AU693159B2 - Pharmaceutical piperazine compounds - Google Patents
Pharmaceutical piperazine compounds Download PDFInfo
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- AU693159B2 AU693159B2 AU16677/95A AU1667795A AU693159B2 AU 693159 B2 AU693159 B2 AU 693159B2 AU 16677/95 A AU16677/95 A AU 16677/95A AU 1667795 A AU1667795 A AU 1667795A AU 693159 B2 AU693159 B2 AU 693159B2
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- benzylidene
- piperazinedione
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Description
WO 95/21832 PCr/GB95/00302 1 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 synthesised 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 0 R, NH
(A)
HN
R
2 0 wherein one or both of R 1 and R 2 which may be the same or different, is: SUBSTITUTE SHEET (RULE 26) WO 95/21832 PTG9100 PCT/GB95/00302 -2 X, or a phenyl group which is substituted by x, C(O)X, OC(O)CH 2 X, OCH 2
CH
2 X, CH 2 X, CONH(CH 2 0O(CH 2 CH (OH) (CH 2 or -cqO)NH{(79.)-(Cus)MX or which is fused to a group X; (II) a phenyl group substituted by CH 2
NR,
2 Rl 3 OC(O) (CH 2 )IZ, CH(OR 12
(OR
13
(CH
2 ),1NR 14 C(O) (CH 2
),NR
12
R
13 1
CH
2
NR
1 2
(CE
2 nNR 15
R
16 or 0 (CHO) CH (OH) (CH 2 ~N (R 1 2
R
13 (III) a group CH=C(W)V; or (IV) a cyclohexyl group; and where appropriate, the other of R, and R 2 is a phenyl group optionally substituted by one or more groups independently selected from halogen, nitro, methoxy, NHC(O) R 1
CO
2 H' O(C 2 12
R
13
CH
2
Y(CH
2
).N(R
12
R
13 )1 Cl-C, alkyl and (CH 2 ),1C(O)OR 12 X is a naphthyl group or a five- or six-membered saturated or unsaturated heterocyclic group containing one or more heteroatoms, which heteroatoms may be the same or different and are independently selected from 0, N and S; the heteroatom(s) when nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl,
(CH
2
),CH
2 OH or SO 2 Me; the heterocyclic ring being optionally substituted by halogen, Me, MeS, phenyl, O (CE 2 nNR 12
R
13
-N(R
12
(CE
2
(R
12
R
13
(CH
2
,N(R,
2
R
13 or
-O(CH
2
).O(CH
2 )nN(R 2
R
13 or the heterocyclic ring optionally containing one or more carbonyl groups and being optionally fused to a benzene ring, which benzene ring is optionally substituted by 1 or 2 alkoxy groups, SUBSTITUTE SHEET (RULE 26) 3 Y is 0 or S; Z is a C 3 cycloalkyl group;
R
12
RI
3 and R 14 which may be the same or different, are hydrogen or Cl-C alkyl; Ris and R 16 which may be the same or different, are hydrogen or Ci-C, alkyl, or R 1 5 and Ri; form, together with the nitrogen atom to which they are attached, a 5- or 6membered heterocyclic group; W is hydrogen or a phenyl group; V is a phenyl group optionally substituted by one or more groups independently selected from nitro, alkoxy,
O(CH
2 )nNR 2 Rj 3 and NR 12
R
3 and m and n are each, independently, 0 or an integer having the value 1, 2, 3 or 4; or a pharmaceutically acceptable salt or ester thereof; with the exception of 3,6-diisonicotinylidenepiperazine-2,5-dione, 3,6-difurfurylidenepiperazine-2,5-dione, 3,6-di-(2-thiophenylidene)piperazine-2,5-dione and I* 20 3,6-dicinnamylidene-2,5-piperazinedione.
A Ci-C 6 alkyl group is, for example, a C,-C 4 alkyl group, such as a methyl, ethyl, propyl, i-propyl, n-butyl, sec-butyl or tert-butyl group.
A halogen may be F, Cl, Br or I.
25 In compounds of formula A free rotation may occur at room temperature about the single bonds connecting substituents R, and R 2 to the double bonds at positions 3 and 6 of the piperazine-2,5-dione ring.
In one embodiment at least one of R, and which may S 30 be the same or different, is chosen from X and a phenyl group which is substituted by X, C(O)X, OC(O)CH2X, OCH 2
CH
2
X,
or CH 2 X or which is fused to a group X; X is a five- or six-membered saturated or WO 95/21832 PCT/GB95/00302 4 unsaturated heterocyclic group containing one or two heteroatoms, which heteroatoms may be the same or different and are independently selected from 0, N and S, the heteroatom(s) when nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl,
-(CH
2 )nCH 2 0H or SO 2 Me, the heterocyclic ring being optionally substituted by hydrogen,'halogen, methyl, MeS, phenyl, (CH 2
NR
2
R
13 O (CH) N (R 1 2
R
1 or
-O(CH
2 )nO(CH,)nN(R 2
R
13 the heterocyclic ring optionally containing one or more carbonyl groups, and being optionally fused to a benzene ring; and the other of R, and
R
2 is a phenyl group optionally substituted at the 2, 3 or 4-position by CHNR, 1
R
1 3 (CH2n)NR 4 C (CH2) NR 1 2
R,
3 halogen, nitro, -NHC(0)R 2
-O(CH
2 )nN(R 12
R
13 or -CH 2
Y(CH
2 )nN(R 1 2
R,)
wherein Y is 0 or S. In a particularly preferred series of compounds the said other of R, and R 2 is a phenyl group substituted at the 4-position by -O(CH 2 )nN(R1 2
R
1
-C
2
(CCH
2 N (R 2
R
3 or (CH 2 )nNR 4 C mNR 12
R
3 In a further embodiment one of R, and R 2 is X, a phenyl group substituted by X, -CH2X, -OCH 2
CH
2
X,
O(CH
2 CH(OH) CH 2 X or wherein X is a or 6-membered saturated or unsaturated heterocyclic group as defined above which is optionally substituted and optionally fused to a benzene ring, for instance a pyridyl, imidazolyl, furyl, pyrrolyl, pyrrolidinyl, thienyl, piperazinyl, piperidinyl, morpholinyl, quinolyl, isoquinolyl or indolyl group; and the other of R, and R 2 is SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 5 a phenyl group optionally substituted at the 4-position by -0 (CH 2 N (R 12
R
13
-CH
2 Y nN (R 12
R
13 or
-(CH
2 )nNR 14 C(O) (CH,)NR 2 R1 3 In this embodiment it is particularly preferred for X to be a furyl, imidazolyl, pyrrolyl, thienyl, morpholinyl, piperidinyl or isoquinolyl group.
In a further embodiment, R 12 and R 13 which may be the same or different, are hydrogen or C 1
-C
3 alkyl and n is an integer of value 1 or 2.
In a yet further embodiment one of R, and R 2 is a phenyl group which is substituted by X, CO(X), OCO(O)CH 2
X,
OCH
2
CH
2 X, CH 2 X or which is fused to a group X, wherein X is a five- or six-membered heterocyclic ring containing one or two heteroatoms which may be the same or different, independently selected from 0, N and S, the heteroatom(s) when nitrogen being optionally substituted by methyl, and the heterocyclic ring being optionally fused to a benzene ring.
In another embodiment one of R, and R 2 is a phenyl group substituted by CH 2
NR
2
RI
3 OC(O) (CH, 2
CH(OR
12
(OR
13
(CH
2 nR 14 C(O) (CH 2 )mN(Ri 2
R
3 wherein R 2
R
1 and R 1 which may be the same or different, are independently selected from hydrogen or C 1
-C
3 alkyl; Z is a Cs or C 6 cycloalkyl group; and m and n are, independently, integers having the values 1, 2 or 3.
In a further embodiment R 12
R
13 and R 14 which may be the same or different, are independently selected from hydrogen and alkyl; Z is a cyclopentyl group; and SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 6 m and n are, independently, integers having the values of 1 or 2.
In a yet further embodiment one of R, and R 2 is a phenyl group optionally substituted by one or more groups independently selected from chloro, nitro, methoxy, NHCOR12, COH and O(CH 2 )nNR 12 .12 and Ra, which may be the same or different, are independently selected from hydrogen or methyl and n is an integer having the value 1 or 2.
In another embodiment one of R, and R 2 is a group CH=C(W)V, W is a phenyl group optionally substituted by one of more groups independently selected from nitro, methoxy and O(CH 2 )nNMe 2 and n is an integer having the value 1, 2,3 or 4.
In a further embodiment n is 1 or 2.
In a yet further embodiment one of R, and R 2 is a phenyl group optionally substituted by NHAc or methoxy.
In another embodiment one of R, and R 2 is cyclohexyl and the other is a phenyl group optionally substituted by NHC(0)R 12 In a further embodiment one of R, and R 2 is cyclohexyl and the other is a phenyl group optionally substituted by NHC(0)Me.
In a further embodiment R 3 is Cl-C 2 alkyl or
(CH
2 )nC(0)OR 12
R
12 is hydrogen or C,-C 2 alkyl and n is an integer of value 1 or 2.
In a yet further embodiment R 3 is methyl or and R.
2 is hydrogen or methyl.
Certain diketopiperazines have been disclosed as SUBSTITUTE SHEET (RULE 26% -7 having utility as bioactive agents. Yokoi et al in LT.
Antibiotics vol XLI No. 4, pp 494-501 (1988) describe structure-cytotoxicity relationship studies on a series of diketopiperazines related to neihumicinr 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 vrincristine.
Examples of specific compounds of formula A are as follows. The compound numbering is adhered to in the rest of the specification: 1926 (3Z,GZ) -3-Benzylidene-6- (4-imidazolyl)methylene-2,5piperazinedione.
15 1930 (3Z,6Z)-3-Benzylidene-6-(4-(l-imidazolyl)benzylidene)- 1929 (3Z,6Z)-3-Benzylidene-6-(4-(1imidazolylmethyl) benzylidene) 1927 (3Z, GZ) -3-Benzylidene-6- methylimidazolyl) )methylene-2, 1921 (0Z,GZ)-3-Benzylidene-6-(4dimethylaminocinnamylidene) 197G (3Z,GZ) (3-Dimethylaminopropoxy)benzylidene) -6- (1-imidazolyl) benzylidene-2, 1910 (3Z,6Z)-3-Benzylidene-6-(4-(2imidazolylethoxy) benzylidene) WO 95/21832 WO 9521832PCT/GB95/00302 8- 1923 (3Z,6Z)-3-Benzylidene-6- (4-nitrocinnamylidene-2,5pipere zinedione.
1657 (3Z,GZ) -3-(4-Aminomethylbenzylidene) (4rethoxybenzylidene) 1693 (3Z,GZ) (1-methanesulfonyl-3-indolyl)methylene-6- (4methoxybenzylidene) 1886 (3Z, 6Z) (4-Methoxybenzylidene) (4phthalimidoacetoxybenzylidene) 1922 (3Z,6Z)-3-Benzylidene-6-(,y-phenylcinnamylidene) piperazinedione.
1618 (3Z,6Z) -3-(1-tert-butoxycarbonyl-3-iridolyl)methylene- 6- (2-thenylidene) 1560 (3Z,6Z)-3-(2,6-Dichlorobenzylidene)-6-(1-tertbutoxycarbonyl-3 -indolyl) methylene-2, 1950 (3Z,6Z) -3-Benzylidene-6-(4- (2-diniethylaminoethoxy) -3methoxycinnamylidene) 1975 (3Z, 6Z) (3-Dimethylaminopropoxy)benzylidene) -6- (l-imidazolyjlmethyl)benzylidene) 1983 (3Z,6Z) -3-Benzylidene-6- (4-N-methyl-N- (Nmethylpiperidinyl) )aminomethylbenzylidene-2, piperazinedione.
1509 (3Z,6Z) -3-Benzylidene-6-(3-indolylmethylene)-2,5piperazinedione.
1542 (3Z,GZ) -3-(2,6-Dichlorobenzylidene)-6-(3furylmethylene) 1545 (3Z, 6Z) (3-Indolylmethylene) (4methoxybenzylidene) 1507 (3Z,EZ)-3-(4-Methoxybenzylidene)-6-(2- (1- SUBSTITUTE SHEET (RULE 26) WO 951'21832 PTG9IOO PCT/GB95/00302 9tertbutoxycarbonyl) pyrrolyl) methylene-2, 1506 (3Z, 6Z) (4-Methoxybenzylidene) (1-tertbutoxycarbonyl) indolyl)mrethylene-2, 1471 (3Z. 6Z) -3-Benzylidene-6- (1-tertbutoxycarbonyl) indolyl) methylene-2, 1474 (3Z,6Z) (4-Methoxybenzylidene) (2thieny2 'we-thylene) -2 1476 (3Z,6Z)-3.-(4-Methoxybenzylidene) (3-furylmethylene) 2, 1672 (3Z, 6Z) (Acetamidobenzylidene) -6cyclohexylmethylene-2, 1676 (3Z,6Z) -3-(4-Acetamidobenzylidene) -6-cinnarnylidene- 2, 1891 (3Z,6Z) -3-Benzylidene-6- (diethoxymnethylbenzylidene) 2, 1982 (3Z,6Z) -3-Benzylidene-6-(4-(N-methyl-N-(2dimethylaminoethyl) aminomethylbenzyl idene piperazinedione hydrochloride.
1884 (3Z,6Z)-3-Benzylidene-6-cyclohexylmethylene-2,5piperazinedione.
1845 (3Z,GZ) (4-Acetamidobenzylidene)-6-(3,4methylenedioxybenzylidene) -2,5 -piperaz inedione.
1950 (3Z,EZ) -3-benzylidene-6- (2-dimethylarninoethoxy) -3m,,ethoxycinnamylidene) SUBSTITUTE SHEET (RULE 26) WO 95/21832 WO 9/2 832PCTI/GB95OO3O2 10 1718 GZ) (2-Indolyjlmethylene) (4rethoxybenzylidene) 1808 (3Z,6Z) -3-Benzylidene-6- (3,4methylenedioxybenzylideie) 1809 (3Z,6Z)-3-(4-Methoxyben-.ylidene)-6-(3,4rethylenedioxybenzylidene) 1470 (3Z,6Z) -3-Benzylidene-6-(2-(1-' tertbutoxycarbonyl) pyrroly.) methylene-2, 5023 (3Z,GZ)-3- (4-Direthylaminomethylbenzylidene) (4-13dimethylarninopropoxy) benzylidene-2, 5026 (3Z,6Z) -3-(4-(3-Dirnethylaminopropoxy)benzylidene) -6- (1-imidazolyl) methylberizylidene) 5030 (3Z, 6Z) (3-Dimethylarninopropoxy)benzylidene) -6- (1-imidazolyl)benzylidene) 5367 Dimethylaminopropoxy) benzylidene) -2,5 -dioxo-3 piperazinylidene)m~ethyJlbenzoyl) -1,2,3,4tetrahydroisoquinoline.
5386 N-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)-4- ((3Z,EZ) -6-(4-(3-dimethylaminopropoxy)benzylidene) dioxo-3 -piperazinylidene) methylberizamide.
5397 N-(4-(1,2,3,4-Tetrahydro-2-isoquinolyl)butyl)-4- ((3Z,6Z)-6-(4-(3-dimethylaminopropoxy)benzylidene) dioxo-3-piperazinylidene) methylbenzamide.
5027 (3Z,GZ) (3-Dimethylaminopropoxy)benzylidene-3-(4pyridylmethylene) 5028 (3Z,6Z)-6- (4-(3-Dimethylaminopropoxy)benzylidene) -3- (3 -pyridylmethylene) SUBSTITUTE SHEET (RULE 26) WO 95/21832 PTG9100 PCT/GB95/00302 11 5041 (3Z, SZ) (3-Direthylaminopropoxy~benzylidene) -3furfurylidene-2, 5042 (3Z, 6Z) (3-Dimethylaminopropoxy)benzylidene) -3- (3 -Thenylidene) 5046 (3Z,6Z)-6- (3-Direthylaminopropoxy)benzylidene) -3- (2-Thenylidenie) 5052 (3Z,6Z) (3-Dimethylaminopropoxy)benzylidene) -3- (3-Furylmethylene) 5188 (3Z,6Z) (4-(3-Dimethylarninopropoxy)benzylidene) -3- (2-Naphthyjlmethylene) 5200 (3Z, EZ) (3--itethylarinopropoxy)benzylidene) -3- (1-Naphthylmethylene) 5032 (3Z,6Z)-6-Benzylidene-3-(4- (3-dimethylarnino-2hydroxypropoxy) benzylidene) 5040 (3Z, 6Z) -6-Benzylidene-3- (2-hydroxy-3morpholinopropoxy) benzylidene) -2,5 -piperazinedione.
5057 (3Z, GZ) -6-Benzylidene-3- (2-hydroxy-3- (1imidazolyl) propoxy) benzylidene) -2,5 -piperazinedione.
5043 (3Z,6Z)-6-Benzylidene-3-(4-(2-hydroxy-3-(4- (2hydroxyethyl) -1-piperazinyl) propoxy) benzylidene) piperazinedione.
5062 (3Z,6Z) (2-Direthylaminoethoxy)benzylidene) (3furylmethylene) 5071 (3Z,6Z) (2-Dimethylaminoethoxy)benzylidene) (3theny2.idene) 5072 (3Z,6Z) (2-Dimethylaminoethoxy)benzylidene) methylthio-2-thenylidene) 5054 (3Z, EZ) -6-Benzylidene-3- (2- SUBSTITUTE SHEET (RULE 26) WO 95/21832 WO 9521832PCT/GB95/00302 12 rorpholinoethoxy)benzylidene) 5055 (3Z, 6Z) -6-Benzylidene-3- (1imidazolyl) ethoxy) benzylidene) 2, 5053 (3Z, EZ) -6-Benzylidene-3- (1pyrrolidinyl) ethoxy) benzylidene) 2, 5069 (3Z, 6Z) (2- Dimethylaminoethoxymethyl) benzylidene) (3 -theriylidene) 2, 5077 Dimethylaminoethoxymethyl)benzylidene) (3furylmethylene) 5074 (3Z, 6Z) (4-Dimethylaminoacetamidomethyl benzylidene) (3-thenylidene) 5079 (3Z, GZ) (2-Bromobenzylidene) (4dimethylaminoacetamidonethylbenzylidene) piperazinedione.
5081 (3Z, SZ) (4-Dimethylaminoacetanidornethylbenzylidene) 3- (3-furylmethylene) 5061 (3Z, 6Z) -6-Benzylidene-3- (4dimethylaminoacetamidomethylbenzylidene) piperazinedione.
5073 (3Z, 6Z) (2- Dirnethylaminoethylthiomethyl) benzylidene) (3furylmethylene) 5078 (3Z, 6Z) (2- Dimethylaminoethyithiomethyl) benzylidene) (3thenylidene) 1912 (3Z,EZ) -6-B3enzylidene-3- (4- SUBSTITUTE SHEET (R~ULE 26) W095/21832 WO 95/ 1832PCTG95OO3OZ -13 dimethylaminoacetamidoaminomethylbenzylidene) piperazinedione.
5324 (3Z,GZ) -6-Benzylidene-3- (2-dimethylaminoethoxy) -2thienylmethylene) 5327 (3Z,6Z) -6-Benzylidene-3-(4- (2-dimethylaminoethoxy) -2thienylmethylene) -2,5 -piperazinedione.
53.35 (3Z,GZ) -6-Benzylidene-3- (2-direthylaminoethyl) -2thienyirnethylene) 5388 (3Z, 6Z) -6-Benzylidene-3- (2dimethylaminoethoxy) ethoxy) -2-thienylmethylene) piperazinedione.
5389 (3Z,SZ)-6-Benzylidene-3-(5- (6-direthylaminohexyloxy) 2-thienylmethylene) 5299 (3Z, GZ) -6-Benzylidene-3- (2dimethylatninoethyl) methylamino-2-thienylnethylene) piperazinedione.
5075 (3Z,6Z) -3-(2,S-Dichloro-3-thenylidene)-6-benzylidene- 2, 5371 1N-(4-(1,2,3,4-Tetrahydro-2-isoquinolyl)buty1)-4- GZ) -6-benzylidene-2, 5-dioxo-3piperazinylidene) methylbenzamide.
5391 N-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)-4- 6Z) -6-benzylidene-2, 5-dioxo-3piperazinylidene) methylbenzamide.
5394 N-(3-(1,2,3,4-Tetrahydro-2-isoquinolyl)propyl)-4gZ) -6-benzylidene-2,5-dioxo-3piperazinyl idene)miethylbenzatnide.
53.93 N-(4-(2-(1,2,3..4-Tetrahydro-2- SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB9500302 14 isoquinolyl)ethyl)phenyl-4- (3Z, 6Z)-6-benzylidene-2, dioxo-3-piperazinylidene)methylbenzamide.
5402 N-(4-(2-(1,2,3,4-Tetrahydro-2isoquinolyl)ethyl)phenyl)-4-((3Z,6Z)-2,5-dioxo-6-(4nitrobenzylidene)-3-piperazinylidene)methylbenzamide.
Compounds of formula A, may be prepared by a process which comprises either condensihg compound of formula
O-
AcN R 2 (i) 0 wherein R 2 is as defined above and -s optionally protected, with a compound of formula (II): RI-CHO (11) wherein R, is as defined above and is optionally protected, in the presence of a base in an organic solvent; or (ii) condensing a compound of formula 0 0 wherein R i is as defined above and is optionally protected, with a compound of formula (III):
R
2 -CHO (III) wherein R 2 is as defined above and is optionally protected, SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 15 in the presence of a base in an organic solvent; aiLd, in either case or 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 and (II) or and (III) may be modified, if desired, by converting R, into a different R, group. These optional conversions may be carried out by methods known in themselves. For example, a compound of formula A in which Ri comprises an ester group may be converted to a compound of formula A wherein the corresponding substituent is a free -COOH or OH group, by acid or alkaline hydrolysis at a suitable temperature, for example from ambient temperature to A compound of formula A in which either or both of R, and R 2 includes an -OH group may be converted into a compound of formula A wherein the corresponding substituent is esterified, for example by treating with a suitable carboxylic acid in the presence of an appropriate coupling agent, acid anhydride or acid chloride in an inert solvent.
A compound of formula A in which either or both of R, and R 2 includes a -CO 2 H group may be converted into a SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 16 compound of formula A wherein the corresponding substituent is esterified, for example by treating the carboxylic acid with a suitable CI-C 6 alkyl alcohol in the presence of 1,3dicyclohexylcarbodiimide in an inert solvent.
A compound of formula A in which either or both of R 1 and R 2 includes a free -COH group may be converted into a compound of formula A in which the corresponding substituent is a group -CON(RR 12 wherein R n and R 12 are as defined above, for example by treatment with ammonia or an amine in the presence of 1,3-dicyclohexylcarbodiimide in an inert solvent.
A compound of formula A in which either or both of R, and R 2 includes a free -C0,H group may be converted into a compound of formula A wherein the corresponding substituent is a -CH20H group by reduction, for example using borane in a suitable solvent such as tetrahydrofuran.
A compound of formula A in which either or both of R, and R 2 is a nitro group may be converted into a compound of formula A in which the corresponding substituent is an amino group by reduction under standard conditions, for example by catalytic hydrogenation.
Protecting groups for substituents on R i and/or R 2 in any of the compounds of formulae (II) and (III) are optionally introduced prior to step or step (ii) when either or both Rl and R 2 include one or more groups which are sensitive to the condensation reaction conditions or incompatible with the condensation reaction, for example a -COOH, -CH 2 OH or amino group. The protecting groups are SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 17 then removed at the end of the process. Any conventional protecting group suitable for the group R, and/or R 2 in question may be employed, and may be introduced and subsequently removed by well-known standard methods.
The condensation reaction between compounds and (II) or 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, potassium t-butoxide in t-butanol, or a mixture of tbutanol and dimethylformamide (DMF). The reaction is typically performed at a temperature from OoC to the reflux temperature of the solvent.
The compounds of formula may be prepared by a process comprising reacting 1,4-diacetyl-2,5piperazinedione with a compound of formula (III) as defined above, in the presence of a base in an organic solvent.
Similarly, the compounds of formula may be prepared by a process which comprises reacting 1,4-diacetyl-2,5piperazinedione 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 or 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 SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCTIGB95/00302 18 condensation between compounds and or and
(III).
The substituted aldehydes 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 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 may also be prepared by the microwave irradiation of a mixture comprising 1,4-diacetyla compound of formula (III) and potassium fluoride on alumina (as base) in the absence of solvent.
Compounds of formula may alternatively be prepared directly from 2,5-piperazinedione (glycine anhydride) by a process which comprises treating the 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 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 SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 19 process comprising the microwave irradiation of a mixture comprising a compound of formula as defined above, a compound of formula (II) and potassium fluoride on alumina, or (ii) a mixture comprising a compound of formula a compound of formula (III) and potassium fluoride on alumina, or (iii) a mixture comprising 1,4-diacetyl-2,5piperazinedione, a compound of formula a compound of formula (III) and potassium fluoride on alumina. The irradiation is performed in the absence of a solvent.
Compounds of formula may also be obtained directly by a process which comprises condensing together 1,4a 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 describeri above for the condensation reaction between, for example, compounds (1) and (II).
An alternative direct process for the preparation of compounds of formula comprises condensing together 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 comprises treating a compound of formula SUBSTITUTE SHEET (RULE 26) PCT/GB95/00302 WO 95/21832 20 0 X -,NH R'O R 2
(V)
0 wherein R 6 to R 10 are as defined above, X is a halogen and R' is a CI-C, alkyl group, with ammonia followed by acetic anhydride.
Compounds of formula may be prepared by an analogous process which comprises treating a compound of formula 0 RI OR' HNc
(V)
0 wherein R, to R 5 X and R' are as defined above, with ammonia followed by acetic anhydride.
X in formula or is typically iodine. R' is, for example, a C 1
-C
4 alkyl group such as a methyl, ethyl, propyl, i-propy-, butyl, sec-butyl or tert-butyl group.
A review of synthetic approaches to unsaturated 3monosubstituted and 3,6-disubstituted-2,5-piperazinediones is provided in Heterocycles, 1983, 20, 1407 (C.Shin).
Compounds of formula may be optionally washed after any of the above preparative procedures with one or more of the following: water, ethanol, ethyl acetate and diethyl ether.
Where appropriate compounds of formula may be SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 21 optionally recrystallised from a suitable solvent such as methanol or acetic acid.
Compounds of formula 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, acids or bases. Examples of inorganic bases include ammonia and carbonates, 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 a- or f-phenylethylamine, and heterocyclic bases such as piperidine, 1-methylpiperidine and morpholine. Examples of inorganic acids include hydrochloric acid, sulphuric acid and orthophosphoric acid.
Examples of organic acids include p-toluenesulphonic acid, methansulphonic acid, mucic acid and succinic acid.
Compounds of formula may also be converted into pharmaceutically acceptable esters. Suitable esters include branched or unbranched, saturated or unsaturated
C,-C
6 alkyl esters, for example methyl, ethyl and vinyl esters.
The diketopiperazines of formula both novel and known 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, SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCTGB95/00302 22 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 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 combiaed 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 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.
SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 23 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 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 (pnitroanili.e) which is detected spectrophotometrically at 405 nm (K.Nilsson et al, Fibrinolysis (1987) 1, 163-168).
The results of the assay are reported below.
The present compounds can be administered in a variety o1 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 to SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 24 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 mg, more typically 0.01 to 5 mg per kg body weight for a compound of the invention and from 5 to 500mg administered intravenously for the tPA. A suitable dosage regimen for the tPA is 100 mg given intravenously over 3 hcurs 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, of the total dose as an infusion over the subsequent 2 hours.
A diketopiperazine of formula or a pharmaceutically acceptable salt or ester thereof is formulated for use as a pharmaceutical or veterinary composition also comprising a pharmaceutically or vecerinarily acceptable carrier or diluent. The compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterlnarily 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 SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT~GB95/00302 25 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 SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 26 in water. A compound may be encapsulated within liposomes.
TESTING OF THE PRESENT COMPOUNDS AS PAI INHIBITORS Compounds of formula 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 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, and/or IC 0 values, of compounds of formula are presented in Table 1. IC, 5 values for some compounds, not shown in Table 1, are listed in Table 2 which follows Table 1.
TABLE 1: INHIBITION OF PAI-1 IN THE S2251 CHROMOGENIC SUBSTRATE ASSAY Compound Concentration in pm No.
100 50 25 12.5 6.25 1470 70 20 2 0 0 1471 80 60 20 6 0 1474 64 52 28 1476 68 48 18 1506 75 58 26 4 2 1507 78 62 45 1 1 SUBSTITUTE SHEET (RULE 26) 27 1509 58 35 1 1 1 1542 75 41 9 1 1 1545 87 64 39 5 1 1560 50 48 46 34 13 1G18 51 32 3 1 1649 34 0 1 0 1657 53 60 46 2 1672 70 44 13 4 2 1676 29 51 52 12 1 1693 89 2 1 0 1718 62 1 0 0 1 1808 76 48 73 2 1 1809 81 76 84 7 1 1845 14 30 49 60 53 1884 40 14 0 0 0 1886 42 40 18 6 0 1891 28 36 17 3 3 1910 27 36G 50 61 63 1912 30 55 29 22 17 1921 65 43 25 14 16 1922 13 11 26 13 14 1923 38 31 20 12 13 1926 36 35 12 6 19.27 33 39 20 22 14 1928 67 60 47 24 19 1929 27 45 59 48 16 1930 54 61 79 38 1975 7 0 0 0 0 197G 3 0 0 0 0 1950 19 3 2 2 1 1982 48 49 28 6 1 1983 34 14 0 0 0 0* a 0 0 0 00 Oe 005000 0 #0 WO 95/21832 CI*9130 PCr/GB95/00302 28 Compound Concentration in gsM ICSO k .100PM 50MM 2OpM 5023 1 5026 34 10 5027 12 8 8 5028 11 4 4 5030 20 7 6 5032 65 62 63 25.0-12.0 5040 0 1 0 5041 1 0 0 5042 77 64 42 20.0-10.0 5043 21 15 1 5048 55 19 11 100.0-50.0 5052 77 76 86 12.0-6.0 5053 68 64 56 25.0-12.0 5054 5 57 48 50.0-25.0 5055 69 69 70 6.0-3.0 5057 44 29 37 5061 43 48 60 25.0-12.0 5062 78 81 87 12.0-6.0 5069 70 71 75 10.0-5.0 5071 80 82 73 10.0-5.0 5072 60 61 61 10.0-5.0 5073 63 70 14 20.0-10.0 5074 47 57 26 20.0-10.0 5075 88 88 52 25.0-12.0 5077 34 46 42 5078 60 67 11 20.0-10.0 5079 44 58 14 20.0-10.0 5081 25 34 50 6.0-3.0 5188 90 94 3.50 5200 10 5205 1 56 33 1100.0 SUBSTITUTE SHEET (RULE 26) WO 95/21832 WO 9521832PCTIGB95O 0302 29 5206 72 78 5299 5324 9.00 5327 5335 5367 __18.00 5371 __12.00 5376 ____12.00 5379 __65 15.00 5386 __18.00 5388 9.00 5388 .HC1 60 12.00 5389 55 2.50 5389 .HC1 57 2.50 5,391 64 6.50 5391.HC1 100 3.50 5393 76 14.00 5393 .HC1 58 20.00 5394 59 16.00 5394 .HC1 17.00 5397 42 5397.HC1 21 5402 37 5402 .HC1 37 TABLE 2 Compound, No. 1C50 (pm) 1470 50.0 100.0 1471 25.0 50.0 1474 25.0 50.0 1476 50.0 100.0 1506 25.0 50.0 1507 25.0 50.0 SUBSTITUTE SHEET (RULE 26), WO 95/21832 WO 95/ 1832PCTIGJI95100302 1509 50.0 100.0 1542 50.0 100.0 1560 50.0 100.0 1618 50.0 100.0 1652 25.0 50.0 1657 25.0 50.0 1672 50.0 100.0 1676 12.0 25.0 1693 50.0 100.0 1718 50.0 100.0 1808 25.0 12.0 1809 25.0 12.0 1845 10.0 1888 50.0 -100.0 1910 5.0 -10.0 1912 25.0 -50.0 1921 100.0 -50.0 1928 25.0 50.0 1929 25.0 12.0 1930 25.0 12.0 1982 50.0 25.0 Reference Example 1: Preparation of (3Z)-1-acetyl-3benzylidene-2, 1,4-Diacetyl-2,5-piperazinedione (25.0g, 126 mind), which is compound mentioned in Reference Example 3, was heated at 120-1300C in DMF (200 ml) with triethylamine (17.6 ml, 126 inmol) and benzaldehyde (13.0 ml, 126 inmol).
After 4 h the mixture was cooled to room temperature and SUBSTITUTE SHEET (RULE 261 WO 95121832 PCTG395IOO302 -31 poured into EtOAc (1000 ml), and washed three times with brine. Any solid formed at this stage was filtered off.
The filtrate was dried (MgSO0 4 and the solvent removed in vacuo. The residue was recrystallised from EtOAc:Hexane to give 11.78 g (38k) of the title compound as a yellow solid.
1H1 NMR (CDC1 3 400 MHz) 5=2.69 (3H, s) 4.54 (2H, s) 7.20 (1H, s) 7.40 (3H1, m),'7.48 (2H, in), 7.93 (1H1, br.s)
MS(DCI,NH
3 262 (MNH 4 2 016), 2 45 (MHW, 5315), 220 (5216), 204 (100k) 203 (100%) Microanalysis C H N Calc 63.93 4.95 11.47 Found 64.11 5.02 11.41 64.5 4.90 11.44 Alternatively (3Z) -1-acetyl-3-benzylidene-2,5piperazinedione can be produced as follows: 0 0 OEt HN
H
0 0 (16) (17) 0 NAc
HN,,
0 (18) SUBSTITUTE SHEET (RULE 26) WO 95/21832PCI)9032 ?C'17G)395/00302 32 Compound 16 is treated with ammonia and subsequently with acetic anhydride to yield the title compound.
Reference Example 2: Preparation of (3Z)-1-acetyl-3-(4acetamidobernzylidene) Diperazi?2edione 1,4-Diacetyl-2, 5-piperazinedione (10.0Og, 50 mmol), prepared by the published procedure mentioned in Example 3, was stirred in DMF (40 ml) with 4-acetatnidobenzaldehyde (8.24 g, 50 mmol) and triethylamine (7 ml, 50 mmol) and heated to 1200C. After 2% h the mixture was cooled to room temperature, diluted with EtOAc (100 ml) and stirred overnight. The solid formed was collected, washed with EtOAc and dried to give 8.46 g of a yellow solid.
1-H NMR (CDCl 3 +TFA, 400 MHz) 6=2.32 (311, s) 2.72 (3H, s) 4.68 (2H, s) 7.36 (11i, s) 7.45 (2H1, d, J=8Hz) 7.60 (2H1, d, J=8Hz) Microanalysis C H N Calc 59.80 5.02 13.95 Found 60.08 5.09 13.89 60.11 5.07 13.86 Reference Example3: Preparation of 1,4-Diacetyl-2,5piperazinedione o 0 r1-NH ?--NAc HN 11ANY 0 0 (7 (8) SUBSTITUTE SHEET (RULE 26) WO 95/21832 FTG9/00 VCTIGD95/00302 33 1,4-Dilacetyl-2,S-piperazine dione was prepared by the published procedure Marcuccio and J.A. Elix, Aust. J. Chemn., 1984, _37, 1791).
Reftrence Exampile 4: (3Z)-1-Acetvl-3-(4n methoxvbenzvlidene) Rii~eraz inedione o 0 NAc NH -~OMe AcN ACN o 0 (9) (3Z) -l-Acetyl-3- (4-methox-ybenzylidene) piperazinedione was prepared by the published procedure Yokoi, L-M. Yang, T. Yokoi, R-Y. Wu, and K-H. Lee, J.
Antibiot., 1988, 41, 494).
Reference ExaM~le 5: Preparation of (3Z)-1-acety1-3-(2,6dichlarobenzvlidene) Diperazinedione 2,4-DiacetyJ-2,5-piperazinedione prepared by the published procedure mentioned in Reference Example 3, was stirred in DMF with 2,6-dichlorobenzaldehyde and triethylamine and heated to 120-1300C for 1-3h. The title compound was obtained with a yield of SUBSTITUTE SHEET (RULE 26) WO 95/21832 WO 9521832PCT/GB95/00302 -34 Reference Exa-mple 6: Preparation of (3Z)-1-acetYl-3-(4dimethyrlamino) propoxvbenzylidene) 2, l,4-Diacetyl-2,5-piperazinedione, prepared by the published procedure mentioned in Reference Example 3, was stirred in DMF with 4- (3 -dimethylamino) propoxybenzaldehyde and triethylamine and heated to 120-1300C for 2-4h to give the title compound.
By the same method, using 4-(2dimethylamino)ethoxybenzaldehyde in place of the abovementioned aldehyde, (3Z) -1-acetyl-3- (2dimethylamino)ethoxybenzylidene) -2,5-piperazinedione was prepared.
is Reference Example 7: (3Z, 6Z) (4-Hvdroxvbenzvlidene) -6 (4-methoxvbenzylidene) piperazinedione (3Z,EZ) (4-Acetoxybenzylidene) (4methoxybenzylidene)-2,5-piperazinedione was treated with aqueous sodium hydroxide in THF at room temperature for 8 hrs to give the title compound (1519) in 3011 yield.
Example 1: Preparation of 1470 3(Z) -1-Acetyl-3-benzylidene-2, 5-piperazinedione (one equivalent), which is compound 18 prepared according to Reference Example 1, was treated with 1-tertbutoxycarbonylpyrrole-2-carboxalde.,;de in the presence of SUBSTITUTE SHEET (RULE 26) CIRC-- IIC IIIIIIIII~111~ C WO 95/21832 PCTIB95/0030211 35 Cs 2
CO
3 (1-1.1 equivalents) in DMF at 80-100oC for 1-6 hours. The title compound was obtained in 24% yield.
The crude product was optionally, washed with water, methanol, ethyl acetate or diethylether and optionally recrystallised from methanol as appropriate.
By the same method, but replacing 1-tertbutoxycarbonylpyrrole-2-carboxaldehyde by the appropriately substituted aldehyde or benzaldehyde, the following compounds were prepared: Compound Yield 1471 52 1652 37 1983 1921 54 1922 43 1924 44 1910 31 1926 27 1927 26 1928 1929 1930 1912 33 5032 5040 5043 24 5053 44 5054 22 5057 43 5058 16 SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB~5/00302 36 Example 2: Preparation of 1474 3(Z)-l-Acetyl-3-(4-methoxybenzylidene)-2,5piperazinedione prepared according to Reference Example 4, was treated with 2-thiophenecarboxaldehyde in the presence of Cs 2 C0 3 (1-1.1 equivalents) in DMF at 80-100oC for 1-6 hours. The title compound was obtained in 76% yield.
By the sanze method, but replacing 2thiophenecarboxaldehyde by the appropriately substituted aldehyde, the following compounds were prepared: Compound Yield 1476 54 1479 84 1506 67 1507 7 The crude product was optionally washed with water, methanol, ethyl acetate and diethylether and optionally recrystallised from acetic acid or methanol as appropriate.
Example 3: Preparation of 1884 3(Z)-l-Acetyl-3-benzylidene-2,5-piperazinedione (1 equivalent), prepared according to Reference Example 1, was treated with cyclohexanecarboxaldehyde (4 equivalents) in the presence of 0.5M potassium tert-butoxide in tertiary butanol (2 equivalents) in DMF at 0-100oC for 2 hours. The title compound was obtained with a yield of 58%.
Purification was effected by recrystallisation from acetic acid.
1672 was prepared as above but replacing the 3(Z)-1- SUBSTITUTE SHEET (RULE 26) I)CT/C.095/00302 WO 95/21832 JCIJ9IOO 37 acetyl-3-benzylidene-2, 5-piperazinedione with 3(Z)-1acetyl-3-(4-acetamidobenzylidene) 5-piperazinedione. The reaction was maintained for 18 hours. A low yield was obtained.
Example 4: g~eparation of 1676 I-Acetyl-3- (4-acetamidobenzylidene) piperazinedione (one equivalent), prepared according to Reference Example 2, was treated with cinnamaldehyde in thp presence of CsCQ3 (1-1.1 equivalents) in DMF at 80-100oC for 1-6 hours. The title compound was obtained in 46k yield.
Example 5: Preparation of 1618 1, 4-Diacetyl-2, 5-piperazinedione, prepared by the published procedure mentioned in Reference Example 3, was stirred in DMF with 2-thiophenecarboxaldehyde (1 equivalent) and triethylamine (1 equivalent) at 1200C for 2-4h. (3Z) -1-Acetyl-3-(2-tnenylidene) was obtained with a yield of 36t.
(3Z) -1-Acetyl-3- (2-thenylidene) (1 equivalent) was stirred in DMF with 3-1-tertbutoxycarbonylirndole-3-carboxyaldehye (1 equivalent) in the presence of CSCO 3 (1-1.1 equivalents) at 80-100CC for 2- 3h. The title compound was obtained with a yield of 14k.
SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 38 Example 6: Preparation of 1542 3(Z)-l-Acetyl-3-(2,6-dichlorobenzylidene)-2,5piperazinedione (1 equivalent), prepared according to Reference Exampl~ 5 was treated with 3-furaldehyde (1 equivalent) i: the presence of CsCO 3 (1-1.1 equivalents) in DMF at 80-100oC for 2-5 hours. The title compound was obtained in 46% yield.
By the same method, but replacing 3-furaldehyde by the appropriately substituted aldehyde, 1560 was obtained with a yield of 39%.
Example 7: Preparation of 1982 3(Z)-l-Acetyl-3-benzylidene-2,5-piperazinedione (1 equivalent), as prepared in Reference Example 1, was treated with 4-(N-(3-dimethylaminoethyl)-Nmethyl)aminomethylbenzaldehyde in the presence of CsCO 3 (1-1.1 equivalents) in DMF at 80-100oC for 1-6h to give (3Z,6Z)-3-Benzylidene-6-(4-(N-dimethylaminoethyl)-Nin a yield of Compound 1982, the hydrochloride salt of (3Z,6Z)-3- Benzylidene-6-(4-(N-(3-dimethylaminoethyl)-Nwas prepared by bubbling HC1 gas through a solution of the corresponding free base in THF, followed by evaporation to dryness. The yield was SUBSTITUTE SHEET (RULE 26) WO 95/21832 WO 95/21832 CJ'1095/00302 39 Examr~le 8: Preparation of 1976 3 -l-Acetyl-3- (3dimethylamino) propoxybenzylidene) -2,5 -piperaz inedione (1 equivalent), prepared according to Reference Example 6 was treated with 3-(imidazol-l-yl)benzaldehyde (1 equivalent) in the presence of CS 2
CO
3 (1-1.1 equivalent) in DMF at 900C for 2-4 hours. The title compbund was obtained in 52 yield.
Examip1e 9: Preparation of 1886 1519 (1 equivalent), prepared in Reference Example 7, was treated in DMF with sodium hydride (1 equivalent) and N-phthaloylglycyl chloride (1 equivalent) in DMF at room temperature for 4h. The title compound was obtained with a yield of Prep~aration of 5026 0 N CHO NH e 10.1A 00 N NH 0N O~ NMe2 I NH 5026 SUBSTITUTE SHEET (RULE 26) WO095121832PCIBIO00 PCT/GB95/00302 40 (3Z) -1-acetyl-3- (3-dimethylamino)propoxyprepared as in Reference Example 6, was treated with compound 10.1 in dimethylforrnamide (DMF) in the presence of CS 2 CO, at a temperature of 80OC-90 0 C for 2-4 hours. Compound 5026 was obtained in 95k~ yield.
By an analogous process, usin the appropriately substituted benzaldehyde in place of compound 10.1, the following compounds were prepared: Compound No. 1Yield 5030 5048 72 5,188 Example-11: Preparation of 5027 CHO 0 NH e 6 AcN
N
5027 SUBSTITUTE SHEET (RULE 26) WO 95/21832 PTG9IOO PCT/GB95/00302 41 (3Z) -1-acetyl-3- (3-dimethylamino) propoxybenzylidene) prepared as in Reference Example 6, was treated with compound 11.1 in DMF in the presence of Cs 2
CO
3 at BOOC-90 0 C for 2-4 hours. Compound 5027 was produced in 33!% yield.
By the same method, but replacing 11.2. by the appropriately substituted aldehyde, 'the following compounds were prepared: Compound No. Yield M% 0 5028 44 5029 5041 39 5042 39 5046 37 50:32 58 Examiple 12: Preparation of 5023
OHC
12.1 Me 2
N.
5023 SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 42 Compound 12.1 was treated with 4-(3dimethylamino)propoxybenzaldehyde in DMF in the presence of Cs 2
CO
3 at a temperature of 80 0 C-90 0 C for 2-4 hours.
Compound 5023 was obtained in 36% yield.
Example 13: Preparation of 5062
CHO
0 NH O NMe 2 AcN0 i 0 13.1 5062
I
(3Z)-l-acetyl-3-(4- piperazinedione, prepared as in Reference Example 6, was treated with compound 13.1 in DMF in the presence of CsCO 3 at a temperature of 80 C-90°C for 2-4 hours. Compound 5062 was obtained in 12% yield.
By the same method, but using the appropriately substituted aldehyde in place of compound 13.1, the following compounds were prepared: SUBSTITUTE SHEET (RULE 26) WO 95/21832 CGBIO02 PCT/GB95/00302 43 Compound No. Yield M% 5071 41 5072 86 Example-14: Preparation of co~mpounds of formula (1) 0 Ar ""NAc HN
C
OHG~aSubst.
14.1 14.2 Compound (1) The 2,5-piperazinedione derivative 14.1 was treated with the aldehyde 14.2, the groups Ar and Subst. being as specified below, in DMF in the presence of CSCO 3 at 80 0
C-
0 C for 2-4 hours. The compounds of formula MI listed below were prepared: SUBSTITUTE SHEET (RULE 26)) WO 95/21832 WO 95/1832 CTGB9SIO 0302 44 Ar Subst. Compound Yield M% of formula Phenyl -CH 2 S (CH 2 2 NMe 2 5058 16 3-furyl -CH 2 S (CH 2 2 NMe 2 5073 33 3-thienyl -CH 2 S (CH 2 2 NMe 2 5078 38 3-thienyl -CI 2 kHC (O)CH 2 NMe 2 5074 83 2-bromophenyl -CH 2 NHC (0)CH 2 NMe 2 59079 28 3-furyl -CH 2 NHC (O)CH 2 N~e 2 5081 68 3-thienyl -CH 2 0 (CH 2 2 NMe 2 5069 29 3-furyl -CH 2 O (CH 2 2 N~e 2 5077 Example 15: Preparation of com~ounds-of formula (I) 0 Ar NAc HN 1 0 15.1 15.2 Compound (I) SUBSTITUTE SHEET (RULE 26) WO 95/21832 pCTGB95IOO302 The 2,5-piperazinedione derivative 15.1 was treated with the aldehyde 15.2 in which R 20 and R 2 1 are both H or are both OMe, the substituent Ar and linking group A being as specified below, in DMF in the presence of CS 2
CO
3 at 80 0 C to 90 0 C for 2-4 hours. The compounds of formula lis~ted below were prepared. In 5391, 5394 and 5371 R 2 and R 2 1 are both H. In 5393 and 5402 R 2 0 and R 2 1* are OMe.
Ar A Compound Yield M% of Formula Phenyl (CH 2 2 5391 21.
Phenyl (CH 2 3 5394 47 Phenyl (CH 2 4 5371 56 [Phenyl H) 5334 4-nitrophenyl 5402 62 Example 16: Preparation of compounds of formula (1) OHC S 16.1 0 HI y 0 SUBSTITUTE SHEET (RULE 26)) WO 95/21832 rTG9IOO pCr/GD95/00302 46 (3Z)-1-acetyl-3-benzylidene-2,5-dione prepared as in Reference Example 1 (compound 18), was treated with the aldehyde 16.1 in which substituent Y was as indicated below, in DMF in the presence of Cs 2
CO
3 at 80*C-90'C for. 2-4 hours. The compounds of formula listed below were prepared: Y Compound of Yield f formula -O0(CHO 2 NMe 2 5324 34 4 -0(CHO) 2 NMe 2 5327 51
-(CHO)
2 NMe. 5335 -O0(CHO) 2 0 (CHO) 2 N4e 2 5388 12 -O0(CHO 2 6 N~e 2 5389 (Me) (CH 2 ),NMe 2 5299 2 By the same method, but using 4-carboxaldehyde in place of compound 16.1, 5075 was prepared in 319. yield.
Examiple 17: Preparation of salts 1. Hydrochloride salts of the following compounds of formula were prepared by bubbling HCl gas through a solution of the corresponding free base in tetrahydrofuran (THFf) at room temperature. The salt was recovered in the yield indicated.
SUBSTITUTE SHEET (RULE 26)' WO 95/21832 rIJso32 PCf/GB95/00302 47 Compound of Hydrochloride Yield(% formula salt 1975 5026 1976 5030 5048 5048.HC1 72 5188 5206 24 5200 5205 31 5367 5376 47 5397 5397.2HC1 36 5041 5041.HC1 63 5042 5042.HC. 51 5046 5046.HC1 32 5052 5052.HC1 58 5023 1988 5062 5062.HCl 5071 5071.HCl 5072 5072.HC1 1910 5055 57 1912 5061 47 5032 5032.HC1 39 5053 5053.HCl 5054 5053.HCl 88 5073 5073.HC1 76 5078 5078.HC1 78 1912 5061 47 5074 5074.HCl 51 5079 5079.HC1 73 5081 5081.HCl 76 5069 5069.HC1 5077 5077.1d 5324 5324.1 68 5336 5336.1 74 5335 5335.1 SUBSTITUTE SHEET (RULE 26)1 WO 95/21832 CI,9102 IICT/CB95/00302 48 5388 5388.HCl 79 5389 5389.HC1 5391 5391.HC.- 5394 5394.HC1 5371 5379 2. Hydrochloride salts of the following compounds of formula were prepared by bubbling HCl gas through a solution of the corresponding free base in hot DMF. The salt was recovered in the yield indicated.
Compound of Hydrochloride Yield formula 5386 5386.2HC1 79 5393 5393.HC1 5402 5402.HC1 52 3. Hydrochloride salts of the following compounds of formula were prepared by treating the free base with 2M HCl: Compound of Hydrochloride Yield M% formula salt 5027 5027.HC1 67 5028 5028.HCl 92 5029 5029.HC1 76 5040 5040.HCl SUBSTITUTE SHEET (RULE 26)0 WO 95/21832 PcT/GD95/00302 49 4. 5043.HC1, the hydrochloride salt of 5043, was prepared by bubbling HC1 gas through a solution of 5043 in MeOH. 5057.HC1, the salt of 5057, was prepared by bubbling HCl gas through a solution of 5057 in THF following by recrystallisation from MeOH.
Example 18: 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 0 ml). The resulting paste is used to granulate the powder. The granulate is dried and bre2en 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.
SUBSTITUTE SHEET (RULE 26) WO 95/21832 PCT/GB95/00302 50 Example 19: Characterisation of compounds of formula
A
The compounds prepared in the preceding Examples, were characterised by mass spectroscopic, microanalytical, proton nuclear magnetic resonance and, in some cases, infra-red techniques. The results are set out in the Tables which follow: SUBSTITUTE SHEET (RULE 26) SNo. Ilol. Formula Mass spec data 1 H nmr data mass mode solvent (field) J 1910 C 23
H
2
GN
4 0 3 401(100) CI d 6 -DMSO/400fflz 4.28-4.32 (2HMt. 4.35-4.40 (2H.t).
(14H~m). 10.15 (2H.brs).
5023 C 26
H
32
N
4 0 3 449(100) El CDCl 3 /40M-z 2.00 2.25 (12H~s). 2.46 (2H.t).
3.45 4.05 6,95-7.42 (lOHin). 8.15 (2H.brs).
5026 C 27
H
29
N
5 0 3 2HC1 d 6 -DMSO/400MHz 2.12 2.73 .21 (2H~m), 4.11 5.48 6.76 (2H.s).
7.00 7.47 7.50 (2H.
7,55 (2HAd) 7.65 (Ills). 7.77 (1H~s).
9.21 10.12 (2H-.brs). 10.45 (H.brs).
5027 C 22
H
24
N
4 0 3 2HC1 COC1 3
+CF
3 COH/400 MHZ 2.00 3.00 (61I~s). 3.45 (2H.m).
3.90 (2Ht). 7.00 7.15 (ills).
7.35 (ills). 7.45 (2HA). 8.00 (2H~d).
(21Ud).
5028 C 22
H
24
N
4 0 3 2HCl CDC1 3
+CF
3 CO/400Mflz 2.35 3.00 (61ks). 3.45 2HAt)i 4.15 7.00 7.15 (il~s).
7.30 (1H.s) 7.45 (2HAd) 8.10 (1H.t).
(1HAd) 8.95 (IH, 9.15 (1H.s).
5030 d 6 -DMSO/40'UMHz 2.18 (2H.rn). 2.77 3.20 (2H~m).
4.10 6.77 (ills). 6.81 (1H~s).
7.00 7.51 (2HAd. 7.65 (2H,m).
7.71 7.85 7.96 (1l-Is).
8.29 9.60 10.21 (1l-.brs). 10.50 (1H~brs), 10.61 (H.brs).
No. Hal. Formula Mass spec. data l nmr data mass mode solvent (field) 6 5032 C 23 H250 3 0 4 HC1 408(20). CI d 6 -DMSO/400MHz 2.83 3.23 (2H~rn). 4.02 (2KAd) 306(30) 4.30 (1H~ni). 5.96 (1H,brd), 6.77 (1H~s).
6.78 7.02 (2HAd) 7.33 (1HAn 7.42 (2H~ni). 7.55 (HMA, 9.70 (1H~brs).
(2H-.br).
5040 C,,H 27
N
3 0 5 HCl 450(10) CI d 6 -DMSO/400MHz 3.20-3.55 3.75-4.00 MA~n. 4.02 (2HAd. 4.39 5.99 (1I-.brs), 6.'77 6.78 7.02 (2HAd. 7.33 (1HAm. 7.45 7.55 MAlni. 10.20 5041 C 21
H,,N
3 0 4 .HIA~ 382(100) El d.-DMSO/400HHz 2.09 (2HAm) 2.80 3.20 (2H~nO.
4.09 6.63 6.64 (1HAm 6.78 (ills). 6.89 (1HAm 7.0 (2H.d).
7.54 7.90 9.45 (1H~brs).
(1H.brs). 10.14 (1H~brs) 5042 C 21
H
23
N
3 0 3 S. HCl 398(35) El d 6 -DMSO/400MHz 2.09 2.79 3.18 (2H, 4.10 MALt) 6.76 (ills). 6.85 (1H,s).
7.00 (2HAd) 7.41 (1HAm. 7.51 (2H.
7.62 (1HAn. 7.94 (lllm. 9.89 (1H~brs).
(1H.brs). 10.10 (1H.brs).
5043 C 27 H32N 4
O
5 -HCI 493(100) CI d 6 -DMSO/400HHz 3.10-3.85 (14Hlm). 4.02 4.40 (1H,brs), 6.77 6.78 (ills). 7.02 7.32 (1HAm. 7.42 (2Wm. 7.55.
10.20 (211.s).
5046 C2,H 2 3 N.0 3 S. HCl 398(23). El d 6 -DMSO/400MHz 2.09 (2HAn. 7.28 3.12 (2H.m).
169(100) 4.10 6,78 (ills). 6.94 (ills).
7.00 (21HA). 7.18 (1HAm. 7.54 (2H-ld), 7.58 (1HAn. 7.76 (1HAm. 9.75 (1H~brs).
(1H.brs).
No. Mol. Formula Mass spec. data H nmr data mass mode solvent (field) is 5048 C 25 1- 2 8
N
4 0 4 HCl 485 (100) El d 6 -OMSO/400MHz 2.05 2.14 2.79 (6H~d), 3.20 (2HAnO 4.13 6.70 (ills).
6.75 (ills). 7.0 7.48 (2H.
7.51 7.62 9.94 (IH.brs).
(1H.brs). 10.20 (1H.brs).
5052 d 6 -DMSO/400MHz 2.15 (2HAm) 2.28 3.20 (2H.m).
4.10 (2HMt, 6.68 6.75 (1H~s), 6.94 7.00 (21-14) 7.54 (2HAd) 8.23 (1H.s).
5053 C 24
H
2 5
N
3 0 3 HC I COC1 3
+CF
3
CO
2 0/400MHz 2.20 3.20 3.70 (2H~m).
4.00 4.45 7.00 (2H.d).
7.39 (ills). 7.45 (7H.m).
5054 C 2 4
H
25
N
3 0 4 HOCDCl 3
+CF
3
CO
2 D/400MHz 3.25 3.67 3.85 (2H.m).
4.05-4.20 4.47 C2H.m). 6.97 (2H.d) 7.20 7.26 C1H~s). 7.39- (7H.m).
5055 C 23
H
20
N
4 0 3 HC1 401(100) ESI d 6 -DMSO/400MHz 4.40 4.60 6.73 (1H~s), 6.75 6.99 (2HAd) 7.30 -7.55 7.65 7.90 9.10 10.10 10.15 (ills).
(1H.brs) 5057 C 2 4 F1 22
N
4 0 4 HO1 d 6 -OtSO/400MHz 4.00-4.05 4.20-4.32 4.48 6.77 6.78 7.03 (2H-1d), 7.32 7.42 7.55 (VA.m. 7.71 (1HAm. 7.77 9.12 10.20 (2H.brs).
No. Hal. Formula Mass spec. data 1Hnmr data mass mode solvent (field)6 (intensity) 5058.HC1 C 23 H-1 2
N
3 0 2 S.I-ICl 409(15) CI d 6 -DMSO/400MHz. 2.70-2.75 (8HAm. 3.20-3.25 (2HA~m, 3.85 (21-ks). 6.78 7.32-7.55 (9H.
9.68 (1H~brs). 10.22 (il-1s). 10.24 (ils) 5061 C 2 3
H
2 4
N
4 0 3 -HC' d 6 -OMSO/400Mlz 2.84 (R1ls). 3.95 (211.s), 4.40 (2HAd 6.75 (ills). 6.77 (ills). 7.33-7.55 O9H~M. 9.15 9.85 (ll-,brs), (1H.brs). 10.25 (iH~brs).
5062 C 20
H
2 jN 3 0 4 HClI d 6 -DMSQ/400HHz 2.76 3.51 (2H. 4.38 (2H.t).
6.66 6.75 (ills). 6.91 (ills).
7.05 7.55 7.74 (ills).
9.76 (Ills).
5069 C 21
F
23 N0 3 S.HC1 397(10) CI d 6 -OMSO/400MHz 2.80 (6Hls). 3.30 3.76 (2H~t).
4.58 (2Hls). 6.82 (ills). 6.87 (1H~s).
7.45 7.58 7.65 QIl1m), 8.00 1l-I~s), 9.78 (ills). 10.02 (ills).
(1H.s).
5071 C 2
,H
2 1 N,0 3 S .HCl d 6 -OMSO/40M-z 2.86 (61Id). 3.53 (2HAm) 4.38 (2H~t), 6.78 (ills). 6.84 7.07 (2H.d).
7.43 (il-ki). 7.58 7.65 (1H.m).
7.96 (iHAm, 9.55 10.05 (H.brs). 10.13 (1H.brs).
5072 C 2
,H
23
N
3 0 3
S
2 HC1 d 6 -DMSO/40M-z 2.58 2.78 (6lls). 3.44 (21km).
I4.36 6.77 6.85 (il-1s).
7.05 (2HAd. 7.12 (ilkd. 7.52 (iH.
10.20 No. Hal. Formula Mass spec. data 'H nmr data mass mode solvent (field)6 (intensity) 5073 C 2 jH 23
N
3 0 3 S 398(15). El CDCl 3
+CF
3
CO
2 D/400MHz 2.75 2.90 3.25 (2HMt) 293(100) 3.78 6.70 7.10 (1H~s).
(4H-Is). 7.60 7.85 5073. HCl C 2 jH 23
N
3 0 3 S. HCl d 6 -DMSO/400HHz 2.75 (611.s). 2.75-2.80 (2H,rn). 3.20 3.84 6.70 6.77 6.90 7.40 7.52 7.75 (111,s). 8.20 9.78 (H.brs), 10.00 (1H.brs). 10.10 (1H.brs) 5074 d 6 -DMSO/400MHz 2.82 4.00 4.41 (2H.d).
6.81 6.88 7.98 (2H.rn).
9.15 (Ih~brs). 9.90 (1H.brs). 10.04 (1H.brs). 10.18 (1H,brs).
5075 C, 6 HI,Cl 2
N
2 0 2 S d 6 -DMSO/400tlHz 6.50 6.80 7.35 (li~t).
(3HAm. 7.55 (2H.d).
5077 C 2
,H
23
N
3 0 4 .H HG]MO/0O~ 2.55 2.80 3.80 (2H.t).
d 6 -MSO400~z4.55 6.70 6.80 (1H.s).
6.95 (ills). 7.45 7.60 7.85 (ills). 8.30 (ills). 9.90 (ills).
(1H~s).
5078 C,,l- 23
N
3 0 2
S
2 414(15). El CDCl 3
+CF.CO
2 D/400MHz 2.75 (2llt). 2.88 3.25 (2Hlt).
309(100) 3.88 7.22-7.28 7.45 (4Hls). 7.50-7.54 (ll-Am) 7.64 (-7.66 No. Mol. Formula Mass spec data 'H nmr data mass mode solvent (field) 16 5078 .HCl C 21
H
2 3
N
3 0 2
S
2 .HCI d 6 -DMSO/400MHz 2.72-2.78 (2H.rn). 2.75 (6H-Is), 3.20-3.25 (2H.ni). 3.84 6.75 6.85 7.40-7.45 (3HAn. 7.55 (2H.d).
7.64-7.67 7.96-7.99 9.85 (1H~brs). 10.05 (IH~brs), 10.18 5079 CH2BrN40 .HCl d.DS/0Mz2.82 4.00 4.41 (2H~d).
23234 d 6 -HSO/40M~z6.74 6.80 7.30 (1H,m).
7.36 7.45 (1HAm. 7.54 (2H~d), 7.60 (1I-Ad) 7.68 (11Hd 9.56 (1H~brt), 9.90 (1H,brs). 10.36 (1Htbrs), 10.48 5081 C 21
H
2 2
N
4 0 4 HCl d 6 -DMSQ/400MHz 2.83 4.01 4.39 (2H~d), 6.68 6.79 6.94 (1H,s).
7.35 7.54 7.76 (1H~s).
8.22 9.12 (1H~brt). 9.82 10.12 (1H.brs).
5188 C 2 7H 2 7N 3 0 3 442(100) ESI d 6 -DMSO/400llHz 1.8-1.9 2.15 2.38 4.05 6.78 6.90 6.99 7.50-7.58 (4H~m).
7,61-7.65 7.39-7.98 8.11 10.28 .(2H.brs).
5200 C 27
H
27
N
3 0 3 442(100) ESI d 6 -DMSO/400MHz 1.81-1.91 (2H.ni), 2.15 2.35 4.09 6.75 6.96 7.21 7.5-7.65 (7H.m).
10.15 (2H.brs).
No. Mol. Formula Mass spec. data 1H nmr data No. Mol. Formula Mass spec, data 'H nmr data r t I mass (intensity) mode solvent (field) 5205 C 27
H
27
N
3 0 3 .HC1 442(40) CI d 6 -DMSO/400MHz 2.12-2.20 (2H.ni). 2.80(611.S). 3.20-3.25 4.10 6.75 7.01 7.24 7.51 -7.67 (6H.m).
7.92 (2HAd. 7.98-8.01 10.1 10.25 (1H~brs).
5206 C 27
H
27
N
3 0 3 HOl d 6 -DMSO/400MHz 2.11-2.21 2.60 2.85-2.98 (2Hjn), 4.09 6.78 6.94 7.0 7.50-7.59 (4H.m), 7.64 1HAd). 7.90-7.99 8.12 10.21 (1H~brs). 10.43 (1H.brs).
5324, C 20
H
2
IN
3 0 3 S.HCl 384(100) CI d 6 -DtSO/400MHz 2.85 3.52 12H.t). 4.50 (2H.t).
6.52 C1H~c). 6.78 6.81 (1H.s).
7.31 (1HAd. 7.32 7.45 (2H.m) ?.57 9.70 10.15 (1H.s).
C1H~brs).
5327 C 20
H
21
N
3 0 3 S 384(20) c I d 6 -DMSO/40M-z 2.22 2.63 4.05 (2H.t).
6.76 6.82j.2xlH.s). 7.30 (1H~s).
7.42 (2H.ni), 7.55 (2H.d).
5335 C 20
H
2 jN 3 0 2 S.HCl 368(20) CI d 6 -DMSQ/40M-z 2.78 3.28 6.78 (1H.s).
6.89 7.02 (1HAd. 7.38-7.45 7.55 9.68 (1H.brs).
(1H~br).
5336 C 20
H
2 1 N3 3 S. HOC 384(10) CI d 6 -DMSO/400MHz 2.82 (6H-fs). 3.49 4.38 (2H.t).
6.78 6.80 6.94 (1H~s).
7.31 7.32 (1H. 7.42 (2H~mO.
7.55 9.78 10.25 (1H~s).
(1H~brs).
No. Mol. Formula Masspc data nmr data mass mode solvent (field)6 (intensity) 5367 C 33 H34N 4
O
4 551(100) CI CfJCl 3
+CF
3
CO
2 0I400MHz 1.72 (2H, 1.95-2.01 2.24 (6HAw. 2.48 2.96 (2HAm. 3.70 4.07 (2HMt, 4.89 7.01 7.15-7.25 (4H.m), 7.35 7.48 (2HAd) 7.57 2HAd).
(2H~brs).
5371 C 32
H
32
N
4 0 3 521(100) CI CDCl 3 /400MHz 1.75-1.80 (HMA. 2.55-2.60 2.75 2.88 (2HMt) 3.50-3.55 (2H.m).
3.65 6.95 (1I1s), 6.98-7.02 (1H, 7.05-7.10 (HMA. 7.15-7.20 (2H~m) 7.38-7.50 (5HAm. 7.65 (2H.d).
7.85 (1H.brs), 8.00 (1H.brs). 8.15 (H~brs).
5379 C 32 32
N
4 0 3 HC1 d 5 -DMSO/400MHz 1.60-1.68 (2HAm. 1.80-1.88 (2H~m).
3.00-3.06 3.15-3.35 (6H~rn). 3.65 -3.75 4.25-4.55 6.80 (2H.brs). 7.18-7.45 7.55-7.65 7.89 8.57 (1I-.brs).
(2H.brs). 10.36 (1H.brs).
5386 C 35
H
39 NS0 4 594(100). ESI d 6 -DMSO/400MHz 1.81-1.90 2.15 2.35 97(50) 2.62-2.70 C2H.m). 2.79-2.83 3.46-3.53 4.02 (2H.t).
6.73 6.75 6.73 (1H~s).
6.75 6.98 7.02-7.11 (1IMA 7.50 2HAd). 7.60 (2HAd. 7.78 8.41-8.48 (1HAm) 10.22 (1H,brs) No. Mol. Formula Mass spec. data 'H nrnr data mass mode solvent (field)6 (intensity) 5386.2HC1 C 3 5
H
3 9 NS0 4 .2HC1 594(100). ESI d.-DtISO/400M~z 2.12-2.21 2.72 3.1-3.25 297(58) 3.76-3.82 4.12 (2H,t).
4.41 (2H~brs). 6.78 6.79 (1H.s).
7.02 9.05 (KIIbrs). 10.19 (H~brs). 10.35 (1H,brs).
5388 C 22
H
25
N
3 0 4 S d 6 -DMSO/400MHz 2.16 (6H~s) 2.42 (2H. 3.55 (2H t) 3.75 4.23 6.43 (IH.
6.72 6.78 7.22 1H.
7.42 7.53 (2H~d).
5388.HCl C 22
H
25
N
3 0 4 S. HC1 428(5) CI d 6 -DMSO/400MHz 2.72 3.25 3.81 (4H.m), 4.32 6.47 6.76 (1H.s).
6.81 7.27 (1HAd. 7.32 (1H,m).
7.42 7.55 10.15 (H~brs).
5389 C 2 4
H
2 9
N
3 0 3 S 440(5) ci d 6 -dMSO/40M-z 1.28-1.45 1.57 (2HAm, 2.12 2.20 4.13 6.41 (Hid). 6.75 6.79 7.23 7.32 7.42 7.55 5389.HCI C 24 H29N 3
O
3 S HC 1 440(5) CI d 6 -DMSO/400MHz 1.36 1.45 1.66 (2H.
1.76 2.72 30.. (2H.t).
4.13 6.42 6.75 (1H~s).
6.80 7.25 (1HAd. 7.32 (1H,m), 7.41 7.55 10.06 (3H.brs).
No. Mol. Formula Mass spec. data 'H nmr data mass mode solvent (field) 6 (intensity) 5391 C 30
H
28
N
4 0 3 493(100). ESI CDCl.3+CF 3
CO
2 D/430MHz 3.15-3.25 3.28-3.40 (1H~m).
489(50) 3.48-3.57 3.60-3.68 (2H~m).
3.92-4.02 4.33 (2HAd) 4.77 (1HAd. 7.11 (1llAd. 7.22-7.56 (12H.m), (2H.
5391.HCl C 30
H
28
N
4 0 3 HCl 493(100) ESI d.-DMSO/400MHZ 3.01-3.10 3.38-3.45 MAnO 3.80-3.85 (3HAm. 4.32-4.41 (1HAm.
4.61-4.70 (1HAn. 6.80 7.18-7.36 7.41 7.58 (2HAd. 7.67 7.99 (2H~cI). 9.02 (lHA). 10.29 (1H.brs). 10.39 (1H~brs). 10.99 (H.brs).
5393 CH3NQ0 d 6 -DMSO/400MHz 2.70 (6HAm. 2.80 3.55 (2H~s).
383453.70 6.63 6.65 (1H.s), 6.80 6.83 7.22 (2H.d), 7.32 (1HAm. 7.42 (2HAm) 7.55 (2HAd) 7.68 7.99 (2HAd. 10.15 (1H.s).
(2H.br).
5393. HCl C 38 H,6N 4
O
5 HC1 629(100) ci d 6 -OMSO/400MHz 2.95-3.45 3.75 (2x3Hs). 4.25- 4.50 (2HAm, 6.79 6.80 (1H.s).
6.82 6.83 (ills). 7.30 (2H.
7.32 (1H, 7.41 (2HAm. 7.55 (2H~d).
7.68 7.77 8.01 (2HA).
10.28 10.40 (ills). 10.80 (H~brs).
5394 C3HO43507(15) CI 6DSO4O~ 1.75-1.85 2.52-2.57 (2Hlm), 2.67
C
31
H
3
N
4 0 3 d 6 -DSO/40M~z(2H.t). 2.84 3.34-3.40 (2H~m), 3.57 (2H-is), 6.75 6.80 (1H-ls).
7.05-7.10 7.30-7.55 7.84 8.57 (1H.brt). *10.25 (2H.brs).
No. Mol. Formula Mass spec. data nmr data mass mode solvent (field) 6Y ~(intensity) 59HC 33O43, Hc ,DS/400MHz 2.02-2.10 2.95-3.01 (1H,m).
3.18-3.43 (6H.rn). 3.65-3.70 (1H, 4.23-4.53 6.79 6.81 7.20-7.45 (7HAm 7.55 (2H~d).
7.65 7.90 8.70 (111.0).
10.25 10.35 10.60 (H.brs).
5397 C 37
H
43 NS0 4 622(80) c I COC] 3 /40OMHz 1.75-1.83 (MA. 1.95-2.00 (2H~rn). 2.251 2.45 2.58-2.61 (2H~m).
2.75 (2H.t0, 2.85-2.90 3.47-3.52 3.62 4.05 (2HAt). 6.90 6.95-7.20 (1OH.m). 7.35 7.65 (1HAd) 7.83 (IH.brs). 8.15 (H.brs).
5397. 2HC1 C3 7
H
43
N
5
O
4 .2HCl d 6 -DMSO/40OMHz 1.60-1.65 1.82-1.90 (2H.m).
2.12-2.20 2.79 (6H, 3.00-3.15 3.25-3.35 3.65-3.75 4.13 (2H.t0, 4.25-4.55 (2H.m).
6.75 6.78 GH.s). 7.00 (2H.d).
8.60 (1H~brt), 10.20 (IH.brs). 10.30 5402 C 38
H
35
N
5 0, d 6 -OMSO/400MHz: 2.70 (6H~m), 3.70 (6H.s).
,6.80 (1H.s).
7.68 MAH,) 8.22 (2H.d).
1H.brs).
2.80 3.55 (2H.s).
6.61 6.63 (1H.s).
6.82 7.22 7.82 7.98 (2H,d., 10.15 10.55 No. Mol. Formula Masspc data 'H nmr data mass mode solvent (field) J (intensity)______ 5402.HCl C 38
H
35
N
5 07.HC1 674(80) ESI d 6 -DMSO/400MHz 3.00-3.50 (8H~ni). 3.73 (2x3H.s). 4.25 C2H-Im). 6.75 6.79 6.86 6.88 7.29 7.69 7.77 (4H.rn), 8.00 (2HAd) 8.25 10.25 10.55 C1H.brs).
C1H.brs).
5376 C 33 H34N 4
O
4 .HCl 551(100) ESI d 6 -DMSO/400MHz 2.11-2.20 2.78 2.83-2.82 C2H.m). 3.20 3.62 (2H.brs), 4.09 4.75 (2H.brs). 6.77 6.79 7.00 2HAd). 7.19 (4H.brs). 7.50 7.55 (2H-Id). 7.60 10.19 (1H~brs), 10.32 (1H.brs). 10.55 (H.brs).
5299 C 2
,H
24
N
4 0 2 S d 6 -DMSOI400MHz 2.18 2.47 3.01 (3H.s), 3.40 5.98 (1H, 6.71 (li~s).
6.85 7.26 (liAd) 7.31 (1H.
7.52 9.85 (lH.brs).
1912 C 2 3
H
2 4
N
4 0 3 404(55) El c 6 -DMSO/400MHz 2.25 2.93 4.30 (2HAd) 6.74 6.76 7.28-7.55 8.25 (lH, 10.20 (2H~brs).
No. Mol. Formula Mass spec 'H nmr Microanalysis (M Wt) mlz. mass intensity (mode) Solvent 65 all 400 MHz __Caic Found 1927 C16H1 4
N
4
O
2 291. 30%: 295. NH* 100% CDC1 3
TFA
2.45 6.85 294 (DCI. NH- 3 (1H~s), 7.38 7.48 (1H.s), 1926 C, 5
H,
2
N
4 0 2 281 MH. 100% CDC1 3
TFA
7.20 7.45 280 (DCI. NH 3 (8H.
1545 C 21
H
17
N
3 0 3 192. 20%; 292. 10%. CDC1 3 CF COD0 MH+ 360 7.82 359 7.75 (1I-Ad) (DCI NH 3 7.65 (1H, 7.48 O3H.
7.35 (2H.m).
7.25 (1I1s), 7.06 (2HAd, 3.98 (3H~s).
No. Mol. Formula Mass spec 1H fnr Microanalysis KH WO) m/z. mass intensity (made) Solvent J all 400 MHz __caic Found 1509 C 2 0
H
1 5
N
3 0 2 3.47 MNH 4 CDC1 3
/TFA
330 MH. 100% 7.22-7.40 (3HAin 7.40-7.52 (6H.m).
(OCI NH 3 7.60 7.78 (lHAd J=7Hz).
7.81 8.10 1507 C 2 2
H
2 3
N
3 0 5 310, 100%; CDC1 3
CF
3
CO
2 D C 64.54 64.45 64.39 336, 20%: 7.65 (1H~s), 407 351. 20%; 7.48 (1H.brs). H 5.66 5.61 5.62 MH* 410, 5% 7.42 7.22
MNH
4 427. 2% N 10.26 10.46 10.43 7.00 (2H.d), (DCI NH 3 6.72 (1H~brd).
6.39 (1H.brd).
3.90 1.65 1506 C 26
H
25
N
3 0 5 360. 100%; C~D 3
CFCO
2 D C 67.96 67.54 67.63 MW" 460. 8.27 (1HAc 459 !MNH4 477. 2% 8.05 (1H S) H 5.48 5.35 5.30 7.70 (DCI NH 3 7.47 N 9.14 9.21 9.22 7.38 (2H~pt).
7.25 (1H~s).
7.05 (2HA).
3.90 (3H~s).
1.65 No. Hol. Formula -Mass spec 'H nmr Microanalysis (K At) Imlz, mass intensity (mode) Solvent J all 400 MHz __Calc Found 1476 Cj 7
H
1 4
N
2 0 4 I279. MH*, 311; COC1 3
CF
3
CO
2 D C 65.80 65.87 65.68
MNH
4 328. 2%7.85 (ills).
310 7.60 (1H~brs). H 4.55 4.44 4.54 (DCI NH 3 7.42 (2H.d).
7.21 N 9.03 9.03 8. 98 7.08 (LH.s).
7.02 (2H~d).
13:90 1474 C 1 7HIAN0 3 279. 16%. MH+. 327 C~DC 3 CF CO 2 D C 62.56 62.41 62.39 7.60 (1HAc? 326 (DCI NH 3 7.45 H 4.32 4.41 4.46 7.35 (1H~s).
7.23 (2H N 8.58 8.57 8.55 7.05 (2H~d).
3,90 1950 C 2 5H 2 7N 3 0 4 MH+ G1§8) 434 C~DC 3 CF COO 400 MHZ C 69.57 68.98 69.06 7.501-7.4i2 6n.5H) H 6.28 6.25 6.25 433 1137.25-7.15 N 9.69 9.59 9.60 Cl/H 3 7.00 (d.1H).
6.96 (d.1H).
6.90 (d.1H).
4.41 (t.2H).
3.90 (2,3H).
3.67 (t.2H).
3.12 (s.6Hi). No. Mol. Formula Mass spec IIH nmr Microanalysis KM WtO mlz. mass intensity (mode) Solvent 6 all 400 MHz alc Found 1718 C 2 jH 17
N
3 0 3 MH* 360. 100% DMSO 11.4 (1H~s), 359 (DCI NH3) 10.08 (1H.s).
9.82 (1H~s), 7.55 (3H.ni).
7.39 O1H.
7.18 (1H.
7.02 (4H.ni) 6.85 C1H.s).
6.78 (1H.s).
1693 C 2 2
H
19
N
3 0 5 S 360. 402, 25%. H438 7.98 (1HAd) 7.88 (1H.s), 437 (DCI NH3) 7.75 (1H.
7.45 7.35 (11.s).
7.02 (2HAd) 3.90 (3H.s).
1618 C 2 3
H
21
N
3 0 4 S 436. 100%: C~DC 3
TFA
336. 82% 1.75 (9H.s), 435 7.22-7.28 (overlapping solvent sample signals), 6H overlappingvsignals).
7.61 (2H. overlappn signals), ppg No. Mol. Formula Mass spec 'H nmr Hicroanalysis (K WtO mlz. mass intensity (mode) Solvent 6 all 400 MHz __Caic Found 1560 C 2 5
H
2 1
N
3 0 4 C1 2 498/500/502 IJMSO-D6 (100/69/15)% 1.68 (9H~s).I 497 3981400/402 6.66 (1F,s).
(49/31/7)% 6.92 (1H.s).
7.30-7.44 (3H,c).
7.49 (2H~d).
7.68 (1HA).
8.08 (1H.
1470 C 21
H
2
IN
3 0 4 397. MNH 4 380. MH*. CDCl 3 132. 280. 100% 1.64 6.33 (1FIbr.s), (DCI NHl 3 6.57 (1H.br.s).
7-00 C1I-.s).
7.35-7.50 (7H.m).
8.10 (1H~br.s).
1471 C 25
H
23
N
3 0 4 447, MNFU. 17%: 430. MH*. CDC] 3 100%: 33b:. 822' 1.7 7.07 7.14 (1H.s).
7.30-7.50 (7HKm, 7.66 (1HAd .=7Hz).
7.84 (1H.s).
8.03 (1H.br.s).
8-18 No. 14o1. Formula -Mass spec 'H nmr Microanalysis (K WOt)z ms intensity (mode) Solvent 65 all 400 MHz Foanc 1729 C 2 3 F1 19
N
3 0 5 435. MNH 4 23%; 418. MH., CDCl 3 i00i 3.09 (4H.s).
3.92 (3H.s), (DCI NH 3 7.07 (2H.d. J=7Hz).
7.28 (1H.s), 7.30 (1H.s).
7.39 (2H.d. 3=6Hz).
7.45 (2H.d, 3=7Hz).
(2H.d. 3=6Hz)_ 1647 C 23
H
21
N
3 0 3 405. M*NH 388. M*H. C~D 3 100i: 317, 43%: 459, 29% 1.84-2.00 MMH.m 387 3.13 3.64 DCI NH 3 (2H.t).
6.98 (HHs). 7.03 (1H~s).
7.32-7.50 (OH.
8.10 (1H~brs).
~~8.32 (IH.brs) 1845 C 2 1
H
17
N
3 0 5 409. M'NH 4 35%: 392. MH*, CDCl 3 IFA C 64.45 63.99 63.94 100% 2.35 (3H.s.Ac).
391 6.05 (2H.s. OCH0), H 4.38 4.42 4.37 (DCI NH 3 6.85-7.60 (9H.Z~ 10.74 10.99 11.01 1809 C 2 8H 16
N
2 0 5 382. M+NH 4 365. MH*. C~D 3 TFA C 65.93 65.85 65.96 100% 3.85 (3H.s.OMe), 364 6.05 (2H~sOCH 2 H 4.43 4.38 4.37 (DCI NH 3 6.90-7.45 (9HAm N 7.69 7.60 7.65 No. Mol. Formula Mass spec 'H nmr Microanalysis] WO) mhz, mass intensity (mode) Solvent 6 all 400 M4Hz ___Caic Found 1808 CjqH 1 4
N
2 0 4 335. 100% CDCl 3 TFA C 68.26 68.07 68.00 6.05 (2H s.QCH 2
O).
334 6.90-7.50 (1OH.m) H 422 4.15 4.17 8.38 8.35 8.35 1929 C 22
HIBN
4 0 2 MH+X 371 CDCI 3
TFA
5.45 (2H.s).
370 (DCI NH3) 7.18 (1H~s).
7.26 (1H.s).
7.30 C1H.s).
7.45 C1OH.m).
1930 MH+. 357. 100% CDC1 3
TFA
7.27 (1H.s).
(DCI NH 3 7.30 (iH~s).
7.50 7.65 7.75 (1H.
9.10 No. Mol. Formula Mass spec 'H nmi' Microanalysis WtO m/z. mass intensity (mode) Solvent 65 all 400 MHz __Calc Found 1975 C 2 JHz9N 5 03 236. 25%: 257. 100%; 376, CDC1 3
TFA
MH
4 472. 20%. 2.35 (2H~m).
3.01 (6H.s).
DCI NH 3 3.45 (2H~t).
4.18 (2H~t).
5.40 (2H.s), 6.95 (2H.d).
7.20 (1H~m).
7.25 (1H.s), 7.40 (3H.m).
7.50 1976 C 26 [HVN5O 3 230. 100%; 247. 60%; MH*. CDC13 TFA 458. 90%. 2.30 (2H,ni).
457 2.05 (6H.s).
DCL N1l 3 3.45 (2H.t).
4.18 (2H.t).
6.98 (2H.d), 7.25 (2H,d).
7.45 (2H.d).
7.55 (3HA,) 7.75 (3HAm, 9.18 (1H.s).J No. Mol. Formula Mass spec 'H niur Microanalysis WOt) m/z. mass intensity (mode) Solvent 6f all 400 MHz Caic Found 1982 C 24
H
28
N
4 0 3 .2HC1 405. 100%. MHI 4 020 2.98 (31.s).
404+73 EV 3.09 (6H.s).
3.75 (4H.brs).
4.50 7.09 (1t.s).
7.13 (IH.s).
7.52-7.68 7. 67-7 .77 (4H.overlapping signals).
1983 C 2 6
H
30
N
4
Q
2 431. 25%. IMSO-D6 332. 30%: 303. 18%: 1.53 (21-I.
84. 92%: 118. 100%. 1.71 (2H.d).
1.83 (2H.t), EI* 2.12 (3H~s).
2.14 (3H~s), 2.35 (1HAm.
2.80 (2h-iA), 3.57 (2H~s).
6.78 (2H4.overlapping signals), 7.34 (3H.overlapping signals).
7.43 (2H.t).
7.50 (2H~d), 7.57 No. Mol. Formula Mass spec nmr Microanalysis K Omlz. mass intensity (mode) Solvent 6 all 400 MHz Caic Found 1886 C 2 9
H
21
N
3 0 7
CD'
3
TFA
3.90 (3H~s).
4.79 (2H,s).
7.01 (2H~d.J=8Hz).
7.21 (1H,s).
7.24 (1H.s).
7.27 (2H~d).J=8Hz).
7.41 (2H~d. J=8Hz), 7.47 (2H.d. J=8Hz).
7.82 (2H~m).
1657 C 20 HIAN0 3 MH*. 350. 12%: MW. 349. 13%; C~DC 3
TFA
333, 100%. 3.92 4.32 349 (2H CI NH 3 7.05 7.24 (2H~d).
7.45 7.52 1891 C 23
H
24 NZ0 4 392. 25%: 347. M- DNSO C 70.39 70.31 70.03
OCH
2
CH
3 100% 1. 15 (6H. t. J-6Hz.
392
CH
3 H 6.16 6.16 6.16 El 3.45-3.60 (4.m.
C1(H~ CH) N 7.14 7.03 7.09 6.75 (2H~s), 7.28-7.55 (9H,Ar).
I I 10.25 (2H.br.s.,NH) I
I
No. Mol. Formula Mass spec 'H1 nmr Microanalysis Wt) m/z. mass intensity (mode) Solvent J all 400 MHz Caic Found 1912 C 2 3 11 24
N
4 0 1 404, 55%: 303. ONSO
NH-C(O)CH
2 NMe 2 30%; 2.25 (6H.s, 2xMe).
404 2.95 (2H~s).
El 4.30 (2H.d.J=6H-z).
6.74 6.76 (1H.s).
7.28-7.55 (9H.m).
8.24-8.27 (1H,br.m.NH).
(2H.br.s. 1676 C 22 11 1 9 0 3
N
3 MH*. 100%, 374 C~D 3
CF
3
CO
2
D
7.65 7.58 373 (DCI/NH 3 (2H~d).
7.48 (2H~d).
7.41-7.35 (4H~rn).
7.24 (1H~s).
7.12-7.07 C2H.m).
2.36+2.23 (3H.s.
*5 S S o No. fMol. Formula Mass spec 'H nmr Microanalysis Wt) m/z, mass intensity (mode) Solvent (5 all 400 MHz {Calc Found 1921 C 22
H
21
N
3 0 2 100%/, 360 CDCI 3
CF
3
CO
2 D C 73.52 73.24 73.11 7.81 (2H,d), 359 Cl/N H 3 7.52 (2H,d), 7.40-7.50 (6H, in), H 5.89 5.82 5.77 7.24 (1 H,s), 6.9 8 (1 H, d), 6.96 (1 N 11.69 11.50 11.52 3.3 3 (6 H, 1922 C 26
H
20
N
2 0 2 MH-, 393, 100%, MNH-, d 6
-DMSO
410, 11. 15 (1 H, brs), 392 10%/ 10.00 (1 H, brs), 7.66 (1 H,d), Cl/N H 3 7.51-7.30 (13H,m), 7.20 (2H,m), 6.78 (1 H,s), 6.83 (1 No. Mol. Formula Mass spec 1Hnrr Microanalysis Wt) mlz. mass intensity (node) Solvent S all 400 MHz __Calc Found 1923 C 2 0
HI
5
N
3
O
4 MH*, 362. 100% CDC' 3 CF CO D C 66.48 66.61 66.54 8,25 (2I,~ 361 (DCI NH 3 7.83 H 4.18 4.23 4.26 7.63 (1H~dd).
7.55-7.45 (SHAn. N 11.63 11.40 11.48 7.35 (1H.s).
7.12 (1H.
(1H.
1672 C 20
H
2 3
N
3
D
3 MH*. 354. 100%: MNH'. 371. CDC1 3 CF CO D 271. 10%; 260. 10% 7.59 (&A.d 353 7.45 C2H~d).
(DCI NH 3 7.18 (1H~s).
6.29 (1H.
2.55-2.47 (IH~m).
2.36-2.22 (3H.s~rotamers), 1.82-1-70 1.51-1.40 (2HArn) 1.32-1.20 (3H.
1884 C 18
H
20
N
2 0 2 MH*. 297. 100%; MNH*. 315. C~D 3 CF COD0 7.487.A8 296 7.21 (1H.s).
(DCI NH 3 6.26 (1H.
2.48 (1HAnO 1.83-1.70 (1H~r).
1.35 (2H~m), No. Mol. Formula Mass spec nmr Mi croanal ysi s Wt) mlz. mass intensity (mode) Solvent J all 400 MHz Calc Found 1570 C 1 7
HI
4
N
2 0 2 S 311. M*H. 100% CDCl 3 C 65.79 65.24 65.20 4.13 (3H.s), 310 DC1-NH 3 6.59 H 4.55 4.53 4.49 7.10 (1H.m).
7.30-7.60 N 9.03 8.73 8.79 (1H.brs).
Claims (10)
1. A piperazine of general formula 0 Ri NH (A) HN R 2 0 wherein one or both of R, and R 2 which may be the same or different, is: X, or a phenyl group which is substituted by X, C(O)X, OC(O)CH 2 X, OCHCH 2 X, CH 2 X, CONH(CH- 2 0 (CHO) 1CH (OH) (CHO) nX or _C/N (CH 2 )mX 15 or which is fused to a group X; a phenyl group substituted by CH 2 NR 1 2 R 13 OC (CHO) nZI CH (0R, 2 (OR3. 3 I (CHO) NR,,C (CHO)rNR, 2 Ri 3 -CH 2 NR 12 (CHO) NR 15 or 0 (CHO) CH (OH) (CR 2 ,N (R 1 2 R 13 (III) a group CH=C(W)V; or 20 (TV) a cyclohexyl group; and where appropriate, the other of R, and R 2 is a phenyl group optionally substituted by one or more groups independently selected from halogen, nitro, methoxy, NRC R 12 CO 2 H, 0 (CR 2 ,N (R 12 R 13 CH 2 Y ,N (R 12 R 13 Cl-c 4 alkyl and (CH 2 ),C(O)OR 12 X is a five- or six-membered saturated or unsaturated heterocyclic group containing one or more heteroatoms, which heteroatoms may be the same or different and are S'78 independently selected from 0, N and S; the heteroatom(s) when nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl, -(CH 2 )nCH 2 0H or S02Me; the heterocyclic ring being optionally substituted by halogen, Me, MeS, phenyl, O (CH) nNR 2 R 3 -N (R 12 (CH 2 N (Ri 2 RI3) nN (R3 2 R 3 or -O(CH)nO(CH 2 )nN(R 12 R 13 or the heterocyclic ring optionally containing one or more carbonyl groups and being optionally fused to a benzene ring, which benzene ring is optionally substituted by 1 or 2 Cl-Cg alkoxy groups; Y is 0 or S; Z is a C 3 -C 6 cycloalkyl group; R 12 R 13 and R 14 which may be the same or different, are hydrogen or Ci-C 6 alkyl; 15 R 1 s and R 16 which may be the same or different, are hydrogen or Ci-C 6 alkyl, or R 1 s and R 16 form, together with the atom to which they are attached, a 5- or 6-membered o heterocyclic group; W is hydrogen or a phenyl group; 20 V is a phenyl group optionally substituted by one or more groups'independently selected from nitro, alkoxy, 0 (CH 2 nNR 12 R 1 3 and NR 1 2 R 1 3 and m and n are each, independently, 0 or an integer having the value 1, 2, 3 or 4; or a pharmaceutically acceptable salt or ester thereof; with the exception of 3,6-diisonicotinylidenepiperazine-2,5-dione, 3,6-difurfurylidenepiperazine-2,5-dione, 3,6-di-(2-thiophenylidene)piperazine-2,5-dione and ~plp 79 3,6-dicinnamylidene-2,5-piperazinedione.
2. A compound according to claim 1, wherein one or both of R, and which may be the same or different, is chosen from X and a phenyl group substituted by X, C(O)X, OC(O)CH2X, OCHCHX, CH 2 X or which is fused to a group X; X is a five- or six-membered saturated or unsaturated heterocyclic ring containing one or two heteroatoms, which heteroatoms may be the same or different and are independently selected from O, N and S, the heteroatoms(s) when nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl, CHOH or SO,Me, the heterocyclic ring being optionally substituted by hydrogen, halogen, methyl, MeS, phenyl, O(CH,) N(R 2 O(CH), nN(R 1 ,R 1 or -O(CH))nO(CH,),nN(RjR:,) the heterocyclic ring optionally containing one or more carbonyl groups and being optionally fused to a benzene ring, and the other of R and R 2 is a phenyl group optionally substituted at the 2,3 or 4-position by CHNR 1 2 R 13 (CH,)nNR 1 4 C(0) (CH,),NR 12 R 13 halogen, nitro, -NHC(0)R,, 1 or 20 -CHY(CH 2 )nN(R 2 and Y, and n are as defined in claim 1. A compound according to claim 1 or 2, wherein R, and which may be the same or different, are hydrogen or Ci-C, alkyl and n is an integer of value 1 or 2.
4. A compound according to claim 1, 2, or 3 wherein one of R, and R, is a phenyl group which is substituted by X, C(O)X, OC(O)CH 2 X, OCH.CH,.X, CHX or which L I 80 is fused to a group X; wherein X is a five or six-membered heterocyclic ring containing one or two heteroatoms which may be the same or different, independently selected from O, N and S, the heteroatoms(s) when nitrogen being optionally substituted by methyl, the heterocyclic ring being optionally fused to a benzene ring. A compound according to claim 1, wherein one of R, and R, is a phenyl group substituted by CHNR.,R,, OC(0) CH(OR 12 (OR 3 (CH2), NR, C(0) ,NRzR,; wherein R 1 R, and R 14 which may be the same or different, are independently selected from hydrogen or Ci-C, alkyl; Z is a C, or C, cycloalkyl group; and m and n are, independently, integers having the values 1, 2 or 3. 15 6. A compound according to claim 1 or 5, wherein R 12 R, 1 and which may be the same or different, are independently selected from hydrogen and C.-C alkyl; Z is a cyclopentyl group; and m and n are, independently, integers having the values of 1 20 or 2.
7. A compound selected from (3Z,6Z)-3-Benzylidene-6-(4-imidazolyl)methylene-2,5- piperazinedione. (3Z,6Z)-3-Benzylidene-6-(4-(1-imidazolyl)benzylidene)-2,5- piperazinedione. (3Z,6Z)-3-Benzylidene-6-(4-(1- (3Z,6Z)-3-Benzylidene-6-(4-(5-methylimidazolyl))methylene- 81 2, (3Z, 6Z) -3-Benzylidene-6- (4-dimethylaminocinnamylidene) piperazinedione. (3Z, GZ) (3-Direthylaminopropoxy)benzylidene) (1- imidazolyl) benzylidene-2, (3Z, 6Z) -3-Benzylidene-6- (4 (2- imidazolylethoxy)benzylidene) (3Z,6Z) -3-Benzylidene-6- (4-nitrocinriamylidene-2,5- piperazinedione. (3Z,6Z) (4-Arinotethylbenzylidene) methoxybenzylidene) -2 (3Z, 6Z) -3-(l-methanesuJlfonyl-3-indolyl) methylene (4- methoxybenzylidene) S-piperazinedione. (3Z, GZ) (4-Methoxybenzylidene) (4- phthalimidoacetoxybenzylidene) (3Z,6Z) -3-Benzylidene-6- (y-phenylcinnamylidene) piperazinedione. (3Z,GZ)-3-(l-tert-butoxycarbonyl-3-indolyl)methylele-6-(2- thenylidene) 5-pi.perazinedione :20 (3Z,6Z)-3-(2,6-DichlorobenzyJlidene)-6-(1-tert- butoxycarbonyl-3-indolyl) methylene-2, (3Z,6Z) -3-Benzylidene-6- (2-dimethylaminoethoxy) -3- *9.99: nethoxycinnarnylidene)-2, 5-piperazinedione (3Z,6Z) (3-Dimethylaminopropoxy)belzylidele) -6- (l-imidazolylmethyl)benzylidele) (3Z, GZ) -3-Benzylidene-6- (4-N-methyl-N- (N- methylpiperidinyl) )aminomethylbenzy-idene-2, piperazinedione. 82 ((3Z,6Z)-3-Benzylidene-6-(3-indolylmethylene-2 (3Z,6Z)-3-(2,6-Diclhdorobenzylidene)-6-(3-furylrnetlhylene)-2 (3Z ,6Z)-3-(3-Indolylrnethylene)-6-(4-niethioxybenzylidene)-2,5-piperazined ionc. (3Z, 6-Dichlorobenzylidene)-6-(3-(1-tertbutoxycarbonyl)indolyl)methylene-2,5- piperazinedione. (3Z,6Z)-3-(4-Metlioxybenzylidene)-6-(2-(1-tertbutoxycarbony)pyrrolyl)metlylene-2,5. piperazinedione. (3Z ,6Z)-3-(4-Methioxybenzylidene)-6-(3-(1 -tertbutoxycarbonyl) indolyl)rnetliylene-2 piperazinedione. lo (3Z,6Z)-3-Benzylidene-6-(3-(1-tertbutoxycarbonyl)indolyl)methiylene-2,5-piperazinedione. (3Z,6Z)-3 -(4-Methoxybenzylidene)-6-(2-thiienylrnetlhylene)-2 (3Z,6Z)-3-(4-Methoxybenzylidene)-6-(3-fiirylmethylene)-2,5-piperazined ione. (3Z ,6Z)-3-(Acetamidobenzylidene)-6-cyclohiexylrnethiylene-2,5-piperazinedione. (3Z ,6Z)-3-(4-Acetarnidobenzylidene)-6-cinnamylidene-2 (3Z ,6Z)-3-Benzylidene-6-(diethoxymetliylbenzylidene)-2,5-piperazinedione. (3Z, 6Z)-3-Benzylidene-6-(4-(N-methyl-N-(2-dimetbylaininbethiy1)aminoethylbenizylidene- hydrochloride. (3Z,6Z)-3-Benizylidene-6-cyclohexylmethylene-2,5-piperazinedionie. (3Z,6Z)-3-(4-Acetamidobenzylidene)-6-(3 ,4-methiylenedioxybenzyl idene)-2 piperazinedione. (3Z, 6Z)-3-(2-Indolylmethylene)-6-(4-methoxybenzylidene)-2 (3Z ,6Z)-3 -Benzylidene-6-(3 ,4-methylenedioxybenzylideiie)-2 V.* [N:\Iibc]03446:KWW 83 (3Z, 6Z) (4-Methoxybenzylidene) (3,4- rethylenedioxybenzylidene) (3Z, 6Z) -3-Benzylidene-6- (1- tertbutoxycarbonyl)pyrrolyl) methyleie-2, (3Z,6Z) (4-Dimethylaminomethylbenzylidene) (3- dimethylaminopropoxy) benzylidene-2, (3Z, 6Z)-3- (3-Direthylarinopropoxy)benzylidene) (1- imidazolyl) methyJlbenzylidene) (3Z, 6Z) (3-Dimethylaminopropoxy)benzylidene) (1- imidazolyl) benzylidene. GZ) (3-Dimethylaminopropoxy)benzylidene) 2, 5-dioxo-3-piperazinylidene)rnethylbenzoyl) 2,3,4- tetrahydroisoquinoline. N-(2-(1,2,3,4-Tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-6- (3-direthylaminopropoxy)benzylidene) 5-dioxo-3- piperazinylidene) methylbenzamide. N-(4-(1,2,3,4-Tetrahydro-2-isoquinaolyl)butyl)-4-((3Z,6Z)-6- (3 -dimethylaminopropoxy) benzylidene) 5-dioxo-3- piperazinylidene)mtethylbenzamide. (3Z,6Z)-6-(4-(3-Dimethyltaminopropoxy)benzylidene-3- (4- pyridylmethylene) (3Z,GZ) (3-Dimethylaminopropoxy)benzylidene) (3- pyridyirnethylene) (3Z, 6Z) (3-Dimethylarninopropoxy)benzylidene) -3- furfurylidene-2, (3Z,6Z) (3-Dimethylaminopropoxy)benzylidene) (3- Thenylidene) (3Z,6Z) (4-(3-Dimethylaminopropoxy)benzylidene)-3-(2- nos4q.- 84 Thenyjlidene) (3Z, 6Z) (3-Dimethylaminopropoxy)benzyvlidene) (3- Furylmethylene) (3Z, 6Z) (3-Dimethylarninopropoxy)benzylidene) (2- Naphthylmethylene) (3Z, 6Z) (3-Dimethylarninopropoxy)benzylidene) (1- Naphthylrnethylene) (3Z, 6Z) -6-Benzylidene-3- (3-dimethylatnino-2- hydroxypropoxy) benzylidene) -2,5 -piperazinedione. C3Z, GZ) -6-Benzylidene-3- (2-hydroxy-3- iorpholinopropoxy) benzylidene) (3Z, 6Z) -6-Benzylidene-3- (2-hydroxy-3- (l- imidazolyl) propoxy)benzylidene) (3Z, 6Z) -6-Benzylidene-3- (2-hydroxy-3- (2- hydroxyethyl) -2-piperazinyl)propoxy) benzylidene) piperazinedione. (3Z, 6Z) (2-Dimethylaminoethoxy)benzylidene) (3- Furylmethylene) (3Z, 6Z) (2-Direthyjlaminoethoxy)benzylidene) (3- thenylidene) (3Z, 6Z) (2-Dimethylaminoethoxy)beizylidene) methylthio-2-thenylidene) (3Z, 6Z) -6-Benzylidene-3- (2- morpholinoethoxy) benzylidene) (3Z, 6Z) -6-Benzylidene-3- (l- itnidazolyl) ethoxy) benzylidene) 2, (3Z, 6Z) -6-Benzylidene-3- (1- pyrrolidinyl) ethoxy) benzylidene) 2, 85 (3Z, SZ) (2-Dimethylatninoethoxymethyl)benzylidene) -3- (3-thenylidene) (3Z,6Z)-6- (2-Dimethylaminoethoxymethyl)benzylidene) -3- furylmethylene) (3Z, 6Z) -6-(4-Dimethylaminoacetamidonethyl benzylidene) -3- (3 -thenylidene) (3Z, 6Z) (2-Bromobenzylidene) (4- dimethylarninoacetarnidomethylbenzylidene) piperazinedione. (3Z, 6Z) (4-Dimethylarninoacetaridomethylbenzylidene) (3- furylmethylene) (3Z, 6Z) -6-Benzylid(.ne-3- (4- dimethylaminoacetamidomethylbenzylidene) piperazinedione (3Z, 6Z) (2-Dimethylaminoethylthiotnethyl)benzylidene) 3- (3-furylmetbhylene) (3Z, 6Z) (2-Direthylaminoethylthiomethyl) benzylidene) 3- (3-thenylidene) (3Z, GZ) -6-Benzylidene-3- (4- dimethylatninoacetamidoaminomethylbenzylidene) piperazinedione. (3Z, 6Z) -6-Benzylidene-3- (2-dimethylarninoethoxy) -2- thienylmethylene) (3Z, 6Z) -6-Benzylidene-3- (2-dimethylaminoethoxy) -2- thienylmethylene) (3Z, 6Z) -6-Benzylidene-3- (2-dimethylaminoethyl) -2- thienylmethylene) S (3Z, 6Z) -6-Benzylidene-3- (2- 86 dimethylaminoethioxy)ethoxy)-2-thienylmethylene)-2,5-piperazinediofle. (3Z,6Z)-6-Benzylidene-3-(5-(6-dimethylaminohexyloxy)-2-thienylmethylene)-2, piperazinedione. (3Z,6Z)-6-Benzylidene-3-(5-(2-dimethiylaminoethyl)methylailo-2-thieflylnlethylene)-2 piperazinedione. (3Z,6Z)-3-(2,5-Dichloro-3-thenylidene)-6-benzylidene-2,5-piperazinedione. ,2,3 ,4-Tetrahydro-2-isoquinolyl)butyl)-4-((3 Z,6Z)-6-benzylidene-2 ,5-dioxo-3- piperazinylidene)methylbenzamide. ,2,3 ,4-Tetrahydro-2-isoquinolyl)ethyl)-4-((3Z,6Z)-6-benzylidene-2,5-dioxo-3- piperazinylidene)methylbenzamide. ,2,3 ,4-Tetrahydro-2-isoquinolyl)propoyl)-4-((3Z,6Z)-6-bezylidele-2,5-dioxo-3 piperazinylidene)methylbenzamide. 3,4-Tetrahydro-2-isoquinolyl)ethiyl)pheflyl-4-((3Z,6Z)-6-benzylidefle-2,5- dioxo-3-piperazinylidene)methylbenzamide. ,2 ,3 ,4Tetrahydro-2-isoquinolyl)etliyl)phenyl)-4-((3Z,6Z)-2,5-dioxo- 6 4 nitrobenzylidene)-3-piperaziniylidene)nlethylbenzamide.
8. A 3,6-dimethylene piperazine-2,5-dioxo derivative, substantially as hereinbefore described with reference to any one of the Examples,
9. A pharmaceutical or veterinary composition. comprising a pharmaceutically or 20 veterinarily acceptable carrier or diluent and, as an active principle, a compound as defined in any one of claims i to 8.
10. A process for preparing a compound of formula as defined in claim 1, the process comprising. condensing a compound of formula [N:\1ibC]01497:MER I 87 0 'NH AcN RY 2 1 0 wherein R 2 is as defined in claim 1 and is optionally protected, with a compound of formula (II): R 1 -CHO (II) wherein Ri is as defined in claim 1 and is optionally protected, in the presence of a base in an organic solvent; or condensing a compound of formula 0 R 1 N.Ac HN 0 wherein Ri is as defined in claim 1 and is optionally protected with a compound of formula (III): R--CHO II) wherein R 2 is as defined in claim 1 and is optionally protected, in the presence of a base in an organic solvent; and if required, removing optionally present protecting groups, and/or, if desired, converting one 88 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 into the single isomers.
11. A method for the treatment or prophylaxis of a condition indicating the administration of an inhibitor of plasminogen activator inhibitor in a mammal requiring said treatment or prophylaxis, which method comprises adminstering to said mammal an effective amount of at least one compound which is diketopiperazine of formula 0 R NH (A) HN R2 0 wherein one or both of Ri and R 2 which may be the same or different, is: 20 X, or a phenyl group which is substituted by X, C(0)X, OC(0)CH 2 X, OCH 2 CH 2 X, CH 2 X, CONH(CH)nX, 0 (CH 2 CH (OH) (CH 2 nX or -C(O)NH (CH)mX or which is fused to a group X; (II) a phenyl group substituted by CH 2 NR 12 R 13 OC(0) Z, CH(OR 12 (OR 13 (CH 2 nNR 1 4 C (CH) mNRi 2 Ri, 3 -CH 2 NR, 2 (CH 2 NR 1 isR 1 or 0 (CH 2 nCH (OH) (CH 2 nN (R 2 R 13 (III) a group CH=C(W)V; or I I I 89 (IV) a cyclohexyl group; and where appropriate, the other of Ri and R 2 is a phenyl group optionally substituted by one or more groups independently selected from halogen, nitro, methoxy, NHC(O)RI 2 COH, 0 (CH) nN (R 2 and CHY (CH 2 N (R, 2 R1 3 X is a five- or six-membered saturated or unsaturated heterocyclic group containing one or more heteroatoms, which heteroatoms may be the same or different and are independently selected from O, N and S; the heteroatom(s) when nitrogen being optionally substituted by hydrogen, methyl, oxygen, tertiary-butyloxycarbonyl, -(CH 2 )nCH 2 OH or SOMe; the heterocyclic ring being optionally substituted by halogen, Me, MeS, phenyl, O(CH,) nNR 2 R,3, -N (R 12 (CH 2 N (R 12 R 13 (CH 2 nN (Rl 2 R 13 or 15 -O(CH,)nO(CH 2 )nN(Ri 2 R) or the heterocyclic ring optionally S* containing one or more carbonyl groups and being optionally fused to a benzene ring, which benzene ring is optionally substituted by 1 or 2 CI-C alkoxy groups; 9 Y is 0 or S; 20 Z is a C3-C6 cycloalkyl group; R 12 and R 14 which may be the same or different, are 6 a" hydrogen or C 1 -C 6 alkyl; W is hydrogen or a phenyl group; V is a phenyl group optionally substituted by one or more groups independently selected from nitro, alkoxy, O(CH2)nNR 12 R 13 and NR 12 R 13 and m and n are each, independently, 0 or an integer having the value 1, 2, 3 or 4; or a pharmaceutically acceptable salt thereof.
12. A process for the preparation of a 3,6-dimethylene derivative, substantially as hereinbefore described with reference to any one of the Examples. Dated 17 April, 1998 Xenova Limited Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON to se** as 0 6 INTERNATIONAL SEARCH REPORT Interr ral Application No PCT/GB 95/00302 A. CLASSIFICATION OF SUBJECT MATTER IPC 6 C07D241/02 C07D401/06 C07D405/06 A61K31/495 According to Internmaonal Patent Classification or to both national classification and IPC B. FIELDS SEARCHED Mimnmum documentation searched (classification system followed by classification symbols) IPC 6 C07D Documentation searched other than minmum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the intcmatonal search (name of data base and, where practical, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A DE,C,621 862 G. WERK) 14 November 1935 1 see claims; example P,A WO,A,94 04512 (XENOVA) 3 March 1994 1-10 see the while document A CHEMICAL ABSTRACTS, vol. 97, no. 6, 1 1982, Columbus, Ohio, US; abstract no. 40323s, page 70 see abstract A JP,A,8 247 357 (RICOH) 18 March 1982 1 Further documents are listed in the continuation of box C. l Patent family members are listed in annex. Special categories of cited documents: T' later document published after international filing date or prnonty date and not in conflict with the application but document defining the general state of the art which is not ted to understand the princple or theory underlying the considered to be of particular relevance invcnuon earlier document but published on or after the international X' document of particular relevance; the claimed Invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on pnonty claim(s) or involve an inventive step when the document is taken alone which is cited to establish the publication date of another document of particular relevance; the claimed Invention citation or other special reason (as specified) cannot be considered to involve an Inventive step when the document referrng to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document published pnor to the nmtmaUonal filing date but in the art. later than the pnonty date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the intemational search report 6 April 1995 11. 04. Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswijk Tel. 31-70) 340-2040, Tx. 31 651 cpo nl, Franco i, J Fax: (+31-70)
340-3016 Form PCT/ISA/210 (second sheet) (July 1992) page 1 of 2 INTEP.NATIONAL SEARCH REPORT ntcn i~al Application No PCT/GB 95/00302 SC.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category' Citation of dloctiment, with indication, where appropriate, of the relevant pamageo A CHEMICAL ABSTRACTS, Vol. 98, no. 28, 1983, Columbus, Ohio, US; abstract no. 160674z, M.L. BARON ET AL. 'THE REACTION OF PIPERAZINE-2, 5-DIONE WITH 2-FORMYLBENZOIC ACID.' page 511 see abstract A AUST.J. CHEM., no.12, 1982, AUSTRALIA pages 2567 2569 Relevant to claim No. 1,9 1,9 I J..1 Form PCTIlSiV21 0 (continuation of second sheet) (JUly 1992) page 2 of 2 INTERNATIONAL SEARCH REPORT Intr ,naI Appilcalion No Info ation on pant(AsmlYmabcns 7PCT/GB 95/00302 Patent document I Publication IPatent family Publication cited in search report j date jmember(s) dame DE-C-621362 NONE WO-A-9404512 03-03-94 AU-B- 4726493 15-03-94 AU-B- 4726593 15-03-94 WO-A- 9404513 03-03-94 JP-A-8247357 NONE 1. Form IMIA15210 (patent family annex) (July IM9)
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| GB9402807A GB9402807D0 (en) | 1994-02-14 | 1994-02-14 | Pharmaceutical compounds |
| PCT/GB1995/000302 WO1995021832A1 (en) | 1994-02-14 | 1995-02-14 | Pharmaceutical piperazine compounds |
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| AU1667795A AU1667795A (en) | 1995-08-29 |
| AU693159B2 true AU693159B2 (en) | 1998-06-25 |
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| AU16677/95A Ceased AU693159B2 (en) | 1994-02-14 | 1995-02-14 | Pharmaceutical piperazine compounds |
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| EP (1) | EP0745070A1 (en) |
| JP (1) | JPH09509157A (en) |
| AU (1) | AU693159B2 (en) |
| CA (1) | CA2182877A1 (en) |
| GB (2) | GB9402807D0 (en) |
| IL (1) | IL112624A0 (en) |
| WO (1) | WO1995021832A1 (en) |
| ZA (1) | ZA951180B (en) |
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| GB9810876D0 (en) | 1998-05-20 | 1998-07-22 | Smithkline Beecham Plc | Compounds |
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| WO2001053290A1 (en) * | 2000-01-18 | 2001-07-26 | Nippon Steel Corporation | Cell division inhibitors and process for producing the same |
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| ATE417614T1 (en) * | 2000-05-09 | 2009-01-15 | Angiorx Corp | PIPERAZINDIONE COMPOUNDS |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU4726593A (en) * | 1992-08-14 | 1994-03-15 | Xenova Limited | Pharmaceutically active diketopiperazines |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE621862C (en) * | 1932-07-01 | 1935-11-14 | Guenther Schiemann Dr | Process for the preparation of condensation products of nucleus fluorinated aryl aldehydes |
| JPH08247357A (en) * | 1995-03-13 | 1996-09-27 | Zexel Corp | Flange joint and forming method thereof |
-
1994
- 1994-02-14 GB GB9402807A patent/GB9402807D0/en active Pending
-
1995
- 1995-02-13 IL IL11262495A patent/IL112624A0/en unknown
- 1995-02-14 WO PCT/GB1995/000302 patent/WO1995021832A1/en not_active Application Discontinuation
- 1995-02-14 EP EP95908314A patent/EP0745070A1/en not_active Withdrawn
- 1995-02-14 GB GB9502874A patent/GB2286395B/en not_active Expired - Fee Related
- 1995-02-14 ZA ZA951180A patent/ZA951180B/en unknown
- 1995-02-14 CA CA002182877A patent/CA2182877A1/en not_active Abandoned
- 1995-02-14 JP JP7521082A patent/JPH09509157A/en not_active Ceased
- 1995-02-14 AU AU16677/95A patent/AU693159B2/en not_active Ceased
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU4726593A (en) * | 1992-08-14 | 1994-03-15 | Xenova Limited | Pharmaceutically active diketopiperazines |
| AU4726493A (en) * | 1992-08-14 | 1994-03-15 | Xenova Limited | Pharmaceutically active diketopiperazines |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1995021832A1 (en) | 1995-08-17 |
| AU1667795A (en) | 1995-08-29 |
| IL112624A0 (en) | 1995-05-26 |
| GB9402807D0 (en) | 1994-04-06 |
| JPH09509157A (en) | 1997-09-16 |
| GB9502874D0 (en) | 1995-04-05 |
| GB2286395B (en) | 1998-08-26 |
| EP0745070A1 (en) | 1996-12-04 |
| ZA951180B (en) | 1996-08-14 |
| CA2182877A1 (en) | 1995-08-17 |
| GB2286395A (en) | 1995-08-16 |
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| Date | Code | Title | Description |
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| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |