(2-Oxo-1,2,3,5-tetrahydroimidazo-/2,1-b/quinnazolinyl)-oxyalkylamides, their preparation, compositions containing them and their use in making medicaments

Claim 2

A compound according to the formula and the pharmaceutically acceptable salts thereof wherein: m and n are integers of 1 to 6; R 1 is hydrogen or alkyl of 1 to 4 carbon; R 2 is hydrogen or R 1 and R 2 are combined to form a carbonyl group; R 3 is hydrogen, alkyl of 1 to 6 carbons, phenyl, benzyl, hydroxy C l - 4 alkyl and its acylates, carbamoyl alkyl, carboxyalkyl, alkoxycarbonylalkyl or amino acid side chains; R 4 is hydrogen, alkyl of 1 to 6 carbons, benzyl, or hydroxy C l-4 alkyl; R 5 is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms wherein the cycloalkyl ring is unsubstituted or substituted with a C l - 4 alkyl, C l - 4 alkoxy, -OH, -OCOR 6 , halo, -NH 2 , -N(R 6 ) 2 , -NHCOR 6 , -COOH, or -COO(R 6 ) group wherein R 6 is C 1-4 alkyl; phenyl or phenyl C l - 4 alkyl wherein phenyl is unsubstituted or substituted with 1 or more Cl-4 alkyl, halo or C l - 4 alkoxy groups or an -NH 2 , -N(R 6 ) 2 , -NHCOR 6 , -COOH, or -COOR 6 group wherein R 6 is C 1-4 alkyl; Y is hydrogen, alkyl or 1 to 4 carbon atoms, halo or C l - 4 alkoxy; and Z is -OR 7 or -NR 7 R 8 wherein R 7 and R 8 are independently hydrogen or C l - 4 alkyl; or a pharmaceutically acceptable salt thereof.

Claim 3

A compound according to claim 1 wherein Z is -OR 7 wherein R 7 is C l - 4 alkyl.

Claim 4

A compound of claim 2 wherein R 1 , R 2 and R 3 are hydrogen, R 4 is hydrogen or methyl, m is 1 - 3 and n is 3 or 4.

Claim 5

A compound according to claim 3 wherein R 4 is hydrogen, m is 1, n is 3 or 4 and R 5 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms.

Claim 6

A compound according to claim 4 wherein n is 3 and R 5 is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms.

Claim 7

Methyl 2-(N-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydro- imidazo[2,1-b]quinazolin-7-yl)oxybutyramidyl)acetate or a pharmaceutically acceptable salt thereof.

Claim 8

Methyl 2-(N-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydro- imidazo[2,1-b]quinazolin-7-yl)oxybutyramidyl)acetate or a pharmaceutically acceptable salt thereof.

Claim 9

A compound according to claim 1 wherein Z is -OR 7 wherein R 7 is hydrogen.

Claim 10

A compound of claim 7 wherein R l , R 2 and R 3 are hydrogen, R 4 is hydrogen or methyl, m is 1 - 3 and n is 3 or 4.

Claim 11

A compound according to claim 8 wherein R 4 is hydrogen, m is 1, n is 3 or 4 and R 5 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms.

Claim 12

A compound according to claim 9 wherein n is 3 and R 5 is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms.

Claim 13

2-(N-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-blquinazolin-7-yl)oxybutyramidyl)acetic acid or a pharmaceutically acceptable salt thereof.

Claim 14

2-(N-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-[2,1-blquinazolin-7-yl)oxybutyramidyl)acetic acid or a pharmaceutically acceptable salt thereof.

Claim 15

A compound according to claim 1 wherein Z-is -NH 2 .

Claim 16

A compound of claim 12 wherein R 1 , R 2 and R 3 are hydrogen, R 4 is hydrogen or methyl, m is 1 - 3 and n is 3 or 4.

Claim 17

A compound according to claim 13 wherein R 4 is hydrogen, m is 1, n is 3 or 4 and R 5 is alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl lower alkyl of 4 to 12 carbon atoms.

Claim 18

A compound according to claim 14 wherein n is 3 and R 5 is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 8 carbon atoms.

Claim 19

2-(N-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-(2,1-b]quinazolin-7-yl)oxybutyramidyl)acetamide or a pharmaceutically acceptable salt thereof.

Claim 20

2-(N-cyclohexyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo-(2,1-b]quinazolin-7-yl)oxybutyramidyl)acetamide or a pharmaceutically acceptable salt thereof.

Claim 21

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of the preceding claims.

Claim 22

A process for preparing compounds of claim 1, which process comprises either: (i) treating a compound of Formula II wherein m, n, R l , R 2 , R 3 , R 5 , Y and Z are as defined in claim 1 but wherein R 5 , R 7 and R 8 are not hydrogen, with an N-alkylating agent, or (ii) treating a compound of Formula III wherein m, n, R 1 , R 2 , R 3 , R 4 and Y are as defined in claim 1 and Z is -OR 7 wherein R 7 is C 1-4 alkyl, with base; or (iii) treating a compound of Formula IV wherein m, n, R 1 , R 2 , R 3 , R 5 , and Y are defined in claim 1, Z is -OR 7 wherein R 7 is C l - 4 alkyl or -NR 7 R 8 wherein R 7 and R 8 are hydrogen or C l - 4 alkyl and R 6 is alkyl of 1 to 6 carbon atoms; serially with a halocyanogen and base to form a compound of Formula I wherein R 4 is hydrogen; or (iv) treating a compound of Formula V with 2-methylthiohydantoin and wherein m, n and Y are defined in claim 1 and Z is -OR 7 wherein R 7 is C l - 4 alkyl or -NR 7 R 8 wherein R 7 and R 8 are defined in claim 1 to yield a compound of Formula I wherein R 1 and R 2 are a carbonyl group and R 3 and R 4 are both hydrogen; or (v) treating a compound of the formula wherein n, R 1 , R 2 , R 3 , R 4 and Y are as defined in claim 1 with an amide-forming reagent to form a compound of Formula I; or (vi) converting the free acid of a compound of Formula I to the corresponding amide; or (vii) converting the free acid of a compound of Formula I to a pharmaceutically acceptable salt; or (viii) converting a salt to the compound of Formula I to the corresponding free acid; or (ix) converting the free base of a compound of Formula I to a pharmaceutically acceptable acid addition salt; or (x) converting a salt of the compound of Formula I to the corresponding free base.

Claim 23

A compound according to any one of claims 1 to 16 for use in the treatment of medical disorders.

Claim 24

The use of a compound of any one of claims 1 to 16 for the manufacture of a medicament for inhibiting 3',5'-cyclic AMP phosphodiesterase, or more generally an antithrombotic medicament.

Claim 25

A compound of claim 19 wherein the use is for treating heart failure.

Claim 26

A compound of claim 19 wherein the use is for inhibiting tumor growth.