Classifications

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  • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
  • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
• • 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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  • 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
  • C07D405/12—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 chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
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  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—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
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• • 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
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
• • 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
  • C07K5/06104—Dipeptides with the first amino acid being acidic
  • C07K5/06113—Asp- or Asn-amino acid
• • 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 invention relates to new therapeutic compounds, in particular to antithrombotic agents, a process for their preparation, pharmaceutical compositions containing the compounds as active ingredients, as well as the use of said compounds for the manufacture of medicaments.
• Drugs differ widely in their pharmacodynamic effects and clinical application, in penetrance, absorption and usual route of administration, in distribution among the body tissues and in disposition and mode of action.
• the physicochemical properties of therapeutically active compounds determine to a great extent the preferred route of their admistration.
• the oral applicability thereof is usually an important selection criterium. For the majority of patients this is obviously the most convenient route for access of the drug to the systemic circulation.
• a drug - administered via oral route - to act it must first be absorbed before it is transported to the appropriate tissue or organ, where it may penetrate to the responding subcellular structure and may subsequently be metabolized, or where it may be bound, stored, or whatever is necessary to elicit a response or to alter ongoing processes.
• compounds which have been found to possess an advantageous therapeutic activity are also sufficiently absorbed in the gastrointestinal tract to display effective oral bioavailability.
• the present invention relates to antithrombotic compounds comprising the group Q, Q having the formula wherein the substructur e is a structure selected from
• X' being independently CH or N; and m is 0, 1, 2 or 3; wherein the group Q is bound through an oxygen atom or an optionally substituted nitrogen or carbon atom, or a pharmaceutically acceptable salt thereof or a prodrug thereof.
• the compounds of the invention are active antithrombotic agents having an improved pharmacological profile, in particular with regard to properties like their absorptive properties and their toxicity.
• antithrombotic compound means any compound having antithrombotic activity. Examples of such compounds are inhibitors of serine proteases that play a role in the blood coagulation cascade or GpIIb/IIIa antagonists.
• the group Q is bound to the molecule through an oxygen atom or an optionally substituted nitrogen or carbon atom.
• Optionally substituted in this respect means any suitable substituent, such as, but not limited to, oxo, alkyl, alkenyl, alkoxy, aryl, halogen and the like.
• prodrug means a compound of the invention in which (an) amino group(s) is (are) protected, e.g. by (a) hydroxy or (l-6C)alkoxycarbonyl group(s), or a compound wherein -if present- (a) carboxylate group(s) is (are) esterified.
• the present invention relates to the surprising finding that the presence of the group Q in antithrombotic compounds gives rise to favourable properties of the compounds. Especially when Q is used to replace a basic moiety in compounds of which is known that they require such a moiety for their activity, an improvement of the pharmacological properties is realized, and in particular when that basic moiety is a (hetero)arylguanidino or (hetero)arylamidino moiety. In particular an improvement of the absorptive properties of those compounds is observed. Also a reduction of the toxicity of compounds of this invention is observed.
• the group Q has the formula
• the Caco-2 model An established in vitro model for the determination of the absorptive properties of drugs is the Caco-2 model (Artursson, P., S.T.P. Pharma Sciences 3(1), 5-10, 1993; Walter, E. et al. Pharmaceutical Research, 3, 360-365, 1995).
• the transepithelial transport properties of a compound are determined in monolayers of a human intestinal cell-line (Caco-2) in terms of a permeability coefficient (apparent permeability).
• This model is useful for the prediction of / ' /; vivo absorption of compounds in the gastrointestinal tract.
• the antithrombotic compounds of the invention have a Caco-2 permeability of 8 nm/s or higher.
• the compounds of the present invention are inhibitors of serine proteases of the blood coagulation cascade, and in particular inhibitors of thrombin and/or factor Xa.
• Preferred compounds inhibit thrombin more effectively than other serine proteases.
• More preferred compounds are thrombin inhibitors having, in addition, an IC 5 o value of less than 1 ⁇ M. The compounds are useful for treating and preventing thrombin-mediated and thrombin- associated diseases.
• thrombotic and prothrombotic states in which the coagulation cascade is activated which include, but are not limited to, deep vein thrombosis, pulmonary embolism, thrombophlebitis, arterial occlusion from thrombosis or embolism, arterial reocclusion during or after angioplasty or thrombolysis, restenosis following arterial injury or invasive cardiological procedures, postoperative venous thrombosis or embolism, acute or chronic atherosclerosis, stroke, myocardial infarction, cancer and metastasis, and neurodegenerative diseases.
• Compounds of the invention may also be used as in vitro anticoagulants or as anticoagulants in extracorporeal blood circuits, such as those necessary in dialysis and surgery.
• Serine proteases are enzymes which play an important role in the blood coagulation cascade. Apart from thrombin and factor Xa, other examples of this group of proteases comprise the factors Vila, IXa, XIa, Xlla, and protein C.
• thrombin is the final serine protease enzyme in the coagulation cascade.
• the prime function of thrombin is the cleavage of fibrinogen to generate fibrin monomers, which are cross-linked to form an insoluble gel.
• thrombin regulates its own production by activation of factors V and VIII earlier in the cascade. It also has important actions at cellular level, where it acts on specific receptors to cause platelet aggregation, endothelial cell activation and fibroblast proliferation.
• thrombin has a central regulatory role in homeostasis and thrombus formation. Since inhibitors of thrombin may have a wide range of therapeutical applications, extensive research is done in this area.
• benzamidine moiety is one of the key structures. It mimics the protonated side-chain of the basic amino acids Arg and Lys of its natural substrates. Compounds with this moiety have been studied extensively and repeatedly.
• a very potent representative of this type of thrombin inhibitors is the amino acid derivative N ⁇ -(2-naphthylsulfonyl)-glycyl-4-amidinophenylalanin- piperidide (NAPAP) (Sturzebecher, J. et al., Thromb. Res. 29, 635-642, 1983).
• NAPAP neuropeptide
• the pharmacological profile of NAPAP is unattractive for therapeutical applications: the compound shows toxic effects after intravenous administration and, in addition, poor oral bioavailability after oral administration.
• the NAPNP-like benzamidine derivatives which have been investigated for use as thrombin inhibitors show these unfavourable pharmacological and pharmacokinetic properties. It was assumed that these properties are due to the strong basicity of the amidino functionality of these compounds (Kaiser, et al., Pharmazie 42, 1 19-121, 1987; Sturzebecher, J. et al., Biol. Chem. Hoppe-Seyler, 373, 491-496, 1992).
• Oral bioavailability is a property of thrombin inhibitors which is urgently searched for. Potent intravenous thrombin inhibitors are clinically effective in acute care settings requiring the treatment of thrombin-related diseases. However, particularly the prevention of thrombin-related diseases such as myocardial infarct, thrombosis and stroke require long-term therapy, preferably by orally dosing an anticoagulant. Consequently, the search for active, orally bioavailable thrombin inhibitors continues unabated. Oral bioavailability is at least in part related to the ability of compounds to be absorbed in the gastrointestinal tract. The low oral bioavailability of NAPAP and its analogues may therefore be related to their deficient absorptive properties in the intestines.
• the present invention provides a solution to the deficient pharmacological properties of the NAPAP-like compounds, in particular with respect to the toxicity and the deficient absorptive properties.
• Preferred serine protease inhibitors of the invention have the formula (I), comprising the group Q; compounds of this type show improved transepithelial transport properties (increased apparent permeability) in comparison with prior art compounds:
• R 1 -Y-[NR 2 -A-C(0)] n -NR 3 -CHR 4 -C(0)-R 5 (I) wherein R 1 is (l-8C)alkyl, (6-14C)aryl-(l-8C)alkenyl, (6-14C)aryl-(l-8C)alkanoyl, (6-14C)aryl,
• R 2 is H or (l-8C)alkyl
• R 3 is Q when R 4 is H, or R 3 is H or
• R 5 is OH or OR 6 , R 6 being (l-8C)alkyl, (3-12C)cycloalkyl or (7-15C)aralkyl, or R 5 is NR 7 R 8 , wherein R 7 and R 8 are the same or different being H, (l-8C)alkyl, (3-12C)cycloalkyl, (6-14C)aryl, (7-15C)aralkyl, optionally subtituted with (l-8C)alkoxy, C(O)OH or C(O)OR 6 , or R 7 and R 8 together with the nitrogen atom to which they are bonded are a nonaromatic (4-8)membered ring optionally containing another heteroatom, which ring may be condensed with another optionally aromatic ring and may be subtituted with OH, an oxo group, (l-8C)alkyl, optionally substituted with one or more halogens or hydroxy groups, (2
• thrombin inhibitors are disclosed in WO 92/16549 and WO 92/08709, wherein respectively para- and meta- substituted phenylalanine derivatives are described having an amidino, guanidino, oxamidino, aminomethyl or amino substituent.
• compounds with the amidino substituent show unfavourable pharmacological properties, whereas the other structures, with a modified amidino moiety, display a loss of activity (vide supra).
• Other modifications are described in EP 555824 where compounds are disclosed having a benzimidazolyl group, which compounds do not contain a primary amino functionality.
• Thrombin inhibitors having a benzamidine moiety have also been modified in other parts of the molecule, however, without improvement of the unfavourable pharmacological properties caused by the amidino substituent. Examples hereof are disclosed in EP 508220, wherein the compounds contain an azaglycyl group instead of the glycyl group of NAPAP; in DE 41 15468, wherein that glycyl group is replaced e.g.
• Preferred compounds of formula (I) are compounds wherein R 1 is phenyl, naphthyl, (iso)quinolinyl, tetrahydro(iso)quinolinyl, 3,4-dihydro- 1 H-isoquinolinyl, 2,3 ,4, 5-tetrahydro- 1 H- benzo[d]azepinyl, 2,3-dihydro-5H-benzo[fJ[l,4]oxazepinyl, dibenzofuranyl, chromanyl, bisaryl, each aryl being a 5- or 6-membered ring and optionally containing a O, S or N-atom, which groups R 1 may optionally be substituted with one or more substituents selected from (l-8C)alkyl, (l-8C)alkoxy the alkyl group of which may be optionally substituted with an alkoxy group or an alkoxyalkyl group, phenyl-(l-8C)alkyl, te
• the interrupted line represents an optional bond, B being CR 17 when the optional bond is present, or B is CHR 17 , R 17 being H, (l-8C)alkyl, optionally substituted with one or more halogens or hydroxy groups, (2-8C)alkenyl, (2-8C)alkynyl, (l-8C)acyl, or (l-8C)alkoxy, or B is O, S, or NR 18 , R 18 being (l-8C)alkyl, (l-8C)acyl, C(O)NR 9 R 10 or SO 2 -(l-8C)alkyl optionally substituted by one or more fluorine atoms. More preferred compounds of formula (I) are compounds wherein R 2 and R 3 are H and Q is
• ⁇ / and B is CH 2 or CH(l -8C)alkyl.
• Preferred groups R 1 are phenyl, naphthyl, tetrahydroisoquinolinyl, 3,4-dihydro-lH-isoquinolinyl, 2,3,4,5-tetrahydro-lH-benzo[d]azepinyl, 2,3-dihydro-5H-benzo[fJ[l,4]oxazepinyl, which groups R 1 may optionally be substituted with one or more substituents selected from (l-8C)alkyl, (l-8C)alkoxy the alkyl group of which may be optionally substituted with an alkoxy group or an alkoxyalkyl group, phenyl-(l-8C)alkyl, tetrahydropyranyloxy, tetrahydropyranyloxy(l-8C)alkyl or NR 15 R 16 .
• Y is preferably SO 2 .
• n preferably has the value 1.
• A is CH(l-8C)alkyl substituted with COR 13 wherein R 13 is OH, (l-8C)alkoxy, morpholino, morpholino(l-8C)alkoxy, N ⁇ R 14 or NR ,4 R 15 , R 14 and R 15 being independently (l-8C)alkyl, or A is CHR 12 , R 12 being -(CH 2 ) S - together with R 3 when R 4 is Q, s being 2 or 3.
• Other preferred compounds are compounds wherein n is 0 and R is
• n 1
• R 2 is H
• A is CHCH 2 C(O)OH, CHCH_C(O)O(l-8C)alkyl, CHCH 2 C(O)morpholine, CHCH 2 C(O)O(l-8C)alkylene-morpholine, CHCH 2 C(O)NHR 14 or CHCH 2 C(O)NR 14 R 15 , R 14 and R 15 being independently (l -8C)alkyl
• R 3 is H
• R 4 is
• n 0, R 3 is H, R 4 is
• (l-8C)alkyl means a branched or unbranched alkyl group having 1-8 carbon atoms, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, hexyl and octyl.
• (2-8C)alkenyl means a branched or unbranched alkenyl group having 2 to 8 carbon atoms, such as ethenyl, 2-butenyl, etc..
• (l-8C)alkylene means a branched or unbranched alkylene group having 1 to 8 carbon atoms, such as -(CH 2 ) ⁇ - wherein a is 1 to 8, -CH(CH 3 )-, -CH(CH 3 )-CH 2 -, etc..
• (l-8C)alkylidene means a branched or unbranched alkylidene group having 1-8 carbon atoms, such as methylene and ethylidene.
• (2-8C)alkynyl means a branched or unbranched alkynyl group having 2-8 carbon atoms, such as ethynyl and propynyl.
• (3-12C)cycloalkyl means a mono- or bicycloalkyl group having 3-12 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl, the camphor group, etc..
• a preferred cycloalkyl group in the definition of R 1 is the camphor group.
• (l-8C)alkoxy means an alkoxy group having 1-8 carbon atoms, the alkyl moiety having the meaning as previously defined.
• (l-8C)acyl means an acyl group having 1-8 carbon atoms, the alkyl moiety having the meaning as previously defined.
• (l-8)alkanoyl means an oxo-alkyl group, the alkyl moiety having the meaning as previously defined.
• (6-14C)aryl means an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, indenyl, which may optinally be substituted with one or more substituents such as -but not limited to- alkyl, alkoxy, the alkyl group of which may be optionally substituted with an alkoxy group or an alkoxyalkyl group (e.g the substituent groups -O-(CH 2 ) 2 -OCH 3 or -O-CH(CH 2 OCH 3 ) 2 ), tetrahydropyranyloxy, tetrahydropyranyloxymethyl, acyl, alkylthio, hydroxyalkyl, haloalkyl, carboxy,
• (7-15C)aralkyl means an aralkyl group having 7 to 15 carbon atoms, wherein the alkyl group is a (l-8C)alkyl group and the aryl group is a (6-14C)aryl as previously defined.
• Phenyl- (l-8C)alkyl groups are preferred aralkyl groups, such as benzyl.
• heteroaryl means a substituted or unsubstituted aromatic group having 4 to 12 carbon atoms, at least including one heteroatom selected from N, O, and S, like imidazolyl, thienyl, benzthienyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, dibenzofuranyl, chromanyl,
• R H, alkoxy, acyloxy
• R H, alkoxy, acyloxy ancj
• R H, alkyl, acyl,S02alkyl, aralkyl
• the substituents on the heteroaryl group may be selected from the group of substituents listed for the aryl group.
• Heteroaralkyl groups are analogs of the (7-15C)aralkyl groups, at least including one heteroatom selected from N, O, and S.
• bisaryl in the definition of R ! means two independently chosen aryl or heteroaryl groups according to the definitions of the term aryl and heteroaryl, connected to each other by a bond or by a short bridge, having a length of one or two atoms, such as CH 2 , N 2 or SO 2 , optionally substituted with a substituent as listed for the aryl group.
• Examples of bisaryls are biphenyl,
• cycloalkyl substituted alkyl in the definition of R 1 means an alkyl group, preferably having 1-8 carbon atoms, carrying a mono-, bi- or polycycloalkyl group, preferably having 5-8,
• heterocycloalkyl means an optionally substituted cycloalkyl group, preferably having 4 or 5 carbon atoms, further containing one heteroatom selected from O, S or N, such as tetrahydrofuran and tetrahydropyran.
• the substituents on the hetercycloalkyl group may be selected from the group of substituents listed for the aryl group.
• nonaromatic (4-8)membered ring in the definition of NR 7 R 8 , where R 7 and R 8 together with the nitrogen atom to which they are bonded are a ring, means a ring containing the nitrogen atom and further having at most 3-7 carbon atoms, which ring may contain unsaturated bonds.
• Examples of such (4-8)membered rings are azetidine, pyrrolidine, piperidine, piperazine morpholine and thiomorpholine.
• serine protease inhibitors of the invention are small synthetic peptides comprising the group Q, and have the formula (XX) in which formula Q is as previously defined; (R') ! is H or (l-4C)alkyl; J is H, optionally substituted D,L ⁇ -hydroxyacetyl, (R') 2 , (R') -O-C(O)-, (R') 2 -C(O)-, (R') 2 -SO 2 -, (R') 7 OOC-(CH(R') 3 ) p -SOr, (R') 7 OOC-(CH(R') 3 ) p -, (R') 3 2 NCO-(CH(R') 3 ) p -,
• (R') 2 is selected from (l-12C)alkyl, (2- 12C)alkenyl, (2-12C)alkynyl and (3-12C)cycloalkyl, which groups may optionally be substituted with (3-12C)cycloalkyl, (l-6C)alkoxy, oxo, OH, COOH, CF 3 or halogen, and from (6-14C)aryl, (7-15C)aralkyl and (8-16)aralkenyl, the aryl groups of which may optionally be substituted with (l-6C)alkyl, (3-12C)cycloalkyl, (l -6C)alkoxy, OH, COOH, CF 3 or halogen; each group (R') 3 is independently H or has the same meaning as (R') 2 ; (R') ?
• Preferred compounds of formula (XX) are those wherein E is an L-amino acid with a hydrophobic side chain, serine, threonine or -N(R') 3 -CH 2 -C(O)- or wherein E-N(R') 1 taken together form the fragment
• More preferred compounds of formula (XX) are those wherein J is H, 2-hydroxy-3-cyclohexyl- propionyl-, 9-hydroxy-fluorene-9-carboxyl, (R') 2 , (R') 2 -SO 2 -, (R') 7 OOC-(CH(R') 3 ) p -SO 2 -, (R') 7 OOC-(CH(R')V, (R') 3 2 N-CO-(CH(R') 3 ) p -, Het-CO-(CH(R') ) p - wherein Het contains as a heteroatom at least a nitrogen atom which is bound to CO, or an N-protecting group, wherein (R') 2 is selected from (l-12C)alkyl, (2-12C)alkenyl, (6-14C)aryl, (7-15C)aralkyl and (8-16)aralkenyl which groups may optionally be substituted (l-6C)alkoxy; each group (
• D is a bond, D-l-Tiq, D-3-Tiq, D-Atc,
• Aic, D-l-Piq, D-3-Piq or a D-amino acid having a hydrophobic side chain; or J and D together are the residue (R') 4 (R') 5 N-CH(R') 6 -C(O)-, wherein at least one of (R') 4 and (R') 5 is (R') 7 OOC-(CH(R')V or (R') 2 -SO 2 - and the other independently is (l-12C)alkyl, (2- 12C)alkenyl, (2-12C)alkynyl, (3-12C)cycloalkyl, (7-15C)aralkyl, (R') 2 -SO 2 - or (R') 7 OOC-(CH(R') 3 ) P -, and (R') 6 is a hydrophobic side chain.
• the group Q in the compounds of formula (XX) has one of the structures:
• the compounds of formula (XX) have an anticoagulant effect and are useful for treating and preventing thrombin-mediated and thrombin-associated diseases, applicable as herein before described.
• optionally substituted D,L ⁇ -hydroxyacetyl means a group of the formula HO-CR a R b -C(O)-, wherein R a and R b independently are H, a hydrophobic side chain, or R a and R b together form a 5- or 6-membered ring, which is optionally fused with one or two aliphatic or aromatic 6-membered rings, and which 5- or 6-membered ring consists of carbon atoms and optionally one heteroatom selected from N, O and S.
• Preferred D,L ⁇ -hydroxyacetyl groups are
• (l-12C)alkyl means a branched or unbranched alkyl group having 1 to 12 carbon atoms, such as methyl, ethyl, t-butyl, isopentyl, heptyl, dodecyl, and the like.
• Preferred alkyl groups are (l-6C)alkyl groups, having 1-6 carbon atoms.
• a (2-12C)alkenyl group is a branched or unbranched unsaturated hydrocarbon group having 2 to
• (l-6C)alkylene means a branched or unbranched alkylene group having 1 to 6 carbon atoms, such as -(CH 2 ) ft - and b is 1 to 6, -CH(CH 3 )-, -CH(CH 3 )-(CH 2 )-, etc.
• a (2-12C)alkynyl group is a branched or unbranched hydrocarbon group containing a triple bond and having 2 to 12 carbon atoms.
• Preferred are (2-6C)alkynyl groups, such as ethynyl and propynyl.
• a (6-14C)aryl group is an aromatic moiety of 6 to 14 carbon atoms.
• the aryl group may further contain one or more hetero atoms, such as N, S, or O, also referred to as heteroaryl groups.
• aryl groups are phenyl, naphthyl, (iso)quinolyl, indanyl, and the like. Most preferred is the phenyl group.
• (7- 15C) Aralkyl and (8-16C)aralkenyl groups are alkyl and alkenyl groups respectively, substituted by one or more aryl groups, the total number of carbon atoms being 7 to 15 and 8 to 16, respectively.
• (l- ⁇ C)alkoxy means an alkoxy group having 1-6 carbon atoms, the alkyl moiety of which having the meaning as previously defined.
• (3-12C)cycloalkyl means a mono- or bicycloalkyl group having 3-12 carbon atoms, being cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl, the camphor group, etc.. Cyclopentyl and cyclohexyl are preferred cycloalkyl groups.
• halogen means fluorine, chlorine, bromine or iodine.
• ester derivative means any appropriate ester derivative, preferably (l-4C)alkyl-esters, such as methyl-, ethyl- or t-butyl-esters.
• 1- and 3-Tiq mean 1,2,3,4-tetrahydroisoquinoline-l- and -3-carboxylic acid, respectively;
• 1- and 3-Piq are perhydroisoquinoline-1- and -3-carboxylic acid, respectively; Ate is
• Aic is amino indane carboxylic acid
• Phe is phenylalanine
• Cha is cyclohexylalanine
• Dpa is diphenylalanine
• Coa is cyclooctylalanine
• Chg is cyclohexylglycine
• Nle is norleucine
• Asp is aspartic acid
• hydrophobic side chain means a (l-12C)alkyl, optionally substituted with one or more
• (3-12C)cycloalkyl groups or (6-14C)aryl groups which may contain a heteroatom, e.g. nitrogen) such as cyclohexyl, cyclo-octyl, phenyl, pyridinyl, naphthyl, tetrahydronaphthyl, and the like, which hydrophobic side chain may optionally be substituted with substituents such as halogen, trifluoromethyl, lower alkyl (for instance methyl or ethyl), lower alkoxy (for instance methoxy), phenyloxy, benzyloxy, and the like.
• substituents such as halogen, trifluoromethyl, lower alkyl (for instance methyl or ethyl), lower alkoxy (for instance methoxy), phenyloxy, benzyloxy, and the like.
• substituted in general means: substituted by one or more substituent.
• Amino acids having a basic side chain are for example, but not limited to, arginine and lysine, preferably arginine.
• amino acids having a neutral side chain refers to amino acids such as methionine sulphon and the like.
• Cyclic amino acids are for example 2-azetidine carboxylic acid, proline, pipecolic acid, 1-amino- l-carboxy-(3-8C)cycloalkane (preferably 4C, 5C or 6C), 4-piperidine carboxylic acid, 4-thiazolidine carboxylic acid, 3,4-dehydro-proline, azaprohne, 2-octahydroindole carboxylic acid, and the like.
• Preferred are 2-azetidine carboxylic acid, proline, pipecolic acid, 4-thiazolidine carboxylic acid, 3,4-dehydro-proline and 2-octahydroindole carboxylic acid.
• serine protease inhibitors of the present invention are compounds of the formula (XXX):
• R is an integer of 0 to 4;
• R" 1 is a hydrogen atom, a carboxyl group, an alkoxycarbonyl group, a carboxyalkyl group, an alkoxycarbonylalkyl group, a carboxyalkoxy group or an alkoxycarbonylalkoxy group;
• R" 2 is a hydrogen atom, a hydroxyl group, a lower alkyl group or a lower alkoxy group;
• M is an alkylene group having a carbon number of 1 to 4, which may have 1 or 2 substituents selected from the group consisting of hydroxyalkyl, carboxyl, alkoxycarbonyl, carboxyalkyl and alkoxycarbonylalkyl;
• T is a single bond, an oxygen atom, a sulfur atom or a carbonyl group;
• K is a saturated or unsaturated 5- or 6-membered heterocyclic moiety or cyclic hydrocarbon moiety optionally having a substituent group, an amino group optionally
• EP 0,540,051 Related compounds are known for instance from EP 0,540,051.
• the compounds of EP 0,540,051 are altered by replacing the aromatic group carrying the amidine substituent by the group Q, thus improving in particular the absorptive properties of the compounds, such as examples having the structure:
• the compounds of structure (XXX) show a strong anticoagulant effect and are applicable as herein described.
• any straight chain, branched chain or cyclic alkyl group having 1 to 6 carbon atoms may be used as the lower alkyl group.
• Illustrative examples include methyl, ethyl, propyl, isopropyl, butyl, sec- or tert- butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
• the lower alkoxy group may have 1 to 6 carbon atoms.
• Illustrative examples include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec- or tert-butoxy and the like.
• alkoxycarbonyl, carboxyalkyl, alkoxycarbonylkalkyl, carboxyalkoxy, alkoxycarbonylalkoxy and hydroxyalkyl groups preferably have 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, respectively.
• alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl and the like.
• carboxyalkyl group include carboxy methyl, carboxyethyl, carboxypropyl and the like.
• Illustrative examples of the alkoxycarbonylalkyl group include methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, methoxycarbonylpropyl, ethoxycarbonylpropyl and the like.
• Illustrative examples of the carboxylalkoxy group include carboxymethoxy, carboxyethoxy, carboxypropoxy and the like.
• Illustrative examples of the alkoxycarbonylalkoxy group include methoxycarbonylmethoxy, ethoxycarbonylmethoxy, propoxycarbonylmethoxy, methoxycarbonylethoxy, ethoxycarbonylethoxy and the like.
• hydroxyalkyl group examples include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and the like.
• the saturated or unsaturated 5- or 6-membered heterocyclic moiety may contain preferably one or two hetero-atom(s) selected from nitrogen and oxygen atoms.
• Illustrative examples of such a preferred type of heterocyclic rings include pyrrolidine, piperidine, imidazoline, piperazine, tetrahydrofuran, hexahydropyrimidine, pyrrole, imidazole, pyrazine, pyrrolidinone, piperidinone, morpholine and the like.
• pyrrolidine and piperidine which contain one nitrogen atom as the hetero-atom.
• saturated or unsaturated cyclic hydrocarbon moiety include cyclopentyl, cyclohexyl and the like.
• aminoalkyl group include aminomethyl, aminoethyl, aminopropyl and the like.
• substituents applicable to these heterocyclic moieties and cyclic hydrocarbon moieties include preferably lower alkyl, lower alkanoyl, carbamoyl, mono- or dialkylcarbamoyl, formimidoyl, alkanoimidoyl, benzimidoyl, carboxyl, alkoxycarbonylimino and the like, more preferably formimidoyl and alkanoimidoyl groups.
• substituents applicable to these amino groups and amino moieties of aminoalkyl groups include preferably lower alkyl, pyradinyl, pyrrolidinyl, carbamoyl, mono- or dialkylcarbamoyl, lower alkanoyl, formimidoyl, alkanoimidoyl, benzimidoyl, alkoxycarbonyl and the like, more preferably pyrazinyi, pyrrolidinyl, formimidoyl, alkanoimidoyl groups.
• each of the alkyl, alkoxy, alkanoyl and the like listed above may preferably have a carbon number of from 1 to 6.
• the compounds of structure (XL) show anticoagulant activity and are applicable as herein described.
• the compounds of structure (XL) display this effect in particular through their specific thrombin- and FXa-inhibiting activity.
• lower means a branched or unbranched group having 1-6 C-atoms.
• Preferred lower alkyl or lower alkanoyl groups contain up to 4 C-atoms, e.g. methyl, isopropyl, butyl, isobutyl, sec-butyl, tert. -butyl, and acetyl, respectively.
• Aryl alone or in combination means groups like phenyl, which may be substituted, for instance with amidino, guanidino, hydroxyamidino, nitro, amino or methylenedioxy.
• Aralkyl means an aryl bound to a lower alkyl, e.g.
• Cycloalkyl means saturated groups having 3-7 C-atoms, like cyclohexyl.
• Heteroaryl means 5- to 10 membered aromatic groups, which may consist of two rings, and contain one (or more) N-atom(s) and may be substituted, e.g. by one or more NH 2 -groups.
• An example is chinazolinyl, such as 2,4-diaminochinazolin-6- or 7-yl.
• Examples of groups having amino, guanidino or N-hydroxyamidino substituents are amino-substituted chinazolinyl and (amino, amidino, guanidino or N-hydroxyamidino)-substituted phenyl, benzyl and lower alkyl groups.
• Q has the previously defined meaning; the distance between the amino substituted carbon atom of the group Q and the carbon atom of the carboxylate moiety has a length of 12-18 A; the spacer is any suitable chemical moiety; and the carboxylate group may be esterified.
• the compounds of structure (L) show anticoagulant effect and are applicable as herein described.
• Preferred compounds of formula (L) have the formula (La):
• More preferred compounds of formula (La) are those wherein m is 0; U is a bond; (R"") 2 is (l-4C)alkyl, phenyl or benzyl, which may optionally be substituted with OH or halogen and V is phenyl, piperidinyl, piperazinyl or thiazolyl, substituted with one substituent selected from -CH 2 - COO(R"") 1 and -O-CH 2 -COO(R"") ⁇
• (R"") ⁇ 4 4 is H, (l -12C)alkyl, (2-12C)alkenyl, (2-12C)alkynyl, (3-8C)cycloalkyl, (6-14C)aryl, (7-15C)aralkyl or (8-16)aralkenyl, which may optionally be substituted with (l-6C)alkyl, (3-8C)cycloalkyl, (l-6C)alkoxy, OH, COOH, CF 3 or halogen; y is 0 or 1 and z is 0 or 1.
• (R"") 5 is independently H, (l-4C)alkyl or benzyl or both (R"") 5 groups are an ethylene bridge to form a 6- or 7-membered ring together with N-(CH 2 ) U -N to which they are bound;
• the present invention further relates to the finding that also in other therapeutic compounds the presence of the group Q gives rise to an improved pharmacological profile.
• Q is used to replace a basic moiety in compounds of which is known that they require such a moiety for their therapeutic activity, an improvement of the absorptive properties is observed, in particular when that basic moiety is a (hetero)arylguanidino or (hetero)arylamidino moiety.
• Preferred therapeutic compounds of the invention have an apparent Caco-2 permeability of 8 nm/s or higher.
• the group Q has the formula
• the compounds of the invention may be used in a broad range of therapeutic applications which require oral administration of a drug or wherein oral administration thereof is considered favourable, such as in particular (but not limited to) CNS-active compounds, compounds useful for treating immunological disorders, antithrombotic agents, and the like.
• Preferred compounds of the present invention are antithrombotic agents.
• therapeutic compound as used herein means any compound which can be used in therapy, which implies the curing of a disease or malfunction of the body and which covers prophylactic treatment
• x i s o or S can be prepared using suitable starting compounds and methods as described in the literature e g 4-amino-6-chloroquinazol ⁇ ne and 4-amino-7-chloroqu ⁇ nazoline as described by A Rosowsky and N Papathanasopoulos in J Heterocycl Chem 9, 1235 (1972), 4-aminothieno[2,3d]pyridazine or 7-aminothieno[2,3d]pyridazine by M Robba, B Roques and Y Le Guen in Bull Soc Chim France 4220, (1967), 4-aminoth ⁇ eno[2,3d]pyrimidine by M Robba, J -M Lecompte and M Cugnon de Sevricourt in Bull Soc Chim France 592, (1975), 4-aminothieno[3,2d]pyrimidine by M Robba, J
• a suitable method starts from a compound of formula ( ⁇ i) (wherein the halogen atom, if present, preferably is Br), the hydroxy group of which is chlorinated, e.g. by treatment with POCl 3 , to give the compound of formula (IV), followed by conversion into the amino analogue of formula (II) , for example by first converting the chloro-substituent into a phenoxy-substituent by reaction with phenol under alkaline conditions, and subsequently treatment with ammonium acetate, or by direct conversion of the chloro-compound into the corresponding amino- compound by heating the former with ammonia under pressure.
• the compound of formula (IV) in this sequence may also be prepared by converting the corresponding unsubstituted compound into the N-oxide salt, e.g. with a peracid, such as m-chloroperbenzoic acid, followed by HCl treatment, and subsequently reacting this N-oxide salt with a chlorinating reagent, like POCl 3 .
• a peracid such as m-chloroperbenzoic acid
• R 1 -Y-[NR 2 -A-C(0)] n -NR 3 -CHR 4 -C(0)-0-G wherein G e.g. is an alkyl or benzyl group, followed by coupling with R 5 -H, or they can be prepared by deprotection of the compound Pg-NR 3 -CHR 4 -C(0)R 5 , wherein Pg is an N-protecting group, followed by coupling with one of the groups R'-Y-NR ⁇ A-CCC -OH, R ! -Y-Lg or R ⁇ OJ-OH, wherein Lg is a leaving group.
• the carboxylic acid group of a compound of formula (V) is esterified, e.g. by treatment with R 6 OH and thionyl chloride, wherein R 6 has the previously defined meaning, to form a compound of formula (VI), or an arylamino protected derivative thereof.
• the ester group of a compound of formula (la) or an arylamino protected derivative thereof may be saponified to form the corresponding acid, after which the protective group, if present, may optionally be removed.
• the acid formed from a compound of formula (la) may be coupled to an amine of formula HNR 7 R 8 , wherein R 7 and R 8 have the previously defined meanings, for example by using DCCI/HOBT or TBTU, followed by removal of the optionally present protective group, to give a compound of formula (lb), which is the compound of formula (I), wherein R 5 is NR 7 R 8 .
• a suitable process for the preparation of the compound of formula (V) is the conversion of a compound of formula (VIII), wherein Pg is an N-protecting group and Lg is a leaving group, such as the mesyl group, into a compound of formula (IX), for example by reaction with an appropriate amino acid derivative of the general formula PgR 3 N-CH[C(O)OR] 2 in the presence of a base, e.g.
• the compound according to formula (VIII) may be prepared by methods known in the art.
• the arylamino group of a compound of formula (II) is protected with an N-protecting group, after which the ring wherein X is located is provided with a formyl substituent either by treatment with a base, like lithium diisopropylamide, or with an organometallic reagent, like n-butyllithium, followed by addition of N,N-dimethylformamide, forming a compound of formula (X).
• a base like lithium diisopropylamide
• an organometallic reagent like n-butyllithium
• the compound of formula (X) is reduced, e.g. using sodium borohydride, into the corresponding alcohol, which then is converted into a leaving group, e.g. an appropriate sulfonate group, thereby forming a compound of formula (VHI).
• a leaving group e.g. an appropriate sulfonate group
• a compound of formula (Id) may be obtained after protection of the N-terminus of (XI) with an N-protecting group Pg, such as Boc, both protecting groups in the molecule being the same or different, and saponification of the ester group to give intermediate (XII), and further derivatization as described for the conversion of a compound of formula (VH) into a compound of formula (lb).
• N-protecting group Pg such as Boc
• R'Y can be introduced as described for the conversion of compounds of formula (VI) into compounds of formula (la).
• the group OR 6 can be modified in the same way as described for the conversion of compounds of formula (la) into compounds of formula (lb) and removal of protecting groups if present gives compounds of formula (Ie).
• compounds of formula (Ie) and (XIII) can be prepared using the methods described by H. Mack et al. in J. Enzyme Inhibition 9, 73 (1995), wherein instead of the cyanophenyl building blocks used in the literature, building blocks containing moiety Q or a arylamino protected derivative thereof (e.g. compounds of formula (VI)) can be used.
• Compounds of formula (XX) can be prepared from compounds of formula (X). Reaction of a compound of formula (X) with an amine of formula (R')'NH 2 gives an imide, which is either directly converted into a compound of formula (XXI) by reduction, using e.g. sodium cyano borohydride, or is isolated and subsequently reduced with a suitable agent like sodium borohydride to form a compound of formula (XXI), wherein (R') 1 has the previously defined meanings.
• a compound of formula (X) is reduced, using e.g. sodium borohydride, into the coresponding alcohol which then is converted into an azide using the method described by A.S. Thompson et al. in J. Org. Chem. 58, 5886 (1993).
• This azide can be reduced into an amine using reagents known in the art such as Pd / CaCO 3 catalyzed hydrogenation to yield a compound of formula (XXI) in which (R') 1 is hydrogen.
• a compound of formula (XXI), or a derivative thereof wherein the arylamino is not protected can be coupled with carboxylate compounds of formula J-D-E-OH, in which J, D and E have the previously defined meanings, or a protected derivative thereof, using peptide coupling methods. Subsequent removal of the optionally present protective groups gives compounds of formula (XX).
• Compounds of formula (XXa) can be prepared by reaction of amines of formula (XXI), wherein (R') 1 is hydrogen with aldehydes of formula PgHNCH((CH 2 ) (u . 1) CHO)COOG, wherein Pg is a N- protecting group and u and G have the previously defined meanings, using the method described for compounds of formula (Ie).
• Compounds of formula (XXX) may be prepared in several ways in which the synthetic connection of moiety Q and the substituted phenyl part is made in moiety M.
• the method described in EP 0540051 may be used to prepare componds of formula (XXX) starting with compounds of formula (VIII).
• Compounds of formula (XL) can be prepared by reaction of a compound of formula (XLI) with a compound of formula (XLII) and a compound of formula (XLIII), wherein (R'") ⁇ (R'") 2 , , (R'") 5 , and (R'") 6 have the previously defined meanings according to the methods described in EP 0728758.
• (R'") 1 or (R'") 2 is the group of formula Q
• compounds of formula (II), (V ⁇ i) or (X) or an arylamino protected derivative thereof can be used to prepare compounds of formula (XLI) or (XLH).
• Compounds of formula (L) can be prepared using methods known in the art described for Gp Hb/IIIa receptor antagonists containing a (hetero)arylamidine moiety instead of moiety Q.
• Compounds of formula (La) can conveniently be prepared from compounds of formula (X).
• An aldehyde of formula (X) is oxidized, using e.g. sodium chlorite, into the corresponding carboxylic acid.
• This carboxylic acid, or a derivative thereof wherein at the arylamino is not protected can be coupled with an amine linker of formula HN(R"") 1 -U-(R"") 1 (R"") 2 -V or a N-protected derivative thereof, wherein (R"") 1 , U, (R"") 2 -and V have the previously defined meanings, using peptide coupling methods (e.g. using the amines and methods described in J. Med. Chem. 35, 4393 (1992), EP 0,505,868 or J. Med. Chem. 39, 3193 (1996)). Subsequent removal of the optionally present protective groups gives compounds of formula (La).
• a linker molecule having one free carboxylate can also be coupled with compound of formula (XXI), or a derivative thereof wherein the arylamino is not protected. Subsequent removal of the optionally present protective groups gives compounds of formula (L). Also halogen containing compounds of formula (II) can be used as starting material.
• the linker molecule can be attached using Pd mediated reactions such as Suzuki coupling, Heck reaction, or first transmetalation, using e.g. n-BuLi, and secondly reaction with a linker molecule containing an electrophilic function. Subsequent removal of the optionally present protective groups gives compounds of formula (L).
• Compounds of the invention can also be prepared using a solid phase synthesis strategy.
• the carboxylic acid of the compounds of formula (VH) can be covalently attached to a polymeric support such as a polystyrene-resin using a ester or amide bond as anchoring bond.
• a polymeric support such as a polystyrene-resin using a ester or amide bond as anchoring bond.
• protection of the arylamino function is preferred.
• anchoring using a ester bond to the Kaiser oxime resin Boc-protection of the N- terminus and acetyl amide protection of the arylamino group.
• Protecting group Pg 2 is a protecting group that can be removed selectively.
• the solid phase synthesis strategy outlined above starting from compounds of formula (VII) can also be applied using the carboxylic acid of compounds of formula (XII) to yield compounds of formula (lc) or (Id). Further, this strategy can be applied to carboxylic acids of formula J-D-E-OH - in which J, D, and E have the previously defined meanings -, a synthetic precursor thereof or a protected derivative thereof. Cleavage of the anchoring bond to the Kaiser oxime resin using amines of formula (XXI) yields compounds of formula (XX) after removal of the optionally present protecting group.
• the arylamino functionality of moiety Q can be used to be covalently attached to a polymeric support using e.g.
• the peptide coupling as mentioned as a procedural step in the above described method to prepare the compounds of the invention, can be carried out by methods commonly known in the art for the coupling - or condensation - of peptide fragments such as by the azide method, mixed anhydride method, activated ester method, or, preferably, by the carbodiimide method, especially with the addition of catalytic and racemisation suppressing compounds like N-hydroxy- succinimide and N-hydroxybenzotriazole.
• An overview is given in The Peptides. Analysis. Synthesis, Biology, Vol 3, E. Gross and J. Meienhofer, eds. (Academic Press, New York, 1981).
• N-protecting group as used in this whole document means a group commonly used in peptide chemistry for the protection of an ⁇ -amino group, like the tert-butyloxycarbonyl (Boc) group, the benzyloxycarbonyl (Z) group, the 9-fluorenylmethyloxycarbonyl (Fmoc) group or the phthaloyl (Phth) group.
• Removal of the protecting groups can take place in different ways, depending on the nature of those protecting groups. Usually deprotection takes place under acidic conditions and in the presence of scavengers. An overview of amino protecting groups and methods for their removal is given in the above mentioned The Peptides, Analysis, Synthesis. Biology. Vol 3.
• Suitable leaving groups are known in the art, for example from A.L. Ternay: Contemporary Organic Chemistry (2 nd ed., W.B. Saunders Company, 1979, see pages 158 and 170-172).
• Preferred leaving groups are chloride, mesylate and tosylate.
• the compounds of the invention which can occur in the form of a free base, may be isolated from the reaction mixture in the form of a pharmaceutically acceptable salt.
• the pharmaceutically acceptable salts may also be obtained by treating the free base of formula I with an organic or inorganic acid such as HCl, HBr, HI, H 2 SO 4 , H 3 PO 4 , acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
• an organic or inorganic acid such as HCl, HBr, HI, H 2 SO 4 , H 3 PO 4 , acetic acid, propionic acid, glycolic acid, maleic acid, malonic acid, methanesulphonic acid, fumaric acid, succinic acid, tartaric acid, citric acid, benzoic acid, ascorbic acid and the like.
• the compounds of this invention may possess one or more chiral carbon atoms, and may therefore be obtained as a pure enantiomer, or as a mixture of enantiomers, or as a mixture containing diastereomers.
• Methods for obtaining the pure enantiomers are well known in the art, e.g. crystallization of salts which are obtained from optically active acids and the racemic mixture, or chromatography using chiral columns.
• the compounds of the invention may be administered enterally or parenterally.
• the exact dose and regimen of these compounds and compositions thereof will neccessarily be dependent upon the needs of the individual subject to whom the medicament is being administered, the degree of affliction or need and the judgment of the medical practitioner.
• parenteral administration requires lower dosages than other methods of administration which are more dependent upon absorption.
• the daily dosages are for humans preferably 0.001-100 mg per kg body weight, more preferably 0.01-10 mg per kg body weight.
• the medicament manufactured with the compounds of this invention may also be used as adjuvant in acute anticoagulant therapy. In such a case, the medicament is administered with other compounds useful in treating such disease states.
• the compounds may also be used with implantable pharmaceutical devices such as those described in US Patent 4,767,628, the contents of which are incorporated by this reference. Then the device will contain sufficient amounts of compound to slowly release the compound (e.g. for more than a month).
• the compounds may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories.
• pharmaceutically suitable liquids the compounds can also be applied in the form of a solution, suspension, emulsion, e.g. for use as an injection preparation, or as a spray, e.g. for use as a nasal spray.
• dosage units e.g. tablets
• conventional additives such as fillers, colorants, polymeric binders and the like
• any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used.
• Suitable carriers with which the compositions can be administered include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts.
• Example 13 l-
• 16b l-[3-(4-aminothieno 3.2c1pyridin-2-yl)-2-[[[(5-dimethylamino naphthalenyl]sulfonyl]- amino - 1 -oxopropyl]-4-methylpiperidine hydrochloride Using the procedure described for 2b, 16a was coupled with 4-methylp ⁇ peridine to give the title compound 16b ⁇ -NMR 200MHz (CD 3 OD) ⁇ 0 1 - 3 3 (12H, m), 2 82 (3H, s), 3 53 - 4 28 (2H, m), 4 41 - 4 52 (IH, m), 7 02- 7 58 (6H, m), 8 12 - 8 24 (2H, m), 8 40 - 8 51 (IH, m)
• Example 21 l-13-(4-aminothienof3,2clpyridin-2-yl)-2-[K7-methoxy-2-naphthalenyl)sulfonyllaminol-l- oxopropyll-4-formylpiperazine hydrochloride
• Example 23 l-.3-(4-aminothienof3.2clpyridin-2-yl)-2-. [(7-methoxy-2-naphthalenyl)sulfonyl]aminol-l- oxopropyll-4-.(trifluormethyl)sulfonyllpiperazine hydrochloride (23b)
• Example 25 l-.3- ( 4-aminothieno.3.2clpyridin-2-yl ) -2-. f ( 7-methoxy-2-naphthalenyl)sulfonyl]aminol-l- oxopropylUhiomorpholine hydrochloride
• Example 27 l-f3-(4-aminothieno[3.2clpyridin-2-yl)-2-[[(7-methoxy-2-naphthalenyl)sulfonv ⁇ amino1-l- oxopropyll-4-(l-oxoethyl)piperidine hydrochloride Using the procedure described for 2b, 14a was coupled with 4-(l-oxoethyl)piperidine to give the title compound 27.
• Boc-4-methylenepiperidine was dissolved in 3N hydrochloric acid in methanol and stirred for 19 hours at room temperature. Evaporation yielded 0.24 g of the title compound 28a.
• Example 30 l-r3-.4-aminothienol3,2clpyridin-2-yl)-2-HH-(l 4S)-(7.7-dimethyl-2- oxobicvclo.2.2.1 _hep.-l-yl)methyllsulfonyllaminol-l-oxopropyll-4-methylpiperidine hydrochloride (30b)
• Example 33 l-
• the procedure described for 30b was used to couple 30a with [5-(2-pyridinyl)thienyl]sulfonyl chloride giving the title compound 33 ⁇ -NMR 200MHz (CD3OD) ⁇ 0 05 - 1 69 (8H, m), 2 25 - 2 60 (IH, m), 2 85 - 3 41 (3H, m), 3 78 - 4 00 (IH, m), 4 17 - 4 37 (IH, m), 4 59 - 4 72 (IH, m), 7 13 - 7 22 (IH, m), 7 29 - 7 60 (5H, m), 7 82 - 7 88
• Example 36 l-[3-(4-aminothienof3.2clpyridin-2-yl)-2-[K4,6-dimethox ⁇ -2-naphthalenyl)stdfonyll- aminol-l-oxopropyll-4-methylpiperidine hydrochloride (36b)
• N-(7-Formylisoquinolinyl)benzamide was prepared from 37e using the procedure described for If but was not purified using column chromatography.
• the crude aldehyde was transformed into the title compound using the procedure described for lg folowed by purification using column chromatography on silica gel (toluene / ethyl acetate : 2 / 1). M.p.137.5 - 139.0 °C
• Compound 37g was prepared from 37f using the procedure described for lh. M.p. 190.5 - 193.0 °C.
• the resin was filtered off and washed with dichloromethane/N,N-dimethylformamide (3:2 v/v) and N,N-dimethylformamide. Further washings were performed by alternate addition of 2-propanol and dichloromethane (three times each). Unreacted oxime functions were capped by treatment of the resin with 35 mL of a mixture of acetic anhydride/N,N-diisopropylethylamine/N,N-dimethylformamide (3: 1 : 12 v/v/v) for 30 minutes at room temperature. The resin was filtered off and washed with N,N- dimethylformamide, 2-propanol and dichloromethane (three times each). The resin was dried in vacuo to give 1.9 g of 39f.
• the resin was washed three times with 6 mL dichloromethane/N,N-dimethylformamide (3 :2 v/v) containing 150 ⁇ l N,N-diisopropylethylamine and immediately reacted with 105 mg benzoic acid in 6ml dichloromethane/N,N- dimethylformamide (3 :2 v/v) containing 150 ⁇ l of N,N-diisopropylethylamine and 400 mg of bromotripyrrolidinophosphonium hexafluorophosphate (PyBrop). The suspension was shaken for 90 minutes at room temperature.
• the resin was filtered off and washed with dichloromethane/ 1- methyl-2-pyrrolidinone (3:2 v/v), followed by washings with l-methyl-2-pyrrolidinone, 2- propanol and l-methyl-2-pyrrolidinone.
• the reaction turned out to be not complete (chloranil test).
• the resin was reacted with 105 mg benzoic acid in 6 mL dichloromethane/N,N- dimethylformamide (3 :2 v/v) containing 150 ⁇ l of N,N-diisopropylethylamine and 400 mg of PyBrop. The suspension was shaken for 60 minutes at room temperature.
• the resin was filtered off and washed with dichloromethane/l -methyl-2-pyrrolidinone (3:2 v/v), followed by washings with l-methyl-2-pyrrolidinone, 2-propanol and l-methyl-2-pyrrolidinone.
• the chloranil test revealed complete conversion. 34 mg of the resin was suspended in 1 mL of a 0.5 M solution of 4-methylpiperidine in distilled tetrahydrofuran and shaken for 16 hours at room temperature. The resin was filtered off and washed with dichloromethane and methanol. The filtrates were collected and concentrated to dryness.
• the aqueous layer was made acid (pH 2) using 2 N hydrochloric acid and several times extracted with dichloromethane. The combined dichloromethane layers were washed with brine, dried over magnesium sulfate and concentrated to give 0.65 g of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]-3- phenylpropanoic acid. This acid (80 mg) was coupled with deprotected 5a (75 mg) according to the procedure described for 5c to afford compound 55 (55 mg) as a mixture of diastereomers (1 : 1).
• This compound was prepared from 0 75 mmol of 4-(2-methoxy-l-methoxymethyl-ethoxy)- benzenesulfonyl chloride and 210 mg (0 5 mmol) of 30a using the procedure described for 58c Yield 120 mg (oil), EI-MS 576 (M + )
• This compound was prepared from 0 15 mL of octane sulfonyl chloride and 210 mg of 30a using the procedure described for 58c Yield 150 mg, m p 101-1 12°C, (+)-FAB-MS 495 (MH + )
• Aminoacetaldehyde dimethyl acetal (79 g) was added to a solution of 106 g of 3-benzyloxy- benzaldehyde in 1 100 mL of toluene. The mixture was refluxed for 6 hours using a Dean-Stark trap and subsequently cooled to 5°C. In a nitrogen atmosphere trifluoracetic acid anhydride (212 mL) and borontrifluoride etherate (185 mL) were added in succession at such a rate, that the temperature of the mixture was kept below 10°C. After stirring for 5 days at room temperature the precipitated material was separated by filtration, washed with diethyl ether and dissolved in 750 mL of water.
• This compound was prepared from 1.5 g of 2,3,4,5-tetrahydro-benzo[f][l,4]oxazepine, 0.81 mL of sulfuryl chloride and 1.8 mL of ethyl diisopropyl amine using the procedure described for 63f.Yield: 0.3 g (oil), EI-MS: 247 (M + ).
• This compound was prepared from 200 mg of 2,3-dihydro-5H-benzo[f][l,4]oxazepine-4-sulfonyl chloride and 210 mg of 30a using the procedure described for 58c. Yield: 80 mg (oil), (+)-FAB-
• This compound was prepared from 1.0 g of 2-(benzylimino-methyl)-4-methoxy-phenol and 0.18 g of sodium borohydride using the procedure described 64b. Yield: 1.0 g (oil), EI-MS: 243 (NT).
• This compound was prepared from 5.7 g of 4-benzyl-7-methoxy-4,5-dihydro-benzo[f][l,4]- oxazepin-3-one and 2.3 g of lithium aluminum hydride using the procedure described for 64d. Yield: 6.1 g (oil), EI-MS: 269 (M + ).
• This compound was prepared from 6.1 g of 4-benzyl-7-methoxy-4,5-dihydro-benzo[f][l,4]- oxazepine and 1.0 g of palladium (10% on carbon) as catalyst using the procedure described for 64e Yield: 2.7 g; m.p. 96-97°C, EI-MS: 179 (M + ).
• This compound was prepared from 210 mg of 7-methoxy-2,3-dihydro-5H-benzo[f][l,4]- oxazepine-4-sulfonyl chloride and 210 mg of 30a using the procedure described for 58c Yield
• Example 68 r3S)-4-f ⁇ -f(l-amino-6-isoquinolinyl)methyll-2-oxo-2-(4-morpholinyl)ethyllaminol-3-rf(4- methoxy-2,3,6-trimethylphenyl)sulfonyl
• Example 70 l-13-(4-Aminothienof3,2clpyridin-2-yl)-2-ff3-(4-chlorophenyl)-l-oxopropyl1aminol-l- oxopropyll-4-methylpiperidine hydrochloride
• reaction mixture was evaporated to dryness, dissolved in methanol/water (1 : 1 v/v) and applied to a DOWEX-NH column (4.5 mL) to remove excess of amine.
• the column was eluted with methanol water (1 : 1 v/v).
• the UV positive fractions were pooled and evaporated to dryness yielding 9.5 mg of 71e.
• the resin was washed three times with 1 mL dichloromethane/N,N-dimethylformamide (3:2 v/v) containing 80 ⁇ mol N,N- diisopropylethylamine and immediately reacted with 80 ⁇ mol 2-pyridinecarboxylic acid in 1ml dichloromethane/N,N-dimethylformamide (3 :2 v/v) containing 80 ⁇ mol of N,N- diisopropylethylamine and 80 ⁇ mol of (O-(benzotriazol-l-yl))-l, l,3,3-tetramethyl uronium tetrafluoroborate. The suspension was shaken for 45 minutes at room temperature.
• the resin was filtered off and washed with dichloromethane/N,N-dimethylformamide (3:2 v/v), followed by washings with dichloromethane, 2-propanol and dichloromethane.
• the ninhydrin test revealed complete conversion of the amine.
• the resin was suspended in 1 mL of a 0.5 M solution of methylbenzylamine in distilled tetrahydrofuran and shaken for 16 hours at room temperature.
• the resin was filtered off and washed with tetrahydrofuran and methanol.
• the filtrates were collected and concentrated to dryness. Further processing of the sample was performed as described for 71e, yielding 8.0 mg of compound 72a.
• Rf 0.46 in ethyl acetate/pyridine/acetic acid/water 63/20/6/11 (v/v/v/v) on silica.
• N-cyclopentyl-Gly-OMe (10.2 g) and 2-(lH-benzotriazol-l -yl)-l, l,3,3-tetramethyluronium tetrafluoroborate (TBTU; 21.2 g) were added to a solution of N-Boc-N-(t-butyloxy- carbonylmethyl)-D-Cha-OH (24 g) in 300 mL of N,N-dimethyl formamide. The pH of the mixture was adjusted to 8.5. The mixture was stirred overnight at room temperature and was concentrated by evaporation. Water and ethyl acetate were added to the residue.
• N-Boc-N-(t-butyloxycarbonylmethyl)-D-Cha-N-cyclopentyl-Gly-OMe 17. g was saponified in a mixture of dioxane/water 1/1 (v/v, 150 mL) and diluted sodium hydroxide and yielded 15 g of an amorphous solid.
• N-[6-(azidomethyl)- 1 -isoquinolinyl]-benzamide To 6.3 g of N-[6-(hydroxymethyl)-l -isoquinolinyl] benzamide (lg) in 40 mL of toluene and 40 mL of dioxane at 0°C 7.8 mL of diphenylphosphoryl azide (DDPA) and 5.4 mL of 1,8- diazabicyclo(5.4.0)undec-7ene (DBU) were added. After 24 hours the reaction mixture was poured into water (pH 7) and extracted with ethyl acetate. The organic layer was dried (sodium sulfate) and concentrated.
• DDPA diphenylphosphoryl azide
• DBU 1,8- diazabicyclo(5.4.0)undec-7ene
• N-Boc-N-(t-butyloxycarbonylmethyl)-D-Phe-Pro-6-Aiq was obtained by the reaction of N-Boc-N-(t-butyloxycarbonylmethyl)-D-Phe-Pro-OH with 1- amino-6-(aminomethyl)isoquinoline hydrochloride (74c).
• FAB-MS: m e 631.
• N-Boc-N-(t-butyloxycarbonylmethyl)-D-Cha-N-cvclohexyl-Glv-OMe was prepared from N-cyclohexyl-Gly-OMe and N-Boc-N-(t-butyloxycarbonylmethyl)-D-Cha- OH analogously to 73h.
• N-Boc-N-(t-butyloxycarbonylmethyl)-D-Cha-N-cyclohexyl-Gly-OH was prepared from N-Boc-N-(t-butyloxycarbonylmethyl)-D-Cha-(N-cyclohexyl)-Gly-OMe analogously to 731. 79d.
• N-Boc-Pro-OH, (1.7 g, 8.0 mmol) and N,N'-dicyclohexylcarbodiimide (0.83 g, 4.0 mmol) in dichloromethane (20 mL) were stirred for 1 hour at 0 deg., the precipitate was removed and the solution was added to Kaiser oxim resin (1.0 g, 1.0 mmol, swollen in dichloromethane for 2 hours prior to the addition of the activated proline derivative). The resin was shaken for 16 h, the solvent was removed, the resin was washed with dichoromethane and diethyl ether (3 times each) and air dried.
• step 2 deprotection. 200mg of the N-Boc-Pro-coupled resin was swollen for 2 hours in dichloromethane (2ml). 4 mL of 25% trifluoroacetic acid in dichloromethane was added and shaken for 2 hours at room temperature. The solvent was removed, the resin was washed with dichloromethane, methanol, and diethylether, and air dried. (step 3; coupling to the second amino acid) 134 mg of the resin from step 2 was swollen in N,N- dimethylformamide for 30 min.
• step 4 cleavage of the product from the resin using an amine).
• 150 mg (0.1 mmol) of the resin from step 3 was swollen in dichloromethane for 2 h.
• step 5 deprotection
• the product from step 4 was dissolved in 0.5 mL 4 M HCl in dioxane and kept at 5 deg for 16 h. The solvent was removed i.vac, and the product triturated with diethylether to give 5 mg (62%) of the target compound.
• N-(6-formyl- l-isoquinolinyl)benzamide (If) was transformed into 3-(l-(benzylamino)-6-isoquinolinyl)acrylic acid.
• This compound was used to prepare 3-(l-amino-6-isoquinolinyl)acrylic acid according to the procedure described in example 81b.
• Reaction of 3-(l-amino-6-isoquinolinyl)acrylic acid with 3-(4-(methylamino)piperidin-l-yl)- 3 -oxopropionic acid methyl ester hydrochloride according to the procedures described in example 81e yielded the title compound.
• Example 85 (7-Methoxynaphthalen-2-yl)sulfonic acid . l-[l-amino-7-isoquinolinylmethyl_-2- oxopyrrolidin-3-(S)-yl. amide hydrochloride (85j.)
• Liquid ammonia (220 mL) was added to a solution of 32.8 g of l-chloro-7-methoxy-isoquinoline in 420 mL of ethanol in a steel vessel. Nitrogen was pressed upon until an initial pressure of 20 atm. was obtained. This reaction mixture was heated for 2 days at 170°C. The solvent was removed in vacuo and the residue dissolved in water. The pH value was adjusted to pH 10 by adding aqueous sodium carbonate solution, followed by extraction with ethyl acetate. The organic extract was washed with brine and dried (Na 2 SO ). Evaporation of the solvent in vacuo gave pure 7-methoxy-isoquinolin-l -ylamine as a white solid. Yield 24.0 g (81%); m.p. 128- 130°C.
• Furo[3,2-c]pyridin-4-ylamine (7.8 g) was dissolved in 175 mL of glacial acetic acid and sodium acetate (14.3 g) added in portions (exothermic!). Subsequently a solution of iodine (44.2g) in 150 mL of tetrahydrofuran was added dropwise and the resulting mixture allowed to stir for 4 d at ambient temperature. The mixture was poured on ice and the pH value adjusted to pH 10 by adding 10 N sodium hydroxide solution, followed by extraction with ethyl acetate. The organic extract was washed several times with sodium thiosulfate solution and brine, dried (Na 2 SO 4 ) and concentrated.
• This compound was prepared from 2-iodo-furo[3,2-c]pyridin-4-ylamine (5.2 g), zinc cyanide (3.6 g), triphenylphosphine (2.1 g) and palladium acetate (1.8 g) in 75 mL of N-methyl- pyrrolidone using the procedure described for l-amino-isoquinoline-7-carbonitrile . Yield: 2.0 g (64%); yellow solid; m.p. 280°C (decomp.).
• This compound was prepared from 4-amino-furo[3,2-c]pyridine-2-carbonitrile (5.7 g), using the procedure described for l-amino-7-(aminomethyl)isoquinoline . Yield: 3.5 g (60%); yellow crystals; m.p. 142-144°C; EI-MS: 163 (M + ).
• Example 90 l-Amino-6-[(2-(3-(benzylsulfonylamino)-6-methyl-2-oxo-l .2-dihvdropyridinyl)-l-oxo- ethvDaminomethyllisoquinoline hydrochloride (89b.)
• Example 96 (3-(2-(S)-[(l-Amino-isoquinoIin-6-ylmethyl)-carbamovH-pyrrolidin-l-yl)-2-(R)-ethoxy- carbonylamino-l .l-dimethyl-3-oxo-propylsulfanyl)-acetic acid tert.-butyl ester hydroacetate (96d)
• N-Ethoxycarbonylmethyl-2-(R -amino-3-(4-methoxyphenyl)-propionic acid benzyl ester (D)-4-Methoxy-phenylalanine benzylester hydrochloride (1.7 g) was dissolved in 7 mL of dry N,N-dimethyl formamide.
• Bromoacetic acid ethyl ester (1.7 mL) and triethylamine (2.6 mL) were added in succession and the reaction mixture was allowed to stir for 16 h at room temperature. The mixture was poured on ice and extracted with ethyl acetate.
• N-Ethoxycarbonylmethyl-N-tert. -butoxycarbonyl-2-(R)-amino-3-(4-methoxyphenyl)-propionic acid benzyl ester (1.50 g) were dissolved in 40 mL of methanol and hydrogenated for 4 h at room temperature using 0.3 g palladium on charcoal (10%>) as catalyst. Filtration followed by concentration in vacuo affords 1.05 g (87%>) of the title compound as a colorless oil.
• N-tert.-Butoxycarbonyl-2-(R,-amino-3-(4-methoxyphenv0-propionic acid benzyl ester ) (D)-4-Methoxy-phenylalanine benzylester hydrochloride (4.3 g) was dissolved in 20 mL of water and a solution of di-tert-butyl dicarbonate (3.5 g) in 20 mL of dioxane was added. The mixture was allowed to stir for 16 h while pH 9.5 was maintained by continious addition of the appropriate amounts of 0.5 N NaOH. The dioxane was distilled off followed by extraction with dichloromethane and removal of the solvent to give 5.2 g ( 100%) of the title compound as a colorless oil.

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