WO1997005160A1 - Bicyclic lactam derivatives as thrombin inhibitors - Google Patents

Bicyclic lactam derivatives as thrombin inhibitors Download PDF

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WO1997005160A1
WO1997005160A1 PCT/EP1996/003167 EP9603167W WO9705160A1 WO 1997005160 A1 WO1997005160 A1 WO 1997005160A1 EP 9603167 W EP9603167 W EP 9603167W WO 9705160 A1 WO9705160 A1 WO 9705160A1
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carbonyl
arginine aldehyde
amino
azepin
benzyl
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PCT/EP1996/003167
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French (fr)
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Aldo Salimbeni
Fabio Paleari
Carlo Scolastico
Marco Criscuoli
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A. Menarini Industrie Farmaceutiche Riunite S.R.L.
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Priority to AU67342/96A priority Critical patent/AU6734296A/en
Publication of WO1997005160A1 publication Critical patent/WO1997005160A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to bicyclic lactam derivatives with antithrombotic activity, the processes for the preparation thereof, pharmaceutical compositions containing them and the use thereof as therapeutical agents.
  • the object of the invention are novel bicyclic lactam derivatives having an arginine residue, the salts and hydrates thereof, in diastereomerically pure forms or as stereoisomeric mixtures, having inhibitory activity on some serine-proteases. More particularly, the compounds turned out to be active in inhibiting the action of the enzyme thrombin and therefore can be used as antithrombotic, antiaggregating or anticoagulant agents.
  • the novel derivatives are characterized by having a bicyclic lactam residue which is capable of acting as a conformationally constricted analogue of a peptidic sequence, such as the one consisting of Phe- Pro-Arg, which is present in fibrinogen structure and is considered important for recognizing the thrombin active site.
  • thrombin inhibitors are known, which are based on structural changes of the sequence Phe-Pro-Arg, see for example Patents US n * 4,478,745, US n * 4,399,065, EP 526,877, US n ⁇ 697,987 and papers by Bajusz et al., J. Med. Chem., 1990, 33, 1729-1735 and Kettner et al., Thromb. Res., 1979, 14, 969-973.
  • m 0, 1, 2 or 3;
  • R 1 is a group of formula -CHO, -CH 2 OH, COOH,
  • R R 3 are independently hydrogen, C00R 7 , C 1 -C 4 alkyl, benzyl, -NO 2'
  • R R 5 are independently hydrogen, NR g R g , straight or branched ⁇ - ⁇ alkyl, C3-C cycloalkyl or an arylalkyl or heteroarylalkyl group, optionally substituted at the ring with one or more substituents such as halogen (Cl, Br, I), methoxyl, trifluoro ethyl, straight or branched C ⁇ -C alkyl;
  • Rg is hydrogen, straight or branched C ⁇ -C 7 alkyl, C3-C7 cycloalkyl or an aryl, heteroaryl, arylalkyl or heteroarylalkyl group, optionally substituted at the ring with one or more substituents such as halogen (Cl, Br, I), methoxy, trifluoromethyl, straight or branched C ⁇ -C alkyl;
  • R 7 is C 1 -C 4 alkyl, benzyl;
  • Rg, R g are independently hydrogen, straight or branched C ⁇ -C 7 alkyl or a group of general formula -W-Q wherein: W can be a group - , Q can be a phenyl, benzyl, naphthyl, quinolyl, naphthylmethyl, tetrahydroquinolyl, tetrahydro- isoquinolyl group, optionally substituted with one or more groups such as halogen (Cl, Br, I), straight or branched c i" c 7 alkyl, methoxy, trifluoromethyl.
  • the compounds of the invention form, with various both inorganic and organic acids, salts which also are an object of this invention.
  • Said salts include for example hydrochlorides, hydrobromides, sulfates, phosphates, maleates, fumarates.
  • Examples of C ⁇ -C 7 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl.
  • Examples of c 3 ⁇ c 7 cycloalkyl groups are cyclopropyl, cyclopentyl, cyclohexyl.
  • Aryl groups are preferably phenyl and naphthyl.
  • Heteroaryl groups are preferably thienyl, quinolyl or tetrahydroquinolyl.
  • Examples of arylalkyl groups include benzyl and phenethyl, preferably benzyl.
  • Examples of heteroarylalkyl groups comprise furylmethyl and thienyl ethyl.
  • R ⁇ and/or Rc groups are benzyl, thienylmethyl, amino, acetylamino, methylamino, dimethylamino, t-butoxycarbonylamino, benzyloxycarbonyl- amino, naphthylsulfonylamino, quinolylsulfonylamino, benzylsulfonylamino, naphthylmethylsulfonylamino, ethyl- amino, tetrahydroquinolylsulfonylamino.
  • Rg groups are phenyl, thienyl, methyl, ethyl .
  • Preferred compounds of formula I are those wherein m is 2, R. ⁇ is -CHO and R 2 , R3, 4 , R5, Rg have the meanings reported above.
  • Other preferred compounds of formula I are those wherein is 1, R 1 is -CHO and R 2 , 3, R 4 , R 5 , Rg have the meanings reported above.
  • Particularly preferred compounds are those wherein R 4 and/or R 5 are an arylalkyl, heteroarylalkyl group optionally substituted as indicated above, or a NRgRg group other particularly preferred compounds are those wherein Rg is an aryl, heteroaryl, arylalkyl or heteroarylalkyl group, optionally substituted as indicated above, and R 4 and/or R5 are a protected amino group.
  • R 4 and/or R 5 are those wherein R 4 and/or R 5 are an arylalkyl, heteroarylalkyl group optionally substituted as indicated above, or a NRgRg group other particularly preferred compounds are those wherein Rg is an aryl, heteroaryl, arylalkyl or heteroarylalkyl group, optionally substituted as indicated above, and R 4 and/or R5 are a protected amino group.
  • Most preferred compounds are the following:
  • R _ 2 > , J ⁇ 3 , R ⁇ 4 , , ⁇ 5 Rg and m have the meanings reported above, removing the protective group(s) on the guanidine residue.
  • the deprotection reaction where R (R 3 ) represents a benzyl, nitro or benzyloxycarbonyl group, can be carried out in solvents such as 1 -C 4 alcohols, ethyl acetate, tetrahydrofuran, in the presence of a Pd or Pt catalyst on charcoal under hydrogen atmosphere, or, where R 2 (R3) is a t- butoxycarbonyl group, by treatment with strong organic or inorganic acids in apolar solvents such as dioxane or tetrahydrofuran.
  • R 2 , R3, R 4 , R5, R and m have the meanings reported above, by reduction with, for example, metal hydrides, such as LiAlH 4 , NaBH 4 , NaCNBH 4 , LiBH 4 , LiBEt H, in both apolar and polar solvents, such as ethyl ether, tetrahydrofuran or ⁇ -C 4 alcohols, at temperatures from -20 * C to room temperature.
  • metal hydrides such as LiAlH 4 , NaBH 4 , NaCNBH 4 , LiBH 4 , LiBEt H
  • apolar and polar solvents such as ethyl ether, tetrahydrofuran or ⁇ -C 4 alcohols
  • the condensation reaction can be carried out according to one of the procedures known in literature, used to form peptide or amido bonds (see for example Bodanszky M. , Peptide Chemistry, chapter V, pag. 55-72, Springer-Verlag Editor).
  • dicyclohexylcarbodiimide, diphenyl phosphoryl azide can be used as carboxy- activating agents, or mixed anhydrides can be prepared by reaction with alkyl chloroformates; subsequently the intermediates can be reacted with the amino derivative of general formula VI , in solvents such as dichloromethane, chloroform, tetrahydrofuran, dimethyl- formamide, at temperatures generally ranging from 0 * C to room temperature.
  • the cyclization reaction can be carried out in the presence of radicalic initiators, such as ⁇ , ⁇ '- azabisisobutyronitrile or dibenzoyl peroxide, by addition of trialkyl- or triphenyl- tin hydrides, in aprotic apolar solvents such as ethyl ether, tetrahydrofuran, benzene, toluene, carbon tetrachloride, at temperatures generally ranging from room temperature to the solvent boiling temperature.
  • radicalic initiators such as ⁇ , ⁇ '- azabisisobutyronitrile or dibenzoyl peroxide
  • trialkyl- or triphenyl- tin hydrides such as ethyl ether, tetrahydrofuran, benzene, toluene, carbon tetrachloride
  • aprotic apolar solvents such as ethyl ether, tetrahydrofuran, benzene, to
  • the compounds of general formula IV can easily be obtained starting from compounds of formula IV , wherein 4 (R5)/ Rg , anc m nav ® the meanings reported above and X is hydroxyl, by transformation of the alcohol into the corresponding mesylate, trifluoro ethanesulfonate or tosylate and subsequent reaction with sodium or potassium bromides or iodides, in dipolar aprotic solvents such as acetone, dimethylformamide, dimethylsulfoxide at the solvent boiling temperature.
  • the transformation can be carried out starting from the corresponding alcohol, by treatment with phenylselenophthalimide, in the presence of tributyl pho ⁇ phine, in solvents such as tetrahydrofuran or dichloromethane at temperatures ranging from O'C to room temperature.
  • the condensation reaction can be carried out in the presence of condensing agents, for example dicyclohexylcarbodiimide, in aprotic apolar solvents such as tetrahydrofuran or dichloromethane, at temperatures ranging from O'C to room temperature.
  • condensing agents for example dicyclohexylcarbodiimide
  • aprotic apolar solvents such as tetrahydrofuran or dichloromethane
  • the compounds described in the present invention act as thrombin inhibitors.
  • an in vitro test for the inhibition of human thrombin in the presence of tosyl- glycyl-prolyl-arginine-4-nitroaniline acetate as substrate
  • the compounds of the invention proved to be active in the above test, showing IC ⁇ Q values lower than 5 ⁇ M.
  • the compounds of the invention can therefore be used as active principles of pharmaceutical compositions with antithrombotic activity.
  • compositions of the invention can be prepared according to conventional techniques and excipients, and will contain typically 1 to 1000 mg of compounds I, and will be administered 1 to 4 times a day through the oral, parenteral, transdermal routes or any other convenient administration route.
  • compound (3S,6S,9aS)-N ⁇ -[[6-[[(3- methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonyl]amino]- octahydropyrrolo[l,2-a]azepin-5-one-3-yl]carbonyl]-L- arginine aldheyde hydrochloride (example 8p) showed to have an I C 5 Q value of 0.018 ⁇ M.
  • AIBN (0.65 g, 3.9 mmoles) in 350 ml of benzene.
  • the mixture is cooled at room temperature, the volume is reduced to about 300 ml and KF saturated solution is added.
  • the crude acid is purified by chromatography on a ion exchange resin (DOWEX) eluting with 2N HCl. Upon removing the solvent under reduced pressure and drying,
  • DOWEX ion exchange resin
  • the reaction mixture is stirred for 30 min a -15*C, after that a solution of N-methylmorpholine (0.36 ml, 3,24 mmoles) and N w -benzyloxycarbonyl-L-arginine lactam hydrochloride (0.6 g, 1.62 mmoles) dissolved in 10 ml of DMF is added.
  • the resulting suspension is stirred for 2 h, left to warm at room temperature and finally the solvent is removed under reduced pressure.
  • the residue is taken up with CH 2 C1 , washed with water and with a NaCl saturated solution, dried (Na S0 4 ) and the solvent is removed under reduced pressure.

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Abstract

Bicyclic lactams containing an arginine residue, which can be of use in therapy as thrombin inhibitors, are disclosed.

Description

BICYCLIC LACTAM DERIVATIVES AS THROMBIN INHIBITORS
The present invention relates to bicyclic lactam derivatives with antithrombotic activity, the processes for the preparation thereof, pharmaceutical compositions containing them and the use thereof as therapeutical agents.
The object of the invention are novel bicyclic lactam derivatives having an arginine residue, the salts and hydrates thereof, in diastereomerically pure forms or as stereoisomeric mixtures, having inhibitory activity on some serine-proteases. More particularly, the compounds turned out to be active in inhibiting the action of the enzyme thrombin and therefore can be used as antithrombotic, antiaggregating or anticoagulant agents. The novel derivatives are characterized by having a bicyclic lactam residue which is capable of acting as a conformationally constricted analogue of a peptidic sequence, such as the one consisting of Phe- Pro-Arg, which is present in fibrinogen structure and is considered important for recognizing the thrombin active site. A number of examples of thrombin inhibitors are known, which are based on structural changes of the sequence Phe-Pro-Arg, see for example Patents US n* 4,478,745, US n* 4,399,065, EP 526,877, US nβ 697,987 and papers by Bajusz et al., J. Med. Chem., 1990, 33, 1729-1735 and Kettner et al., Thromb. Res., 1979, 14, 969-973.
The compounds of the invention have general formula I:
Figure imgf000004_0001
wherein: m is 0, 1, 2 or 3;
R 1 is a group of formula -CHO, -CH2OH, COOH,
-B(OH)2
R R3 are independently hydrogen, C00R7, C1-C4 alkyl, benzyl, -NO 2'
R R5 are independently hydrogen, NRgRg, straight or branched ~ι~-η alkyl, C3-C cycloalkyl or an arylalkyl or heteroarylalkyl group, optionally substituted at the ring with one or more substituents such as halogen (Cl, Br, I), methoxyl, trifluoro ethyl, straight or branched C^-C alkyl; Rg is hydrogen, straight or branched C^-C7 alkyl, C3-C7 cycloalkyl or an aryl, heteroaryl, arylalkyl or heteroarylalkyl group, optionally substituted at the ring with one or more substituents such as halogen (Cl, Br, I), methoxy, trifluoromethyl, straight or branched C^-C alkyl; R7 is C1-C4 alkyl, benzyl;
Rg, Rg are independently hydrogen, straight or branched C^-C7 alkyl or a group of general formula -W-Q wherein: W can be a group - ,
Figure imgf000005_0001
Q can be a phenyl, benzyl, naphthyl, quinolyl, naphthylmethyl, tetrahydroquinolyl, tetrahydro- isoquinolyl group, optionally substituted with one or more groups such as halogen (Cl, Br, I), straight or branched ci"c7 alkyl, methoxy, trifluoromethyl. The compounds of the invention form, with various both inorganic and organic acids, salts which also are an object of this invention. Said salts include for example hydrochlorides, hydrobromides, sulfates, phosphates, maleates, fumarates. Examples of C^-C7 alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl.
Examples of c3~c7 cycloalkyl groups are cyclopropyl, cyclopentyl, cyclohexyl.
Aryl groups are preferably phenyl and naphthyl. Heteroaryl groups are preferably thienyl, quinolyl or tetrahydroquinolyl. Examples of arylalkyl groups include benzyl and phenethyl, preferably benzyl. Examples of heteroarylalkyl groups comprise furylmethyl and thienyl ethyl. Examples of R^ and/or Rc groups are benzyl, thienylmethyl, amino, acetylamino, methylamino, dimethylamino, t-butoxycarbonylamino, benzyloxycarbonyl- amino, naphthylsulfonylamino, quinolylsulfonylamino, benzylsulfonylamino, naphthylmethylsulfonylamino, ethyl- amino, tetrahydroquinolylsulfonylamino.
Examples of Rg groups are phenyl, thienyl, methyl, ethyl .
Preferred compounds of formula I are those wherein m is 2, R.^ is -CHO and R2, R3, 4, R5, Rg have the meanings reported above. Other preferred compounds of formula I are those wherein is 1, R1 is -CHO and R2, 3, R4, R5, Rg have the meanings reported above.
Particularly preferred compounds are those wherein R4 and/or R5 are an arylalkyl, heteroarylalkyl group optionally substituted as indicated above, or a NRgRg group other particularly preferred compounds are those wherein Rg is an aryl, heteroaryl, arylalkyl or heteroarylalkyl group, optionally substituted as indicated above, and R4 and/or R5 are a protected amino group. Most preferred compounds are the following:
Nα-[C6-acetylamino-octahydropyrrolo[1,2-a]azepin-5- one-3-y1]carbonyl]-L-arginine aldehyde,
Nα-[[6-methylamino-octahydropyrrolo[1,2-a]azepin-5- one-3-yl]carbonyl]-L-arginine aldehyde, - Nα-[[6-[(benzylsulfonyl)amino]-octahydropyrrolo-[1,2- a]azepin-5-one-3-yl]carbonyl]-L-arginine aldehyde,
Nα-[[6-[[[(naphthalen-1-yl)methyl]sulfonyl]amino]- octahydropyrrolo[l,2-a]azepin-5-one-3-yl]carbony1]-L- arginine aldehyde, - Nα-[[6-[[[(naphthalen-2-yl)methyl]sulfonyl]amino]- octahydropyrrolo[1,2-a]azepin-5-one-3-yl]carbonyl]-L- arginine aldehyde,
Nα-[[6-[[(3-meth lquinolin-8-y1)sulfony1]amino]-octa- hydropyrrolotl,2-a]azepin-5-one-3-y1]carbonyl]-L-argini- ne aldehyde,
- Nα-[[6-benzyl-octahydroindolizin-5-one-3-yl]carbonyl]- L-arginine aldehyde,
Nα-[ [6-[ (thiophen-2-yl )methyl]-octahydroindolizin-5- one-3-yl]carbonyl]-L-arginine aldehyde,
Nα-[ [6-[ (naphthalen-2-yl)methyl]octahydroindolizin-5- one-3-yl]carbonyl]-L-arginine aldehyde,
- Nα-[ [6-[ (naphthalen-l-yl)methyl]-octahγdroindolizin-5- one-3-yl]carbonyl]-L-arginine aldehyde,
Nα-[ [6-acetγlamino-6-benzyl-octahydroindolizin-5-one- 3-yl]carbonyl]-L-arginine aldehyde,
-Nα-[ [6-benzγl-6-methγlamino-octahydroindolizin-5-one-3- yl]carbonyl]-L-arginine aldehyde,
-Nα-[ [6-benzyl-6-[ (t-butoxycarbonyl)amino]-octahγdroin- dolizin-5-one-3-yl]-L-arginine aldehyde, -Nα-[ [6-amino-7-phenyl-octahydroindolizin-5-one-3-yl]- carbonyl]-L-arginine aldehyde,
-Nα-[ [6-(methylamino)-7-phenyl-octahydroindolizin-5-one- 3-yl]carbonyl]-L-arginine aldehyde,
-Nα-[ [6-(acetylamino)-7-phenyl-octahydroindolizin-5-one- 3-yl]carbonyl]-L-arginine aldehyde.
According to the invention, compounds of general formula I can be obtained starting from intermediates of ge
Figure imgf000007_0001
wherein R _2> , JΛ3, RΛ4, , Λ5 Rg and m have the meanings reported above, removing the protective group(s) on the guanidine residue. The deprotection reaction, where R (R3) represents a benzyl, nitro or benzyloxycarbonyl group, can be carried out in solvents such as 1-C4 alcohols, ethyl acetate, tetrahydrofuran, in the presence of a Pd or Pt catalyst on charcoal under hydrogen atmosphere, or, where R2 (R3) is a t- butoxycarbonyl group, by treatment with strong organic or inorganic acids in apolar solvents such as dioxane or tetrahydrofuran.
The intermediates of general formula VIII can be obtained from compounds of general formula VII
Figure imgf000008_0001
wherein R2, R3, R4, R5, R and m have the meanings reported above, by reduction with, for example, metal hydrides, such as LiAlH4, NaBH4 , NaCNBH4, LiBH4, LiBEt H, in both apolar and polar solvents, such as ethyl ether, tetrahydrofuran or ^-C4 alcohols, at temperatures from -20*C to room temperature. Intermediates of general formula VII can be obtained by condensation of compounds of general formula VI, the preparation of which is described in literature (see for example Balasubramanian N. et. al, J. Med. Chem., 1993, 36, 300-303) and wherein R2 and R have the meanings reported above,
Figure imgf000009_0001
with compounds of general formula V, wherein R4, R5, Rg, and m have the meanings reported above and R 10 is hydrogen.
Figure imgf000009_0002
The condensation reaction can be carried out according to one of the procedures known in literature, used to form peptide or amido bonds (see for example Bodanszky M. , Peptide Chemistry, chapter V, pag. 55-72, Springer-Verlag Editor).
By way of example, dicyclohexylcarbodiimide, diphenyl phosphoryl azide can be used as carboxy- activating agents, or mixed anhydrides can be prepared by reaction with alkyl chloroformates; subsequently the intermediates can be reacted with the amino derivative of general formula VI , in solvents such as dichloromethane, chloroform, tetrahydrofuran, dimethyl- formamide, at temperatures generally ranging from 0*C to room temperature. Compounds of general formula V can be obtained by cyclization starting from intermediates of general formula IV, wherein R4 ( 5) Rg and m have the meanings reported above, R^Q can be alkyl C1~C4, X can be Br, I or phenylselenyl.
Figure imgf000010_0001
The cyclization reaction can be carried out in the presence of radicalic initiators, such as α,α'- azabisisobutyronitrile or dibenzoyl peroxide, by addition of trialkyl- or triphenyl- tin hydrides, in aprotic apolar solvents such as ethyl ether, tetrahydrofuran, benzene, toluene, carbon tetrachloride, at temperatures generally ranging from room temperature to the solvent boiling temperature. Generally the cyclization reaction is stereoselective and among the various possible stereoisomers, a diastereoisomer mainly forms. When a mixture of stereoisomers is obtained, the single diastereoisomers can be separated and purified by means of crystallization and/or chromatographic techniques.
The compounds of general formula IV can easily be obtained starting from compounds of formula IV , wherein 4 (R5)/ Rg ,
Figure imgf000010_0002
anc m nav® the meanings reported above and X is hydroxyl, by transformation of the alcohol into the corresponding mesylate, trifluoro ethanesulfonate or tosylate and subsequent reaction with sodium or potassium bromides or iodides, in dipolar aprotic solvents such as acetone, dimethylformamide, dimethylsulfoxide at the solvent boiling temperature. When X represents a phenylselenyl group, the transformation can be carried out starting from the corresponding alcohol, by treatment with phenylselenophthalimide, in the presence of tributyl phoεphine, in solvents such as tetrahydrofuran or dichloromethane at temperatures ranging from O'C to room temperature.
The intermediates of general formula IV can be obtained starting from intermediates of general formula III, the preparation of which is described in literature, (see for example, J. Am. Chem. Soc, 1984, 106, 4439-4547), wherein X, R^ and m have the meanings reported above
Figure imgf000011_0001
H
(III) by coupling with compounds of general formula II, wherein R4 (R5) and R have the meanings reported above.
Figure imgf000011_0002
(ID The condensation reaction can be carried out in the presence of condensing agents, for example dicyclohexylcarbodiimide, in aprotic apolar solvents such as tetrahydrofuran or dichloromethane, at temperatures ranging from O'C to room temperature.
Intermediates of general formula II, wherein g has the meanings reported above and R4 (R5) can be an acetyla ino, t-butoxycarbonylamino or benzyloxycarbonyl- amino group, are generally commercially available or easily obtainable starting from the corresponding amino acids, according to what described in literature (see for example Kolar A. J. et al, Synthesis, 1977, 457-459 and Ranganathan D. et al., J. Chem. Soc. Chem. Commun. , 1992, (16), 1145-1147).
The compounds described in the present invention act as thrombin inhibitors. In order to characterize and evaluate the efficacy thereof, an in vitro test for the inhibition of human thrombin (in the presence of tosyl- glycyl-prolyl-arginine-4-nitroaniline acetate as substrate) has been selected (Lotte berg et al., Methods in Enzymology, 1981, (80), 341-361). The compounds of the invention proved to be active in the above test, showing IC^Q values lower than 5 μM. The compounds of the invention can therefore be used as active principles of pharmaceutical compositions with antithrombotic activity. The compositions of the invention can be prepared according to conventional techniques and excipients, and will contain typically 1 to 1000 mg of compounds I, and will be administered 1 to 4 times a day through the oral, parenteral, transdermal routes or any other convenient administration route. For example, compound (3S,6S,9aS)-Nα-[[6-[[(3- methyl-1,2,3,4-tetrahydroquinolin-8-yl)sulfonyl]amino]- octahydropyrrolo[l,2-a]azepin-5-one-3-yl]carbonyl]-L- arginine aldheyde hydrochloride (example 8p) showed to have an IC5Q value of 0.018 μM. Another compound,
(3S,6R*,8aS)-Nα-[[6-benzyl-octahydroindolizin-5-one-3- yl]carbonγl-L-arginine aldehyde hydrochloride (example
8g) proved to have an IC5Q value of 4.60 μM.
The following examples further illustrate the invention, without limiting it.
Melting points are not corrected, the identity of the compounds and their purity have been determined by elementary analysis (C, H, N), NMR, IR and mass spectroscopies. Example 1 (2S,5R)-l-T2-(acetylaminoIpropenoyl1-2-(t-butoxycarbo- nyl)-5-(2-hydroxyethyl)pyrrolidine
A solution of (2S,5R)-2-(t-butoxycarbonyl)-5-(2- hydroxyethyl)-pyrrolidine (10 g, 46.5 mmoles) in 150 ml of anhydrous THF is added with DCC (14.4 g, 70 mmoles). When dissolution has been completed, 2-acetylamino- acrylic acid is added (6 g, 46.5 mmoles) and stirring for 18 h at room temperature. The solution is diluted with Et20 to decrease the solubility of the formed urea, then it is filtered and concentrated to dryness. After purification by flash chromatography (AcOEt-MeOH 85:15), 12.1 g of the product are obtained, as a yellow spongy solid (80% yield) . iH-N R (CDC13)
5: 1.44 (9H, s), 1.51-2.45 (6H, m) , 2.00 (3H, s); 3.65 (3H, m), 4.45 (IH, m), 4.65 (IH, m), 4.82 (IH, s), 5.32 (IH, s), 8.5 (IH, s) 13C-NMR (CDCI3) δ: 23.78, 28.49, 30.35, 30.70, 38.91, 55.82, 59.97,
64.72, 82.73, 104.75, 169.93.
Analogously are prepared: a) (2S,5R)-l-[2-(acetylamino)-3-phenylpropenoyl]-2-(t- butoxycarbonyl)-5-(2-hydroxyethyl)pyrrolidine,
Η-NMR (CDC13) δ: 1.28 (9H, s), 1.6-2.50 (6H, m), 2.1 (3H, s), 3.55 (2H, m), 3.9 (IH, m), 4.5 (IH, m), 4.9 (IH, dd) , 5.9 (IH, s), 7.2-7.6 (5H, m), 8.5 (IH, s)
Figure imgf000014_0001
δ: 22.36, 27.65, 29.52, 30.31, 38.37, 54.59, 59.15, 64.78, 81.70, 120.44, 128.31, 128.47, 128.80, 129.72, 129.76, 133.25, 170.25, 171.38, 172.01. b) (2S,5R)-l-[2-(acetylamino)-2-butenoyl]-2-t-butoxy- carbonyl-5-(2-hydroxyethyl)pyrrolidine
Figure imgf000014_0002
δ: 1.5 (9H, s), 1.65 (3H, d), 1.6-2.4 (6H, m) , 3.65 (2H, m), 4.51 (IH, s), 4.85 (IH, dd), 4.52 (IH, q) , 8.52 (IH, s)
Figure imgf000014_0003
δ: 11.76, 21.94, 27.73, 29.49, 30.08, 38.21, 54.49, 59.07, 64.69, 81.60, 118.45, 131.57, 170.11, 171.54, 172.20. c) (2S,5R)-l-[2-(acetylamino)-3-phenylpropenoyl]-2-t- butoxycarbonyl-5-(hydroxymethyl)pyrrolidine, d) (2S,5R)-l-[2-(acetylamino)-2-butenoyl]-2-t-butoxy- carbonyl-5(hydroxymethyl)pyrrolidine, e) (2S,5R)-1-[2-(acetylamino)propenoyl]-2-t-butoxycar- bonyl-5-(hydroxymethylJpyrrolidine, f) (2S,5R)-2-[(t-butoxycarbonyl)amino]-5-(2-hydroxy- ethyl)-l-( 3-phenylpropenoylJpyrrolidine, g) (2S,5R)-l-[2-[ (benzyloxycarbonyl)amino]propenoyl]-
2-(t-butoxycarbonyl)-5-(2-hydroxyethyl)-pyrrolidi- ne, Η-NMR (CDC13): 1.25-2.15 (m, 6H); 1.52 (S, 9H); 3.47 (m, 2H); 4.20 (m, 2H); 5.05 (m, 2H); 5.66 (S; IH); 7.20- 7.40 ( , 6H), h) (2S,5R)-1-[2-C(benzyloxycarbonyl)amino]-3-phenyl- propenoy1]-2(tbutoxycarbonyl)-5-(2-hydroxyethyl)- pyrrolidine, i) (2S,5R)-l-[2-[(benzyloxycarbonyl)amino]-3-(thio- phen-2-yl)propenoyl]-2-(t-butoxycarbonyl)-5-(2-hy¬ droxyethyl)pyrrolidine, 1) (2S,5R)-l-(3-phenylpropenoyl)-2-(t-butoxycarbonyl)- 5-(2hydroxyethyl)-pyrrolidine, Η-NMR (CDCI3): 1.47 (S, 9H); 1.55-2.51 ( , 6H); 3.71 (m, 2H); 4.50 (t, IH); 4.75 ( , 2H); 6.59 (d, IH); 7.30- 7.60 (m, 5H); 7.70 (d, IH). ) (2S,5R)-l-[2-[(benzylsulfonyl)amino]-propenoyl]-2- (t-butoxycarbonyl)-5-(2-hydroxyethγl)-pyrrolidine, n) (2S,5R)-2-(t-butoxycarbonyl)-l-[2-[[[(naphthalen-1- yl)methyl]sulfonyl]amino]propenoyl]-5-(2-hydroxy¬ ethyl)-pyrrolidine, o) (2S,5R)-2-(t-butoxycarbonyl)-1-[2-[[(3-methylquino- lin-8-y1)sulfony1]amino]propenoyl]-5-(2-hydroxy- ethyl)-pyrrolidine, p) (2S,5R)-2-(t-butoxycarbonyl)-1-[2-[[[(naphthalen-2- y1)methyl]sulfonyl]amino]propenoyl]-5-(2-hydroxy¬ ethyl)-pyrrolidine, q) (2S,5R)-2-(t-butoxycarbonyl)-1-(3-phenylpropenoyl)- 5-(3-hydroxypropyl)-pyrrolidine. Example 2
(2S,5R)-l-f2-(acetylamino) ropenoyl]-2-(t-butoxycarbo¬ nyl)5-T2-(phenylselenyl)ethv11pyrrolidine
A solution of (2S,5R)-l-[2-(acetylamino)propenoyl]- 2-(tbutoxycarbonyl)-5-(2-hydroxyethyl)-pyrrolidine (3.5 g, 10.8 mmoles) in 50 ml of anhydrous THF under N2 atmosphere and at O'C, is added with tributyl phosphine (4.4 g, 21.6 mmoles) and N-phenylselenophthalimide (6.5 g, 21.6 mmoles). The mixture is stirred for 2h at O'C, after that solvent is removed under reduced pressure and the residue is purified by flash chromatography (EtOAc- hexane 6:4). 3.2 g of product are obtained, as a slightly yellow solid (54% yield). Η-NMR (CDC13) δ: 1.46 (9H, s), 2.06 (3H, s), 1.5-2.28 (5H, m) , 2.09- 2.51 (IH, m), 2.8-3.1 (2H, m) , 4.12-4.4 (IH, m) , 4.61 (IH, m), 4.83 (IH, s), 5.51 (IH, s), 7.07-7.63 (5H, ), 8.42 (IH, s)
Figure imgf000016_0001
δ: 23.12, 24.13, 27.79, 29.20, 39.76, 58.78, 63.56, 81.65, 103.79, 126.61, 128.90, 132.291, 137.35, 169.34, 171.63. MS (FAB+): m/e 467 (MH+)
Analogously are prepared: a) (2S,5R)-l-[2-(acetylamino)-3-phenylpropenoyl]-2-t- butoxycarbony1-5-[2-(phenylselenyl)ethyl]pyrrolidi¬ ne
Figure imgf000016_0002
δ: 1.21 (9H, s), 2.15 (3H, s), 1.1-2.4 (6H, m), 2.89 (2H, ), 4.22 (IH, m) , 4.85 (IH, d), 5.61 (IH, s), 7.0- 7.6 (10H, ), 10.25 (IH, s)
Figure imgf000017_0001
δ: 22.27, 24.27, 27.70, 29.45, 29.79, 34.63, 58.24,
64.23, 81.28, 121.08, 126.51, 128.29, 128.41, 128.67,
128.91, 130.31, 132.11, 133.38, 170.25, 170.65, 171.80 b) (2S,5R)-l-[2-(acetylamino)-2-butenoyl]-2-t-butoxy- carbonyl-5-[2-(phenylselenyl)ethyl]pyrrolidine,
Figure imgf000017_0002
δ: 1.52 (9H, s), 2.33 (3H, s), 1.2-2.51 (9H, m) , 2.95
(2H, m), 4.33 (IH, m) , 4.82 (IH, m), 5.23 (IH, q), 7.1- 7.60 (5H, m), 9.65 (IH, s)
Figure imgf000017_0003
δ: 11.91, 22.33, 24.33, 27.84, 29.48, 35.99, 58.04,
63.26, 81.31, 118.908, 126.51, 128.85, 132.41 c) (2S,5R)-l-[2-(acetylamino)-3-phenylpropenoyl]-2-t- butoxycarbonyl-5-C(phenylselenyl)methγl]pyrrolidi- ne, d) (2S,5R)-l-[2-(acetylamino)2-butenoyl]-2-t-butoxy- carbonyl-5-[ (phenylselenyl)methyl]pyrrolidine, e) (2S,5R)-1-[2-(acetylamino)-propenoyl]-2-t-butoxy- carbonyll-5[ (phenylselenyl)methyl]pyrrolidine, f) (2S, 5R)-1-[2-[ (benzyloxycarbonyl)amino]propenoyl]- 2-(t-butoxycarbonyl)-5-[2-(phenylselenyl)ethyl]- pyrrolidine, g) (2S,5R)-l-[2-[ (benzyloxycarbonyl)amino]-3-(thio- phen-2-yl)propenoyl]-2-(t-butoxycarbonyl)-5-[2-
(phenylselenyl)ethyl]pyrrolidine, h) ( 2S, 5R)-2-(t-butoxycarbonyl)-5-[2-(phenylsele¬ nyl)ethyl]-l-(3-phenylpropenoyl)-pyrrolidine, Η-NMR (CDCI3): 1.47 (S, 9H); 1.70-2.50 (m, 6H); 2.90- 3.15 (m, 2H); 4.31-4.52 (m, 2H) ; 6.85 (d, IH); 7.10-7.80 (m, 11H) i) (2S,5R)-2-(t-butoxycarbonyl)-5-[2-( henylselenyl)- ethyl]-l-[3(thiophen-2-yl)propenoyl]-pyrrolidine, 1) (2S,5R)-2-(t-butoxycarbonyl)-5-[3-(phenylselenyl)- propyl]-l-(3-phenylpropenoyl)-pyrrolidine. Example 3
(2S,5R)-l-T2-(acetylamino)propenoyl12-(t-butoxycarbo¬ nyl)-5-(2-iodoethyl)-pyrrolidine
A solution of (2S,5R)-l-[2-(acetylamino)propenoyl]- 2-(t-butoxycarbonyl)-5-(2-hydroxyethyl)pyrrolidine (10.3 g, 31.5 mmoles) in 200 ml of anhydrous CH C1 , under N2 atmosphere and cooled at O'C, is added with the triethylamine (6.1 ml, 44.1 mmoles) and subsequently a solution of methanesulfonyl chloride (3.1 ml, 39.7 mmoles) in 70 ml of CH2C1 < The mixture is stirred O'C until the starting product disappears, then it is washed repeatedly with water, dried over Na S04 and solvent is removed under reduced pressure. The resulting crude mesylate is redissolved in 300 ml of acetone , the solution is added with sodium iodide (22.8 g, 150 mmoles), finally it is refluxed and after 3 h the solvent is removed under reduced pressure. The residue is redissolved in CH2C12, washed with water, dried (Na2S04) and concentrated to dryness. After purification by flash chromatography (EtOAc- MeOH 95:5), 11.0 g of a slightly yellow solid are obtained. (80% yield) m.p. 48-50'C (dec)
Η-NMR (CDC13): 1.45 (S, 9H); 1.52-2.15 (m, 8H); 2.08 (S, 3H); 3.27 (m, 2H); 4.28 ( , IH) 4.53 (S, IH); 4.89 (S, IH); 5.76 (S, IH); 7.90 (S, IH) Analogously are prepared: a) (2S,5R)-2-(t-butoxycarbonyl)-5-(2-iodoethyl)-1-(3- phenylpropenoyl)-pyrrolidine, b) (2S,5R)-2-(t-butoxycarbonyl)-5-(2-iodoethyl)-1-[3- (thiophen-2-yl)propenoyl]-pyrrolidine, c) (2S,5R)-2-(t-butoxycarbonyl)-5-(2-bromomethyl)-l-[- 2-(acetylamino)propenoyl]-pyrrolidine, d) (2S,5R)-2-(t-butoxycarbonyl)-l-[2-[(benzyloxycarbo¬ nyl)amino]propenoyl]-5-(2-iodoethyl)-pyrrolidine,
Η-NMR (CDC13): 1.33 (s, 9H); 1.30-2.20 (m, 4H); 2.80- 3.20 ( , 4H); 4.12 ( , IH); 4,22 (m, IH); 4.80 (s, IH); 4.86 (s, 2H); 5.72 (s, IH); 6.90 (s, IH); 7.35 (m, 5H). e) (2S,5R)-2-(t-butoxycarbonyl)-1-(2-butenoyl)-5-(2- iodoethyl)-pyrrolidine, f) (2S,5R)-l-[2-[(benzylsulfonyl)amino]-propenoyl]-2- (t-butoxycarbonyl)-5-(2-iodoethyl)-pyrrolidine, g) (2S,5R)-2-(t-butoxycarbonyl)-1-[2-[[[(naphthalen-1- y1)methy1]sulfonyl]amino]propenoyl]-5-(iodoethyl)- pyrrolidine, h) (2S,5R)-2-(t-butoxycarbonyl)-1-[2-[[(3-methylquino- lin-8-yl)sulfonyl]amino]propenoyl]-5-(2-iodoethyl)- pyrrolidine, i) (2S,5R)-2-(t-butoxycarbonyl)-1-[2-[[[ (naphthalen-2- y1)methyl]sulfonyl]amino]propenoyl]-5-(2-iodo¬ ethyl)-pyrrolidine. Example 4
(3S,6S,9aS)-6-acetylamino-3-(t-butoχycarbonyl)-octa- hydropyrroloπ .2-a1azepin-5-one
A solution of (2S,5R)-2-(t-butoxycarbonyl)-5-(2- iodoethyl)-1-[2-(acetylamino)propenoyl]-pyrrolidine (8.5 g, 19.5 mmoles) in 1500 ml of anhydrous benzene under reflux and N atmosphere, is added drop by drop during 6 h with a solution of B^SnH (6.5 ml, 23.1 mmoles) and
AIBN (0.65 g, 3.9 mmoles) in 350 ml of benzene.
When the reaction is complete, the mixture is cooled at room temperature, the volume is reduced to about 300 ml and KF saturated solution is added.
Stirring is continued for 8 h, salts are filtered off through celite, the phases are separated and the organic phase is dried over Na2S0 . Upon removal of the solvent under reduced pressure and purification by flash chromatography (EtOAc-MeOH 95:5) 3.7 g of a white foamy solid are obtained (62% yield). Η-NMR (CDC13) δ: 1.46 (9H, s), 1.97 (3H, s), 1.50-2.29 (10H, m) , 3.78- 3.88 (IH, m), 4.43 (IH, ) , 4.50 (IH, dd), 6.94 (IH, d)
Figure imgf000020_0001
δ: 23.29, 27.95, 27.49, 27.69, 31.14, 32.83, 34.21, 53.24, 59.15, 61.33, 81.48, 169.13, 170.05. MS (El) : m/e 310
Analogously are prepared: a) (3S,6S,7R,9aS)-6-(acetylamino)-3-(t-butoxycarbo- nyl)7-methyloctahydropyrrolo[1,2-a]azepin-5-one,
Figure imgf000020_0002
δ: 1.50 (9H, s), 1.50-2.52 (7H, m), 3.83 (IH, ) , 4.41- 4.63 (IH, m), 4.61 (IH, m), 7.12 (IH, db). b) (3S,6R,8aR)-6-(acetylamino)-6-(benzyl)-3-(t-buto- xycarbonyl)-octahydroindolizin-5-one,
Figure imgf000020_0003
δ: 1.46 (9H, s), 2.0 (3H, s), 1.5-2.1 (6H, ) , 2.32 (IH, m), 2.72 (IH, m), 3.1 (IH, m), 3.32 (IH, d), 3.42 (IH, d), 4.25 (IH, m) , 6.55 (IH, s), 7.0-7.4 (5H, ) 13C-NMR (CDCI3) δ: 24.27, 26.98, 27.75, 27.75, 27.84, 28.16, 30.21,
31.54, 42.18, 58.40, 60.04, 77.43, 126.63, 127.63,
127.28, 127.79, 127.91, 128.22, 130.24. c) (3S,6R*,7aR)-6-acetylamino-6-benzy1-3-(t-butoxycar- bonyl)-hexahydropyrrolizin-5-one, d) (3S,6R*,7aR)-6-acetylamino-6-ethy1-3-(t-butoxycar¬ bonyl)-hexahydropyrrolizin-5-one, e) (3S,6R*,7aR)-6-acetylamino-6-methy1-3-(t-butoxycar¬ bonyl)-hexahydropyrrolizin-5-one, f) (3S,6R*,7R*,8aR)-6-acetylamino-7-phenyl-3-(t-buto- xycarbonyl)-octahydroindolizin-5-one, g) (3S,6R*,7R*,8aR)-6-acetylamino-7-methyl-3-(t-buto¬ xycarbonyl)-octahydroindolizin-5-one, h) (3S,6R*,8aR)-6-acetylamino-3-(t-butoxycarbonyl)- octahydroindolizin-5-one, i) (3S,6R*,8aR)-6-benzy1-3-(t-butoxycarbonyl)octahy- droindolizin-5-one, 1) (3S,6R*,8aR)-3-(t-butoxycarbonyl)-6-[(thiophen-2- y1)methyl]-octahydroindolizin-5-one, m) (3S,6R*,8aR)-6-[(benzyloxycarbonyl)amino]-3-(t-bu¬ toxycarbonyl)-6-[(thiophen-2-y1) ethyl]-octahydro- indolizin-5-one, n) (3S,6S,9aS)-3-(t-butoxycarbonyl)-6-[(benzylsulfo- ny1)amino]-octahydropyrrolo[l,2-a]azepin-5-one, o) (3S,6S,9aS)-3-(t-butoxycarbonyl)-6-[(benzyloxycar¬ bonyl)amino]-octahydropyrrolotl,2-a]azepin-5-one, Η-NMR (CDC13) δ: 1.53 (s, 9H); 1.50-2.45 (m, 10H); 3.80 q, IH); 4.20 (m, IH); 4.55 (t, IH); 5.09 (s, 2H); 6.21 (m, IH); 7.35 (m, 5H). p) (3S,6S,9aS)-3-(t-butoxycarbonyl)-6[[[(naphthalen-l- yl)methy1]sulfonyl]amino]-octahydropyrrolo[1,2- a]azepin-5-one, q) (3S,6S,9aS)-3-(t-butoxycarbonyl)-6-[[(3-methylqui- nolin-8-y1)sulfonyl]amino]-octahydropyrrolo[1,2- a]azepin-5-one. Example 5
(3S,6S,9aS)-6-acetylamino-octahydropyrrolo-π ,2-alaze- pin-5-one-3-carboχylic acid
A solution of (3S,6S,9aS)-3-(t-butoxycarbonyl)-6- acetylamino-octahydropyrrolo[l,2-a]azepin-5-one (0.88 g, 2.9 mmoles) in 10 ml of anhydrous CH2C12 at room temperature, is added with 10 ml of CF3COOH. The mixture is stirred until the starting tert-butyl ester disappears and the solvent is removed under reduced pressure. The residue is redissolved in CH C1 and extracted with 2M Na2C03. The alkali aqueous phase is acidified to pH = 2 with 2N HCl and the solvent is evaporated under reduced pressure.
The crude acid is purified by chromatography on a ion exchange resin (DOWEX) eluting with 2N HCl. Upon removing the solvent under reduced pressure and drying,
0.48 g of a white solid are obtained (67% yield).
Η-NMR (CDCI3): 0.95-2.43 (m, 10H); 1.99 (S, 3H); 3.84
(m, IH); 4.51 (m, IH); 4.63 (m, IH); 7.05 (d, IH).
Analogously are prepared: a) (3S,6R,8aR)-6-acetylamino-6-benzyl-octahydroindo- lizin-5-one-3-carboxylic acid, m.p. 170-174'C (dec)
Η-NMR (CDCI3): 1.35-2.20 (m, 7H); 2.09 (S, 3H); 2.80
(m, IH); 3.47 (AB syst . , 2H ) ; 4.07 (m, IH); 4.51 (m, IH); 7.10-7.25 ( , 5H) b ) ( 3S , 6R* , 8aS )-6-benzyl-octahydroindolizin-5-one-3- carboxylic acid,
Η-NMR (CDCI3) δ: 0.95-2.45 (m, 7H); 2.81 (m, 2H ) ; 3.45
(m, 2H); 4.51 (d, IH); 7.45 (m, 5H), c) {3S,6R*,7R*,9aS)-6-acetylamino-7-methyl-octahydro- pyrrolo[l,2-a]azepin5-one-3-carboxylic acid, d) (3S,6R*,8aR)-6-acetylamino-octahydroindolizin-5- one-3-carboxylic acid, e) (3S,6S,9aS)-6-[(benzyloxycarbonyl)amino]-octahy¬ dropyrroloCl,2-a]azepin-5-one-3-carboxylie acid, f) 6-[(thiophen-2-yl)methyl]-octahydroindolizin-5-one- 3-carboxylic acid, g) (3S,6S,9aS)-6-[[(naphthalen-1-yl)sulfonyl]amino]- octahydropyrroloCl,2-a]-azepin-5-one-3-carboxγlic acid, m.p. 192-197'C, h) (3S,6S,9aS)-6-CC(naphthalen-2-yl)εulfonyl]amino]- octahydropyrroloCl,2a]azepin-5-one-3-carboxylic acid, i) (3S,6R*,7R*,8aR)-6-methylamino-7-phenyl-octahydro- indolizin-5-one-3-carboxylic acid,
1) (3S,6S,9aS)-6-CC(benzyl)sulfonyl]amino]-octa¬ hydropyrroloCl,2-a]azepin-5-one-3-carboxylic acid, Η-NMR (CDCI3) δ: 1.15-2.37 (m, 10H); 3.17-3.52 (m, 2H); 4.12-4.48 (m, 2H); 4.57 (m, IH); 5.87 (d, IH); 7.37 (m, 5H), m) (3S,6S,9aS)-6-CC(3-methγlquinolin-8-yl)sulfonyl]- amino]-octahydropyrroloC1,2-a]azepin-5-one-3-car- boxylic acid, m.p. 228-232'C, n) (3S,6S,9aS)-6-CCC(naphthalen-l-yl)methyl]sulfo- nyl]amino]-octahydropyrroloCl,2-a]azepin-5-one-3- carboxylic acid, o ) ( 3S , 6R* , 9aS )-6-benzyl-octahydropyrrolo- [ 1 , 2-a] - azepin-5-one-3-carboxylic acid, m.p. 105-110'C (dec. ) . Example 6
( 3S ,6S ,9aS)-Nα-r ( 6-acetylamino-octahydropyrrolori , Σ-al- azepin-S-one-S-yncarbonvπ-NW-benzyloxycarbonyl-L-arσi- nine lactam
A solution of ( 3S,6S,9aS)-6-(acetylamino)-octa- hydropyrrolo[l,2-a]azepin-5-one-3-carboxylic acid (0.41 g, 1.62 mmoles) in 10 ml of anhydrous DMF under N atmosphere and cooled at -15*C is added with a syringe with, in turn, N-methylmorpholine (0.18 ml, 1.62 mmoles) and isobutyl chlorofor ate (0.23 ml, 1.62 mmoles). The reaction mixture is stirred for 30 min a -15*C, after that a solution of N-methylmorpholine (0.36 ml, 3,24 mmoles) and Nw-benzyloxycarbonyl-L-arginine lactam hydrochloride (0.6 g, 1.62 mmoles) dissolved in 10 ml of DMF is added. The resulting suspension is stirred for 2 h, left to warm at room temperature and finally the solvent is removed under reduced pressure. The residue is taken up with CH2C1 , washed with water and with a NaCl saturated solution, dried (Na S04) and the solvent is removed under reduced pressure. After purification by flash chromatography (CH2Cl2-Me0H 95:5) and grinding with Et20-hexane, 0.63 g of product are obtained, as a white amorphous solid (54% yield), m.p. 145-150'C (dec); Η-NMR (CDCI3): 0.95 (d, IH); 1.20-2.50 (m, 13H); 2.05 (S, 3H); 3.49 (m, IH); 3.80 (m, IH); 4.57 (m, 2H); 4.70 (d, IH); 4.91 ( , IH); 5.14/5.2H); 6.89 (d, IH); 7.20-7.50 (m, 10H); 7.63 (d,
IH); 9.50 (m, 2H); MS ( FAB+ ) : m/z 527.
Analogously are prepared: a) (3S,6R,8aR)-Nα-[(6-acetylamino-6-benzyl-octahydro- indolizin-5-one-3-yl)carbonyl]-Nw-benzyloxycarbo- nyl-L-arginine lactam, m.p. 121-125'C (dec); Η-NMR (CDC13): 0.95 (d, IH); 1.20-2.35 (m, 13H); 2.04 (S, 3H); 3.70 (m, 2H); 4.40- 4.73 (m, 3H); 5.12 (S, 2H); 6.25 (d, IH); 7.05-7.41 (m, 10H); 7.80 (d, IH); 9.20-9.50 (m, 2H) MS (FAB+): m/z 603 b) -Nα-[[(6-acetamido-7-methyloctahydroCl,2-a]azepin- 5one3y1]carbonyl]-Nw-benzyloxycarbonyl-L-arginine lactam, c) -Nα-CC6-acetamido-6-benzyl-hexahydropyrrolizin-5- one3-yl]carbonyl]-Nw-benzyloxycarbonyl-L-arginine lactam, d) -Nα-CC6-acetamido-6-benzyl-hexahydropyrrolizin-5- one-3-yl]carbonyl]-Nw-benzyloxycarbony1-L-arginine lactam, e) -Nα- C6-acetamido-6-ethyl-hexahydropyrrolizin-5- one-3-yl]carbonyl]-Nw-benzyloxycarbonyl-L-arginine lactam, f) -Nα-CC6-acetamido-6-methγl-hexahydropyrrolizin-5- one-3-yl]carbonyl]-Nw-benzyloxycarbonyl-L-arginine lactam, g) (3S,6S,9aS)-Nα-CC6-CC(3-methylquinolin-8-yl)sulfo- nyl]amino]-octahydropyrroloC1,2-a]azepin-5-one-3- yl]carbonyl]-Nw-benzyloxycarbonyl-L-arginine lactam, m.p. 205-210'C (dec), h) (3S,6S,9aS)-Nα-[[6-[[[(naphthalen-1-yl)methyl]sul- fonyl]amino]-octahydro-pyrrolo[1,2-a]azepin-5-one-
3-yl]carbonyl]-Nw-benzyloxycarbonyl-L-arginine lactam, i) (3S,6S,9aS)-Nα-CC6-C(benzylsulfonyl)amino]-octahy- dro-pyrrolo[l,2-a]azepin-5-one-3-yl]carbonyl]-Nw- benzyloxycarbonyl-L-arginine lactam, m.p. 88-95"C (dec. ) ,
1) (3S,6S,9aS)-Nα-[[6-[[(naphthalen-1-yl)sulfonyl]ami- no]-octahydro-pyrrolo[l,2-a]azepin-5-one-3-γl]car- bony1]-Nw-benzyloxycarbonyl-L-arginine lacta , m.p. 130-135*C (dec. ) ) (3S,6R*,9aS)-Nα-[C6-benzyl-octahydropyrroloCl,2-a]- azepin-5-one-3-yl]carbonyl]-Nw-benzyloxycarbonyl-L- arginine lactam,
Η-NMR (CDC13) 6: 0.95-2.50 (m, 13H); 2.83-3.52 ( , 5H);
4.02 ( , IH); 4.43-4.95 ( , 3H), 5.14 (s, 2H); 7.15-7.50
(m, 10H); 7.80 (d, IH); 9.50 ( , 2H), n) (3S,6R*,9aS)-Nα-C[6-benzyl-octahydroindolizin-5- one-3-yl]carbonyl-N -benzyloxycarbonyl-L-arginine lactam,
^-NMR (CDCI3) δ: 1.40-2.20 ( , 8H); 2.50-2.83 ( , 4H);
3.21-3.52 (m, 4H); 4.37 (d, IH); 4.64 (m, IH); 4.86 ( ,
IH); 5.14 (s, 2H); 6.94 (d, IH); 7.20-7.48 (m, 10H); 9.50 ( , 2H).
Example 7
(3S,6S.9aS)-Nα- ϊT(6-acetylamino-octahydropyrrolor1.2-al- azepin-5-one)-3-v11carbonyl1-Nw-benzyloxycarbonyl-L-ar- qjnine aldehyde A solution of (3S,6S,9aS)-Nα-[ (6-acetylamino-octa- hydropyrrolo[1,2-a]azepin-5-one)-3-yl]carbonyl]-N -ben- zyloxycarbonyl-L-arginine aldehyde lactam (0.2 g, 0.38 mmoles) in 5 ml of anhydrous THF, cooled at -20'C and under N2 atmosphere, is added drop by drop with a suspension of LiAlH4 (0.010 g, 0.23 mmoles) in 4 ml of anhydrous THF. After 2 h stirring at -20'C, IN HCl is added to pH 7. The mixture is left to warm at room temperature and the suspension is filtered through
Na2S04. The solvent is removed under reduced pressure and the resulting residue is purified by flash chromatography (CH2Cl2-MeOH 95:5). 0.18 g of a white amorphous solid are obtained (92% yield).
Η-NMR (CDC13): 0.88 (d, IH); 1.20-2.25 (m, 16H); 2,05 (S, 3H); 3.10 ( , IH); 3.50 (m, IH); 3.82 (m, IH); 4.40- 4.75 ( , 3H); 5.09 (S, 2H); 5.82 (s, IH); 6.82 (d, IH); 7.37 (m, 5H); MS (FAB+): m/z 529 (MH+) Analogously are prepared: a) (3S,6R,8aR)-Nα-[[(6-acetylamino-6-benzyl-octahydro- indolizin-5-one)3-yl]carbonyl]-Nw-benzyloxycarbo¬ nyl-L-arginine aldehyde m.p. 95-100'C (dec); Η-NMR (CDCI3): 0.7 (m, 2H); 1.20- 2.10 (m, 14H); 2.10 (S, 3H); 3.05-3.20 (m, 2H); 3.70- 4.30 (m, 3H); 5.05 (S; 2H); 5.51 ( , IH); 6.27 (d, IH); 7.15-7.49 (m, 10H); MS (FAB+): m/z 605 (MH+). b) (3S,6R*,7R*,9aS)-Nα-[[(6-acetylamino-7-methγlocta- hydro[1,2-a]azepin-5-one)-3-yl]carbonyl]-Nw-benzy- loxycarbonyl-L-arginine aldehyde, c) -Nα-CC(6-acetylamino)-6-benzyl-hexahydropyrrolizin- 5-one)-3-yl]carbonyl]-Nw-benzyloxycarbonyl-L-argi¬ nine aldehyde, d) -Nα-CC(6-acetylamino-6-ethylhexahydropyrrolizin-5- one)-3-yl]carbonyl]-Nw-benzyloxycarbonyl-L-arginine aldehyde , e) -Nα-CC(6-acetylamino-6-methylhexahydropyrrolizin-5- one)-3-yl]carbonyl]-Nw-benzyloxycarbonyl-L-arginine aldehyde, f) (3S,6R*,7R*,8aR)-Nα-CC(6-amino-7-phenyl-octahydro- indolizin-5-one)-3-yl]carbonyl]-Nw-benzyloxycarbo¬ nyl-L-arginine aldehyde, g) (3S,6R*,8aS)-Nα-CC6-benzyl-octahydroindolizin-5- one)-3-yl]carbonyl]-Nw-benzyloxycarbonyl-L-arginine aldehyde, m.p. 105-113'C (dec. ) , h) (3S,6S,9aS)-Nα-CCC6- (benzylsulfonyl)amino]-octahy- dropyrrolo[1,2-a]azepin-5-one]3-yl]carbonyl]-Nw- benzyloxycarbonyl-L-arginine aldehyde, i) (3S,6S,9aS)-Nα-[C 6-C(-l-naphthylsulfonyl)amino]- octahydropyrroloC1,2-a]azepin-5-one]-3-yl]carbo¬ nyl]-Nw-benzyloxycarbonyl-L-arginine aldehyde,
1) (3S,6S,9aS)-Nα- CC6-C(2-naphthylsulfonyl)amino]- octahydropyrrolo[1,2-a]azepin-5-one]-3-yl]carbo- nyl]-Nw-benzyloxycarbonyl-L-arginine aldehyde, ) (3S,6S,9aS)-Nα-[ C6- [(1-naphthylmethyl)sulfonyl]- amino]octahydropyrroloCl,2-a]-azepin-5-one]-3-yl]- carbonyl]-Nw-benzyloxycarbonyl-L-arginine aldehyde, n) (3S,6S,9aS)-Nα-CC6-[[(3-methylquinolin-8-yl)sulfo- ny1]amino]-octahydropyrroloCl,2-a]azepin-5-one-3- yl]carbonyl]-Nw-benzyloxycarbonyl-L-arginine alde¬ hyde, m.p. 98-110'C (dec), o) (3S,6R*,9aS)-Nα-[[6-benzyl-octahydropγrrolo[1,2-a]- azepin-5-one-3-yl]carbonyl]-N -benzyloxycarbonyl-L- arginine aldehyde. Example 8
(3S,6S,9aS)-Nα-r ϊ ϊ6-acetylamino-octahydropyrrolon ,2-al- azepin-5-one1-3-yπcarbonyπ-L-arginine aldehyde hydro¬ chloride A solution of (3S,6S,9aS)-Nα-[[(6-acetylamino-octa- hydropyrroloC1,2-a]azepin-5-one]-3-yl]carbonyl]-Nw-ben- zyloxycarbonyl-L-arginine aldehyde (0.18 g, 0.34 mmoles) in 10 ml of THF is added with palladium on charcoal (10%, 35 mg) and 0.35 ml of IN HCl. The mixture is placed under hydrogen atmosphere and left to react under stirring until the starting product disappears, then it is filtered through Celite and the solvent is removed under reduced pressure. Upon grinding with Et 0, 0.13 g of a white amorphous solid are obtained (88% yield). m.p. 125-135'C (dec); Η-NMR (DMSO-dg): 0.95 (m, IH); 1.30-2.20 (m, 13H); 2.07 (S, 3H); 3.07-3.42 (m, 3H); 3.82 (m, 2H); 4.50 (m, 2H); 7.03 (m, IH); 7.51-7.85 (m, 4H); 9.45 (S, IH); MS (FAB+): m/z 395 (MH+). Analogously are prepared: a) (3S,6R,8aR)-Nα-CC(6-acetylamino-6-benzyloctahydro- indolizin-5-one)-3-yl]carbonyl]-L-arginine aldehyde hydrochloride m.p. 148-152'C (dec); Η-NMR (DMSO-dg): 0.71-1.05 (m, 2H); 1.25-2.30 (m, 12H); 2.07 (S, 3H); 3.20-3.48 (m, 2H); 3.60-3.75 (m, IH); 4.05-4.46 (m, 3H); 6.51 (S, IH); 7.05-7.20 (m, 5H); 7.58 (m, 4H); 9.52 (S, IH) MS (FAB+): m/z 471 (MH+). b) (3S,6R*,7R*,9aS)-Nα-[ (6-acetylamino-7-methylocta- hydropyrrolo 1,2-a]azepin-5-one)-3-y1]carbonyl]-L- arginine aldehyde hydrochloride, c) (3S,6R*,7aR)-Nα-[[(6-acetylamino-6-benzyl-hexahy- dropyrrolizin-5-one )3-yl]carbonyl]-L-arginine aldehyde hydrochloride, d) ( 3S,6R*,7aR)-Nα-[ [ ( 6-acetylamino-6-ethylhexahydro- pyrrolizin-5-one)3-yl]carbonyl]-L-arginine aldehyde hydrochloride, e) (3S,6R*,7aR)-Nα-[ [( 6-acetylamino-6-methylhexahydro- pyrrolizin-5-one)-3-yl]carbonyl]-L-arginine aldehy¬ de hydrochloride, f) ( 3S,6R*,7R*,8aR)-Nα-[ [ (6-amino-7-phenyl-octahydro- indolizin-5-one)-3-yl]carbonyl]-L-arginine aldehyde hydrochloride, g) ( 3S,6R*,8aS)-Nα-[ [ (6-benzyl-octahydroindolizin-5- one)3-yl]carbonyl]-L-arginine aldehyde hydrochlo¬ ride, m.p. 115-122'C (dec ); MS (FAB+): m/z 414 (MH+) h) (3S,6S,9aS)-Nα- C[6-[ (benzylsulfonyl)amino]-octahy¬ dropyrroloCl,2a]azepin-5-one]3-yl]carbonyl]-L-argi¬ nine aldehyde hydrochloride, m.p. 95-110'C (dec); MS (FAB+): m/z 507 (MH+) i) (3S,6S,9aS)-Nα-C[[6-C(l-naphthylsulfonyl)amino]- octahydropyrrolo[l,2-a]azepin-5-one]-3-yl]carbo- nyl]-L-arginine aldehyde hydrochloride, m.p. 103-107'C (dec); MS (FAB+): m/z 543 (MH+) 1) (3S,6S,9aS)-Nα-[[[6-[ (2-naphthylsulfonyl)amino]- octahydropyrrolo[1,2-a]azepin-5-one]-3-yl]carbo¬ nyl]-L-arginine aldehyde hydrochloride, m) ( 3S,6S,9aS)-Nα-[ [ [6-[ [ (1-naphthylmethyl)sulfonyl]- amino]-octahydropyrroleCl,2-a]-azepin-5-one]-3-yl]- carbonyl]-L-arginine aldehyde hydrochloride, n) (3S,6S,9aS)-Nα-[[6-CC(3-methylquinolin-8-yl)sulfo- nyl]amino]-octahydropyrrolo[l,2-a]azepin-5-one-3- yl ] carbonyl ] -arginine aldehyde hydrochloride ,
MS ( FAB+ ) : m/ z 558 ( MH+ ) , o ) ( 3S , 6R* , 9aS ) -Nα- [ [ 6-benzyl-octahydropyrrolo t l , 2-a ] - azepin-5-one-3-yl]carbonyl]-L-arginine aldehyde hy- drochloride, m.p. 92-105'C (dec); MS (FAB+): m/z 428 (MH+), p) (3S,6S,9aS)-Nα-[[6-[[(3-methyl-l,2,3,4-tetrahydro- quinolin-8-y1)sulfonyl]amino]-octahydropyrrolo[1,2- a]azepin-5-one-3-γl]carbonyl]-L-arginine aldehyde hydrochloride, m.p. 170-175'C (dec); MS (FAB+): m/z 562 (MH+). Example 9
(3S,6S,9aS)-6-amino-3-(t-butoxycarbonyl)-octahydropyrro- loTl,2-a1azepin-5-one A solution of (3S,6S,9aS)-6-C(benzyloxycarbonyl)- amino]-3-(t-butoxycarbonyl)-octahydropyrroloC1,2-a]aze- pin-5-one (5.03 g, 12.4 mmoles) in 200 ml of MeOH, si added with palladium on charcoal (10%, 0.35 g). The mixture is placed under hydrogen atmosphere and reacted with stirring until the starting compound disappears. The suspension is filtered through celite, solvent is removed under reduced pressure and the residue is dried in a drier with P205 at room temperature. 2.77 g of a transparent, sticky residue are obtained (83% yield). Η-NMR (CDC13) δ: 1.47 (ε, 9H); 1.50-2.31 (m, 10H); 3.42 (d, IH); 3.75 (m, IH); 4.52 (m, IH) . Example 10
(3S,6S.9aS)-6-r(benzylsulfonyl)amino1-3-(t-butoxycarbo¬ nyl)-octahydropyrroloCl,2-a1azepin-5-one A solution of (3S,6S,9aS)-6-amino-3-(t-butoxycar¬ bonyl)-octahydropyrrolo[l,2-a]azepin-5-one (1.2 g, 4.47 mmoles) in 30 ml of CH2C12 is added with triethylamine
(1 ml, 5.81 mmoles), then with benzylsulfonyl chloride
(1.02 g, 5.36 mmoles).
The mixture is stirred at room temperature for 4 h, washed with a 5% citric acid solution, with water, finally with a NaCl saturated solution, then it is dried over Na2S0 and solvent is removed under reduced presεure. The reεulting sticky residue is purified by flash chromatography (eluent: hexane/EtOAc 1:1). After purification, 1.70 g of the pure product are obtained in the form of a waxy solid (89% yield). Η-NMR (CDC13) δ: 1.48 (s, 9H); 1.48-2.20 (m, 10H); 3.17 (m, IH); 3.32 (m, IH); 4.10-4.48 (m, 3H); 5.87 (d, IH); 7.25-7.48 (m, 5H). Analogously are prepared:
(3S,6S,9aS)-6-[[(naphthalen-1-yl)sulfonyl]amino]-3-(t- butoxycarbonyl)-octahydropyrrolo[l,2-a]azepin-5-one Η-NMR (CDCI3) 8: 1.47 (s, 9H); 1.50-2.23 (m, 10H); 3.56 (s, IH); 3.88 (s, IH); 4.34 (t, IH); 6.50 (d, IH); 7.48- 7.72 (m, 3H); 7.95 (d, IH); 8.04 (d, IH); 8.23 (d, IH); 8.68 (d, IH).
(3S,6S,9aS)-3-(t-butoxycarbonyl-6-[[(3-methylquinolin-8- yl)εul onyl]amino]-octahydropyrroloCl,2-a]azepin-5-one Η-NMR (CDCI3) 6: 1.48 (ε, 9H); 1.50-2.37 (m, 10H); 2.63 (ε, 3H); 3.60 (m, IH); 4.04 ( , IH); 4.29 (m, IH); 7.52 (m, 2H); 8.01 (m, 2H); 8.28 (d, IH); 8.93 (d, IH) .

Claims

Compounds of general formula I
Figure imgf000033_0001
wherein: m is 0, 1, 2 or 3;
R^ is a group of formula -CHO, -CH2OH, COOH,
-B(OH)2;
R R3 are independently hydrogen, COOR7, C1-C4 alkyl, benzyl, -N0
R4, R5 are independently hydrogen, NRgRg, εtraight or branched C1-C7 alkyl, C3-C7 cycloalkyl or an arylalkyl or heteroarylalkyl group, optionally εubεtituted at the ring with one or more εubstituents such as halogen (Cl, Br, I), methoxyl, trifluoromethyl, straight or branched C^-C-j alkyl; Rg is hydrogen, straight or branched C- -Cη alkyl, C3-C7 cycloalkyl or an aryl, heteroaryl, arylalkyl or heteroarylalkyl group, optionally εubstituted at the ring with one or more subεtituentε εuch aε halogen (Cl, Br, I), methoxy, trifluoromethyl, εtraight or branched C1-C alkyl; R7 is C^-C alkyl, benzyl; ς8 Rg are independently hydrogen, straight or branched C^-Cy alkyl or a group of general formula
-W-Q wherein:
,
Figure imgf000034_0001
Q can be a phenyl, benzyl, naphthyl, quinolyl, naphthylmethyl, tetrahydroquinolyl, tetrahydroiso- quinolyl group, optionally subεtituted with one or more groupε εuch aε halogen (Cl, Br, I), εtraight or branched ^-Cy alkyl, methoxy, trifluoromethyl, the stereoisomeric formε thereof and the saltε thereof with pharmaceutically acceptable acidε.
2. Compoundε according to claim 1, wherein m is 2, R^ is -CHO, R is hydrogen and R2, R3, R4, R5 have the meanings reported above.
3. As compounds according to claim 2:
(3S,6S,9aS)-Nα-[[6-acetylamino-octahydropyrroloC1,2-a]- azepin-5-one-3-yl]carbonyl]-L-arginine aldehyde,
(3S,6S,9aS)-Nα-C[6-methylamino-octahydropyrroloC1,2-a]- azepin-5-one-3-yl]carbonyl]-L-arginine aldehyde,
(3S,6S,9aS)-Nα-C 6-[[(naphthalen-l-yl)sulfonyl]amino]- octahydropyrolo-[l,2-a]azepin-5-one-3-yl]carbonyl]-L- arginine aldehyde, (3S,6R*,9aS)-Nα-[[6-benzyl-octahydropyrrolo-[1,2-a]aze- pin-5-one-3-yl]carbonyl]-L-arginine aldehyde,
(3S,6S,9aS)-Nα-[[6-[(benzylsulfonyl)amino]-octahydropyr¬ rolo-[1,2-a]azepin-5-one-3-yl]carbonyl]-L-arginine alde¬ hyde, (3S,6S,9aS)-Nα-[C6-C Cnaphthalen-1-yl)methyl]sulfonyl]- amino]-octahydropyrrolo[l,2-a]azepin-5-one-3-yl]carbo- nyl]L-arginine aldehyde, (3S,6S,9aS)-Nα-[[6-[ [ [(naςhthalen-2-yl)methyl]sulfonyl]- amino]-octahydropyrroloL1,2-a]azepin-5-one-3-yl]carbo¬ nyl]-L-arginine aldehyde,
(3S,6S,9aS)-Nα-[[6-[[(3-methylquinolin-8-yl)sulfonyl]- amino]-octahydropyrroloCl,2-a]azepin-5-one-3-yl]carbo¬ nyl]-L-arginine aldehyde,
(3S,6S,9aS)-Nα-[[6-CC(3-methyl-l,2,3,4-tetrahydroquino- lin-8-yl)sulfonyl]amino]octahydropyrrolo[l,2-a]azepin-5- one-3-yl]carbonyl]-L-arginine aldehyde.
4. Compounds according to claim 1, wherein m is 1, R^ is -CHO and R , R , R , R5, R have the meanings reported above.
5. As compounds according to claim 4: (3S,6S,8aS)-Nα-CC6-benzyl-octahydroindolizin-5-one-3- yl]carbonyl]-L-arginine aldehyde,
(3S,6R,8aS)-Nα-[C6-benzyl-octahydroindolizin-5-one-3- yl]carbonyl]-L-arginine aldehyde,
(3S,6S,8aS)-Nα- C6- (thiophen-2-yl)methyl]-octahydroin- dolizin-5-one-3-yl]carbonyl]-L-arginine aldehyde, (3S,6R,8aS)-Nα-[[(6-[(thiophen-2-yl)methyl]-octahydroin- dolizin-5-one-3-yl]carbonyl]-L-arginine aldehyde, (3S,6S,8aS)-Nα-CC6-C(naphthalen-2-yl)methyl]octahydroin- dolizin-5-one-3-yl]carbonyl]-L-arginine aldehyde, (3S,6R,8aS)-Nα-[C6-C(naphthalen-2-yl)methyl]octahydroin- dolizin-5-one-3-yl]carbonyl]-L-arginine aldehyde,
(3S,6S,8aS)-Nα-[[6- (naphthalen-1-yl)methyl]-octahydro- indolizin-5-one-3-yl]carbonyl]-L-arginine aldehyde, (3S,6R,8aS)-Nα-[[6-[(naphthalen-1-yl)methyl]-octahydro- indolizin-5-one-3-yl]carbonyl]-L-arginine aldehyde, (3S,6R,8aR)-Nα- C6-acetylamino-6-benzyl-octahydroindoli- zin-5-one-3-yl]carbonyl]-L-arginine aldehyde, (3S,6S,8aR)-Nα-[ [6-acetylamino-6-benzy1-octahydroindo- lizin-5-one-3-yl]carbonyl]-L-arginine aldehyde,
(3S,6S,8aR)-Nα-[ [6-benzyl-6-methylamino-octahydroindo- lizin-5-one-3-yl]carbonyl]-L-arginine aldehyde, ( 3S,6R,8aR)-Nα-[ (6-benzyl-6-methylamino-octahydroindo- lizin-5-one-3-yl]carbonyl]-L-arginine aldehyde,
(3S,6S,8aR)-Nα-CC6-benzyl-6-[ (t-butoxycarbonyl)amino]- octahydroindolizin-5-one]-3-yl]-L-arginine aldehyde,
(3S,6R,8aR)-Nα- C6-benzy1-6- (t-butoxycarbonyl)amino]- octahydroindolizin-5-one]-3-yl]-L-arginine aldehyde,
(3S,6R*,7R*,8aR)-Nα-C C6-amino-7-phenyl-octahydroindoli- zin-5-one-3-yl]carbonyl]-L-arginine aldehyde, (3S,6R*,7R*,8aR)-Nα-CC6-(methylamino)-7-phenyl-octahy- droindolizin-5-one-3-yl]carbonyl]-L-arginine aldehyde, (3S,6R*,7R*,8aR)-Nα-[ 6-(acetylamino)-7-phenγl-octahy- droindolizin-5-one-3-yl]carbonyl]-L-arginine aldehyde, (3S,6R*,7R*,8aR)-Nα- C6-(acetylamino)-7-methyl-octahy- droindolizin-5-one-3-yl]carbonyl]-L-arginine aldehyde.
6. A procesε for the preparation of the compoundε of general formula I, which co priεeε the condensation reaction of intermediates of general formula III wherein m and R^Q have the meanings reported above and X is -OH, with compounds of general formula II, wherein R4 (Rc) and Rg have the meanings reported above
Figure imgf000036_0001
(IH)
(II) to give compounds of general formula IV , which are transformed into compounds of general formula IV, wherein X is Br, I, Se-C H^
Figure imgf000037_0001
which are cyclized to compounds of general formula V
Figure imgf000037_0002
which are subjected to hydrolyεiε of the carboxylic group (RiQ = H^ an<^ coupled with intermediateε of general formula VI
Figure imgf000037_0003
to give compoundε of general formula VII
Figure imgf000038_0001
which are reduced to give compoundε of general formula
Figure imgf000038_0002
which are εubjected to removal of the protecting groupε R (R3) and treatment with organic or inorganic acids, to yield compounds of general formula I.
7. The use of the compounds of claims 1-5 as therapeutical agents for uεe as antithrombotic, anticoagulant or antiplatelet agents.
8. Pharmaceutical compositions containing as active principle an effective amount of one or more compounds of claimε 1-5, in admixture with εuitable excipients.
PCT/EP1996/003167 1995-08-01 1996-07-18 Bicyclic lactam derivatives as thrombin inhibitors WO1997005160A1 (en)

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US6525076B1 (en) 1996-10-11 2003-02-25 Millennium Pharmaceuticals, Inc. Selective factor Xa inhibitors
US6194435B1 (en) 1996-10-11 2001-02-27 Cor Therapeutics, Inc. Lactams as selective factor Xa inhibitors
US6369080B2 (en) 1996-10-11 2002-04-09 Cor Therapeutics, Inc. Selective factor Xa inhibitors
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US6333321B1 (en) 1997-08-11 2001-12-25 Cor Therapeutics, Inc. Selective factor Xa inhibitors
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WO1999007730A1 (en) * 1997-08-11 1999-02-18 Cor Therapeutics, Inc. SELECTIVE FACTOR Xa INHIBITORS CONTAINING A FUSED AZEPINONE STRUCTURE
JP2002503674A (en) * 1998-02-12 2002-02-05 モレキュメティックス リミテッド Beta sheet mimics and methods for their use
EP1058549A1 (en) * 1998-12-23 2000-12-13 Du Pont Pharmaceuticals Company THROMBIN OR FACTOR Xa INHIBITORS
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KR100887045B1 (en) 2004-01-16 2009-03-04 더 리젠츠 오브 더 유니버시티 오브 미시간 Conformationally constrained smac mimetics and the uses thereof
US7932382B2 (en) 2004-01-16 2011-04-26 The Regents Of The University Of Michigan Conformationally constrained Smac mimetics and the uses thereof
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ITMI951688A0 (en) 1995-08-01
AU6734296A (en) 1997-02-26
IT1277405B1 (en) 1997-11-10

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