l-Inύt κolyl)-5-(2-fhicnyl)-4-(l,3-dioxatn- daιι-5-yl)mcthylamlnopyrimldute or 2-(1 -ln^daw)1yl)-5-(2-thtcnyl)-4-(bcnzimidtu»l-5 -yl)ra- clhylamlnopyrimidiDC. 4

-75-

European published paten t application No. 0728759 discloses compounds of the formula

wherein

03 is a heterocyde selected from

n is O, 1 or 2;

Y is single bond or C1-6 alkylene;

Z is single bond, Cl-2 alkylene or vinylene;

E is

(i) 4-15 membered, unsaturated, partially saturated or fully saturated, mono or bicycBc hetero ring containing one or two hetero atoms, chosen from nitrogen, oxygen and sulfur, not more than one hetero atom being sulfur, (ii) 4-15 membered, unsaturated or partiaBy saturated, mono or blcycfic carbocycOc ring, or (iii) -OR⁴; in which R⁴ is hydrogen atom, C1-4 alkyl or C1-4 alkyl substituted by a hydroxy group;

Cyc is 5-7 membered, unsaturated, partially saturated or fully saturated, monocyclic hetero ring containing one or two nitrogen atoms or 5-7 membered, unsaturated or partially saturated, monocyclic carbocydic ring;

R^τ is hydrogen atom or C1-4 alkyl;

R² is hydrogen atom, C1 -4 alkyl, CI -4 alkoxy or halogen atom;

R³ is hydrogen atom, C1 -4 alkyl, C1 -4 βB<oxy or -COOR⁵; in which R⁵ is hydrogen atom or Ci -4 alkyl; with the proviso that

(1) a Cyc ring does not bond to 2 through a nitrogen atom in the Cyc ring where Z is vinylene and that

(2) Y is not a single bond, when E is -OR⁴; or a pharmaceutically acceptable add addition salt, pharmaceutically acceptable salt or hydrate thereof. U.S. Patent No. 5,541 ,187 discloses compounds of the o formula

1 wherein: ^R<

R- is hydrogen, alkyl, cycloalkyl, cycloalkyl substituted by alkyl or hydroxyl, 2- or 3-tetrahydronιranyl, 3-tct- raliydrothieuyl 1,1,-dioxide, cycloalkyl-alkyl, carboxy- alkyl, carbo-lower-aikoxy-alkyl, dialkylaminoalkyl, phenyl-lowcr-alkyl, phenyl-lower-aDcyl in which the phenyl ring is substituted in tlie 2, 3, or 4-position by one or two substituents, the same or different, selected from the group cσπsάεting of amino, halogen, alkyl, carboxyl, carbo-lowcr-alkoxy, carbamoyl, NHS0₂-

(quinolinyl), nitro and cyano: ¹ is hydrogen, lower-alkyl, pbcnyl-lower-alkyl, lower- alkoxyphenyl-lower-alkyl, dilower-alkoxy-phenyl- lowcr-alkyl, pyridyl-lowcr-alkyl, cycloalkyl-lower- alkyl, phenylamino, dialkyiamino, halogen, trifluoromethyl, lower-alkylthio, cyano or nitro; and R° is a five or six membered heterocyclic ring containing from one to two nitrogen atoms, substituted — or unsub- stituted — at any available carbon atom by one or two substilucπls, the same or different, selected from the group consisting of lower-alkyl, halogen, lower-alkoxy, cycloalkyloxy, 4-moιpholiπyl,. lower-alkoxy-lowcr- alkoxy, hydroxy, imidazolyl, oxo and 4-morpholinyl- lower-alkoxy; or at any available nitrogen atom by lowcr-alkyl, luwer-alkauoyl, or trifluorσacetyl; or a pharmaceutically acceptable acd-addiπbn salt thereof.

Preferred compounds include: l-Cyclopcώyl-3-methyl-6-<4-pyridyl)pyraa lol3,4-d] ρyrimidin-4-otιe, l-Cyclopcπtyl-3-cmyl-fr(3-cιioxy-4-ρyridχl)ρyra- •_∑o!o[3,4- 3]pyrirrιidm-4-one,

1 -C^clopontyl-3-cmyl-6-(3-memoxy-4-ρyridyl)pyra- zoIo[3,4-d]pyomidiπ-4-oπc, l-Cyclopcntyl-3-trifluoromcthyl-6-(3-ethoxy-4-py- ri yl)pyrazolo[3,4-ffJpyrimidin-4-one, l-Cycloρentyl-3-ethyl-6-(2-( l-imidazolyl -4-py- ridyl)ρyr₈-ωlo[3,4-clρyrirMdin_r4-oπe, U.S. Patent No. 5,721 ,238 discloses compounds of the formula

in which

A represents oxiranyl, which is optionally substituted by straight-chain or branched alkyl having up to 8 carbon atoms, which in turn can be substituted by phenyl, or represents a radical of the formula

^•wherein

R¹ denotes hydrogen or st φit-chain or

wherein

R* and R⁹ are identical or different and denote hydrogen, phenyl or straight-chain or branched alkyl having up to

6 caibon atoms, which is optionally substituted by hydroxyl, or, together with the nitrogen atom, form a 5- to 6-membered saturated heterocyclic radical -which has up to 2 further hetero atoms from the series consisting of S, K and or O aad Is optionally substituted, including via a free N junction, by straight- chain or branched alkyl having up to 6 carbon atoms, which in tarn can be substituted by hydroxyl, tad

E represents straight-chain or branched alkyl having up to 8 carbon atoms, and tautomers and salts thereof. Preferred compounds include:

84

-79-

U.S. Patent No. 5,294,612 discloses compounds of the formula

wherein:

R¹ is hydrogen, alkyl, C* to C? cyclo*lkyL G« to C₇ cycloalkyl substituted by Q to Cjo alkyl or hydroxyl, 2- or 3-tetrahydrofuraπyl, 3-tet ah drothie- nyl 1,1, -dioxide, C< to C₇ cycloalkyl-Ci to Cjo alkyl, carboxy-Ci to Cio alkyl, carbo-Cj to G» low- cr-alkoxy-Ci to Cio alkyl, dialkyiamino Cj to C₁₀ βlkyl, phenyl- to lower-alkyl, phenyl-Ci to C lower-alkyl in which the phenyl ring is substituted in the 2, 3, or 4-position by one or two substituents, the same or different, selected from the group consisting of amino, halogen, Cj to Cioalkyl, carboxyl, carbo-Ci to Ci lower-alkoxy, carbamoyl, NHSC - (quinolinyl), nitro and cyano:

R³ is, Cj to Q lower-alkyl, phenyl-Ci to C loweralkyl, lower-alkoxyphenyl-Ci to C lower-alkyl, diCj to C₄ lower-aJkoxy-phenyl-Cj to C₄ loweralkyl, pyridyl-C] to G» lower-alkyl, C₄ to -η cycloalkyl -Ci to lower-alkyl, phenylamino, diC- to Cioalkylamino, halogen, trifluoromethyl, Ci to C lower-alk lthio, -cyano or πitro; and ⁶ is a nine or ten membered bicyclic .ring having carbon and from one to two nitrogen atoms, and the heterocyde is made up of fused 5 or 6 membered rings or such ring substituted at any available carbon atom by one or two substituents, the same or different, selected from the group consisting of Ci to C* lower-alkyl, halogen, O to C« lower- alkoxy, C4 to C7 cycloalkyloxy, -morpholiπyl, C- to CA lower-alkoxy-Ci to Cj, lσwer-aBcσxy. hydroxy, imidazolyl, oxo and 4-morpholinyl-Cι to C₄ lower-alkoxy, or at any available nitrogen atom by Ci to C+ lower-alkyl, C₂ to C4 lower-«lkanoyL or triiluoroacetyl; or & pharmaceutically acceptable acid-addition salt thereof.

Preferred compounds include:

pyr»^j»lop,4-d]pyrimidin^- ne WO 93/12095 discloses compounds of the formula

or a pharmaceutically acceptable salt thereof , wherein R¹ is H, -Q, alkyl, C C₄ . alkoxy or CONR^R⁶; R² is H or C_j- i alkyl;

R³ is Cϊ-C_t alkyl

K* is H, C₂-c₄ alkanoyl optionally substituted with NR⁷R^ε, (hydroxy) C_J--C₄ alkyl optionally substituted with NR⁷R*, CH=CHC0₂R _f CH=CHCO R⁷R*, CBjCH₂CO-R⁹, CH₂CH₂CONR⁷R^** , SO_jN ' ⁸,

Sθ₂NH (CH₂)_nNR⁷R⁸ or imidazolyl;

R^s and R^β are each independently H or 0^0₊ alkyl;

R⁷ and R* are each independently H or C₁-c₄ alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, ^•morpholino or 4~(KR^l0)-l- piperazinyl group wherein any of said groups is optionally substituted with C0NR^sR^lS;

R⁹ is H or Cι~C₄ alkyl;

R¹⁰ is H, Ci-Cj alkyl or (hydroxy) C₂-C, alkyl; and n is 2, 3 or 4; with the proviso that R⁴ is not H when R¹ is H, C_j-^ alkyl or Cι~C₄ alkoxy. Preferred compounds include:

2— T2-ethoxy-5- [4- (2-hydroxyethyl) -l-piperazinyl- sulphonyl]phenyl>-8-methylguinazolin-4- (3H) -one;

2 -{5— [4— (2 -hydroxy ethyl) -1-piperaz nylsulphonyl] - 2-n-propoxyphenyl>-8-^*methylquinazσlin-4 (3H) -one;

8-methyl-2— C5- [2- (4-methyl-l-pipera-zinylσarbonyl) - ethenyl]-2-n-propoxyphenyl>guinazolin-4 (3H) -one;

8-σarbamoyl-2-{ 2-ethoxy-5- [ 4- (2-hydroxyethyl) -1- piparazinylsulphonyl]phenyl}guinaz.olin-4 (3H) -one; and 8-ethylcarbamαyl-2- (2-n-propoxyphenyl) quinazolin- 4 (3H) -one; and pharmaceutically acceptable salts thereof .

WO 93/07149 discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein R¹ is C_j-C^ alky ;

R² is H, methyl or ethyl; R³ is Cz-C alkyl;

R⁴ is Cj-Cn alkyl optionally substituted with NR^SR⁶, CN, CONR^sR^fi or COjR⁷; C^-^ alkenyl optionally substituted with CN_r -CpNR^R¹-^* or CO_zR⁷; C₂-C₄ alkanoyl optionally substituted with NR'⁶; S0₂NR-^*R⁶; CONR^⁶; Cθ₂R⁷; or halo; R⁵ and R⁶ are each independently H or C,-C₄ alkyl, or together with the nitrogen atom to which they are attached form a pyrrolidino, piperidino, morpholino, 4- (NR*) -1-ρiperazinyl or 1-imidazolyl group wherein said group is optionally substituted by one or two C,-C₄ alkyl groups; R⁷ is H or Cj-C₄ alkyl; and R* is H, C,^'-C, alkyl or hydroxy C^-c, alkyl- Preferred compounds include:

6- (5-bromo-2-n-propoxyphenyl) -3 -methyl-1-n-prαpyl- 1, 5-dihydro-4H-pyrazolof 3 ,4-d Jpyr imidin- -one ;

₃-methyl-6- (5«_"morpholinosulphon l-2-n- propoxyphenyl) -1-n-prop l-l, 5-dihydro-4H-pyrazolo[ , 4- ] y imidin-4 -on ;

6-[5- (2-carboxyvinyl) -2-n-propoxyphenyl] -3-methyl- 1-n-propyl-l, 5-dihydro-4H-pyrazolo£ , -d] pyrimidin-4- one;

6- [5- (2-t-butoxycarbonyl vinyl) -2-n-propoxyphenyl] - 3 - ethy 1-1-n-pr opyl-1 , -dihydro-4H-pyr azol o [3, 4- d] yrimidin-4-one ;

3 -methy 1-6- [5- (2-morpholinocarbonyl inyl) -2-n- propoxyphenyl] -1-n-propyl-l, 5-dihydro-4H-pyrazolo [3 ,4- dJpyrimidin-4-one; and 3-methyl-6-[S- (2-morpholinocar-bonylethyl) -2-n- propoxyphenyl] -1-n-propyl-l, 5-dihydro-4H-pyrazolo [3 , 4- d ] pyr imidin-4 -one ; and pharmaceutically acceptable salts thereof .

European published patent application No. 0607439 discloses compounds of the formula

R

[in formula (1), ring A represents a benzene ring, a pyridine ring or a cyclohexane ring; ring B represents a pyridine ring, a pyrimidine ring, or an imidazole ring.

Provided that the ring A and the ring B are combined sharing two atoms and the atoms shared may be either a carbon atom or a nitrogen atom.

^• In the case where the ring A is a pyridine ring and that except the case where the ringre shares the nitrogen atom of this pyridine ring to combine therewith, the ring A is represented by

R , R², R³ and R⁴, each of which may be the same or different from one another, represent each a hydrogen atom, a halogen atom, a lower alky! group which may be substituted with a halogen atom, a cycloalkyl group which may be substituted, a lower alkoxy group, a hydroxyalkyl group, a πitro group, a cyano group, an acylamino group, a carboxyl group which may be protected, a group represented by the formula

( 0 ) _B

-S-R⁷

(wherein R⁷ represents a lower alkyl group, and n represents 0 or an integer of 1 to 2), or a group represented by the formula

_R45

/

-N

\ _R4S

(wherein R"⁵ and R ⁶, each of which may be the same or different from each other, represent each a hydrogen atom or a lower alkyl group; or R^4S and R^iS can form a ring which may contain another nitrogen atom or oxygen atom together with the nitrogen atom to which they are bonded with the proviso that this πng may be substituted); or, two of R\ R², R³ and R⁴ may together form methylenedioxy. ethylenedioxy or a phenyl ring.

R⁵ represents a hydrogen atom, a halogen atom, a hydroxyl group, a hydrazino group, a lower alkyl group, a cycloalkyl group which may be substituted, a lower alkoxy group, a lower alkenyl group, a carboxyalkyl group which may be protected, a carboxyalkenyl group which may bo protected, a hydroxyalkyl group, a carboxyl group which may be protected, a group represented by the formula

-S-R⁸

(wherein R^B represents a lower alkyl group, and m represents 0 or an Integer of 1 to 2), a group represented by the formula -0-R° (wherein R^D represents a hydroxyalkyl group which may be protected, a carboxyalkyl group which may be protected or a benzyl group which may be substituted), a group represented by the formula

R²³ represents a hydroxy - R^J

(wherein l group, a lower alkyl group, a lower alkoxy group, a hydroxyalkyl group or a hydroxyalkyloxy group), a heteroaryl group which may be substituted, a 1,3-benzdioxolyl group which may be substituted, a 1 ,4-beπzdioxyl group which may be substituted, a 1,3-beπzdiox- olylalkyl group which may be substituted, a 1 ,4-benzdioxylalkyl group which may be substituted, a group represented by the formula -C(R²*) =X [wherein X represents an oxygen atom, a sulfur atom or a group represented by the formula =N-R^,fl (wherein R¹⁰ represents a hydroxyl group, a cyano group or a carboxyalkyioxy group which may be protected); and R^z< represents a hydrogen atom or a lower alkyl group], or a group represented by the formula -NR'-R¹-^* (wherein R¹¹ and R¹-*, each of which may be the same or different from each other, represent each a hydrogen atom, a lower alkyl group, a hydroxyalkyl group, an aminoalkyl group, a carboxyalkyl group which may be protected, an alkylcar- bamoyi group, a carboxyalkylcarbamoyl group which may be protected, a heteroarylalkyl group which may be substituted, a 1 ,3-beπzoxolyla!kyI group or a 1 ,4-benzdιoxylalkyl group, or, further, R' ¹ and R¹² can form a ring which may contain another nitrogen atom or oxygen atom together with a nitrogen atom to which they are bonded with the proviso that this ring may be substituted).

R⁶ represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a lower alkyl group, a lower alkoxy group, a lower alkenyl group, a ι ,3-benzdioxolylalky(oxy group, a 1 ,4-benzdiox- ylalkyloxy group, a phenylalkyloxy group which may be substituted, a group represented by the formula

(wherein R¹³ and Rⁿ , each of which may be the same or different from each other, represent each a hydrogen atom, a lower alkyl group or a lower alkoxy group; or, further, R¹³ and R^u may together form methylenedioxy or ethylenedioxy), a group represented by the formula

a group represented by the formula

a group represented by the formula

a group represented by the formula

(in these formulas, R'⁵ and R¹⁶. each of which may be the same or different from each other, represent each a hydrogen atom, a lower alkyl group or a lower alkoxy group; or, further, R^*5 and R* may together form methylenedioxy or ethylenedioxy), a pi x dπe-4-spiro-2^*<iioxan-1 -yl group, a group represented by the formula CHa)<; - Al

(wherein R^4δ and R⁴⁵ , each of which may be the same or different from each other, represent each a hydrogen atom, a lower alkyl group or a lower alkoxy group; or, further, R^4S and R*⁵ may together form methylenedioxy cr ethylenedioxy; and Z represents a sulfur atom or an oxygen atom), a group represented by the formula

(wherein R-^*0 represents a hydroxyl group, a halogen atom, a lower alkyl group, a lower alkoxy group, a carboxyl group which may be protected, a cyano group, a hydroxyalkyl group or a carboxyalkyl group), a group represented by the formula

-N-Y-R¹⁸

[wherein R¹⁷ represents a hydrogen atom, a lower alkyl group, an acyl group, a lower alkoxyalkyl group, a carboxyalkyl group which may be protected or a hydroxyalkyl group; Y represents a group represented by the formula -(CH₂)(,- (wherein q is 0 or an integer of 1 to 8), or a group represented by

the formula

0

I

-C- ;

further, in the group represented by the formula -(CH_)_q-, when q is an integer of 1 to 8, each carbon atom may have 1 to 2 substituent(s); and R^1S represents a hydrogen atom, a hydroxyl group, a carboxyl group which may be protected, a cyano group, an acyl group, a heteroaryl group which may be substituted or a cycloalkyl group which may be substituted], or a group represented by the formula

(wherein R¹³ represents a hydrogen atom, a lower alkyl group, a lower alkoxyalkyl group, an acyl group, a carboxyalkyl group which may be protected or a hydroxyalkyl group; R*⁰, R-^and R", each of which may be the same or different from one another, represent each a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, a πitro group, a lower alkyl group, a lower alkoxy group, a lower alkoxyalkyl group, a lower alkenyl group, an acyl group, an acylamino group, an alkylsul- fonylamino group, a hydroxyiminoalkyl group, an alkyloxycarbonylamino group, an alkyloxycarbonyloxy group or a heteroaryl group which may be substituted; or. further, two of R²⁰, R²¹ and R²² may together form a saturated or unsaturated ring which may contain a nitrogen atom, a sulfur atom or an oxygen atom; and r represents 0 or an Integer of 1 to 8)]. WO 93/06104 discloses compounds of the formula

or a pharmaceutically acceptable salt thereof , wherein R^* is methyl or ethyl;

R² is ethyl or n-propyl; and R³ and R⁴ are each indepdendently H, or c,-c₆ alkyl optionally substituted with C₃-Cη cycloalkyl or with morpholino .

Preferred compounds include:

5-[2-ethoxy-5- (3- orpholinopropylsulphamoyl) - phenylj-l, 3-dimethyl-l, 6-dihydro-7H-pyrazolofj , 3-d] - pyrimidin-7-one ;

1-ethy 1-5- [5-(n-hexylsulphaιaoyl) -2-n-proρoxy- phenyl] -3 -methy 1-1 , 6^dihydro-7H-pyrazoϊo[4 , 3r- djpyrimidin— 7-one ; l-ethyl-5- (5-diethy lεulphamoyl-2 -n-propoxy- phenyl } -3 -methyl- 1 , 6-dihydro-7H-pyrazolo [ , 3-d] - pyrimidin-7 -on ; and 5-[5-(N-cyclohexylmethyl-N-methylsulρhamoyl) -2-n- propoxyphenyl] -l-ethyl-3-methyl-l, β-d.ihydro-7H- pyrazolo[4 , 3-d]pyrimidin-7-one; and pharmaceutically acceptable salts thereof - U.S. Patent No. 5,346,901 discloses compounds of the formula

wherein R¹ is H, C1-C3 alkyl. C₃-C5 cycloalkyl or -C3 perfluoro-Jkyl; R⁷ is H. Ci-Cβ alkyl optionally substituted hy OH,

C1-C3 alkoxy or C3-CG cycloalkyl, or C₁-C₃ per- fluoroalkyl; R³ is Cι-C_ alkyl, C3-C6 alkenyl, C₃- alkynyl,

C3-C7 cycloalkyl, Cj- ; pcrfluoroalkyl or (Cv-Cβ cycloalkyl)Cι-C6 alkyl; R* taken together with the nitrogen atom to which it is attached completes a pyrrolidinyl, piperidino, or morpholino group; R⁵ is H. C1-C4 alkyl, C1-C3 alkoxy, NR⁷R⁸, or

CONR7R*; R⁷ and R⁸ are each independently H, C₁-C₄ alkyl,

(C1-C3 sJioxy)C2-C₄ alkyl or hydroxy C₂-C₄ alkyl; and phaπ-jaceutically acceptable salts thereof.

European published patent application No. 0442204 discloses compounds of the formula

or a pharmaceutically acceptable salt thereof, wherein

vided that the carbon atom adjacent to the nitrogen atom is not substituted by εakf -SfpJnC βalkyf , -OR^β or -NR»R⁹ groups ;

R is halo,

cyano, -CONR¹⁰R», COj ", C₁ alkylS(0)_r. -NO* -NH_2l -NHCOR* or SOs R ^,s wherein n is 0, 1 or 2 and Rⁱo to R« are independently hydrogen or C^ alkyl ; and

a ring ol sub-formula (a) or (b)

(a) (b) .

Preferred compounds include:

2-{5-cyano-2-propoxyphenyl)-7-me ylthioρ^*-τimidc44₁5-d])pyπmidin-4(3H)-onθ,

2-(5-carboxamido-2-propoxyphenyl)-7-methylthiopyrimidor4,5-d]pyrimldo^(3H)-oπe, or

2-(5-carboxamido-2-propoxyphenyl)-7-cyclopropylamino[4,5-d]pyr-nido-4(3H)-one, or a pharmaceutically acceptable salt thereof.

U.S. Patent No. 5,010,086 discloses compounds of the formula

wherein R_l and R₃ are hydrogen or lower-alkyl; R₅ is lower-alkyl or Quorinated lower-alkyl; and the pyridine-N-oxide is attached at the 4- or 3-position; or a pharmaceutically acceptable acid-addition salt thereof.

Preferred compounds include:

_l ,3-D_thydrc-6-₍4-pyridiπyD-5-trifluoromethyl-2H- ύnida_2θ[4_t5-b]pyridin-2-one N-tøy -OMde U.S. Patent No. 5,290,933 discloses compounds of the formula (1)

or a pharmaceutically acceptable salt thereof, wherein Ri is C₁-talkyl, C₁-salkeπyl, C₃.jcycloalkylC]-«alkyl, phenylCι-_$aIkyl or d-βalkyl substituted by 1 to 6 fiuoro groups; and ₂ is hydrogen, -NHCO 3, or -CONR'R*, whereⁱn

RJ is Ci-βalkyl. R+ is C_i^alkyl and R^s is hydrogen or Ci-βalkyl.

Preferred compounds include:

N-π-ctbyl 1 ,6-dih^ydro-6-oxo-2-θpropoxypnen yl)- pyrimid inc-5-carbσxami d e, N,N-dimethyl 1 ,6-dihydrc-6-oxc-2-(2-propoxypheπyl)- pyrimidine-5-carboxamide, 5-acetamido-2-(2-propoxyphenyi)ρyrimidin-4(3H)-one_l

2-(2-propoxypheπyI)pyrimidin-4 3H)-θJie, or a pharmaceutically acceptable salt thereof.

U.S. Patent No. 5,073,559 discloses compounds of the formula

Preferred compounds include:

2-(2 2-[2A2-trifluoroethoxy}phcnyl)purin-6-one,

2-(2 2-cyclopropyIniethoxyphenyl)purin-6-one,

2-(2 2-bemyloxyρhenyl)ρurin-6,&-dionc,

2-Q. 2-prc^*r3θxypheπyI>-S-tτifluoromethylpurin-6-one.

2-(2 2-prorx3xyphenyl>-8-phenylpurin-6-onc,

2-(2 2-pτopoxyphenyl>-g-methylpurin-6 )ne,

2-(2-propoxyphenyl)-8-mercapiopurm-6-one,

2-(2 2-propoxyphenyI>-8-methylthiopura-6-one,

2-(2 2-pτopoxyphenyl>-8-anώoρurift-6-one,

2-(2 2-prciX)xy-5-nh^ophenyl)ouriιv6-one.

2-(2 2-pτopoxy-S-»mπιophenyl^3urin-6-one,

2-(2-(2-propoxy-5-acetι-^oρheπyl)purijι-6-one.

2-{2 2-ρrc )θxy-4-methoxyp"henyI)puriι -6-oαe,

.2-(2 2-propoxy-$-methoxyphenyl)purin-6-oαe,

2-(2 2-propoxy-4-ιncthylρhenyl)purin-6-one,

2-(2 2-propoxy-5-fluorophenyl)purin-6-one,

2-(2 2-proρoxy-5-diraethyIsulphamoyIphenyl)purin-

6-one, 2-(2 2-prαpoxy-5-methyl5ulρhamoylphenyl)puπn-

6-oπe, 2-(2 2-propoxy-5-sulpha oylpbcπyl)puτin-6-one, 2-{2 2-propoxy-4-methylthlophenyl)puτin-6-one, 2-{2 2-propoxy-5-cyaπophenyl)ρuriπ-6-one, and 2-{2^-propoxy-5-carhamoylphenyl)purin-^one, or a phaπnaceutically acceptable salt thereof.

International Patent Publication PCT/EP96/03024 (WO97/03675) discloses compounds of the formula:

and salts and solvates (e.g. hydrates) thereof, in which:

R° represents hydrogen, halogen or C-j_6 alkyl;

R¹ represents hydrogen. C3_βcyciαalkyl, C3_8cyclαalk

IC k l l i

R2 represents an optionally substituted moπocydic aromatic ring selected from benzene, thiophene, furan and pyridine or an optionally substituted bicy ic

ring

attached to the rest of the molecule via one of the benzene ring carbon atoms and wherein the fused ring A is a 5- or 6-membered ring which may be saturated or partially or fully unsaturated and comprises carbon atoms and optionaUy one or two heteroatoms selected from oxygen, sulphur and nitrogen; and

R³ represents hydrogen or C,_₃ alkyl, or R¹ and R³ together represent a 3- or A- membered alkyi or alkenyl chain. Preferred compounds include:

Cis-2_τ3,6,7,12,12a-hexahydro-2-butyl-6-(4-metrιy pheπyl)- pyraziπo[2', 1 ':6, 1 ]pyrido[3,4-b]indole -1 ,4-dione;

(6R,12aR)-2,3,6,7_l12.12a-Hexahydro-2-«opropyl-6-(3,4-methyleπedioxyphenyl)- pyrazϊnoP'.l^e.lJpyridσp^bJindole -1,4-dioπe;

(6R, 12aR)-2,3.6 ,7, 12, 12a-Hexahydro-2-cydopeπtyl-6-(3.4- methyleπedioxypheπyl)-pyrazino[2\1':6,1Jpyrido[3,4-b3rndole -l ,4-dione;

(6R,12aR)-2,3,6.7.12,12a-HexahyndrcH2-cydopropylmethyl-6-(4.methαxyphenyl)- pyrazinσ[2\1 ":6.1 ]pyrido[3,4-bJindole -1 ,4-dione;

(6R.12aR)-2,3,6,7.12, 12a-Hexahydrc^-(3^hiorr>-4-methoxypheny[)-2--methyl- pyrazJno 2',1':6,1]ρyrido[3,4-bJ(πdole -1 ,4-dione;

(6R.12aR)-2,3,6,7,12,l2a-Hexahydro-2-meth t-6-(3,4-methyienedioxypheπyl)- ρyrazino[2^*, 1 ':6 , 1 ]pyrido[3,4-b]ϊndole-1 ,4-dione;

(6R, l2aR)-2,3,6,7.12_τ12a-Hexahydro-6-(3,4-methylenedioxyρhenyl)- pyraziπo[2\ V : 6,1] pyrido [3,4-b] iπdole-1 ,4-dione;

(5aR. 12R, l4aS)-1 , 2,3,5,6.11 , 12,l4a-Octahydrc-12-(3,4- methyienedioxypheny -pyrrolofr'. ' : ^, _l5']p raziπo[2^,,1^, : 6,1]pyrido[3,4- b]ϊndoIe-5-1 ,4-dione;

Cis-2,3,6.7, 12, 12a-hexahydro-2-cyclopropyl-&-{3,4-methylenedioxyρheny/)- pyrazino[2',1 ':6, 1 ]pyrido[3,4-b]indole -1 ,4-dione;

(3S. 6R_l12aR)-2_I3,6,7,12,12a-hexahydro-3-rnethyl-€-(3,4- ethylenedioxyphenyl)-pyraziπo[2',1':6,1]pyrido[3,4-b]iπdole -1 ,4-dione; and physiologically acceptable salts and solvates (e.g. hydrates) thereof.

The specific compounds of the invention are:

(6R.12aR)-2.3,6,7,12,12a-hexahydro-2-memy1-6-(3.4 nethylenedroxypheπyl)- pyrazino[2^,,1':6,1]pyrido[3,4-b]indole -1 ,4-dione (Compound A); and

(3S, 6R. 12aR)-2,3₍6.7.12.12a-hexahydro-2.3-dimethyl-6-(3.4- methylenedioxyphenyl)-pyrazino[2',1 ' : 6, 1]pyrido[3,4-b]ϊπdole-1 ,4-dione (Compound B); and physiologically acceptable salts and solvates (e.g. hydrates) thereof.

Examples of cGMP PDE inhibitors contemplated in this invention are also described in JJnited States Patent No. 5,346,901 and published International Patent Publication WO 94/28902, both of which documents are incorporated herein by reference.

Sildenafil, 1-[[3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1 H- pyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]suIfonyl]-4-methyl- piperazine, and salts thereof are disclosed in WO 94/28902.

Phentoiamine, 3-[[(4,5-dihydro-1 H-imidazol-2-yl)methyl](4- methylpheny[)amino]phenol, and salts and esters thereof, and the use of phentoiamine in the treatment of sexual dysfunction is disclosed in United States Patent No^'. 5,731 ,339, also incorporated herein by reference.

Sildenafil and phentoiamine are each known to treat sexual dysfunction. The effectiveness of phentoiamine for treatment of sexual dysfunction is demonstrated by test procedures described in U.S 5,731 ,339. Similar procedures can be used to determine the effectiveness of sildenafil and combinations of phentoiamine and sildenafil.

Since the present invention relates to a method of treatment comprising the administration of a combination of two components, the components can be co-administered simultaneously or sequentially. Alternatively, a single pharmaceutical composition comprising sildenafil, or a pharmaceutically acceptable salt thereof, and phentoiamine, or a pharmaceutically acceptable salt or ester thereof, in a pharmaceutically acceptable carrier can be administered. The components of the combination can be administered individually or together in any conventional oral dosage form such as a capsule, tablet, chewable tablets, powder, cachet, suspension or solution. The formulations can be prepared using conventional pharmaceutical excipients and additives using conventional techniques. Such pharmaceutically acceptable excipients and additives include non-toxic compatible fillers, binders, disintegrants, buffers, preservatives, anti-oxidants, lubricants, flavorings, thickeners, coloring agents, emulsifiers and the like.

Information on formulations comprising sildenafil are disclosed in WO 94/28902. Representative formulations comprising phentoiamine are disclosed in U.S. 5,731 ,339. It is contemplated that where the two active ingredients are administered as a single composition, the dosage forms as disclosed in the aforementioned patent or application may readily be modified using the knowledge of one skilled in the art.

A typical formulation for sildenafil comprises 25, 50 or 100 mg of active and as inactive ingredients, microcrystalline cellulose, anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesium stearate, hydroxypropylmethylcellulose, titanium dioxide, lactose, triacetin, and FD&C Blue #2 aluminum lake.

A typical formulation for phentoiamine is as follows:

Component mg/Tablet (w/w%) phentoiamine mesylate, USP 40 (10)

Microcrystalline Cellulose, NF 341.6 (85.4)

Croscarmellose Sodium, NF 16 (4.0)

Colloidal Silicon Dioxide, NF 0.4 (0.1)

Magnesium Stearate, NF 2 (0.5)

Total 400 (100)

The following are exemplary formulations for the phentoiamine mesylate/sildenafil citrate combination: Direct Compression Formulation Component mg Tablet

Phentoiamine Mesylate 80

Sildenafil Citrate 100

Microcrystalline Cellulose 207.5-209.0

Croscarmellose Sodium 10

Silicon Dioxide 0.5

Magnesium Stearate 0.5-2

Total 400

The direct -compression formulation is manufactured by blending the active ingredients and excipients and compressing the mixture into tablets.

Wet-Granulation Formulation

Component mg/Tablet

Phentolaminα Mesylate 80

Sildenafil Citrate 100

Microcrystalline Cellulose 80

Lactose 114-115.5

Sodium Starch Glycolate 12

Povidone 12

Water (evaporates)

Magnesium Stearate 0.5-2

Total 400

The wet-granulation formulation is manufactured using the following steps:

1. the active ingredients are combined with microcrystalline cellulose, lactose and sodium starch glycolate in a mixer/granulator;

2. povidone is added to water to form a solution;

3. the granulating solution (from step 2) is added to the powder blend (from step 1) with agitation to form a granulation, and the resulting granulation is dried;

4. the dry granulation is blended with magnesium stearate; and 5. the mixture is compressed into tablets.

Fast-Dissolvinα Formulations A

Component mg/Tablet

Phentoiamine Mesylate 40

Sildenafil Citrate 50

Gelatin 30

Mannitol 29

Flavor 1

Water (evaporates)

Total Dry Tablet Weight 150

The above tablet form is manufactured by:

1. forming a uniform dispersion achieved by adding the active ingredients and excipients to water with agitation;

2. filling aliquots of the dispersion into molds; and

3. lyophilizing to form dry tablets.

B

Component mg/Tablet

Phentoiamine Mesylate 40

Sildenafil Citrate 50

Microcrystalline Cellulose 95

Crospovidone 10

Sodium Bicarbonate 2

Citric Acid 2

Flavor 1

Total 200

The tablets are made by blending the combination of the actives and excipients and compressing the mixture into tablets.

The compounds in the combination of this invention for treating sexual dysfunction are administered in accordance with the treatment regimens described in each of the above listed publications. For example, for a combination of a Type V cGMP PDE inhibitors such as Sildenafil in combination with phentoiamine, the typical dosage is 5 to 100 mg of Sildenafil and 5 to 75 mg of phentoiamine per dose, usually administered approximately one hour prior to intercourse. It is expected that the dosage of the individual components in the combination will be less than the dosage required when the individual components are administered alone. The exact dose of either component of the combination to be administered and the timing thereof is determined by the attending clinician and is dependent on the potency of the compound administered, the age, weight, condition and response of the patient. Where the components of a combination are administered separately, the separate dosage forms need not be administered simultaneously.

Since the present invention relates to treatment with a combination of active ingredients wherein said active ingredients may be administered separately, the invention also relates to combining separate pharmaceutical compositions in kit form. That is, a kit is contemplated wherein two separate units are combined: for example, a sildenafil pharmaceutical composition and a phentoiamine pharmaceutical composition. The kit will preferably include directions for the administration of the separate components. The kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g. tablet and capsule) or are administered at different dosage intervals.

Claims

What is claimed is:

1. A pharmaceutical composition for the treatment of human sexual dysfunction comprising a therapeutically effective amount of phentoiamine or a pharmaceutically acceptable salt or solvate or ester thereof, a therapeutically effective amount of a cGMP PDE V inhibitor or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

2. A composition of claim 1 wherein the cGMP PDE V inhibitor is sildenafil or a pharmaceutically acceptable salt or solvate thereof.

3. The composition of claim 1 wherein the phentoiamine is phentoiamine mesylate.

4. The composition of claim 1 wherein the sildenafil is sildenafil citrate.

5. The composition of claim 1 wherein the phentoiamine is phentoiamine mesylate and the cGMP PDE V inhibitor is sildenafil citrate.

6. A method of treating human sexual dysfunction comprising the simultaneous or sequential administration of a therapeutically effective amount of phentoiamine or a pharmaceutically acceptable salt, solvate or ester thereof, and a therapeutically effective amount of a cGMP PDE V inhibitor or a pharmaceutically acceptable salt thereof.

7. The method of claim 6 wherein the cGMP PDE V inhibitor is sildenafil or a pharmaceutically acceptable salt or solvate thereof.

8. The method of claim 6 wherein the phentoiamine is phentoiamine mesylate.

9. The method of claim 6 wherein the cGMP PDE V inhibitor is sildenafil citrate.

10. The method of claim 6 wherein the phentoiamine is phentoiamine mesylate and the cGMP PDE inhibitor V is sildenafil citrate.

11. A kit comprising in separate containers in a single package, pharmaceutical compositions for use in combination to treat sexual dysfunction which comprises in one container a therapeutically effective amount phentoiamine or a pharmaceutically acceptable salt, solvate or ester thereof in a pharmaceutically acceptable carrier and in a second container a therapeutically effective amount of a cGMP PDE V inhibitor or a pharmaceutically acceptable salt of solvate thereof in a pharmaceutically acceptable carrier.

12. A pharmaceutical composition for the treatment of human sexual dysfunction comprising a therapeutically effective amount of a first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof, a therapeutically effective amount of a second vasodilating agent or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 12 wherein said first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is an adrenergic blocker.

14. The pharmaceutical composition of claim 13 wherein said adrenergic blocker is an alpha-adrenergic blocker.

15. The pharmaceutical composition of claim 14 wherein alpha adrenergic blocker is selected from the group consisting of an alphal - adrenergic blocker, an alpha2-adrenergic blocker or both an alphal - adrenergic blocker and an alpha2-adrenergic blocker.

16. The pharmaceutical composition of claim 12 wherein said second vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is a cGMP PDE inhibitor.

17. The pharmaceutical composition of claim 12 wherein said first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is an adrenergic blocker and said second vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof is a cGMP PDE inhibitor.

18. The pharmaceutical composition of claim 17 wherein the adrenergic blocker is selected from the group consisting of phentoiamine, phentoiamine mesylate, phentoiamine hydrochloride, phenoxybenazmine, tolazoline, dibenamine, yohimbine, terazosin, doxazosin and prazosin.

19. The pharmaceutical composition of claim 17 wherein the cGMP PDE inhibitor is a cGMP PDE V inhibitor.

20. The pharmaceutical composition of claim 17 wherein the cGMP PDE V inhibitor is selected from the group consisting of: sildenafil,

(6R, 12aR)-2,3,6,7, 12, 12a-hexahydro-2-methyl-6-(3,4- methylenedioxyphenyl)-pyrizino[2',r:6,1]pyrido[3,4-b]indole-1 ,4-dione

(Compound A), and

(3S.6R, 12aR)-2,3,6,7, 12, 12a-hexahydro-2,3-dimethyl-6-(3,4- methylenedioxyphenyl)-pyrazino[2',1':6,1]pyrido[3,4-b]indole-1,4-dione

(Compound B) or a pharmaceutically acceptable salt or solvate thereof.

21. A method of treating human sexual dysfunction comprising the simultaneous or sequential administration of a therapeutically effective amount of a therapeutically effective amount of a first vasodilating agent or a pharmaceutically acceptable salt or solvate or ester thereof, a therapeutically effective amount of a second vasodilating agent or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.