Pharmaceutical piperazine compounds

The present invention relates to compounds useful as inhibitors of plasminogen activator inhibitor (PAI), to their preparation and to pharmaceutical and veterinary compositions containing them.
Plasminogen activators (PAs) are serine proteases which control the activation of the zymogen, plasminogen, to the active enzyme plasmin. Plasmin is important in a number of physiological and pathological processes including fibrinolysis, tissue remodelling, tumour growth and metastasis. The glycoprotein plasminogen activator inhibitor (PAI) is an endogenous fast-acting inhibitor of PA activity. PAI is a member of the serpin family and is synthesized by a variety of cells including endothelial cells. An imbalance between PAs and PAI contributes to a number of pathological conditions including haemostasis, inflammation, tumour growth and metastasis.
The present invention provides a diketopiperazine of formula (A): ##STR2## wherein R.sub.1 is H, a halogen, --COOR.sub.11, C.sub.1 -C.sub.6 alkyl, NO.sub.2, C.sub.1 -C.sub.6 alkoxy, --NHCOCH.sub.3 or CF.sub.3 ;
R.sub.2 is H, --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12), C.sub.1 -C.sub.6 alkyl, NO.sub.2, CN, halogen, C.sub.1 -C.sub.6 alkoxy, CF.sub.3, OCF.sub.3, --NHCOCH.sub.3 or phthalimido;
R.sub.3 is H, --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12), halogen, C.sub.1 -C.sub.6 alkoxy, NO.sub.2, C.sub.1 -C.sub.6 alkyl, CF.sub.3, CN, --CON(R.sub.11 R.sub.12), --NHCOCH.sub.3, --CO.sub.2 R.sub.11, --CONH(CH.sub.2).sub.n Ph, SR.sub.13 or --(CH.sub.2).sub.n N(R.sub.11 R.sub.12); or R.sub.2 and R.sub.3 together form a methylenedioxy group --OCH.sub.2 O--;
R.sub.4 is H, halogen, NO.sub.2 or --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12);
R.sub.5 is H or a halogen;
R.sub.6 is H, a halogen or --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12);
R.sub.7 is H, --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12) or C.sub.1 -C.sub.6 alkoxy; and
R.sub.8 is H, a halogen, --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12), --CH.sub.2 Y(CH.sub.2).sub.n N(R.sub.11 R.sub.12), --OC(O) (CH.sub.2).sub.n R.sub.11, C.sub.1 -C.sub.6 alkoxy, --(CH.sub.2).sub.n NHCO(CH.sub.2).sub.n CO.sub.2 R.sub.11, --(CH.sub.2).sub.n N(R.sub.11 R.sub.12) --CH.sub.2 N�(CH.sub.2).sub.n N(R.sub.11 R.sub.12)!.sub.2, or --O(CH.sub.2).sub.n CO.sub.2 H
wherein n is 0 or an integer of 1 to 6, Y is O or S, each of R.sub.11 and R.sub.12 is, independently, hydrogen or a straight or branched C.sub.1 -C.sub.6 alkyl and R.sub.13 is straight or branched C.sub.1 -C.sub.6 alkyl; or a pharmaceutically acceptable salt or ester thereof;
with the exception of compounds wherein
(i) each of R.sub.1 to R.sub.8 is H;
(ii) R.sub.1 and R.sub.6 are both Cl or Br and the rest of R.sub.1 to R.sub.8 are H;
R.sub.3 and R.sub.8 are the same and are both F, Cl or OMe and the rest of R.sub.1 to R.sub.8 are H; and
(iii) R.sub.8 is OMe and the rest of R.sub.1 to R.sub.10 are H.
The numerals 1 to 10 denote ring positions on the phenyl groups in formula A. The letters a and b refer to the two phenyl rings themselves.
A C.sub.1 -C.sub.6 alkyl group is typically a C.sub.1 -C.sub.4 alkyl group, for example a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group. A halogen is, for example, fluorine, chlorine, bromine or iodine.
A C.sub.1 -C.sub.6 alkoxy group is typically a C.sub.1 -C.sub.4 alkoxy group, for example a methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, sec-butoxy or tert-butoxy group.
A group --CH.sub.2 Y(CH.sub.2).sub.n N(R.sub.11 R.sub.12) is preferably a group --CH.sub.2 O(CH.sub.2).sub.n NMe.sub.2 or --CH.sub.2 S(CH.sub.2).sub.n NMe.sub.2 wherein n is from 1 to 3.
In compounds of formula A free rotation may occur at room temperature about the single bonds connecting rings a and b to the double bonds at positions 3 and 6 of the piperazine-2,5-dione ring. Positions 2 and 6, and positions 3 and 5, in both rings a and b can therefore be considered as equivalent. As a consequence the following pairs of substituents can be viewed as interchangeable: R.sub.1 and R.sub.5 ; and R.sub.2 and R.sub.4.
Preferably one of rings a and b is unsubstituted or is mono-substituted whilst the other ring is unsubstituted or is substituted at one or more of positions 2 to 6. The ring which is mono-substituted may carry the substituent at any one of positions 2 to 6, for instance position 3 or 4, especially position 4. Thus for instance, when ring b is mono-substituted, one of R.sub.6 to R.sub.8 is other than hydrogen, preferably R.sub.7 or R.sub.8, especially R.sub.8. When ring a is mono-substituted, one of R.sub.1 to R.sub.5 is other than hydrogen, preferably R.sub.2 or R.sub.3, especially R.sub.3. When one of rings a and b is mono-substituted the substituent R.sub.1 to R.sub.5, or R.sub.6 to R.sub.8 respectively, is preferably selected from --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12), especially --O(CH.sub.2).sub.2 NMe.sub.2 or --O(CH.sub.2).sub.3 NMe.sub.2 ; --CH.sub.2 Y(CH.sub.2).sub.n N(R.sub.11 R.sub.12); a halogen, for instance fluorine or chlorine; and an alkoxy group, for instance OMe.
When one of rings a and b is unsubstituted, or is mono-substituted as described in the above paragraph, the other ring may bear any desired substitution pattern. For instance, the other ring may be unsubstituted or may be mono-, di- or tri-substituted at any of positions 2 to 6 in the case of ring a, or at any of positions 2 to 4 in the case of ring b.
The said other ring may, for instance, be mono-substituted at any of positions 2 to 6, when it is ring a, or positions 2 to 4 when it is ring b. Ring a may also be 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-disubstituted, or 2,3,4-, 2,3,5-, 2,3,6- or 3,4,5-trisubstituted. Ring b may be 2,3 or 2,4 disubstituted, or 2,3,4-trisubstituted. Thus, when the said other ring is a and is mono-substituted, four of R.sub.1 to R.sub.5 are hydrogen and one is other than hydrogen. When the said other ring is ring a and is disubstituted, three of R.sub.1 to R.sub.5 are hydrogen and two are other than hydrogen. For example R.sub.1 and R.sub.2, or R.sub.1 and R.sub.3, or R.sub.1 and R.sub.4, or R.sub.1 and R.sub.5, or R.sub.2 and R.sub.3, or R.sub.2 and R.sub.4 are other than hydrogen whilst, in each case, the other three of R.sub.1 to R.sub.5 are hydrogen.
When the said other ring is ring a and is trisubstituted, two of R.sub.1 to R.sub.5 are hydrogen and three are other than hydrogen. For example, R.sub.1, R.sub.2 and R.sub.3, or R.sub.1, R.sub.2 and R.sub.4, or R.sub.1, R.sub.2 and R.sub.5, or R.sub.2, R.sub.3 and R.sub.4 are other than hydrogen whilst, in each case, the other two of R.sub.1 to R.sub.5 are hydrogen.
When the said ring is b and is mono-substituted, two of R.sub.6 to R.sub.8 are hydrogen and one is other than hydrogen. When the said other ring is b and is di-substituted, one of R.sub.6 to R.sub.8 is hydrogen and two are other than hydrogen. For example R.sub.6 and R.sub.7, or R.sub.6 and R.sub.8 are other than hydrogen. When the said other ring is b and is trisubstituted, all three of R.sub.6 to R.sub.8 are other than hydrogen.
In a preferred series of compounds of formula A each of R.sub.6 and R.sub.7 is hydrogen and R.sub.8 is --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12) or --CH.sub.2 Y(CH.sub.2).sub.n N(R.sub.11 R.sub.12) as defined above. In another preferred series of compounds, R.sub.8 is --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12), one of R.sub.6 and R.sub.7 is --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12) or halogen and the other of R.sub.6 and R.sub.7 is H. Preferably --O(CH.sub.2).sub.n N(R.sub.11 R.sub.12) is --O(CH.sub.2).sub.2 NMe.sub.2 or --O(CH.sub.2).sub.3 NMe.sub.2.
In the above-mentioned series of preferred compounds R.sub.1 to R.sub.5 are all hydrogen, or one or two of R.sub.1 to R.sub.5 are other than hydrogen whilst the others are hydrogen. For instance one of R.sub.1, R.sub.2 and R.sub.3 is other than hydrogen. Alternatively R.sub.1 and R.sub.3, or R.sub.2 and R.sub.3, are other than hydrogen.
Particularly preferred compounds are those wherein R.sub.8 is --O(CH.sub.2).sub.n NMe.sub.2 or --CH.sub.2 Y(CH.sub.2).sub.n N(R.sub.11 R.sub.12) wherein n is 2 or 3, R.sub.6 and R.sub.7 and each of R.sub.1 to R.sub.5 is as specified above.
In one embodiment, R.sub.1 is H, Cl Me, MeO, NO.sub.2 or --COOMe;
R.sub.2 is H, Me, MeO, Cl, Br or --O(CH.sub.2).sub.n NMe.sub.2 ; or R.sub.2 and R.sub.3 together form a methylenedioxy group --OCH.sub.2 O--;
R.sub.3 is H, OCH.sub.3, OC.sub.6 H.sub.14, O(CH.sub.2).sub.n NMe.sub.2 wherein n is 2 or 3, or CH.sub.2 NMe.sub.2 ;
R.sub.4 is H or --O(CH.sub.2).sub.2 NMe.sub.2 ;
R.sub.5 is H or Cl;
R.sub.6 is H, Cl or F or --O(CH.sub.2).sub.2 NMe.sub.2 ;
R.sub.7 is H, --O(CH.sub.2).sub.n NMe.sub.2 wherein n is 1 or 2, or OMe; and
R.sub.8 is H, F, OMe, --O(CH.sub.2).sub.n NMe, --CH.sub.2 S(CH.sub.2).sub.n NMe.sub.2 or --CH.sub.2 O(CH.sub.2).sub.n NMe.sub.2 wherein n is 1, 2 or 3, --CH.sub.2 NHCO(CH.sub.2).sub.3 CO.sub.2 Me, --CH.sub.2 NH.sub.2, --(CH.sub.2).sub.n NMe.sub.2 wherein n is 1, 2, 3 or 4; --OCH.sub.2 CO.sub.2 H, --CH.sub.2 N�(CH.sub.2).sub.3 NMe.sub.2 !, or --OCO(CH.sub.2).sub.n R.sub.11 wherein n is from 1 to 5 and R.sub.11 is CH.sub.3 or t-butyl.
In a second embodiment R.sup.8 is --O(CH.sub.2).sub.n NMe.sub.2 wherein n is 2 or 3, each of R.sub.6 and R.sub.7 is H; R.sub.1 is H or Cl; R.sub.2 is H, R.sub.3 is H, C.sub.1 -C.sub.6 alkoxy such as OMe, --O(CH.sub.2).sub.n NMe.sub.2 wherein n is 2 or 3, or --CH.sub.2 NMe.sub.2 ; R.sub.4 is H and R.sub.5 is H or Cl.
In a further embodiment, R.sub.1 is H, Cl or --COOMe; R.sub.2, R.sub.3 and R.sub.4 are each independently H or --O(CH.sub.2).sub.n NMe.sub.2 wherein n is 1 or 2;
R.sub.5 is H or Cl;
R.sub.6 is H or F;
R.sub.7 is H, OMe or --O(CH.sub.2).sub.n NMe.sub.2 wherein n is 1 or 2; and
R.sub.8 is H, F, or --O(CH.sub.2).sub.2 NMe.sub.2.
In another embodiment R.sub.8 and one of R.sub.6 and R.sub.7 is, independently, --O(CH.sub.2).sub.n NMe.sub.2 wherein n is 2 or 3, the other of R.sub.6 and R.sub.7 is H; and each of R.sub.1 to R.sub.5 is H.
In a further embodiment R.sub.8 is --O(CH.sub.2).sub.n NMe.sub.2 wherein n is 2 or 3, R.sub.6 is Cl and R.sub.7 is H, or R.sub.6 is H and R.sub.7 is OMe; and each of R.sub.1 to R.sub.5 is H.
In a yet further embodiment each of R.sub.1 to R.sub.5 is H;
R.sub.6 is H, --O(CH.sub.2).sub.n NMe.sub.2, Cl or F;
R.sub.7 is H, --O(CH.sub.2).sub.n NMe.sub.2 wherein n is 1 or 2, or OMe; and
R.sub.8 is H, --OCOCH.sub.2 -.sup.t Bu, --O(CH.sub.2).sub.n NMe.sub.2 wherein n is 1 or 2, --NCH.sub.2 NH.sub.2, --CH.sub.2 N�(CH.sub.2).sub.3 NMe.sub.2 ! or --OCH.sub.2 CO.sub.2 H.
Certain diketopiperazines have been disclosed as having utility as bioactive agents. Yokoi et al in J. Antibiotics vol XLI No. 4, pp 494-501 (1988) describe structure-cytotoxicity relationship studies on a series of diketopiperazines related to neihumicin, a compound obtained from the micro-organism Micromonospora neihuensis. Kamei et al in J. Antibiotics vol XLIII No. 8, 1018-1020 disclose that two diketopiperazines, designated piperafizines A and B, have utility as potentiators of the cytotoxicity of vincristine.
Examples of specific compounds of formula A are as follows. The compound numbering is adhered to in the rest of the specification:
1962 (3Z,6Z)-3,6-Di-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione dihydrochloride.
1953 (3Z,6Z)-3-Benzylidene-6-(4-bis(2-dimethylaminopropyl)aminomethylbenzylidene-2,5-piperazinedione.
1961 (3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1957 (3Z,6Z)-3,6-Di-(4-(2-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione bis methane sulfonate (1:2).
1949 (3Z,6Z)-3-Benzylidene-6-(3,4-di-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1952 (3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(4-(2-dimethylaminoethoxy)benzylidene-2,5-piperazinedione.
1955 (3Z,6Z)-3,6-Di-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione bis hydrogen succinate (1:2).
1913 (3Z,6Z)-3-Benzylidene-6-(4-dimethylaminomethylbenzylidene)-2,5-piperazinedione.
1909 Methyl 4-(4-((3Z,6Z)-6-(4-Methoxybenzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzylcarbonyl)butanoate.
1885 (3Z,6Z)-3-(4-(3,3-dimethylbutanoyloxy)benzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.
1665 (3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(2-fluorobenzylidene)-2,5-piperazinedione.
1951 (3Z,6Z)-3-Benzylidene-6-(2-chloro-4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1969 (3Z,6Z)-3-Benzylidene-6-(2,4-di-(2-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
1984 (3Z,6Z)-3-Benzylidene-6-(2,4-di-(2-dimethylaminoethoxy)benzylidene-2,5-piperazinedione.
1981 (3Z,6Z)-3-Benzylidene-6-(4-bis(3-dimethylaminopropyl)aminomethylbenzylidene)-2,5-piperazinedione.
1908 (3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1977 (3Z,6Z)-3-(2,4-Difluorobenzylidene)-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1911 (3Z,6Z)-3-(4-(2-Dimethylaminoethoxy)benzylidene)-6-(4-methoxybenzylidene-2,5-piperazinedione.
1946 (3Z,6Z)-3-Benzylidene-6-(2-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1924 (3Z,6Z)-3-Benzylidene-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1925 (3Z,6Z)-3-(4-Aminomethylbenzylidene)-6-benzylidene-2,5-piperazinedione trifluoroacetate.
1914 (3Z,6Z)-3-Benzylidene-6-(4-dimethylaminobenzylidene)-2,5-piperazinedione hydrochloride.
1907 (3Z,6Z)-3-(4-Hexyloxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.
5233 (3Z,6Z)-3-(4-Chlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
5236 (3Z,6Z)-3-(3,4-Dichlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
5237 (3Z,6Z)-3-(3-Chlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
5245 (3Z,6Z)-3-(4-Cyanobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
5250 (3Z,6Z)-3-(4-Butoxybenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
5260 (3Z,6Z)-3-(4-Aminobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
5348 (3Z,6Z)-3-(4-Cyanobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
5360 (3Z,6Z)-3-(4-Bromobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
5366 (3Z,6Z)-3-(4-Chlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
5234 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.
5235 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-methylbenzylidene)-2,5-piperazinedione.
5238 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-tert-butylbenzylidene)-2,5-piperazinedione.
5239 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-trifluoromethylbenzylidene)-2,5-piperazinedione.
5365 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-fluorobenzylidene)-2,5-piperazinedione.
5385 (3Z,6Z)-3-(4-(3-Dimethylaminopropoxy)benzylidene)-6-(4-methylthiobenzylidene)-2,5-piperazinedione.
5401 Methyl 4((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzoate.
5246 4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.
5343 4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzanilide.
5344 N-Benzyl-4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.
5345 N-Phenethyl-4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.
5346 N-(3-Phenylpropyl)-4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.
5347 N-(4-Phenylbutyl)-4-((3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-2,5-dioxo-3-piperazinylidene)methylbenzamide.
5186 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-methylbenzylidene)-2,5-piperazinedione.
5187 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-methylbenzylidene)-2,5-piperazinedione.
5201 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3,4-methylenedioxybenzylidene)-2,5-piperazinedione.
5208 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-nitrobenzylidene)-2,5-piperazinedione.
5209 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-nitrobenzylidene)-2,5-piperazinedione.
5210 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-nitrobenzylidene)-2,5-piperazinedione.
5242 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-methoxybenzylidene)-2,5-piperazinedione.
5241 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-methoxybenzylidene)-2,5-piperazinedione.
5251 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(2-trifluoromethylbenzylidene)-2,5-piperazinedione.
5252 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-trifluoromethylbenzylidene)-2,5-piperazinedione.
5255 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-phthalimidobenzylidene)-2,5-piperazinedione.
5373 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-fluorobenzylidene)-2,5-piperazinedione.
5374 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3-trifluoromethoxybenzylidene)-2,5-piperazinedione.
5378 (3Z,6Z)-6-(4-(3-Dimethylaminopropoxy)benzylidene)-3-(3,5-dinitrobenzylidene)-2,5-piperazinedione.
5065 (3Z,6Z)-6-Benzylidene-3-(4-(2-diethylaminoethoxy)benzylidene-2,5-piperazinedione.
5070 (3Z,6Z)-3-(2-Bromobenzylidene)-6-(4-(2-dimethylaminoethoxymethyl)benzylidene)-2,5-piperazinedione.
5080 (3Z,6Z)-3-(2-Bromobenzylidene)-6-(4-(2-Dimethylaminoethylthiomethyl)benzylidene)-2,5-piperazinedione.
1634 Methyl 2-((3Z,6Z)-6-benzylidene-2,5-dioxo-3-piperazinylidene)methylbenzamide.
1852 (3Z,6Z)-6-Benzylidene-3-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
1887 (3Z,6Z)-3-(4-Heptanoyloxybenzylidene)-6-(4-methoxybenzylidene)-2,5-piperazinedione.
1889 (3Z,6Z)-6-Benzylidene-3-(4-(3,3-dimethylbutanoyloxy)benzylidene)-2,5-piperazinedione.
1920 (3Z,6Z)-3-(4-Butoxybenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
1947 (3Z,6Z)-3,6-Di-(3-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1954 (3Z,6Z)-6-Benzylidene-3-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1978 (3Z,6Z)-6-Benzylidene-3-(3,4-di-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1979 (3Z,6Z)-Benzylidene-3-(2-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
1980 (3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione.
5060 (3Z,6Z)-3-(2-Bromobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
5249 (3Z,6Z)-3-(2-Chlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
5248 (3Z,6Z)-3-(2-Acetamidobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene-2,5-piperazinedione.
5256 (3Z,6Z)-3-(3-Acetamidobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
5372 (3Z,6Z)-3-(3,5-Dichlorobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
5375 (3Z,6Z)-3-(3-Bromobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
5398 (3Z,6Z)-3-(4-Chloro-3-nitrobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
5023 (3Z,6Z)-3-(4-Dimethylaminomethylbenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
5048 (3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
5068 (3Z,6Z)-3-(4-Dimethylaminobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
5232 (3Z,6Z)-3-(3-Cyanobenzylidene)-6-(4-(3-dimethylaminopropoxy)benzylidene)-2,5-piperazinedione.
1960 (3Z,6Z)-6-Benzylidene-3-(2-chloro-4-(2-dimethylaminoethoxy)benzylidene)-2,5-piperazinedione, hydrochloride.
5228 (3Z,6Z)-3-(4-(3-dimethylaminopropoxy)benzylidene)-6-(4-nitrobenzylidene)-2,5-piperazinedione.
5058 (3Z,6Z)-6-Benzylidene-3-(4-(2-Dimethylaminoethylthiomethyl)benzylidene)-2,5-piperazinedione.
Compounds of formula A may be prepared by a process which comprises either (i) condensing a compound of formula (I) ##STR3## wherein R.sub.6 to R.sub.10 are as defined above and are optionally protected, with a compound of formula (II): ##STR4## wherein R.sub.1 to R.sub.5 are defined above and are optionally protected, in the presence of a base in an organic solvent; or (ii) condensing a compound of formula (I'): ##STR5## wherein R.sub.1 to R.sub.5 are as defined above and are optionally protected, with a compound of formula (III): ##STR6## wherein R.sub.6 to R.sub.10 are as defined above and are optionally protected, in the presence of a base in an organic solvent; and, in either case (i) or (ii), if required, removing optionally present protecting groups and/or, if desired, converting one compound of formula A into another compound of formula A, and/or, if desired, converting a compound of formula A into a pharmaceutically acceptable salt or ester thereof, and/or, if desired, converting a salt or ester into a free compound, and/or, if desired, separating a mixture of isomers of compounds of formula A into the single isomers.
A compound of formula A produced directly by the condensation reaction between (I) and (II) or (I') and (III) may be modified, if desired, by converting one or more of groups R.sub.1 to R.sub.10 into different groups R.sub.1 to R.sub.10. These optional conversions may be carried out by methods known in themselves. For example, a compound of formula A in which R.sub.1 is an ester group may be converted to a compound of formula A wherein the corresponding substituent is a free --COOH group, by acid or alkaline hydrolysis at a suitable temperature, for example from ambient temperature to 100.degree. C.
A compound of formula A in which R.sub.1 is a --CO.sub.2 H group may be converted into a compound of formula A wherein R.sub.1 is esterified by esterification, for example by treating the carboxylic acid with a suitable C.sub.1 -C.sub.6 alkyl alcohol in the presence of 1,3-dicyclohexylcarbodiimide in an inert solvent.
Protecting groups for R.sub.1 to R.sub.8 in any of the compounds of formulae (I), (I'), (II) and (III) are optionally introduced prior to step (i) or step (ii) when any of groups R.sub.1 to R.sub.8 are groups which are sensitive to the condensation reaction conditions or incompatible with the condensation reaction, for example a --COOH or amino group. The protecting groups are then removed at the end of the process. Any conventional protecting group suitable for the group R.sub.1 to R.sub.8 in question may be employed, and may be introduced and subsequently removed by well-known standard methods.
The condensation reaction between compounds (I) and (II) or (I') and (III) is suitably performed in the presence of a base which is potassium t-butoxide, sodium hydride, potassium carbonate, sodium carbonate, caesium carbonate, sodium acetate, potassium fluoride on alumina, or triethylamine in a solvent such as dimethylformamide, or in the presence of potassium t-butoxide in t-butanol or a mixture of t-butanol and dimethylformamide. The reaction is typically performed at a temperature from 0.degree. C. to the reflux temperature of the solvent.
The compounds of formula (I) may be prepared by a process comprising reacting 1,4-diacetyl-2,5-piperazinedione with a compound of formula (III) as defined above, in the presence of a base in an organic solvent. Similarly, the compounds of formula (I') may be prepared by a process which comprises reacting 1,4-diacetyl-2,5-piperazinedione with a compound of formula (II) as defined above, in the presence of a base in an organic solvent.
If necessary, the resulting compound of formula (I) or (I') can be separated from other reaction products by chromatography.
The reaction of 1,4-diacetyl-2,5-piperazinedione with the compound of formula (III) or (II) is suitably performed under the same conditions as described above for the condensation between compounds (I) and (II), or (I') and (III).
The substituted benzaldehydes of formulae (II) and (III) are known compounds or can be prepared from readily available starting materials by conventional methods. The 1,4-diacetyl-2,5-piperazinedione used as a starting material in the preparation of compounds of formula (I) may be prepared by treating 2,5-piperazinedione (glycine anhydride) with an acetylating agent. The acetylation may be performed using any conventional acetylating agent, for example acetic anhydride under reflux or, alternatively, acetic anhydride at a temperature below reflux in the presence of 4-dimethylaminopyridine.
Compounds of formula (I) may also be prepared by the microwave irradiation of a mixture comprising 1,4-diacetyl-2,5-piperazinedione, a compound of formula (III) and potassium fluoride on alumina (as base) in the absence of solvent.
Compounds of formula (I) may alternatively be prepared directly from 2,5-piperazinedione (glycine anhydride) by a process which comprises treating the 2,5-piperazinedione with a mixture comprising a compound of formula (III), sodium acetate and acetic anhydride at an elevated temperature, for example under reflux.
Compounds of formula (I') may be prepared by analogous processes, replacing compound (III) in each case by a compound of formula (II).
Compounds of formula A may also be prepared by a process comprising the microwave irradiation of (i) a mixture comprising a compound of formula (I) as defined above, a compound of formula (II) and potassium fluoride on alumina, or (ii) a mixture comprising a compound of formula (I') a compound of formula (III) and potassium fluoride on alumina, or (iii) a mixture comprising 1,4-diacetyl-2,5-piperazinedione, a compound of formula (II), a compound of formula (III) and potassium fluoride on alumina. The irradiation is performed in the absence of a solvent.
Compounds of formula (A) may also be obtained directly by a process which comprises condensing together 1,4-diacetyl-2,5-piperazinedione, a compound of formula (II) and a compound of formula (III) in the presence of a base in an organic solvent. Suitable bases, solvents and reaction conditions are as described above for the condensation reaction between, for example, compounds (I) and (II).
An alternative direct process for the preparation of compounds of formula (A) comprises condensing together 2,5-piperazinedione, a compound of formula (II) and a compound of formula (III) in the presence of sodium acetate and acetic anhydride at elevated temperature, for example under reflux.
An alternative process for the preparation of compounds of formula (I) comprises treating a compound of formula (V): ##STR7## wherein R.sub.6 to R.sub.8 are as defined above, X is a halogen and R' is a C.sub.1 -C.sub.6 alkyl group, with ammonia followed by acetic anhydride.
Compounds of formula (I') may be prepared by an analogous process which comprises treating a compound of formula (V'): ##STR8## wherein R.sub.1 to R.sub.5, X and R.sup.1 are as defined above, with ammonia followed by acetic anhydride.
X in formula (V) or (V') is typically iodine. R.sup.1 is, for example, a C.sub.1 -C.sub.4 alkyl group such as a methyl, ethyl, propyl, i-propyl, butyl, sec-butyl or tert-butyl group.
A review of synthetic approaches to unsaturated 3-monosubstituted and 3,6-disubstituted-2,5-piperazinediones is provided in Heterocycles, 1983, 20, 1407 (C.Shin).
Compounds of formula (A) may be converted into pharmaceutically acceptable salts, and salts may be converted into the free compound, by conventional methods. Suitable salts include salts with pharmaceutically acceptable, inorganic or organic, bases, or pharmaceutically acceptable inorganic or organic acids. Examples of inorganic bases include ammonia and carbonate, hydroxides and hydrogen carbonates of group I and group II metals such as sodium, potassium, magnesium and calcium. Examples of organic bases include aliphatic and aromatic amines such as methylamine, triethylamine, benzylamine, dibenzylamine or .alpha.- or .beta.-phenylethylamine, and heterocyclic bases such as piperidine, 1-methylpiperidine and morpholine. Examples of inorganic acids include hydrochloric acid, sulphuric acid and orthophosphoric acid. Examples or organic acids include p-toluenesulphonic acid, methanesulphonic acid, mucic acid and butan-1,4-dioic acid.
Compounds of formula (A) may also be converted into pharmaceutically acceptable esters. Suitable esters include branched or unbranched, saturated or unsaturated C.sub.1 -C.sub.6 alkyl esters, for example methyl, ethyl and vinyl esters.
Preferred compounds of formula A are depicted by means of their substitution patterns in Table 1 which follows. The compound numbering is adhered to in the rest of the specification. Characterising data for the compounds are set out in Table 2 in Example 16.
The diketopiperazines of formula (A) and their pharmaceutically acceptable salts and esters (referred to hereinafter as the "present compounds") have utility as inhibitors of PAI. Elevated levels of PAI-1, by reducing the net endogenous fibrinolytic capacity, can contribute to the pathogenesis of various thrombotic disorders including myocardial infarction, deep vein thrombosis and disseminated intravascular coagulation. The present compounds therefore can act as inhibitors of the tPA/PAI-1 interaction. The present compounds can be used in the treatment of haemostatic disorders. A human or animal, e.g. a mammal, can therefore be treated by a method comprising administration of a therapeutically effective amount of a diketopiperazine of formula (A) or a pharmaceutically or veterinarily acceptable salt thereof.
Tissue plasminogen activator (tPA) is used as a fibrinolytic agent in the treatment of thrombotic disorders. The efficacy of the tPA in this role may be enhanced if it is administered together with a PAI inhibitor. A human or animal, e.g. a mammal, can therefore be treated by a method comprising the combined administration of a therapeutically effective amount of tPA and a therapeutically effective amount of any one of the present compounds. The present invention also provides products containing a diketopiperazine of formula (A) or a pharmaceutically acceptable salt or ester thereof and tPA as a combined preparation for simultaneous, separate or sequential use in the treatment of thrombotic disorders, for example where there is inappropriate PAI activity. In such products the present compound is formulated for oral or parenteral (intravenous, intramuscular or subcutaneous) administration and the tPA is formulated for intravenous administration.
As one example, during acute myocardial infarction (MI) one of the present compounds may be administered to a patient together with tPA to enhance the efficacy of the tPA treatment. As a further example, early re-occlusion following treatment of a patient with tPA may be prevented by the post-MI administration of one of the present compounds.
The compounds of formula (A) have been tested in a PAI functional assay. In this assay, a compound is incubated with PAI-1 prior to addition to the tPA assay system. Inhibition of PAI-1 results in the production of plasmin from plasminogen. In turn, plasmin cleaves the chromogenic substrate S2251 (Kabi Vitrum) producing pNA (p-nitroaniline) which is detected spectrophotometrically at 405 nm (K. Nilsson et al, Fibrinolysis (1987) 1, 163-168). The results of the assay are reported in Example 1 which follows.
The present compounds can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously. The present compounds may therefore be given by injection or infusion.
The dosage depends on a variety of factors including the age, weight and condition of the patient and the route of administration. Typically, however, the dosage adopted for each route of administration when a compound of the invention is administered alone to adult humans is 0.001 lo 10 mg/kg, most commonly in the range of 0.01 to 5 mg/kg, body weight. Such a dosage may be given, for example, from 1 to 5 times daily by bolus infusion, infusion over several hours and/or repeated administration. When one of the present compounds is administered in combination with tPA to adult humans, the dosage adopted for each route of administration is typically from 0.001 to 10 mg, more typically 0.01 to 5 mg per kg body weight for a compound of the invention and from 5 to 500 mg administered intravenously for the tPA. A suitable dosage regimen for the tPA is 100 mg given intravenously over 3 hours as follows: 10% of the total dose as an i.v. bolus over 1-2 minutes, 50% of the total dose as an infusion over 1 hour, 40% of the total dose as an infusion over the subsequent 2 hours.
A diketopiperazine of formula (A) or a pharmaceutically acceptable salt or ester thereof is formulated for use as a pharmaceutical or veterinary composition also comprising a pharmaceutically or veterinarily acceptable carrier or diluent. The compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterinarily suitable form. An agent for use as an inhibitor of PAI comprising any one of the present compounds is therefore provided.
For example, the solid oral forms may contain, together with the active compound, diluents such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, or polyvinyl pyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs, sweeteners; wetting agents such as lecithin, polysorbates, lauryl sulphates. Such preparations may be manufactured in known manners, for example by means of mixing, granulating, tabletting, sugar coating, or film-coating processes.
Liquid dispersions for oral administration may be syrups, emulsions and suspensions. The syrups may contain as carrier, for example, saccharose or saccharose with glycerol and/or mannitol and/or sorbitol. In particular, a syrup for diabetic patients can contain as carriers only products, for example sorbitol, which do not metabolise to glucose or which only metabolise a very small amount to glucose. The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose or polyvinyl alcohol.
Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and, if desired, a suitable amount of lidocaine hydrochloride. Some of the present compounds are insoluble in water. A compound may be encapsulated within liposomes.

The following Examples illustrate the invention:
EXAMPLE 1
Testing of the Present Compounds as PAI Inhibitors
Compounds of formula (A) were tested in a PAI chromogenic substrate assay. In the assay (K.Nilsson, Fibrinolysis (1987) 1, 163-168) each compound was incubated with PAI-1 prior to addition to the tPA assay system. Inhibition of PAI-1 by the compound of formula (Aa) resulted in the production of plasmin from plasminogen. In turn, the plasmin cleaved the chromogenic substrate S2251 (Kabi-Vitrum) producing pNA (p-nitroaniline) which was detected spectrophotometrically at 405 nm.
The degrees of inhibition observed in the chromogenic substrate assay at various concentrations of compounds of formula (A), or the IC.sub.50 values, are presented in Table 1.
TABLE 1______________________________________Compound Concentration in .mu.MNo. 100 50 25 12.5 6.25______________________________________1852 72 71 74 67 41920 68 66 57 50 331954 16 43 67 57 371955 9 2 3 2 01956 61 69 69 65 311957 10 1 2 1 11960 32 64 67 63 561962 2 2 1 1 11969 52 20 6 0 21978 50 41 11 0 31981 51 41 26 7 --1885 54 31 2 0 01887 83 46 24 5 01889 49 38 15 3 01907 80 69 37 23 101908 74 69 66 29 121909 17 31 53 57 391911 38 23 15 20 131913 71 54 19 14 151924 64 38 18 7 91946 7 1 1 1 --1947 1 1 1 1 01949 3 1 1 1 11951 43 23 2 1 01952 63 37 19 1 01953 0 0 1 1 11977 54 47 47 20 01979 37 0 0 0 01980 66 41 51 13 01984 17 0 0 0 --______________________________________Compound Concentration in .mu.MNo. 60 30 15 7.5 3.75______________________________________1914 27 17 15 15 201961 48 49 41 11 1______________________________________Compound Concentration in .mu.MNo. 100 .mu.M 50 .mu.M 20 .mu.M IC.sub.50______________________________________5058 67 68 75 6.0-3.05060.HCl 75 65 52 25.0-12.05065.HCl 85 80 12 50.0-20.05068.HCl 75 76 81 12.0-6.05070.HCl 40 6 65080.HCl 62 48 10 50.0-25.05186 46 105187 58 10 100.05201 47 43 2.505208 32 105209 1.405210 67.05228 1.105229 3.705230 9 30 0.755231 36 42 1.505232 105233 50 47 2.505234 105235 6.05236 2.805237 67 72 4.05238 36 35239 68 65 7.05240 46 65 6.505241 21 15245 1.805246 345248 105249 55 105250 25 10 14.05251 71 67.05254 79 76 35.05255 33 80 15.05256 65 10 100.05259 10 105260 17.05343 205344 405345 395346 155347 395348 155360 59 3.505365 6.505365.HCl 3.305372 11.05373 13.05374 15.05375 4.505378 50 20.05380 15.05381 15.05385 2.05398 54 4.205401 42______________________________________
EXAMPLE 2
Pharmaceutical Composition
Tablets, each weighing 0.15 g and containing 25 mg of a compound of the invention can be manufactured as follows:
Composition for 10,000 tablets
compound of the invention (250 g)
lactose (800 g)
corn starch (415 g)
talc powder (30 g)
magnesium stearate (5 g)
The compound of the invention, lactose and half of the corn starch are mixed. The mixture is then forced through a sieve 0.5 mm mesh size. Corn starch (10 g) is suspended in warm water (90 ml). The resulting paste is used to granulate the powder. The granulate is dried and broken up into small fragments on a sieve of 1.4 mm mesh size. The remaining quantity of starch, talc and magnesium stearate is added, carefully mixed and processed into tablets.
Reference Example 1
Preparation of (3Z,6Z)-3-benzvyidene-6-(4-methoxybenzylidene)-2,5-piperazinedione (3) ##STR9## 1,4-Diacetyl-2,5-piperazinedione (8)
1,4-Diacetylpiperazine-2,5-dione (8) was prepared by the published procedure (S. M. Marcuccio and J. A. Elix, Aust. J. Chem., 1984, 37, 1791).
(3Z)-1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9)
(3Z)-1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9) was prepared by the published procedure (T. Yokoi, L-M. Yang, T. Yokoi, R-Y. Wu, and K-H. Lee, J. Antibiot., 1988, 41, 494).
(3Z,6Z)-3-Benzylidene-6-(4-methoxybenzylidene)-2,5-piperazinedione (3)
A mixture of (3Z)-1-acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (9) (1.0 g, 3.6 mmol), benzaldehyde (430 .mu.l, 4.2 mmol) and triethylamine (1.14 ml), 8.2 mmol), in dry DMF (20 ml), was heated at 130.degree. C. for 18 h. The reaction mixture was cooled to room temperature and poured into ethyl acetate (100 ml). A yellow solid precipitated which was filtered off and dried. Yield 360 mg (31%). C.sub.19 H.sub.16 N.sub.2 O.sub.3
.sup.1 H nmr (400 MHz d.sub.6 -DMSO): .delta.: 3.80 (3H, s, o-Me); 6.77 (1H, s, CH.dbd.C); 6.78 (1H, s, CH.dbd.C); 6.98 (2H, d, J=8 Hz, 2.times.C-H on Ar-OMe); 7.30-7.56 (7H, m, Ph and 2.times.C-H on Ar-OMe); 10.15 (2H, br.s, N-H).
.sup.13 C nmr (100 MHz d.sub.6 -DMSO); .delta.: 58.68; 117.66; 118.03; 118.77; 128.11; 128.92; 129.95; 131.53; 132.11; 132.69; 134.44; 136.59; 161.39; 161.62; 162.71. ms (desorption chemical ionisation, ammonia): m/z (% relative intensity): 321 (100) MH.sup.+. ir: KBr (diffuse reflectance): max (cm.sup.-1): 1620, 1700, 3100, 3220. Elemental analysis: Calculated for C.sub.19 H.sub.16 N.sub.2 O.sub.3 : C 71.24, H 5.03, N 8.74. Found: C 70.92, H 5.02, N 8.80. C 70.89, H 5.06, N 8.79%
Reference Example 2
Preparation of (3Z,6Z)-3-benzylidene-6-(4-methoxybenzylidene)-1-methyl-2,5-piperazinedione (1) ##STR10##
Compound 16 is treated with ammonia and subsequently with acetic anhydride to yield 1-acetyl-3-benzylidenepiperazine-2,5-dione (18).
Compound 18 is then condensed, in the presence of caesium carbonate or triethylamine in DMF, with 4-methoxybenzaldehyde to yield compound 3.
Reference Example 3
Preparation of 1-acetyl-3-benzylidene-2,5-piperazinedione
1,4-Diacetyl-2,5-piperazinedione (25.0 g, 126 mmol), which is compound (8) mentioned in Reference Example 1 was heated at 120-130.degree. C. in DMF (200 ml) with triethylamine (17.6 ml, 126 mmol) and benzaldehyde (13.0 ml, 126 mmol). After 4 h the mixture was cooled to room temperature and poured into EtOAc (1000 ml), and washed three times with brine. Any solid formed at this stage was filtered off. The filtrate was dried (MgSO.sub.4) and the solvent removed in vacuo. The residue was recrystallised from EtOAc:Hexane to give 11.78 g (38%) of the title compound as a yellow solid.
.sup.1 H NMR (CDCl.sub.3 400 MHz) .delta.=2.69 (3H, s) 4.54 (2H, s) 7.20 (1H, s) 7.40 (3H, m), 7.48 (2H, m), 7.93 (1H, br.s); MS(DCI,NH.sub.3): 262 (MNH.sub.4.sup.+, 20%), 245 (MH.sup.+, 53%), 220 (52%), 204 (100%), 203 (100%)
______________________________________Microanalysis C H N______________________________________Calc 63.93 4.95 41.47Found 64.11 5.02 11.41 64.05 4.90 11.44______________________________________
EXAMPLE 3
Preparation of compound 1908
1-Acetyl-3-benzylidene-2,5-piperazinedione (one equivalent), prepared according to Reference Example 2, was treated with 4-(3-dimethylaminopropoxy)benzaldehyde in the presence of Cs.sub.2 CO.sub.3 (1-1.1 equivalents) in DMF at 80-100.degree. C. for 1-8 hours. The title compound was obtained in 51% yield.
By the same method, but replacing 4-(3-dimethylaminopropoxy)benzaldehyde by the appropriately substituted benzaldehyde, the following compounds were prepared:
______________________________________Compound Yield (%) Compound Yield (%)______________________________________1889 41 1950 241913 37 1951 491924 44 1953 91946 32 1984 151949 33.5______________________________________
Characterising data for the compounds are set out in Example 14.
Reference Example 4
Preparation of (3Z,6Z)-3-(4-hydroxybenzylidene)-6-(4-methoxybenzylidiene)-2,5-piperazinedione
(3Z)-1-Acetyl-3-(4-methoxybenzylidene)-2,5-piperazinedione (1 equivalent), which is compound (9) mentioned in Reference Example 1, was treated with 4-acetoxybenzaldehyde (1 equivalent) in the presence of Cs.sub.2 CO.sub.3 (1 to 1.1 equivalents) in DMF at 80 to 100.degree. C. for 1 to 6 hours. The compound (3Z,6Z)-3-(4-acetoxybenzylidene)-6-(4-methoxybenzylodiene)-2,5-piperazinedione was obtained in 21% yield. That compound was then treated with aqueous sodium hydroxide in THF at room temperature for 8 hours to give (3Z,6Z)-3-(4-hydroxybenzylidene)-6-(4-methoxybenzyladine)-2,5-piperazinedione (compound 1519) in 30% yield.
EXAMPLE 4
Preparation of Compounds 1885, 1887 and 1909
Compound 1519, prepared as described in Reference Example 4, was treated with (CH.sub.3).sub.3 CCH.sub.2 C(O)Cl (1 equivalent) in DMF in the presence of sodium hydride (2 equivalents) at room temperature for 4 hours. Compound 1885 was obtained in 29% yield.
Under the same conditions, but replacing the acid chloride by CH.sub.3 (CH.sub.2).sub.5 COCl (1 equivalent) compound 1887 was obtained in 83% yield.
Under conditions analogous to those used in Reference Example 4, but using the appropriately substituted benzaldehyde and heating at 80.degree. C. for five hours, Compound 1909 was obtained.
EXAMPLE 5
Preparation of Compound 36 and 1947
1,4-Diacetyl-2,5-piperazinedione, Compound (8) mentioned in Reference Example 1, was treated with 4-(3-dimethylaminopropoxy)benzaldehyde (2 equivalents) in DMF in the presence of Cs.sub.2 CO.sub.3 (2.1 equivalents) at 90.degree. C. for two hours. Compound 36 was obtained in 50% yield.
Under the same conditions, but using 4-(2-dimethylaminoethoxy)benzaldehyde, Compound 1947 was obtained in 30% yield.
EXAMPLE 6
Preparation of Compounds 1907 and 1911
Compound (9), prepared as described in Reference Example 1, was treated with 4-n-hexyloxybenzaldehyde in DMF in the presence of Cs.sub.2 CO.sub.3 at 90.degree. C. for two hours. Compound 1907 was obtained in 78% yield.
Under analogous conditions, but replacing the substituted benzaldehyde by 4-(2-dimethylaminoethoxy)benzaldehyde and heating at 80.degree. C. for four hours, Compound 1911 was obtained in 39% yield.
EXAMPLE 7
Preparation of Compound 1952
1,4-Diacetyl-2,5-piperazinedione, Compound (8) mentioned in Reference Example 1, was treated with 2,5-dichlorobenzaldehyde in DMF in the presence of triethylamine to give 1-acetyl-(2,6-dichlorobenzyladiene)-2,5-piperazinedione. This was treated with 4-(2-dimethylaminoethoxy)benzaldehyde in DMF in the presence of Cs.sub.2 CO.sub.3 for two hours to give Compound 1952 in 59% yield.
Reference Example 5
Preparation of (3Z)-1-acetyl-3-(4-(3-dimethylamino)propoxybenzylidene)-2,5-piperazinedion
1,4-Diacetyl-2,5-piperazinedione, which is compound 8 described in Reference Example 1, was stirred in DMF with 4-(3-dimethylamino)propoxybenzaldehyde and triethylamine and heated to 120.degree. C.-130.degree. C. for 2-4 hours, to yield the title compound.
EXAMPLE 8
Preparation of 5186
(3Z)-1-acetyl-3-(4-(3-dimethylamino)propoxy)-benzylidene-2,5-piperazinedione, prepared as in Reference Example 5, was treated with 2-methylbenzaldehydre in DMF in the presence of Cs.sub.2 CO.sub.3 at 80-90.degree. C. for 2-4 hours. Compound 5186 was obtained in 47% yield.
By the same method, but replacing 2-methylbenzaldehyde by the appropriately substituted benzaldehyde, the following compounds were prepared:
______________________________________Compound Yield (%) Compound Yield (%)______________________________________5060 41 5246 515068 48 5247 505187 61 5248 315201 41 5251 625229 45 5252 635208 55 5255 205209 55 5343 495228 44 5344 225232 63 5345 685233 45 5346 465234 70 5347 595235 78 5348 465236 82 5360 735237 73 5365 765238 45 5366 895239 72 5373 595241 67 5374 465242 55 5398 285375 25 5401 535385 71______________________________________
EXAMPLE 9
Preparation of 5249
(3Z)-1-acetyl-3-(2-chloro)benzylidene-2,5-piperazinedione was treated with 4-(3-dimethylamino)propoxybenzaldehyde, in DMF in the presence of Cs.sub.2 CO.sub.3 at 80.degree. C.-90.degree. C. for 2-4 hours. Compound 5249 was obtained in 68% yield.
By the same method, but using a corresponding piperazinedione derivative in which the 2-chloro substituent on the phenyl group of the benzylidene moiety was replaced by the substituents shown below, the following compounds of formula (I) were prepared:
______________________________________Substitution on phenyl group Compound of formula (I) Yield (%)______________________________________4-n-butoxy 5250 583,5-dichloro 5372 583,5-dinitro 5378 72______________________________________
By the same method but using (3Z)-1-acetyl-3-benzylidene-2,5-piperazinedione, prepared as in Reference Example 3, and 4-(2-diethylamino)ethoxybenzaldehyde the compound 5065 was prepared in 45% yield.
EXAMPLE 10
Preparation of compounds of formula (I) ##STR11##
(3Z)-1-acetyl-3-(2-bromo)benzylidene was treated with the benzaldehyde derivative 10.1 in which Y was O or S, in DMF in the presence of Cs.sub.2 CO.sub.3 at 80.degree. C.-90.degree. C. for 2-4 hours, to give compounds 5070 and 5080, respectively, in respective yields of 15% and 28%.
EXAMPLE 11
Preparation of Salts
1. Compound 1981, the salt with hydrochloric acid of Compound 1953, was prepared by bubbling HCl gas through a solution of Compound 1953 (the corresponding free base) in THF at room temperature, followed by evaporation to dryness and recrystallization. The salt was obtained in 66% yield.
By the same procedure, the following salts were prepared:
______________________________________No of Compounds of Formula (I) No of Salt Yield (%)______________________________________1913 19141951 19601984 19691949 19781946 19791952 19805060 5060.HCl 995068 5068.HCl 505186 5204 325187 5203 425201 5229 455208 5210 275209 5231 575237 5240 645246 5254 185247 5256 305248 5259 715360 5360.HCl 195365 5365.HCl 465401 5401.HCl 815249 50845372 5380 865378 5381 635065 5065.HCl 835080 5080.HCl 975070 5070.HCl 315058 5058.HCl 28______________________________________
2. By bubbling HCl gas through a solution of the free base in hot DMF, the following hydrochloride salts of compounds of formula (I) were prepared:
______________________________________No of Compounds of Formula (I) No of Salt Yield (%)______________________________________5228 5230 675248 5245 465385 5385.HCl 955398 5398.HCl 65______________________________________
EXAMPLE 12
Preparation of Compound 1977
1-Acetyl-3-(2,4-difluorobenzylidene)-2,5-piperazinedione was prepared by a process analogous to that described in Reference Example 3, but replacing benzaldehyde by 2,4-difluorobenzaldehyde. That compound was treated with 4-(3-dimethylaminopropoxy)benzaldehyde in the presence of Cs.sub.2 CO.sub.3 (1 to 1.1 equivalents) in DMF at 80 to 100.degree. C. for 1 to 8 hours to yield Compound 1977. Compound 1977 was converted to its salt by the method described in Example 11.
EXAMPLE 13
Preparation of 5260
Compound 5260 was prepared by treating the corresponding phthalimide derivative with hydrazine in H.sub.2 O and THF at room temperature for 5 hours.
EXAMPLE 14
Characterization of the Present Compounds
The compounds and salts of the invention were characterised by conventional mass spectroscopic, nmr and microanalytical techniques. The resulting data are set out in the following Tables:
__________________________________________________________________________ Mass spec .sup.1 H nmrMol. Formula m/z. mass Solvent MicroanalysisNo. (M. Wt) intensity (mode) .delta. all 400 MHz Calc Found__________________________________________________________________________XR1920 C.sub.27 H.sub.34 O.sub.4 N.sub.3 Cl 464, 99%. D.sub.4 -MeOH 400 MHz 499.5 C2.sup.+ 1.1 (3H, t); 1.6 (2H, m); 2.1 (2H, m); 2.3 (2H, m); 3.0 (6H, s); 3.5 (2H, m); 4.1 (2H, t); 4.3 (2H, t); 4.9 (methanol); 7.0 (2H, 2.times.s); 7.1 (2H, d); 7.15 (2H, d); 7.4 (4H, t).XR1914 C.sub.21 H.sub.22 N.sub.3 O.sub.2 Cl 348 (M.+-.Cl) 100% DMSO 2.72 (6H, s, NMe.sub.2); 4.25 (2H, s, CH.sub.2 N); 6.80 (2H, s); 7.32-7.62 (9H, m, Ar); 9.95 (1H, br.s, NH); 10.25 (2H, br.s, 2.times.NH).XR1913 C.sub.21 H.sub.21 N.sub.3 O.sub.2 347 (M+, 30%), DMSO 347 303 (M+-NMe.sub.2, 2.15 (6H, s, 2.times.Me); 3.40 (2H, s, CH.sub.2 Ar); 80%), 130 (75%); 58 6.75 (2H, s); 7.35-7.55 (9H, m, aryl CH); (100%, possibly 10.20 (2H, br.s, 2.times.NH). CH.sub.2 NMe.sub.2). EIXR1911 C.sub.23 H.sub.25 N.sub.3 O.sub.4 408 (MH+, 12%), CDCl.sub.3 /TFA 407 350 (MH+-CH.sub.2 NMe.sub.2, 3.08 (6H, s, NMe.sub.2); 3.64-3.67 (2H, m); 3.88 10%), 58 (100%). (3H, s, OMe); 4.38-4.44 (2H, m); 6.95-7.45 EI (10H, m, aryl CH).XR1909 C.sub.26 H.sub.27 N.sub.3 O.sub.6 495 (M.sup.+ +NH.sub.4, CDCl.sub.3 +TFA 477 13%); 478 (M.sup.+ +1, 2.00-2.17 (2H, m); 2.45-2.52 (4H, m); 100%); 446 (M.sup.+- 3.75 (3H, s, Me); 3.88 (3H, s, Me); 4.50 OMe, 15%). (2H, s); 7.00-7.40 (10H, m). EIXR1908 C.sub.22 H.sub.23 N.sub.3 O.sub.3 378 (M.sup.+ +1, 100%). CDCl.sub.3 +TFA 377 EI 3.10 (6H, s, 2.times.Me); 3.65 (2H, t, CH.sub.2); 4.40 (2H, t, CH.sub.2); 6.95-7.50 (11H, m).XR1907 C.sub.25 H.sub.28 O.sub.4 N.sub.2 421 (98%) CDCl.sub.3 400 MHz C2+ 0.90 (3H, t); 1.3 (4H, m); 1.5 (2H, m); 1.8 (2H, m); 3.9 (3H, s); 4.1 (2H, t); 7.0 (4H, d.times.d); 7.2 (4H, s); 7.25 (1H, s); 7.4 (4H, d.times.d); 10.1 (1H, s).XR1889 C.sub.24 H.sub.24 N.sub.2 O.sub.4 405 (MH+, 23%); 306 CDCl.sub.3 /TFA 400 (100%). 1.16 (9H, s); 2.51 (2H, s); 7.20 (2H, d, J= DCl 8 Hz); 7.23 (1H, s); 7.29 (1H, s); 7.40-7.54 NH (7H, m).XR1887 C.sub.26 H.sub.28 N.sub.2 O.sub.5 449 (MH+, 58%); 448 CDCl.sub.3 /TFA 400 MHZ 448 (50%); 336 (100%); 0.95 (3H, t, J=6 HZ); 1.30-1.41 (4H, m); 146 (43%). 1.41-1.52 (2H, m); 1.75-1.84 (2H, m); 2.65 (2H, t, J=6 Hz); 3.95 (3H, s); 7.05 (2H, d, J=8 Hz); 7.20-7.31 (4H, m); 7.46 (2H, d, J=8 Hz); 7.51 (2H, d, J=8 HZ).XR1885 C.sub.25 H.sub.26 N.sub.2 O.sub.5 400 MHZ CDCl.sub.3 TFA 1.18 (9H, s); 4.54 (2H, s); 3.90 (3H, s); 7.01 (2H, d, J=8 Hz); 7.15-7.28 (4H, m); 7.40- 7.49 (4H, m).XR1852 C.sub.23 H.sub.26 N.sub.3 O.sub.3 Cl 392 (�M-Cl!+, 100%). DMSO 400 MHz 63.16 ESI 2.15 (2H, m); 3.18 (2H, m); 3.25 (6H, 6.06 4.10 (2H, t, J=6 Hz); 6.75 (1H, s); 6.77 9.19 s); 7.00 (2H, d, J=8 Hz); 7.34 (1H, m); 7.42 (2H, m); 7.52-7.59 (4H, m).XR1955 C.sub.32 H.sub.42 N.sub.4 O.sub.8.2H.sub.2 O DMSO 400 MHz C 59.43 59.23 59.22 1.87 (4H, m); 2.21 (12H, s); 2.39 (4H, H); 7.17 7.14 7.07 2.48 (4H, t, J=6 Hz); 4.06 (4H, t, J=6 Nz); 8.66 8.48 8.57 6.75 (2H, s); 7.00 (4H, d, J=8 Hz); 7.52 (4H, d, J=8 Hz).XR1954 C.sub.26 H.sub.29 N.sub.3 O.sub.7 DMSO 400 MHz C 63.02 62.75 63.02 2.29 (6H, s); 2.43 (4H, s); 2.72 (2H, t, H= 5.90 5.81 5.87 6 Hz); 4.10 (2H, t, J=6 Hz); 6.74 (1H, N); 8.48 8.50 8.49 6.75 (1H, s); 7.00 (2H, d, J=8 Hz); 7.31 (1H, m); 7.40 (2H, m); 7.46-7.58 (4H, m).XR1953 C.sub.29 H.sub.39 N.sub.5 O.sub.2 489 18% CDCl.sub.3 400 MHz 489 403 24% 1.66 (4H, OUI), 2.22 (12H, s), 2.28 (4H, t), 303 100% 2.48 (2H, t), 3.60 (2H, s), 7.04 (2H, over- 186 62% lapping signals), 7.32-7.50 (9H, over- 141 68% lapping signals). 85 97% 58 85% EI+XR1952 C.sub.22 H.sub.21 N.sub.3 O.sub.3 Cl.sub.2 MH+ (20%) CDCl.sub.3, CF.sub.3 CO.sub.2 D 400 CHz 59.20 58.97 58.96 446/447/449 445 9 7.43 (m, 4H); 7.33 (m, 1H); 7.25 (s, HH); 4.74 4.73 4.72 9:6:1 447 6 7.13 (s, 1H); 7.00 (d, 2H); 4.42 (t, NH); 9.41 9.23 9.24 449 1 3.67 (t, 2H); 3.09 (s, 6H). CI/NH.sub.3XR1951 C.sub.22 H.sub.22 N.sub.3 O.sub.3 Cl MH+ (100%) 412 CDCl.sub.3 TFAA 411/413 (3:1) (35%) 414 7.51-7.41 (m, 5H), 7.36 (d, 1H), 7.22 378 (10%) (2.times.s, 2H), 7.07 (d, 1H), 6.90 (dd, 1H), CI/NH.sub.3 4.42 (t, 2H), 3.65 (t, 2H), 3.07 (s, 6H).XR1949 C.sub.26 H.sub.32 N.sub.4 O.sub.4 MH+ (100%) 465 CDCl.sub.3 400 MHz 464 393 (70%) 8.11 (broad s, 2H), 7.47 (m, 2H), 7.40 (m, 349 (40%) 3H), 7.05-6.90 (m, 5H), 4.14 (m (2 merged 194 (20%) triplets), 4H), 2.79 (m (2 merged triplets), 4H), 2.38 (s, 12H).XR1948 C.sub.26 H.sub.34 N.sub.4 O.sub.4 Cl.sub.2 MH+ (100%) 465 D.sub.2 O 400 MHz 537 (free amine) 7.6-7.0 (m, 10H), 4.53 (m, 4H), 3.75 (t, 4H), 3.15 (s, 12H).XR1947 C.sub.26 H.sub.32 N.sub.4 O.sub.4 MH+ (100%) 465 CDCl.sub.3 400 MHz 464 8.18 (broad s, 2H), 7.35 (m, 2H), 7.0-6.9 (m, 8H), 4.11 (t, 4H), 2.78 (t, 4H), 2.38 (s, 12H).XR1946 C.sub.22 H.sub.23 N.sub.3 O.sub.3 MH+ (100%) 378 CDCl.sub.3 400 MHz 377 8.96 (broad, s, 1H), 8.10 (broad s, 1H), 7.47-7.32 (m, 7H), 7.06-7.01 (m, 4H), 4.24 (t, 2H), 2.85 (t, 2H), 2.35 (s, 6H).XR1924 C.sub.22 H.sub.23 N.sub.3 O.sub.3 MH+ (100%) 378 CDCl.sub.3 400 MHz 377 CI/NH.sub.3 8.12 (br, 2.times.s, 2H), 7.50-7.35 (m, 7H), 7.05 (s, 1H), 7.0-6.95 (m, 3H), 4.11 (t, 2H), 2.78 (t, 2H), 2.85 (s, 6H).XR1962 C.sub.26 H.sub.34 N.sub.4 O.sub.4 Cl.sub.2 233 (100%), CDCl.sub.3 +TFA 465 (10%), 3.05 (12H, s), 3.55 (4H, m), 4.45 (4H, m), 929 (50%). 7.00 4H, d), 7.20 (2H, s), 7.42 (4H, d).XR1961 C.sub.22 H.sub.24 N.sub.3 O.sub.3 Cl MH+ (100%) free d.sub.6 -DMSO 400 MHz 413.5 amine 378 10.23 (br, 2H), 7.55-7.30 (m, 6H), 7.17 (m, CI/NH.sub.3 2H), 6.96 (m, 1H), 6.80 (s, 1H), 6.79 (s, 1H), 4.35 (t, 2H), 3.33 (broad t, 2H), 2.71 (s, 6H).XR1960 C.sub.22 H.sub.23 N.sub.3 O.sub.3 Cl.sub.2 MH+ (100%) 412 d.sub.6 -DMSO 448 (30%) 414 bath free 10.30 (s, 1H); 10.23 (s, 1H); 10.10 (broad, s, amine 1H); 7.62 (d, 1H); 7.55 (d, 2H); 7.42 (m, 2H); 7.35 (m, 1H); 7.22 (d, 1H); 7.05 (dd, 1H); 6.81 (s, 1H); 6.80 (s, 1H); 4.41 (t, 2H); 3.52 (t, 2H); 2.84 (s, 6H).XR1957 C.sub.30 H.sub.44 N.sub.4 O.sub.10 S.sub.2 D.sub.2 O 400 MHz 52.62 52.69 52.70 2.26 (4H, m); 2.89 (6H, s); 2.99 (12H, 6.48 6.46 6.47 3.38 (4H, m); 4.24 (4H, m); 6.92 (2H, 8.18 8.13 8.13 7.18 (4H, d, J=8 Hz); 7.57 (4H, d, J=8 Hz).XR1956 C.sub.23 H.sub.27 N.sub.3 O.sub.6 S DMSO 400 MHz 2.33 (3H, s); 2.90 (6H, s); 3.55 (2H, J= 6 Hz); 4.34 (2H, t, J=6 Hz); 6.78 (2H, s); 7.08 (2H, d, J=8 Hz); 7.35 (1H, m); 7.42 (2H, m); 7.53-7.62 (4H, m).XR1984 C.sub.26 H.sub.32 N.sub.4 O.sub.4 MH+ (100%) 465 CDCl.sub.3 400 MHz 464 (20%) 393 9.07 (s, br, 1H), 8.08 (s, br, 1H), 7.48-7.35 CI/NH.sub.3 (m, 5H), 7.25 (d, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 6.60 (m, 2H).XR1981 C.sub.29 H.sub.39 N.sub.5 O.sub.2.3HCl 526 7% (MHCl) DMSO d.sub.6 400 MHz 489+106.5 490 4% (MH+) 2.28 (4H, V. BROAD SIGNAL), 2.78 266 100% (12H, s), 3.15 (8H, V. BROAD SIGNAL(s)), 4.40 (2H, BROAD PEAK), 6.82 (2H, OVERLAPPING SIGNALS), 7.36 (2H, BROAD SIGNAL), 7.44 (2H, t), 7.56 (2H, d), 7.64 (2H, BROAD SIGNAL), 7.75 (1H, BROAD SIGNAL).XR1980 C.sub.22 H.sub.22 N.sub.3 O.sub.3 Cl.sub.3 MH+ (100%) 446, d.sub.6 -DMSO 400 MHz C 54.73 54.43 54.20 482.5 (60%) 448, (10%) 450, 10.47 (s, 1H); 10.25 (s, 1H); 10.10 (br, H, 4.59 4.67 4.63 all free amine; 412 1H); 7.54 (d, 2H); 7.49 (d, 2H); 7.38 Nd, 8.70 8.56 8.51 (30%). 1H); 7.06 (d, 2H); 6.79 (s, 1H); 6.58 (s, Cl); 22.05 21.40 4.38 (t, 2H); 3.48 (t, 2H); 2.83 (s, 6H).XR1979 C.sub.22 H.sub.24 N.sub.3 O.sub.3 Cl d.sub.6 -DMSO 413.5 10.18 (s, 1H); 10.02 (s, 1H); 9.83 (br, s, 1H); 7.55-7.32 (m, 7H); 7.12 (d, 1H); 7.06 (m, 1H); 6.86 (s, 1H); 6.78 (s, 1H); 4.39 (t, 2H); 3.50 (br, 2H); 2.81 (s, 6H).XR1978 C.sub.26 H.sub.34 N.sub.4 O.sub.4 Cl.sub.2 MH+ (45%) 465 free D.sub.2 O 400 MHz 537 amine 7.56 (m, 2H); 7.32 (m, 1H); 7.25-7.20 (m, 393 (30%), 4H); 7.05 (s, 2H), 4.52 (t, 4H); 3.72 (t, 4H); 349 (20%), 3.06 (s, 12H). 219 (100%).XR1977 C.sub.22 H.sub.21 N.sub.3 O.sub.3 F.sub.2 MH+ 414 (100%) CDCl.sub.3 +TFA 413 DCI, NH.sub.3 3.08 (6H, s); 3.12 (2H, m); 4.40 (sH, m); 6.97 (4H, m); 7.15 (1H, s); 7.25 (1H, s); 7.45 (3H, m).XR1969 C.sub.26 H.sub.34 N.sub.4 O.sub.4 Cl.sub.2 MH+ (100%) 465 free D.sub.2 O 400 MH.sub.2 537 amine 7.65-7.52 (m, 6H); 7.07 (m, 2H); 6.92 (d, 393 (15%); 1H); 6.82 (s, 1H); 4.50 (m, 4H); 3.74 (br, 270 (30%). 2H); 3.68 (br, 2H); 3.07 (s, 12H). CI/NH.sub.3XR1634 C.sub.20 H.sub.16 N.sub.2 O.sub.4 366 (M.sup.+ NH.sub.4, 20%), CDCl.sub.3 -TFA 400 MHz 348 349 (M.sup.+ OH, 72%), 3.94 (3H, s); 7.17 (1H, s); 7.23 (1H, s); 317 (100%). 7.31-7.55 (8H, m); 8.03 (1H, d). CI__________________________________________________________________________ Mass spec. data mass .sup.1 H nmr dataNo. Mol. Formula (intensity) mode solvent (field) .delta.__________________________________________________________________________5210 C.sub.23 H.sub.24 N.sub.4 O.sub.5.HCl 437 (100) CI d.sub.6 -DMSO/400 MHz 2.15-2.20 (2H, m), 2.80 (6H, m), 3.19-3.26 (2H, m), 4.11 (2H, t), 6.78 (1H, s), 6.98 (1H, s), 7.01 (2H, d), 7.55 (2H, d), 7.58-7.69 (2H, m), 7.76-7.81 (1H, m), 8.15 (1H, d), 10.25 (1H, brs), 10.39 (1H, brs), 10.44 (1H, brs).5060 C.sub.23 H.sub.24 BrN.sub.3 O.sub.3.HCl 472 (100), EI d.sub.6 -DMSO/400 MHz 2.16 (2H, m), 2.76 (6H, d), 3.20 (2H, m), 4.10 470 (100). (2H, t), 6.73 (1H, s), 6.77 (1H, s), 7.01 (2H, d), 7.26 (1H, m), 7.43 (1H, m), 7.53 (2H, d), 7.59 (1H, m), 7.70 (1H, d), 10.30 (1H, brs), 10.38 (1H, brs), 10.65 (1H, brs).5065 C.sub.24 H.sub.27 N.sub.3 O.sub.3 406 (10) CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 1.42 (6H, t), 3.34-3.50 (4H, m), 3.65 (2H, t), 4.37 (2H, t), 6.95 (2H, d), 7.24 (1H, s), 7.26 (1H, s), 7.40-7.52 (7H, m).5068 C.sub.25 H.sub.30 N.sub.4 O.sub.3.HCl CDCl.sub.3 /400 MHz 2.35 (2H, m), 2.98 (6H, s), 3.27 (6H, s), 3.40 (2H, m), 4.14 (2H, t), 6.96 (1H, s), 6.99 (1H, s), 7.18 (2H, d), 7.40 (2H, d), 7.59 (2H, d), 7.75 (2H, d).5070 C.sub.23 H.sub.24 BrN.sub.3 O.sub.3.HCl 472 (25), CI d.sub.6 -DMSO/400 MHz 2.79 (6H, s), 3.35 (2H, t), 3.80 (2H, t), 4.57 470 (25). (2H, s), 6.79 (1H, s), 6.81 (1H, s), 7.28 (1H, m), 7.40-7.45 (3H, m), 7.55-7.60 (3H, m), 7.70 (1H, m), 9.82 (1H, s), 10.31 (1H, s), 10.43 (1H, s).5058 C.sub.23 H.sub.25 N.sub.3 O.sub.2 S 408 (10) CI CDCl.sub.3 /400 MHz 2.32 (6H, s), 2.50 (4H, brs), 3.75 (2H, s), 7.00 (1H, s), 7.02 (1H, s), 7.35-7.50 (9H, m), 8.10 (2H, brs).5080 C.sub.23 H.sub.24 BrN.sub.3 O.sub.2 S.Hcl d.sub.6 -DMSO/400 MHz 2.74 (6H, s), 2.80 (2H, m), 3.26 (2H, m), 3.87 (2H, s), 6.76 (1H, s), 6.79 (1H, s), 7.28 (1H, m), 7.44 (2H, d), 7.49 (1H, m), 7.55 (2H, d), 7.60 (1H, d), 7.74 (1H, d), 10.32 (1H, brs), 10.44 (1H, brs), 10.49 (1H, brs).5084 C.sub.23 H.sub.24 N.sub.3 O.sub.2.HCl d.sub.6 -DMSO/400 MHz 2.16 (2H, m), 2.80 (6H, d), 3.22 (2H, m), 4.12 (2H, t), 6.79 (1H, s), 6.81 (1H, s), 7.02 (2H, d), 7.40 (2H, m), 7.55 (3H, m), 7.62 (1H, m).5186 C.sub.24 H.sub.27 N.sub.3 O.sub.3 406 (100) ESI d.sub.6 -DMSO/400 MHz 1.8-1.9 (2H, m), 2.17 (6H, s), 2.29 (3H, s), 2.38 (2H, t), 4.05 (2H, t), 6.72 (1H, s), 6.79 (1H, s), 6.99 (2H, d), 7.22-7.31 (3H, m), 7.40- 7.45 (1H, m), 7.52 (2H, d), 9.90 (1H, brs), 10.28 (1H, brs).5187 C.sub.24 H.sub.27 N.sub.3 O.sub.3 406 (100) ESI d.sub.6 -DMSO/400 MHz 1.81-1.90 (2H, m), 2.12 (6H, s), 2.34-2.40 (5H, m), 4.08 (2H, t), 6.75 (2.times.1H, s), 6.99 (2H, d), 7.12-7.18 (1H, m), 7.30-7.35 (2H, m), 7.39 (1H, brs), 7.51 (2H, d), 9.9 (1H, brs), 10.18 (H, brs).5201 C.sub.24 H.sub.25 N.sub.3 O.sub.5 436 (100) ESI d.sub.6 -DMSO/400 MHz 1.82-1.89 (2H, m), 2.15 (6H, s), 2.35 (2H, t), 4.1 (2H, t), 6.09 (2H, s), 6.7 (2H, d), 6.95- 7.0 (3H, m), 7.01-7.08 (1H, m), 7.18 (1H, s), 7.5 (2H, d), 10.12 (2H, brs).5203 C.sub.24 H.sub.27 N.sub.3 O.sub.3.HCl 406 (100) ESI d.sub.6 -DMSO/400 MHz 2.12-2.21 (2H, m), 2.35 (3H, s), 2.77 (6H, s), 3.19-3.23 (2H, m), 4.11 (2H, t), 6.71 (1H, s), 6.73 (1H, s), 7.01 (2H, d), 7.11-7.15 (1H, m), 7.29-7.32 (2H, m), 7.39 (1H, s), 7.52 (2H, d), 10.15 (2H, d), 10.60 (1H, brs).5204 C.sub.24 H.sub.27 N.sub.3 O.sub.3.HCl 406 (100) ESI d.sub.6 -DMSO/400 MHz 2.12-2.21 (2H, m), 2.28 (3H, s), 2.78 (6H, s), 3.19-3.23 (2H, m), 4.11 (2H, t), 6.76 (1H, s), 6.81 (1H, s), 7.0 (2H, d), 7.23-7.29 (3H, m), 7.40-7.45 (1H, m), 7.54 (2H, d), 9.4 (1H, brs), 10.19 (1H, brs), 10.50 (1H, brs).5208 C.sub.23 H.sub.24 N.sub.4 O.sub.5 437 (100) CI d.sub.6 -DMSO/400 MHz 1.81-1.90 (2H, m), 2.18 (6H, s), 2.38 (2H, t), 4.05 (2H, t), 6.75 (1H, s), 6.98 (1H, s), 7.00 (2H, d), 7.50 (2H, d), 7.61 (1H, t), 7.69 (1H, d), 7.79 (1H, t), 8.15 (1H, d), 10.35 (2H, brs).5210 C.sub.23 H.sub.24 N.sub.4 O.sub.5.HCl 437 (100) CI d.sub.6 -DMSO/400 MHz 2.15-2.20 (2H, m), 2.80 (6H, s), 3.19-3.26 (2H, m), 4.11 (2H, t), 6.78 (1H, s), 6.98 (1H, s), 7.01 (2H, d), 7.55 (2H, d), 7.58-7.69 (2H, m), 7.76-7.81 (1H, m), 8.15 (1H, d), 10.25 (1H, brs), 10.39 (1H, brs), 10.44 (1H, brs).5229 C.sub.24 H.sub.25 N.sub.3 O.sub.5.HCl 436 (40) CI d.sub.6 -DMSO/400 MHz 2.12-2.19 (2H, m), 2.75 (6H, s), 3.15-3.20 (2H, m), 4.10 (2H, t), 6.08 (2H, s), 6.70 (1H, s), 6.72 (1H, s), 6.95-7.09 (4H, m), 7.16 (1H, s), 7.51 (2H, d), 10.11 (1H, brs), 10.18 (1H, brs).5230 C.sub.23 H.sub.24 N.sub.4 O.sub.5.HCl 473 (100) CI d.sub.6 -DMSO/400 MHz 2.10-2.19 (2H, m), 2.78 (6H, s), 3.10-3.22 (2H, m), 4.11 (2H, t), 6.78 (1H, s), 6.80 (1H, s), 7.0 (2H, d), 7.55 (2H, d), 7.79 (2H, d), 8.22 (2H, d), 10.28 (1H, brs).5231 C.sub.23 H.sub.24 N.sub.4 O.sub.5.HCl 437 (100) CI d.sub.6 -DMSO/400 MHz 2.15-2.20 (2H, m), 2.80 (6H, s), 3.19-3.26 (2H, m), 4.11 (2H, t), 6.79 (1H, s), 6.83 (1H, s), 7.00 (2H, d), 7.55 (2H, d), 7.69 (1H, t), 7.90 (1H, d), 8.11-8.18 (1H, m), 10.28 (1H, brs), 10.65 (1H, brs), 10.69 (1H, brs).5232 C.sub.24 H.sub.24 N.sub.4 O.sub.3 417 (100) CI CDCl+CF.sub.3 CO.sub.2 D/400 MHz 2.29-2.48 (2H, m), 3.05 (6H, s), 3.43-3.48 (2H, m), 4.15-4.20 (2H, m), 6.96 (2H, d), 7.24 (1H, s), 7.25 (1H, s), 7.44 (2H, d), 7.60-7.78 (4H, m).5233 C.sub.23 H.sub.24 ClN.sub.3 O.sub.3 428 (33), CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 2.28 (2H, m), 3.00 (6H, s), 3.40 (2H, m), 4.14 426 (100). (2H, t), 7.00 (2H, d), 7.18 (1H, s), 7.22 (1H, s), 7.38 (2H, d), 7.42 (2H, d), 7.50 (2H, d).5234 C.sub.24 H.sub.27 N.sub.3 O.sub.4 422 (52) CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 2.30 (2H, m), 3.02 (6H, s), 3.40 (2H, m), 3.89 (3H, s), 4.15 (2H, t), 7.00 (2H, d), 7.04 (2H, d), 7.20 (1H, s), 7.22 (1H, s), 7.40 (2H, d), 7.42 (2H, d).5235 C.sub.24 H.sub.27 N.sub.3 O.sub.3 406 (28) CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 2.26 (2H, m), 2.40 (3H, s), 3.04 (6H, s), 3.39 (2H, m), 4.15 (2H, t), 6.97 (2H, d), 7.15 (1H, s), 7.18 (1H, s), 7.28 (2H, d), 7.35 (2H, d), 7.40 (2H, d).5236 C.sub.23 H.sub.23 Cl.sub.2 N.sub.3 O.sub.3 464 (4), CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 2.30 (2H, m), 3.03 (6H, s), 3.42 (2H, m), 4.15 462 (24), (2H, t), 3.98 (2H, d), 6.96 (2H, d), 7.10 (1H, 460 (36), s), 7.23 (1H, s), 7.27 (1H, m), 7.41 (2H, d), 216 (31). 7.52 (1H, m), 7.56 (1H, d).5237 C.sub.23 H.sub.24 ClN.sub.3 O.sub.3 428 (13), CI d.sub.6 -DMSO/400 MHz 1.85 (2H, m), 2.14 (6H, s), 2.37 (2H, t), 4.04 426 (39). (2H, t), 6.73 (1H, s), 6.77 (1H, s), 6.97 (2H, d), 7.34 (1H, m), 7.40 (1H, m), 7.42 (1H, m), 7.50 (2H, d), 7.60 (1H, s), 10.30 (2H, brs).5238 C.sub.27 H.sub.33 N.sub.3 O.sub.3 448 (54) CI d.sub.6 -DMSO/400 MHz 1.29 (9H, s), 1.84 (2H, m), 2.15 (6H, s), 2.36 (2H, t), 4.02 (2H, t), 6.71 (2H, s), 6.98 (2H, d), 7.40-7.51 (6H, m), 10.15 (2H, brs).5239 C.sub.24 H.sub.24 F.sub.3 N.sub.3 O.sub.3 460 (62) CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 2.30 (2H, m), 3.05 (6H, s), 3.43 (2H, t), 4.15 (2H, t), 6.96 (2H, d), 7.23 (1H, s), 7.24 (1H, s), 7.41 (2H, d), 7.54 (2H, d), 7.72 (2H, d).5240 C.sub.23 H.sub.24 ClN.sub.3 O.sub.3.HCl d.sub.6 -DMSO/400 MHz 2.16 (2H, m), 2.75 (6H, s), 3.18 (2H, m), 4.10 (2H, t), 6.72 (1H, s), 6.78 (1H, s), 7.00 (2H, d), 7.36 (1H, m), 7.41 (1H, m), 7.43 (1H, m), 7.51 (2H, d), 7.60 (1H, s), 10.21 (1H, s), 10.48 (1H, s), 10.66 (1H, brs).5241 C.sub.24 H.sub.27 N.sub.3 O.sub.4 d.sub.6 -DMSO/400 MHz 1.83 (2H, m), 2.12 (6H, s), 2.36 (2H, t), 3.85 (3H, s), 4.03 (2H, t), 6.75 (1H, s), 6.85 (1H, s), 7.00 (2H, d), 7.02 (1H, m), 7.09 (1H, d), 7.31 (1H, m), 7.49 (1H, d), 7.51 (2H, d), 9.90 (1H, brs), 10.10 (1H, brs).5242 C.sub.24 H.sub.27 N.sub.3 O.sub.4 CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 1.95 (2H, m), 2.28 (6H, s), 2.45 (2H, t), 3.83 (3H, s), 4.05 (2H, t), 6.89 (1H, s), 6.92 (1H, s), 7.00 (5H, m), 7.31-7.42 (3H, m).5245 C.sub.24 H.sub.24 N.sub.4 O.sub.3 HCI 417 (100) ESI d.sub.6 -DMSO/400 MHz 2.10-2.20 (2H, m), 2.80 (6H, d), 3.18-3.25 (2H, m), 4.11 (2H, t), 6.79 (2.times.1H, s), 7.0 (2H, d), 7.52 (2H, d), 7.70 (2H, d), 7.84 (2H, d), 10.10 (1H, brs), 10.26 (1H, brs), 10.50 (1H, brs).5246 C.sub.24 H.sub.28 N.sub.4 O.sub.4 435 (100) CI d.sub.6 -DMSO/400 MHz 1.82-1.88 (2H, m), 2.15 (6H, s), 2.35 (2H, t), 4.05 (2H, t), 6.75 (1H, s), 6.77 (1H, s), 6.98 (2H, d), 7.31 (1H, br), 7.51 (2H, d), 7.62 (2H, d), 7.9 (2H, d), 7.96 (1H, br), 10.23 (1H, brs).5247 C.sub.25 H.sub.28 N.sub.4 O.sub.4 449 (100) CI d.sub.6 -DMSO/400 MHz 1.84-1.90 (2H, m), 2.08 (3H, s), 2.15 (6H, s), 2.35 (2H, t), 4.05 (2H, t), 6.69 (1H, s), 6.75 (1H, s), 6.99 (2H, d), 7.20 (2H, d), 7.37 (1H, t), 7.50 (2H, d), 7.61 (2H, d), 7.67 (1H, s), 9.98 (2H, s), 10.05 (1H, brs).5248 C.sub.25 H.sub.28 N.sub.4 O.sub.4 449 (100) CI d.sub.6 -DMSO/400 MHz 1.83-1.90 (2H, m), 2.03 (3H, s), 2.17 (6H, s), 2.39 (2H, t), 4.04 (2H, t), 6.72 (1H, s), 6.74 (1H, s), 6.98 (2H, d), 7.16-7.21 (1H, m), 7.29- 7.32 (1H, m), 7.46-7.52 (3H, m), 7.60-7.64 (1H, m), 9.52 (1H, brs), 10.03 (1H, brs).5249 C.sub.23 H.sub.24 ClN.sub.3 O.sub.3 426 (10) CI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 2.31 (2H, m), 3.02 (6H, d), 3.42 (2H, m), 4.18 (2H, t), 6.95 (2H, d), 7.20 (1H, s), 7.28 (1H, s), 7.40 (5H, m), 7.55 (1H, m).5250 C.sub.27 H.sub.33 N.sub.3 O.sub.4 CDCl.sub.3 +D.sub.2 O/400 MHz 1.00 (3H, t), 1.50 (2H, m), 1.80 (2H, m), 2.00 (2H, m), 2.25 (6H, s), 2.50 (2H, t), 4.00 (2H, t), 4.05 (2H, t), 6.98-7.04 (6H, m), 7.30-7.40 (4H, m).5251 C.sub.24 H.sub.24 F.sub.3 N.sub.3 O.sub.3 460 (100) CI d.sub.6 -DMSO/400 MHz 1.82 (2H, m), 2.15 (6H, s), 2.36 (2H, t), 4.01 (2H, t), 6.78 (1H, s), 6.83 (1H, s), 6.98 (2H, d), 7.46-7.58 (3H, m), 7.60-7.72 (2H, m), 7.75 (1H, d).5252 C.sub.24 H.sub.24 F.sub.3 N.sub.3 O.sub.3 460 (52) CI d.sub.6 -DMSO/400 MHz 1.83 (2H, m), 2.19 (6H, s), 2.38 (2H, t), 4.02 (2H, t), 6.78 (1H, s), 6.83 (1H, s), 6.98 (2H, d), 7.53 (2H, d), 7.62 (2H, m), 7.79 (1H, d), 7.83 (1H, s), 10.20 (2H, brs).5254 C.sub.24 H.sub.26 N.sub.4 O.sub.4 HCl 435 (100) CI d.sub.6 -DMSO/400 MHz 2.10-2.19 (2H, m), 2.79 (6H, s), 3.20-3.25 (2H, m), 4.08-4.15 (2H, m), 6.77 (1H, s), 6.79 (1H, s), 7.0 (2H, d), 7.35 (1H, br), 7.55 (2H, d), 7.60 (2H, d), 7.91 (2H, d), 7.99 (1H, br), 10.19 (1H, brs), 10.32 (1H, brs).5255 537 (70), CI d.sub.6 -DMSO/400 MHz 407 (50), 166 (35), 86 (100).5256 C.sub.25 H.sub.28 N.sub.4 O.sub.4.HCl 449 (100) CI d.sub.6 -DMSO/400 MHz 2.05 (3H, s), 2.18-2.28 (2H, m), 2.78 (6H, s), 3.15-3.25 (2H, m), 4.11 (2H, t), 6.69 (1H, s), 6.75 (1H, s), 7.0 (2H, d), 7.18-7.20 (1H, m), 7.34 (1H, t), 7.55 (2H, d), 7.59-7.62 (1H, m), 7.69 (1H, s), 9.48 (2H, brs), 10.15 (1H, brs).5259 C.sub.25 H.sub.28 N.sub.4 O.sub.4.HCl 449 (100) CI d.sub.6 -DMSO/400 MHz 2.01 (3H, s), 2.11-2.18 (2H, m), 2.77 (6H, s), 3.19-3.25 (2H, m), 4.11 (2H, t), 6.74 (1H, s), 6.76 (1H, s), 7.0 (2H, d), 7.18-7.22 (1H, m), 7.28-7.33 (1H, m), 7.48-7.50 (1H, m), 7.53 (2H, d), 7.56-7.60 (1H, m), 9.41 (1H, brs), 9.89 (1H, brs), 10.09 (1H, brs), 10.18 (1H, brs).5260 C.sub.23 H.sub.26 N.sub.4 O.sub.3 407 (70) CI d.sub.6 -DMSO/400 MHz 1.80-1.90 (2H, m), 2.18 (6H, s), 2.39 (2H, t), 4.03 (2H, t), 5.52 (2H, s), 6.60 (2H, d), 6.65 (1H, s), 6.69 (1H, s), 6.98 (2H, d), 7.28 (2H, d), 7.48 (2H, d), 9.80 (1H, brs), 11.58 (1H, brs).5343 C.sub.30 H.sub.30 N.sub.4 O.sub.4 511 (10) CI d.sub.6 -DMSO/400 MHz 1.85 (2H, m), 2.45 (6H, s), 2.37 (2H, t), 4.05 (2H, t), 4.05 (2H, t), 6.78 (1H, s), 6.81 (1H, s), 6.99 (2H, d), 7.10 (1H, m), 7.35 (2H, m), 7.52 (2H, d), 7.70 (2H, d), 7.79 (2H, d), 8.01 (2H, d), 10.2-10.3 (3H, br).5344 C.sub.31 H.sub.32 N.sub.4 O.sub.4 525 (10) CI d.sub.6 -DMSO/400 MHz 1.85 (2H, m), 2.15 (6H, s), 2.35 (2H, t), 4.05 (2H, t), 4.49 (2H, d), 6.76 (1H, s), 6.78 (1H, s), 6.97 (2H, d), 7.22 (1H, m), 7.32 (4H, m), 7.50 (2H, d), 7.61 (2H, d), 7.91 (2H, d), 9.05 (1H, t), 10.2-10.4 (2H, br).5345 C.sub.32 H.sub.34 N.sub.4 O.sub.4 539 (100) CI d.sub.6 -DMSO/400 MHz 1.85 (2H, m), 2.15 (6H, s), 2.35 (2H, t), 2.85 (2H, t), 3.49 (2H, m), 4.05 (2H, t), 6.76 (1H, s), 6.78 (1H, s), 6.99 (2H, d), 7.18-7.32 (5H, m,), 7.52 (2H, d), 7.61 (2H, d), 7.85 (2H, d), 8.55 (1H, brt), 10.20 (2H, br).5346 C.sub.33 H.sub.36 N.sub.4 O.sub.4 553 (5) CI d.sub.6 -DMSO/400 MHz 1.76-1.86 (4H, m), 2.15 (6H, s), 2.34 (2H, t), 2.62 (2H, t), 3.30 (2H, m), 4.02 (2H, t), 6.73 (1H, s), 6.76 (1H, s), 6.96 (2H, d), 7.12-7.28 (5H, m), 7.49 (2H, d), 7.59 (2H, d), 7.86 (2H, d), 8.45 (1H, brt), 10.20 (2H, br).5347 C.sub.34 H.sub.36 N.sub.4 O.sub.4 567 (5) CI d.sub.6 -DMSO/400 MHz 1.52-1.65 (4H, m), 1.85 (2H, m), 2.15 (6H, s), 2.35 (2H, t), 2.61 (2H, t), 3.30 (2H, m), 4.02 (2H, t), 6.73 (1H, s), 6.76 (1H, s), 6.96 (2H, d), 7.12-7.27 (5H, m), 7.50 (2H, d), 7.61 (2H, d), 7.86 (2H, d), 8.43 (1H, brt), 10.20 (2H, br).5348 C.sub.24 H.sub.24 N.sub.4 O.sub.3 417 (100) CI CDCl.sub.3 /400 MHz 2.26-2.35 (2H, m), 3.01 (6H, s), 3.39-3.45 (2H, m), 4.17-4.20 (2H, t), 6.96 (2H, d), 7.20 (1H, s), 7.25 (1H, s), 7.40 (2H, d), 7.55 (2H, d), 7.76 (2H, d).5360 C.sub.23 H.sub.24 BN.sub.3 O.sub.3 472 (100), ESI d.sub.6 -DMSO/400 MHz 1.80-1.91 (2H, m), 2.12 (6H, s), 2.30-2.38 470 (100). (2H, m), 4.00-4.08 (2H, m), 6.69 (1H, s), 6.74 (1H, s), 6.99 (2H, d), 7.45-7.52 (4H, m), 7.59 (2H, d), 10.19 (1H, brs).5360.HCl C.sub.23 H.sub.24 BrN.sub.3 O.sub.3.HCl 471 (100) CI d.sub.6 -DMSO/400 MHz 2.10-2.20 (2H, m), 2.79 (6H, s), 3.19-3.25 (2H, m), 4.09-4.25 (2H, m), 6.70 (1H, s), 6.75 (1H, s), 7.0 (2H, d), 7.45-7.80 (6H, m), 9.38 (1H, brs), 10.15 (1H, brs), 10.30 (1H, brs).5365 C.sub.23 H.sub.24 FN.sub.3 O.sub.3 410 (100) ESI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 2.28-2.35 (2H, m), 3.05 (6H, s), 3.41-3.48 (2H, m), 4.18-4.21 (2H, m), 6.96 (2.times.1H, s), 7.13-7.27 (4H, m), 7.39-7.48 (4H, m).5365.HCl C.sub.23 H.sub.24 FN.sub.3 O.sub.3.HCl 410 (100) ESI d.sub.6 -DMSO/400 MHz 2.10-2.20 (2H, m), 2.79 (6H.2), 3.09 (2H, m), 4.09 (2H, t), 6.75 (2H, s), 7.0 (2H, d), 7.24 (2H, t), 7.55 (2H, d), 7.58-7.61 (2H, m), 10.12 (1H, br.s), 10.25 (1H, brs).5366 C.sub.23 H.sub.24 ClN.sub.3 O.sub.3 416 (100) ESI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 2.29-2.35 (2H, m), 3.03 (6H, s), 3.45 (2H, t), 4.19 (2H, t), 6.97 (2H, d), 7.21 (1H, s), 7.26 (1H, s), 7.37-7.42 (4H, m), 7.48 (2H, d).5375 C.sub.23 H.sub.24 BrN.sub.3 O.sub.3 472 (50), CI d.sub.6 -DMSO/400 MHz 1.83 (2H, m), 2.15 (6H, s), 2.35 (2H, t), 4.02 470 (50). (2H, t), 6.70 (1H, s), 6.75 (1H, s), 6.97 (2H, d), 7.35 (1H, m), 7.50 (4H, m), 7.69 (1H, s), 10.30 (2H, br.).5373 C.sub.23 H.sub.24 FN.sub.3 O.sub.3 410 (100) CI d.sub.6 DMSO/400 MHz 1.85 (2H, m), 2.15 (6H, s), 2.35 (2H, t), 4.03 (2H, t), 6.75 (1H, s), 6.77 (1H, s), 6.99 (2H, d), 7.14 (1H, m), 7.32-7.47 (3H, m), 7.50 (2H, d), 10.20 (2H, br).5374 C.sub.24 H.sub.24 F.sub.3 N.sub.3 O.sub.4 476 (100) CI d.sub.6 -DMSO/400 MHz 1.85 (2H, m), 2.15 (6H.2), 2.35 (2H, t), 4.02 (2H, t), 6.75 (2.times.1H, s), 6.97 (2H, d), 7.29 (1H, m), 7.49-7.52 (5H, m), 10.20 (2H, br).5378 C.sub.23 H.sub.23 N.sub.5 O.sub.7 482 (100) CI d.sub.6 -DMSO/400 MHz 1.80-1.90 (2H, m), 2.15 (6H, s), 2.47 (2H, t), 4.05 (2H, m), 6.75 (1H, s), 6.85 (1H, s), 6.95 (2H, d), 7.50 (2H, d), 8.70 (3H, m).5380 C.sub.23 H.sub.23 Cl.sub.2 N.sub.3 O.sub.3.HCl d.sub.6 -DMSO/400 MHz 2.15 (2H, m), 2.77 (6H, s), 3.20 (2H, t), 4.10 (2H, t), 6.70 (1H, s), 6.78 (1H, s), 7.00 (2H, d), 7.50-7.55 (5H, m), 10.10 (1H, brs), 10.25 (1H, brs), 10.65 (1H, brs).5381 C.sub.23 H.sub.23 N.sub.5 O.sub.7.HCl d.sub.6 -DMSO/400 MHz 2.10-2.15 (2H, m), 2.80 (6H, s), 3.20 (2H, t), 4.10 (2H, t), 6.80 (1H, s), 6.90 (1H, s), 7.00 (2H, d), 7.54 (2H, d), 8.65-8.75 (3H, m), 10.30 (1H, brs), 10.90 (1H, brs).5385 C.sub.24 H.sub.27 N.sub.2 O.sub.3 S 438 (100) ESI CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 2.19-2.37 (2H, m), 2.52 (3H, m), 2.56 (6H, s), 3.43-3.49 (2H, m), 4.18-4.21 (2H, m), 6.96 (2H, d), 7.25 (2.times.1H, s), 7.32-7.46 (6H, m).5385.HCl C.sub.24 H.sub.27 N.sub.2 O.sub.3.HCl 438 (100) ESI d.sub.6 -DMSO/400 MHz 2.08 (3H, s), 2.10-2.17 (2H, m), 2.81 (6H, d), 4.11 (2H, d), 6.73 (1H, s), 6.75 (1H, s), 7.00 (2H, d), 7.30 (2H, d), 7.50 (2H, d), 7.52 (2H, d), 9.76 (1H, brs), 10.10 (1H, brs), 10.18 (1H, brs).5398 C.sub.23 H.sub.21 ClN.sub.4 O.sub.5 CDCl.sub.3 +CF.sub.3 CO.sub.2 D/400 2.29-2.35 (2H, m), 3.05 (6H, s), 3.42-3.49 (2H, m), 4.17-4.21 (2H, m), 6.98 (2H, d), 7.18 (1H, s), 7.29 (1H, s), 7.43 (2H, d), 7.55-7.60 (1H, dd), 7.68 (1H, d), 7.97 (1H, d).5398.HCl C.sub.23 H.sub.21 ClN.sub.4 O.sub.5.HCl d.sub.6 -DMSO/400 MHz 2.09-2.19 (2H, m), 2.72 (6H, s), 3.18 (2H, t), 4.11 (2H, t), 6.78 (1H, s), 6.80 (1H, s), 7.00 (2H, d), 7.55 (2H, d), 7.78 (2H, s), 8.18 (1H, s), 10.25 (1H, brs), 10.64 (1H, brs).5401 C.sub.25 H.sub.27 N.sub.3 O.sub.5 450 (20) CI d.sub.6 -DMSO/400 MHz 1.85 (2H, m), 2.15 (6H, s), 2.35 (2H, t), 3.85 (3H, s), 4.05 (2H, t), 6.75 (1H, s), 6.77 (1H, s), 6.97 (2H, d), 7.50 (2H, d), 7.65 (2H, d), 7.95 (2H, d), 10.25 (2H, brs).5401.HCl C.sub.25 H.sub.27 N.sub.3 O.sub.5.HCl d.sub.6 -DMSO/400 Mz 2.10-2.20 (2H, m), 2.80 (6H, s), 3.20-3.25 (2H, m), 3.86 (3H, s), 4.12 (2H, t), 6.78 (1H, s), 6.80 (1H, s), 7.00 (2H, d), 7.55 (2H, d), 7.65 (2H, d), 7.95 (2H, d), 10.10 (1H, brs), 10.22 (1H, brs), 10.40 (1H,__________________________________________________________________________ brs).

Number	Date	Country	Kind
9402806	Feb 1994	GBX
9402889	Feb 1994	GBX

Number	Date	Country
C 621862	Nov 1934	DEX
WO A 9404513	Mar 1994	WOX
9404512	Mar 1994	WOX

Pharmaceutical piperazine compounds

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Non-Patent Literature Citations (12)

Entry
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