WO2004052366A1 - 2-aminocarbonyl-quinoline compounds as platelet adenosine diphosphate receptor antagonists - Google Patents

2-aminocarbonyl-quinoline compounds as platelet adenosine diphosphate receptor antagonists Download PDF

Info

Publication number
WO2004052366A1
WO2004052366A1 PCT/US2003/039079 US0339079W WO2004052366A1 WO 2004052366 A1 WO2004052366 A1 WO 2004052366A1 US 0339079 W US0339079 W US 0339079W WO 2004052366 A1 WO2004052366 A1 WO 2004052366A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
hydrogen
aminocarbonyl
aralkyl
carboxy
Prior art date
Application number
PCT/US2003/039079
Other languages
French (fr)
Other versions
WO2004052366A9 (en
Inventor
Judi Bryant
Brad Buckman
Imadul Islam
Raju Mohan
Michael Morrissey
Guo Ping Wei
Wei Xu
Shendong Yuan
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2003297763A priority Critical patent/AU2003297763A1/en
Priority to UAA200506729A priority patent/UA83648C2/en
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to EA200500899A priority patent/EA200500899A1/en
Priority to AP2005003363A priority patent/AP2005003363A0/en
Priority to AT03796831T priority patent/ATE477800T1/en
Priority to EP03796831A priority patent/EP1578423B1/en
Priority to NZ540872A priority patent/NZ540872A/en
Priority to JP2004558607A priority patent/JP4662777B2/en
Priority to CA2507657A priority patent/CA2507657C/en
Priority to MXPA05006302A priority patent/MXPA05006302A/en
Priority to YUP-2005/0450A priority patent/RS20050450A/en
Priority to DE60333866T priority patent/DE60333866D1/en
Priority to BR0317222-8A priority patent/BR0317222A/en
Publication of WO2004052366A1 publication Critical patent/WO2004052366A1/en
Publication of WO2004052366A9 publication Critical patent/WO2004052366A9/en
Priority to NO20053335A priority patent/NO20053335L/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to quinoline derivatives, their use as platelet adenosine diphosphate receptor antagonists, compositions containing them and processes for their preparation.
  • Platelets interact with the coagulation and fibrinolysis systems in the maintenance of hemostasis and in the pathogenesis of thrombosis and thromboembolism. Platelets rapidly adhere to damaged vascular tissue, and release a variety of prothrombotic, chemotactic, and mitogenic factors, aimed at prompting hemostasis and wound healing. Platelets also play an important role in arterial thrombosis, a common cause of death and disability in patients with cardiovascular disease. Platelet inhibitors have been successfully used for secondary prevention of arterial thrombosis in patients with coronary, cerebral, and peripheral vascular disease. Platelets adhere to exposed subendothelium after vessel wall injury by binding to von
  • Willebrand factor (vWf) and collagen This induces platelets to change shape from a disc shape to a round form with pseudopodia, which enforces platelet adhesion and aggregation.
  • the final common pathway for platelet aggregation is the activation of the fibrinogen receptor (GPIIb-llla).
  • GPIIb-llla fibrinogen receptor
  • Activated platelets secrete their granule contents, many of which act directly on blood cells, including platelets themselves, and endothelium. Platelets contain several kinds of secretory granules. The dense-granules contain adenosine diphosphate ("ADP"), adenosine triphosphate ("ATP”) and serotonin. The ⁇ -granules contain several platelet-specific proteins (platelet factor 4 and ⁇ -thromboglobulin), growth factors (PDGF, TGF- ⁇ , EGF and ECGF) and coagulation factors (fibrinogen, Factor V and vWf). Platelets also secrete biologically active arachidonic acid products. Well known is TxA 2 which is inhibited by aspirin through irreversible inactivation of the cyclooxygenase producing TxA 2 .
  • thrombin many stimuli, such as thrombin, collagen, ADP and thromboxane A2 (TxA 2 ), activate platelets by binding to their cell surface receptors. Most of these receptors are G-protein- coupled-reeeptors.- Activation-of-G-proteins-has been-shown to be-an-essential-event in- platelet activation. For example, platelets from Gq-/- mice do not aggregate in response to thrombin, collagen, ADP or TxA 2 (Offermans, S. et al., Nature (1998), Vol. 389, No. 11, pp. 183-185).
  • ADP plays a pivotal role in platelet activation.
  • ADP not only causes primary aggregation of platelets but is also responsible for the secondary aggregation following activation by other agonists such as thrombin and collagen. Contained at ver high concentrations in the platelet dense-granules, ADP is released when platelets are activated to reinforce platelet aggregation.
  • ADP-induced platelet activation plays an important role in maintaining normal hemostasis.
  • ADP-induced platelet activation also plays a key role in the initiation and propagation of thrombosis.
  • Administration of ADP has been shown to induce thrombus formation in rat and mice mesenteric venules.
  • ADP-removing enzymes have been shown to dramatically reduce platelet deposition on collagen and to inhibit laser-induced thrombosis in rat mesenteric arterioles and venules, supporting the theory that ADP plays a role in mediating platelet recruitment in thrombus formation.
  • ADP-induced early signaling events in platelets have been described.
  • P2Y A c is the best target for a platelet ADP receptor antagonist for several reasons.
  • P2Y A c is predominately platelet specific.
  • it is required for ADP-induced aggregation.
  • it plays an important role in sustaining thrombin or collagen-induced aggregation.
  • anti-aggregatory drugs such as Clopidogrel and Ticlopidine.
  • the compounds of the invention are antagonists of the platelet ADP receptor, P2Y AC , and are therefore useful in treating disease-states characterized by thrombotic activity and in so doing are useful as antithrombotic agents in the treatment and prevention of thrombosis. Accordingly, in one aspect, the invention is directed to compounds selected from the group consisting of the following formula (I):
  • R 1 is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl; R 2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl, aminoalkyl, haloalkylsulfonylaminoalkyl,
  • R 3 is aryl or aryloxy each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , -R 8 -C(O)R 7 , -R 8 -N(R 7 ) 2 , -R 8 -N(R 7 )C(O)R 7 , -R 8 -N(R 7 )C(O)OR 9 , -R 8 -N(R 7 )-S(O) 2 -R 7 ,
  • each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino
  • R 6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R 7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R 8 is a bond or a straight or branched alkylene chain; and each R 9 is hydrogen, alkyl, aralkyl or haloalkyl; as a single stereoisomer, a mixture of individual stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt thereof.
  • this invention is compounds selected from the group consisting of the following formula (II):
  • R 1 is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl;
  • R 2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl, aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl, alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl, carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl, aminocarbonylalkyl, aralkoxycarbonylaminoalkyl, alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl, (alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl, (
  • R 3 is heteroarylalkoxy, wherein the alkoxy radical in the heteroarylalkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , -R 8 -C(O)R 7 , -
  • heteroaryl radical in the heteroarylalkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , -R 8 -C(O)R 7 , -R 8 -N(R 7 ) 2 , -R 8 -N(R 7 ) 2 , -R 8 -N(R 7 )C(O)R 7 , -R 8 -N(R 7 )C(O)OR 9 , -R 8 -N(R 7 )-S(O) 2 -R 7 , and -R 8 -C[N
  • this invention is directed to pharmaceutical compositions useful in treating a mammal having a disease-state characterized by thrombotic activity, which composition comprises a pharmaceutically acceptable excipient and a compound of formula (I) or a compound of formula (II) as defined above.
  • this invention is directed to methods of treating disease-states characterized by thrombotic activity, which methods comprise administering to a mammal having a disease-state characterized by thrombotic activity a therapeutically effective amount of a compound of formula (I) or formula (II) as defined above.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, ⁇ -propyl, 1-methylethyl (/so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (f-butyl), and the like. Unless stated otherwise specifically in the specification, it is understood that for radicals, as defined below, that contain a substituted alkyl group that the substitution can occur on any carbon of the alkyl group.
  • Alkylene chain refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like.
  • Alkylcarbonyl refers to a radical of the formula -C(O)-R a where R a is an alkyl radical as defined above, e.g., acetyl, ethylcarbonyl, n-propylcarbonyl, and the like.
  • Alkylcarbonylamino refers to a radical of the formula -N(H)-C(O)-R a where R a is an alkyl radical as defined above, e.g., acetylamino, ethylcarbonylamino, n-propylcarbonylamino, and the like.
  • Alkylthio refers to a radical of the formula -S-R a where R a is an alkyl radical as defined above, e.g., methylthio, ethylthio, n-propylthio, and the like.
  • Alkylsulfonylalkyl refers to a radical of the formula -R a -S(O) 2 -R a where each R a is independently an alkyl radical as defined above, e.g., methylsulfonylmethyl, - _ _ .
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (/so-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (f-butoxy), and the like.
  • Alkoxycarbonyl refers to a radical of the formula -C(O)OR a where R a is an alkyl radical as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and the like.
  • Alkoxycarbonylalkyl refers to a radical of the formula -R a -C(O)OR a where each R a is independently an alkyl radical as defined above, e.g., methoxycarbonylmethyl, (1,1- dimethylethoxy)carbonylmethyl, 2-(methoxycarbonyl)ethyl, and the like.
  • Alkoxycarbonylaminocarbonyl refers to a radical of the formula -C(O)-N(H)-C(O)OR a where R a is an alkyl radical as defined above, e.g., methoxycarbonylaminocarbonyl, ethoxycarbonylaminocarbonyl, n-propoxycarbonylaminocarbonyl, and the like.
  • Alkoxyalkoxyalkylcarbonyl refers to a radical of the formula -C(O)-R a -O-R a -O-R a where each R a is independently an alkyl radical as defined above, e.g., 2-(ethoxy)ethoxymethylcarbonyl, 3-(2-(n-butoxy)ethoxy)propylcarbonyl, and the like.
  • Alkoxycarbonylalkyl refers to a radical of the formula -R a -C(O)OR a where each R a is independently an alkyl radical as defined above, e.g., methoxycarbonylmethyl, 2-(ethoxycarbonyl)ethyl, 2-(methoxycarbonyl)propyl, and the like.
  • Alkoxycarbonylalkoxy refers to a radical of the formula -O-R a -C(O)OR a where each R a is independently an alkyl radical as defined above, e.g., methoxycarbonylmethoxy, 2- (ethoxycarbonyl)ethoxy, 2-(methoxycarbonyl)propoxy, and the like.
  • Alkoxycarbonylalkylcarbonyl refers to a radical of the formula -C(O)-R a -C(O)OR a where each R a is independently an alkyl radical as defined above, e.g., methoxycarbonylmethylcarbonyl, 2-(ethoxycarbonyl)ethylcarbonyl, 2-(methoxycarbonyl)propylcarbonyl, and the like.
  • R a is independently an alkyl radical as defined above, e.g., methoxycarbonylmethylcarbonyl, 2-(ethoxycarbonyl)ethylcarbonyl, 2-(methoxycarbonyl)propylcarbonyl, and the like.
  • Alkoxycarbonylalkylaminocarbonylalkyl refers to a radical of the formula
  • each R a is independently an alkyl radical as defined above, e.g. , methoxycarbonylmethyl, 2-(ethoxycarbonyl)ethylaminocarbonylmethyl, 2-(2-(methoxycarbonyl)propylaminocarbonyl)propyl, and the like.
  • Alkoxycarbonylalkylthioalkyl refers to a radical of the formula -R a -S-R a -C(O)OR a where each R a is independently an alkyl radical as defined above, e.g., methoxycarbonylmethylthiomethyl, 2-(ethoxycarbonyl)ethylthiomethyl, 2-(2-(methoxycarbonyl)propylthio)propyl, and the like.
  • Alkoxycarbonylalkoxycarbonylalkyl refers to a radical of the formula -R a -C(O)-O-R a -C(O)OR a where each R a is independently an alkyl radical as defined above, e.g., methoxycarbonylmethoxy, 2-(ethoxycarbonyl)ethoxycarbonylmethyl,
  • (AlkoxycarbonylaIkyl)(alkyl)aminocarbonylalkyl refers to a radical of the formula -R a -C(O)-N(R a )-R a -C(O)OR a where each R a is independently an alkyl radical as defined above, e.g., (methoxycarbonyImethyl)(methyl)aminocarbonylmethyl, 2-((ethoxycarbonylmethyl)(methyl)aminocarbonyl)ethyI, and the like.
  • “Amino” refers to the -NH 2 radical.
  • Aminoalkyl refers to a radical of the formula -R a -NH 2 , e.g., aminomethyl, 2-aminomethyl, 2-aminopropyl, and the like.
  • Aminocarbonyl refers to the -C(O)NH 2 radical.
  • Aminocarbonylalkoxy refers to a radical of the formula -O-R a -C(O)NH 2 , e.g., aminocarbonylmethoxy, 2-(aminocarbonyl)ethoxy, 2-(aminocarbonyl)propoxy, and the like.
  • Aminocarbonylalkyl refers to a radical of the formula -R a -C(O)NH 2 , e.g., aminocarbonylmethyl, 2-(aminocarbonyl)ethyl, 2-(aminocarbonyl)propyl, and the like.
  • Aryl refers to a phenyl or naphthyl radical. Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , -R 8 -C(O)R 7 , -R 8 -N(R 7 ) 2 , -R 8 -N(R 7 )C(O)R 7 , -R 8 -N(R 7 )C(O)OR 9 , -R 8 -N(R 7 )-S(O) 2 -R 7 , -R 8 -C[
  • Alkyl refers to a radical of the formula -R a R b where R a is an alkyl radical as defined above, substituted by R b , an aryl radical, as defined above, e.g., benzyl.
  • the R a radical may be optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , -R 8 -C(O)R 7 , -R 8 -N(R 7 ) 2 , -R 8 -N(R 7 )C(O)R 7 , and -R 9 -N(R 7 )C(O)OR 9 , wherein each R 7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl, each R 8 is a bond or a straight or branched alkylene chain, and each R 9 is hydrogen, alkyl, aralkyl or haloalkyl as defined herein.
  • the R b radical may be optionally substituted one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , -R 8 -C(O)R 7 , -R 8 -N(R 7 ) 2 , -R 8 -N(R 7 )C(O)R 7 , -R 8 -N(R 7 )C(O)OR 9 , -R 8 -N(R 7 )-S(O) 2 -R 7 , -R 8 -C[N(R 7 ) 2 ]-C(O)OR 7 , wherein each R 7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl, each R 8 is a bond or
  • Aryloxy refers to a radical of the formula -OR b where R b is an optionally substituted aryl radical as defined above, e.g., phenoxy.
  • Arylcarbonyl refers to a radical of the formula -C(O)-R b -where-R b- is anjjptionally substituted aryl radical as defined above, e.g., phenylcarbonyl, (4-acetylaminophenyl)carbonyl, (2-methoxyphenyl)carbonyl, and the like.
  • arylcarbonyl radicals are those radicals wherein the R b group is optionally substituted by by one or more substituents independently selected from the group consisting of acetylamino, carboxy, aminocarbonyl, alkoxycarbonyl, haloalkoxy, alkoxy, and alkyl.
  • Aryloxycarbonyl refers to a radical of the formula -C(O)OR b where R b is an optionally substituted aryl radical as defined above, e.g., phenoxycarbonyl.
  • Aryloxyalkylcarbonyl refers to a radical of the formula -C(O)OR b R a where R a is an alkyl radical, as defined above, substituted by R b , an optionally substituted aryl radical, as defined above, e.g., phenoxymethylcarbonyl, (2-phenoxyethyl)carbonyl, and the like.
  • R a is an alkyl radical, as defined above, substituted by R b , an optionally substituted aryl radical, as defined above, e.g., phenoxymethylcarbonyl, (2-phenoxyethyl)carbonyl, and the like.
  • Aralkoxy refers to a radical of the formula -OR ⁇ where R e is an optionally substituted aralkyl radical as defined above, e.g., benzyloxy, 3-phenylpropoxy, and the like.
  • Alkoxyalkyl refers to a radical of the formula -R a -OR e where R a is an alkyl radical as defined above and R e is an optionally substituted aralkyl radical as defined above, e.g., benzyloxymethyl, 2-(benzyloxy)ethyl, 2-(benzyloxy)propyl, and the like.
  • R a is an alkyl radical as defined above and R e is an optionally substituted aralkyl radical as defined above, e.g., benzyloxymethyl, 2-(benzyloxy)ethyl, 2-(benzyloxy)propyl, and the like.
  • Aralkoxycarbonyl refers to a radical of the formula -C(O)OR e where R e is an optionally substituted aralkyl radical as defined above, e.g., benzyloxycarbonyl, and the like.
  • Alkoxycarbonylalkyl refers to a radical of the formula -R a -C(O)OR e where R a is an alkyl radical as defined above and R e is an optionally substituted aralkyl radical as defined above, e.g., benzyloxycarbonylmethyl, 2-(benzyloxycarbonyl)ethyl, 3-((naphthalen-2- yl)oxy)carbonyl)propyl, and the like.
  • Alkoxycarbonylaminoalkyl refers to a radical of the formula -R a -N(H)-C(O)OR e where R a is an alkyl radical as defined above and R e is an optionally substituted aralkyl radical as defined above, e.g., benzyloxycarbonylaminomethyl, 2-(benzyloxycarbonylamino)ethyl, 2- (benzyloxycarbonylamino)propyl, and the like.
  • Carboxy refers to the -C(O)OH radical.
  • Carboxyalkyl refers to a radical of the formula -R a -C(O)OH, where R a is an alkyl radical as defined above, e.g., carboxymethyl, 2-carboxyethyl, 2-carboxypropyl and the like.
  • Carboxyalkoxy refers to a radical of the formula -O-R a -C(O)OH, where R a is an alkyl radical as defined above, e.g., carboxymethoxy, 2-carboxyethoxy, 2-carboxypropoxy, and the like.
  • Carboxyalkylcarbonyl refers to a radical of the formula -C(O)-R a -C(O)OH, where R a is an alkyl radical as defined above, e.g., 2-carboxyethylcarbonyl, carboxymethylcarbonyl, 3-carboxypropylcarbonyl, and the like.
  • Carboxyalkylamino refers to a radical of the formula -N(H)-R a -C(O)OH where R a is an alkyl radical as defined above, e.g., carboxymethylamino, 2-carboxyethyiamino, 3- carboxypropylamino, and the like.
  • Carboxyalkylaminocarbonylalkyl refers to a radical of the formula -R a -C(O)-N(H)-R a -C(O)OH where each R a is independently an alkyl radical as defined above, e.g., carboxymethylaminocarbonylmethyl, 2-(carboxymethylaminocarbonyl)ethyl, 2-(2- carboxyethyl)aminocarbonyl)ethyl, 3-(2-carboxyethyl)aminocarbonyl)butyl, and the like.
  • Carboxyalkylthioalkyl refers to a radical of the formula -R a -S-R a -C(O)OH were each R a is independently an alkyl radical as defined above, e.g., carboxymethylthiomethyl, (1-carboxyethyl)thiomethyl, 2-((1-carboxypropyl)thio)ethyl, and the like.
  • Carboxyalkoxyalkyl refers to a radical of the formula -R a -O-R a -C(O)OH where each R a is independently an alkyl radical as defined above, e.g., 2-(carboxymethoxy)ethyl, (2-carboxyethoxy)methyl, 3-(2-carboxypropoxy)propyl, and the like.
  • Carboxyalkoxycarbonylalkyl refers to a radical of the formula -R a -C(O)-O-R a -C(O)OH where each R a is independently an alkyl radical as defined above, e.g., carboxymethoxycarbonylmethyT, 2-(carboxymethoxycarbonyl)ethyl, 2-((2- carboxyethoxy)carbonyl)propyl, and the like.
  • Cycloalkyl refers to a stable 3- to 10-membered monocyclic or bicyclic radical which is saturated, and which consist solely of carbon and hydrogen atoms, e.g., cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, decalinyl and the like.
  • cycloalkyl is meant to include cycloalkyl radicals which are optionally substituted one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , -R 8 -C(O)R 7 , -R 8 -N(R 7 ) 2 , -R 8 -N(R 7 )C(O)R 7 , -R 8 -N(R 7 )C(O)OR 9 , -R 8 -N(R 7 )-S(O) 2 -R 7 , -R 8 -C[N(R 7 ) 2 ]-C(O)OR 7 , wherein each R 7 is hydrogen, alkyl, ary
  • Cycloalkylcarbonyl refers to a radical of the formula -C(O)-R c where R c is a cycloalkyl radical as defined above, e.g., cyclobutylcarbonyl, cyclopropylcarbonyl, and the like.
  • R c is a cycloalkyl radical as defined above, e.g., cyclobutylcarbonyl, cyclopropylcarbonyl, and the like.
  • a preferred cycloalkylcarbonyl radical is that radical wherein the R c group is optionally substituted by a phenyl group.
  • (Carboxy)(hydroxy)alkyl refers to a radical of the formula -R a (OH)-C(O)OH wherein R a is an alkyl radical defined above substituted by an hydroxy radical and a carboxy radical, as defined herein, e.g., 1-carboxy-3-hydroxypropyl, 2-carboxy-4-hydroxybutyl, 1-carboxy-5- hydroxypent-2-yl, and the like.
  • (Carboxyalkyl)(alkyl)aminocarbonylalkyl refers to a radical of the formula -R a -C(O)-N(R a )-R a -C(O)OH wherein each R a is independently an alkyl radical as defined above, and wherein the nitrogen atom is substituted by the R a group and the -R a -C(O)OH group, e.g., (carboxyethyl)(ethyl)aminocarbonylmethyl r 2-((2 - - carboxyethyl)(methyl)aminocarbonyl)ethyl, and the like.
  • Cyano refers to the -C ⁇ l radical.
  • Dialkylamino refers to a radical of the formula -N(R a )-R a where each R a is independently an alkyl radical, e.g., dimethylamino, diethylamino, methylethylamino, and the like.
  • “Dialkylaminocarbonyl” refers to a radical of the formula -C(O)-N(R a )-R a where each R a is independently an alkyl radical, e.g., dimethylaminocarbonyl, diethylaminocarbonyl, methyl(ethyl)aminocarbonyl, and the like.
  • Dialkylaminoalkyl refers to a radical of the formula -R a -N(R a )-R a where each R a is independently an alkyl radical as defined above, e.g., dimethylaminomethyl, 2-(diethylamino)ethyl, 3-(methyl(ethyl)amino)propyl, and the like.
  • Dialkylaminoalkoxy refers to a radical of the formula -O-R a -N(R a )-R a where each R a is independently an alkyl radical as defined above, e.g., dimethylaminomethoxy, 2-(diethylamino)ethoxy, 3-(methyl(ethyl)amino)propoxy, and the like.
  • Di(alkylcarbonyl)amino refers to a radical of the formula -N(C(O)-R a )-C(O)-R a where each R a is independently an alkyl radical as defined above, e.g., di(acetyl)amino, di(ethylcarbonyl)amino, and the like.
  • Halo refers to bromo, chloro, iodo or fluoro.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
  • Haloalkylsulfonylaminoalkyl refers to a radical of the formula -R a -N(H)-S(O) 2 R f where R a is an alkyl radical as defined above and R f is a haloalkyl radical as defined above, e.g., 2-(trifluoromethoxysulfonylamino)ethyl, 3-(trifluoromethoxysulfonylamino)propyl, and the like.
  • Haloalkoxy refers to a radical of the formula -OR f where R f is an haloalkyl radical as defined above, e.g., trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy, and the like.
  • Haloalkenyloxy refers to a radical of the formula -OR g where R g is an haloalkenyl radical as defined above, as defined above, e.g., 1 ,2-difluoroethenyloxy, 3-bromo-2-fluoroprop- 1-enyloxy, 1 ,2-dibromoethenyloxy, and the like.
  • Haloalkoxycarbonyl refers to a radical of the formula -C(O)OR f where R f is an haloalkyl radical as defined above, e.g., trifluoromethoxycarbonyl, difluoromethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 1-fluoromethyl-2-fluoroethoxycarbonyl, 3-bromo-2-fluoropropoxycarbonyl ⁇ 1-bromomethyl-2-bromoethoxycarbonyl,. and the like. _ _ .
  • Hydroxy refers to the -OH radical.
  • Hydrophilalkyl refers to a alkyl radical as defined above that is substituted by a hydroxy radical, e.g., hydroxy methyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, and the like.
  • Heterocyclyl refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be aromatic or partially or fully saturated.
  • the heterocyclyl radical may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclyl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, carbazolyl, cinnolinyl, decahydroisoquinolyl, dioxolanyl, furanyl, furanonyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, indanyl, indolizinyl, isoxazolyl, isoxazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, octahydroind
  • heterocyclyl is meant to include heterocyclyl radicals as defined above which are optionally substituted one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , -R 8 -C(O)R 7 , -R 8 -N(R 7 ) 2 , -R 8 -N(R 7 )C(O)R 7 , -R 8 -N(R 7 )C(O)OR 9 , -R 8 -N(R 7 )-S(O) 2 -R 7 , -R 8 -C[N(R 7 ) 2 ]-C(O)OR 7 , wherein each R 7 is hydrogen, alkyl,
  • Heteroaryl refers to a heterocyclyl radical as defined above wherein the heterocyclyl radical is partially or fully aromatic.
  • Heterocyclylalkyl refers to a radical of the formula -R a -R h where R a is an alkyl radical as defined above and R h is an heterocyclyl radical as defined above, e.g., imidazol-3-yImethyl, - triazol-3-ylmethyl r 2-tetrazolylethyl, and the like.
  • R a is an alkyl radical as defined above
  • R h is an heterocyclyl radical as defined above, e.g., imidazol-3-yImethyl, - triazol-3-ylmethyl r 2-tetrazolylethyl, and the like.
  • R 2 preferred heterocyclylalkylradicals are MISSING UPON TIME OF PUBLICATION
  • Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services.
  • Prodrugs is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention.
  • prodrug refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable.
  • a prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention.
  • Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood.
  • the prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam).
  • a discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery
  • prodrug is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject.
  • Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention.
  • Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention and the like.
  • “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, giycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
  • organic acids such as acetic
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but ire not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, ⁇ /-ethylpiperidine, polyamine resins and the like.
  • Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and
  • “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for a disease-state characterized by thrombotic activity.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating covers the treatment of a disease-state in a mammal, preferably a human, which disease-stated is characterized by thrombotic activity, and includes:
  • certain compounds of the invention or pharmaceutically acceptable salts thereof may exist in, and be isolated in, isomeric forms, including tautomeric forms, cis- or /rans-isomers.
  • certain compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, such as (R)- or (S)-.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents by methods known to those of ordinary skill in the art, or resolved using conventional techniques.
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • the nomenclature used herein is a modified form of the I.U.P.A.C. nomenclature system wherein the compounds of the invention are named herein as derivatives of the quinoline moiety.
  • the compounds of the invention act as reversible, selective antagonists of the platelet ADP receptor, P2Y AC . Accordingly, the compounds are useful in treating disease-states which are characterized as having thrombotic activity.
  • the compounds are useful as inhibitors of platelet activation, aggregation and degranulation, anti-thrombotic agents or in the treatment or prophylaxis of unstable angina, coronary angioplasty (PTCA), myocardial infarction, perithrombolysis, primary arterial thrombotic I complications of atherosclerosis such as thrombotic or embolic stroke, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic disease such as angioplasty, endarterectomy, stent placement, coronary and other vascular graft surgery, thrombotic complications of surgical or mechanical damage such as tissue salvage following accidental or surgical trauma, reconstructive surgery including skin and muscle flaps, conditions with a diffuse thrombotic/platelet consumption component such
  • platelet concentrates, or shunt occlusion such as in renal dialysis and plasmapheresis, thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and organ graft rejection, conditions such as migraine, Raynaud's phenomenon, atheromatous plaque formation/progression, vascular stenosis/restenosis and asthma, in which platelet-derived factors are implicated in the disease process.
  • the compounds of formula (I) are also useful as standard or reference compounds, for example, as a quality standard or control, in tests or assays involving the inhibition of the platelet ADP receptor, P2Y AC .
  • Such compounds may be provided in a commercial kit, for — example, for use in pharmaceutical research involving the platelet ADP- receptor, P2Y AC .
  • a compound of formula (I) could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure that the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound.
  • compounds of formula (I) could be used to test their effectiveness.
  • the ability of the compounds to inhibit the platelet adenosine diphosphate receptor known as the P2Y AC receptor, and its biological effects may be tested in a variety of in vitro , ex vivo and in vivo assays.
  • the ability of the compounds to bind to the P2Y AC receptor may be measured by methods similar to those described in Gachet, C. et al., Br. J. Haemotol. (1995), Vol. 91, pp. 434-444 and Mills, D.C.B., Thromb. Haemost. (1996), Vol. 76, No. 6, pp. 835-856, and by the method described below in Example 4.
  • the ability of the compounds to inhibit ADP-induced aggregation of platelets may be measured by methods similar to those described in R.G. Humphries, Br. J. Pharm. (1995), Vol. 115, pp. 1110-1116 and Methods in Enzymology, Vol. 169, p. 3 and by the method described below in Example 5.
  • the ability of the compounds to inhibit thrombus formation in vivo or ex vivo may be measured by methods similar to those described in J.M. Herbert, Cardiovasc. Drug Reviews (1993), Vol. 11, No. 2, pp. 180-198 or J.D. Folts, Circulation (1976), Vol. 54, No. 3, p. 365, or by the methods described below in Example 6.
  • the results of these assays clearly demonstrate that the compounds of the invention are functional antagonists of the platelet adenosine diphosphate receptor and are thereful useful in inhibiting platelet aggregation and thrombus formation.
  • Administration of the Compounds of the Invention can be carried out via any of the accepted modes of administration or agents for serving similar utilities.
  • administration can be, for example, orally, nasally, parenterally, topically, transdermally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
  • compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
  • the pharmaceutically ⁇ acceptable compositions will contain about 1 % to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient.
  • the composition will be about 5% to 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical exdpients.
  • a pharmaceutically acceptable composition containing a compound(s) of the invention, or a pharmaceutically acceptable salt thereof is formed by the incorporation of any of the normally employed exdpients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like.
  • Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
  • compositions will take the form of capsule, caplet or tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, and the like
  • a disintegrant such as croscarmellose sodium or derivatives thereof
  • a lubricant such as magnesium stearate and the like
  • a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
  • the compounds of the invention, or their pharmaceutically acceptable salts may also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).
  • a carrier that slowly dissolves within the body
  • PEG polyoxyethylene glycols and polyethylene glycols
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a compound(s) of the invention (about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
  • a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, ' butylated hydroxytoluene, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, ' butylated hydroxytoluene, etc.
  • compositions to be administered will, in -any-event, contain-a therapeutically effective amount of a ompound of the ⁇ nvention, or a _ - pharmaceutically acceptable salt thereof, for treatment of a disease-state characterized by thrombotic activity in accordance with the teachings of this invention.
  • the compounds of the invention are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease-states; and the host undergoing therapy.
  • a therapeutically effective daily dose is from about 0.14 mg to about 14.3 mg/kg of body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof; preferably, from about 0.7 mg to about 10 mg/kg of body weight per day; and most preferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day.
  • the dosage range would be from about 10 mg to about 1.0 gram per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably from about 50 mg to about 700 mg per day, and most preferably from about 100 mg to about 500 mg per day.
  • a preferred group of compounds is that group of compounds wherein: m is 1; n is 1 or 2;
  • R 1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl
  • R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
  • R 3 is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 ,
  • each R 4 is is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; R 5 is hydrogen;
  • a preferred subgroup of compounds is that subgroup of compounds wherein: m is 1 ; n is 1 or 2;
  • R 1 is hydrogen or alkoxycarbonyl
  • R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl
  • R 3 is aryl optionally substituted by one or more substituents selected from the group consisting of carboxy or alkoxycarbonyl
  • each R 4 is is independently selected from the group consisting of hydrogen, alkyl, halo, or haloalkyl
  • R 5 is hydrogen
  • R 6 is hydrogen.
  • a preferred compound is 2-[1 S-(4-
  • Another preferred group of compounds of formula (I) is that group of compounds wherein: m is 1 ; n is 1 or 2;
  • R 1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl
  • R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
  • R 3 is aryloxy optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 ,
  • each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; R 5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralky
  • R 6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl
  • each R 7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl
  • each R 8 is a bond or a straight or branched alkylene chain
  • R 9 is hydrogen, alkyl, aralkyl or haloalkyl.
  • a preferred subgroup of compounds is that subgroup of compounds wherein: m is 1 ; n is 1 or 2;
  • R 1 is hydrogen or alkoxycarbonyl
  • R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
  • R 3 is aryloxy optionally substituted by one or more substituents selected from the group consisting of alkyl, tetrazolyl, -R 8 -C(O)OR 7 , -R 8 -N(R 7 ) 2 , -R 8 -N(R 7 )-S(O) 2 -R 7 , and
  • each R 4 is is independently selected from the group consisting of hydrogen, alkyl, halo, or haloalkyl;
  • R 5 is hydrogen;
  • R 6 is hydrogen;
  • each R 7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and
  • each R 8 is a bond or a straight or branched alkylene chain.
  • preferred compounds are selected from the group consisting of the following:
  • Another preferred group of compounds of formula (I) is that group of compounds wherein: m is 1 ; n is 1 or 2;
  • R 1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl
  • R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl
  • R 3 is aralkyl wherein the alkyl radical in the aralkyl substituent i optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R 8 -OR 7 ,
  • aryl radical in the aralkyl substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 ,
  • each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; R 5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralky
  • R 6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R 7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R 8 is a bond or a straight or branched alkylene chain; and R 9 is hydrogen, alkyl, aralkyl or haloalkyl.
  • Another preferred-group of compounds-of formula (I) is-that group of compounds — wherein: m is 1; n is 1 or 2;
  • R 1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl
  • R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
  • R 3 is aralkoxy wherein the alkyl radical in the aralkyl substituent is not optionally substituted and wherein the aryl radical in the aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , -R 8 -C(O)R 7 , -R 8 -N(R 7 ) 2 , -R 8 -N(R 7 )C(O)R 7 , -R 8 -N(R 7 )C(O)OR 9 , -R 8 -N(R 7
  • R 5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
  • R 6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl;
  • each R 7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl;
  • each R 8 is a bond or a straight or branched alkylene chain; and
  • R 9 is hydrogen, alkyl, aralkyl or haloalkyl.
  • a preferred subgroup of compounds is that subgroup of compounds wherein: m is 1; n is 1 or 2;
  • R is hydrogen, aryl, aralkyl, or alkoxycarbonyl
  • R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl
  • R 3 is aralkoxy wherein the aryl radical in the aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , and -R 8 -N(R 7 ) 2 ; each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, or haloalkyl;
  • R 5 is hydrogen;
  • R 6 is hydrogen;
  • Another preferred group of compounds of formula (I) is that group of compounds wherein: m is 1; n is 1 or 2;
  • R 1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl
  • R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
  • R 3 is aralkoxy wherein the alkyl radical in the aralkoxy substituent is substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R 8 -OR 7 ,
  • each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, 5 aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbony()amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; R 5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, 10 alkoxycarbonyl, aralkoxycarbonyl, carboxyal
  • R 6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R 7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R 8 is a bond or a straight or branched alkylene chain; and R 9 is hydrogen, alkyl, aralkyl or haloalkyl.
  • a preferred subgroup of compounds is that subgroup of compounds wherein: m is 1 ; n is 1 or 2;
  • R 1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl
  • 20 R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl
  • R 3 is aralkoxy wherein the alkyl radical in the aralkoxy substituent is substituted by
  • each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino;
  • R 5 is hydrogen; '
  • R 6 is hydrogen; each R 7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and 30 each R 8 is a bond or a straight or branched alkylene chain.
  • preferred compounds are selected from the group consisting of the following: 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1 ,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(1 -phenyl-1 - -35- -methoxycarbonyl)methoxyquinoline; - - - — — — — _ __ _ ____ - -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1-phenyl-
  • a preferred group of compounds is that group of compounds wherein: m is 1; n is 1 or 2;
  • R 1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl
  • R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl
  • R 3 is heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , and -R 8 -N(R 7 ) 2 ; each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino; R 5 is hydrogen; R 6 is hydrogen; each R 7 is ⁇ hydrogen alkyl r aryl,-aralkyl, or haloalkyl; and each R 8 is a bond or a straight or branched alkylene chain.
  • a preferred compound is 2-[1 S-(4- (ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1, 2,3,4- tetrahydroisoquinolin-2-yl)quinoline in trifluoroacetic acid.
  • Another preferred group of compounds of formula (II) is that group of compounds wherein: m is 1; n is 1 or 2;
  • R is hydrogen, aryl, aralkyl, or alkoxycarbonyl
  • R 2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl
  • R 3 is heteroarylalkoxy, wherein the alkoxy radical in the heteroarylalkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo and -R 8 -C(O)OR 7 , and wherein the heteroaryl radical in the heteroarylalkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, -R 8 -OR 7 , -R 8 -C(O)OR 7 , -R 8 -C(O)N(R 7 ) 2 , and -R 8 -N(R 7 ) 2
  • each R 4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dial
  • preferred compounds are selected from the group consisting of the following:
  • the compounds of the invention are prepared according to the methods described below in the following Reaction Schemes. It is understood that those compounds of the invention which are not specifically prepared in the following Reaction Schemes may be prepared by similar synthetic processes with the appropriately substituted starting materials and reagents. It is also understood that during the preparation of the compounds of the invention, as described below, additional reactive groups (for example, hydroxy, amino or carboxy groups) on the intermediate compounds utilized in the preparation may be protected as needed by the appropriate protecting group by treating the intermediate compound prior to the desired reaction with the appropriate protecting group precursor by methods known to those of ordinary skill in the art. The protecting groups may then be removed as desired by methods known to those of ordinary skill in the art, for example, by acidic or basic hydrolysis. Such protecting groups and methods are described in detail in Greene, T.W.
  • compounds of formula (H) are prepared by first treating a compound of formula (F) in a protic solvent, such as methanol, with an equimolar amount of a compound of formula (E) with stirring at ambient temperature for about 30 minutes to about an hour, preferably for about 30 minutes. The solvent is removed by evaporation to form a residue.
  • aprotic polar solvent such as diphenyl ether
  • heated to between about 200°C and about 250°C preferably to about 250°C is then added the residue and the temperature of the reaction mixture is maintained at the high temperature for about 30 minutes to an hour, " preferably f ⁇ fab ⁇ t 30 mirTutesTat whicfrpoint the " reaction mixture is allowed to cool to- ambient temperature.
  • the resulting precipitate is collected and washed with a aprotic polar MISSING UPON TIME OF PUBLICATION
  • compounds of formula (Gb) are prepared by first treating a compound of formula (Fa) with a reducing agent, such as tin (II) chloride dihydrate, under standard chemical reduction conditions, such as in a protic solvent, to form the compound of formula (Fb), which is isolated from the reaction mixture by standard isolation techniques.
  • a reducing agent such as tin (II) chloride dihydrate
  • a protic solvent such as methanol
  • the compound of formula (Fb) in a protic solvent such as methanol
  • a slightly excess molar amount of a compound of formula (E) at reflux temperatures for about 2 to about 4 hours, preferably for about 4 hours.
  • the reaction mixture is then concentrated.
  • An organic solvent is heated to a non-boiling point temperature of between about 240°C and about 260°C, and the concentrate is then added to the solvent.
  • the temperature of the mixture is maintained at the non-boiling point temperature for about 10 to 20 minutes, preferably for about 20 minutes.
  • the reaction mixture is then cooled slowly to ambient temperature and diluted with an organic solvent.
  • the compound of formula (Ga) is isolated from the reaction mixture by standard isolation techniques, such as filtration.
  • the compound of formula (Ga) is treated with a hydrolyzing agent under standard hydrolysis conditions and then treated under standard reducing conditions, such as hydrogen gas and palladium over carbon, to form a compound of formula (Gb).
  • Compounds of formulae (D) and (H) are prepared by methods disclosed herein.
  • Compounds of formula (J) are commercially available, for example, from Aldrich Co., or can be prepared according to methods known to one of ordinary skill in the art.
  • compounds of formula (la) are prepared by first treating a compound of formula (H) under standard Williamson synthesis conditions, such as in the presence of a base in an aprotic solvent, for example, cesium carbonate in ⁇ , ⁇ -dimethylformamide (“DMF"), with an equimolar amount of a compound of formula (J) at temperatures between about ambient temperature and about 100°C.
  • aprotic solvent for example, cesium carbonate in ⁇ , ⁇ -dimethylformamide ("DMF")
  • DMF ⁇ , ⁇ -dimethylformamide
  • the compound of formula (L) in an aprotic solvent mixture for example, methylene chloride and DMF or methylene chloride and triethylamine, is then treated with a slightly excess molar amount of a peptide coupling reaction additive, such as 1-hydroxybenzotriazole (“HOBT”) and a slightly excess molar amount a coupling agent for amide formation, such as 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide (“EDCI”) at ambient temperature.
  • a peptide coupling reaction additive such as 1-hydroxybenzotriazole (“HOBT)
  • EDCI 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide
  • An equimolar amount of a compound of formula (D) in an aprotic solvent, such as methylene chloride is then added to the reaction mixture.
  • the reaction mixture is stirred at ambient temperature for about 4 to about 12 hours, preferably for about 12 hours.
  • compounds of formula (la) may be deprotected to yield the corresponding free acid or free amine derivatives.
  • compounds of formula (la) wherein R 1 is a nitrogen-protecting group, such as an alkyl carbonyl can be hydrolyzed under standard acid hydrolysis conditions to yield the corresponding compound of formula (la) wherein R 1 is hydrogen, which can then be treated with the appropriately substituted acid halide, carbamoyl halide or isocyanate to yield the appropriately substituted R 1 compound of formula (la).
  • compounds of formula (lb) are prepared by first treating a suspension of a compound of formula (H) in an aprotic solvent mixture, such as methylene chloride and DMF, with a slightly excess molar amount of a peptide coupling reaction additive, such as 1- hydroxybenzotriazole (“HOBT”) and a slightly excess molar amount a coupling agent for amide formation, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (“EDCI”) at ambient temperature.
  • a peptide coupling reaction additive such as 1- hydroxybenzotriazole (“HOBT)
  • EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • the reaction mixture is stirred at ⁇ ambient temperature for a period oftime of between-about 4 hours ⁇ and about 12 hours,- preferably for a period of time of between about 6 hours and about 12 hours.
  • the compound of formula (M) is then isolated from the reaction mixture by standard isolation techniques, such as evaporation of the solvents, extraction and concentration.
  • the compound of formula (M) is then treated under standard Williamson synthesis conditions, such as in the presence of base in an aprotic solvent, for example, cesium carbonate in acetonitrile:DMF, with an an equimolar amount of a compound of formula (J) at a temperature of between about ambient temperature and 100°C.
  • the reaction mixture is stirred for a period of time of between 30 minutes and about 10 hours, preferably for abou 30 minutes.
  • the compound of formula (lb) is then isolated from the reaction mixture by standard isolation techniques, such as organic extraction and concentration. If desired, compounds of formula (lb) can be treated under standard hydrolysis conditions to yield the corresponding free amine or acid.
  • Compounds of formulae (H) and (D) are prepared as described herein or can be prepared according to methods known to one of ordinary skill in the art.
  • Compounds of formulae (P), (Q) and (R) are commercially available, for example, from Aldrich Chemical Co., or can be prepared according to methods known to one of ordinary skill in the art.
  • compounds of formulae (lc), (Id) and (le) are prepared by first treating a compound of formula (H) with a halogenating agent, such as phosphorus pentachloride or phosphorus oxychloride, under standard halogenating conditions.
  • a halogenating agent such as phosphorus pentachloride or phosphorus oxychloride
  • the compound of formula (N) is isolated from the reaction mixture by standard isolation techniques.
  • the compound of formula (N) is then treated with a compound of formula (D) under standard peptide coupling conditions, as described herein, to yield a compound of formula (O), which is isolated from the reaction mixture by standard isolation techniques.
  • the compound of formula (O) in an polar aprotic solvent, such as DMSO, in the presence of a base, such as cesium carbonate, is then treated with a compound of formula (P).
  • a compound of formula (P) is then treated with a compound of formula (P).
  • the resulting reaction mixture is heated to a temperature of between about 40°C and about 60°C, preferably at about 60°C for a period of time of between about 4 hours and about 16 hours, preferably for about 16 hours.
  • the compound of formula (lc) is then isolated from the reaction mixture by standard isolation techniques, such as filtration and purification by preparative HPLC. If desired, the compound of formula (lc) can be treated under standard hydrolysis conditions to further yield the corresponding free acid or amine.
  • a mixture of a compound of formula (O) and a compound of formula (Q) in a polar aprotic solvent, such as DMSO is heated to a temperature of between about 80°C and 105°C, preferably to about 100°C, for a period of time of between about 6 hours and 18 hours, preferably for about 18 hours.
  • the compound of formula (Id) is then isolated from the reaction mixture by standard isolation techniques, such as purification by reverse phase HPLC. If desired, the compound of formula (Id) can be hydrolyzed under standard hydrolysis conditions to further yield the corresponding amine or acid.
  • a compound of formula (O) is treated with a compound of formula (R) under standard boronic acid/palladium coupling conditions to yield the corresponding compound of formula (le), which is isolated from the reaction mixture by standard isolation techniques.
  • the compound of formula (le) can be hydrolyzed under standard hydrolysis conditions to further yield the corresponding amine or acid.
  • All compounds of the invention as prepared above which exist in free base or acid form may be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid. Salts of the compounds prepared above may be converted to their free base or acid form by standard techniques.
  • PREPARATION 1 Compounds of-formula-(D)- A.
  • THF tetrahydrofuran
  • EDCI 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide
  • ADP platelet adenosine diphosphate
  • One day old platelet concentrates were purchased from a local blood bank. The platelet concentrates were spun at 680 g for 10 minutes and the resulting pellets were resuspended in modified Tyrode's buffer ( 135 mM NaCI, 3.6 mL KCI, 1.8 mM MgCI 2 , 9 mM HEPES, 0.18 mg/mL BSA, 4.5 mM glucose, pH 6.6) supplemented by 2% acid citrate dextrose (ACD).
  • modified Tyrode's buffer 135 mM NaCI, 3.6 mL KCI, 1.8 mM MgCI 2 , 9 mM HEPES, 0.18 mg/mL BSA, 4.5 mM glucose, pH 6.6
  • ACD acid citrate dextrose
  • Platelet suspension was spun at 680 g for 10 minutes and the final pellet was resuspended in platelet binding buffer (20mM Tris buffer, pH 7.5, 140 mM NaCI, 4 mM KCI, 2 mM MgCI 2 ⁇ 1 mM EDTA, 0.1% BSA, 5 mM glucose, 2 g/mL aprotinin, and 2 g/mL leupeptin).
  • platelet binding buffer (20mM Tris buffer, pH 7.5, 140 mM NaCI, 4 mM KCI, 2 mM MgCI 2 ⁇ 1 mM EDTA, 0.1% BSA, 5 mM glucose, 2 g/mL aprotinin, and 2 g/mL leupeptin).
  • Platelets were isolated from rat whole blood as described in Example 13 with the final pellet resuspended in platelet binding buffer.
  • the platelet number for binding to rat platelets (5 x 10 6 per well) was normalized to the number of platelets for
  • Binding reactions were initiated by mixing [ 33 P]-2-methylthio-ADP (0.3-0.5 nM), test compounds and washed platelets in 96-well plates. The reactions were kept at ambient temperature for 60 minutes under constant shaking and were stopped by fast-filtration onto 96-well, glass-fiber (GFC) filter plates followed by washing 5 times with ice-cold 50 mM Tris buffer (pH 7.5). The amount of [ 33 P]-2-methylthio-ADP bound to the filters was measured by scintillation counting. Non-specific binding was determined in the presence of 10 ⁇ M unlabelled 2-methylthio-ADP. Competition studies were done using a single concentration of [ 33 P]-2-methylthio-ADP (0.3 nM) and varying concentrations of test compounds. Results:
  • Washed platelets were prepared from the PRP by centrifugation at 680 g for 15 minutes and the platelet pellet resuspended in Tyrode's buffer (137 mM NaCI, 2.7 mM KCI, 12 mM NaHCO 2 , 0.42 mM NaH 2 PO, 1 mM MgCI 2 , 2 M CaCI 2 , 0.35% BSA, 5.5 mM glucose, 5 mM HEPES, pH 7.35 supplemented with f.c. 10% ACD solution. The platelets were washed a total of two times under these acidic conditions and the platelet pellet collected by centrifugation at 680 g for 15 minutes at ambient temperature.
  • Tyrode's buffer 137 mM NaCI, 2.7 mM KCI, 12 mM NaHCO 2 , 0.42 mM NaH 2 PO, 1 mM MgCI 2 , 2 M CaCI 2 , 0.35% BSA, 5.5 mM glucose, 5 mM HEPES
  • the final platelet pellet was resuspended at 2 X 10 8 platelets/mL in Tyrode's buffer containing 0.02 units/mL apyrase. This platelet suspension was kept at 37°C for at least 30 minutes prior to studies.
  • the compounds of the invention when tested in this assay, demonstrated the ability to inhibit ADP-induced platelet aggregation in vitro in human and rat washed platelets.
  • the amount of thrombus deposited on the silk thread was measured as dry weight (24 hours at ambient temperature )r- A compound of- the invention- ⁇ r 3 and 10 mg/kg)-(as-the-appropriate salt form) or vehicle (15% DMSO in saline, 1 mlJkg) was injected via the jugular vein catheter 5 minutes before the A-V shunt. Blood samples (1 mL) were taken immediately before the dosing and at the end of the A-V shunt for measurements of ex vivo platelet aggregation and plasma levels of the compound of the invention. Results:
  • This example illustrates the preparation of representative pharmaceutical compositions for oral administration containing a compound of the invention, or a pharmaceutically acceptable salt thereof:
  • A. Ingredients % wt./wt.
  • Polyethylene glycol 400 20.0 g
  • Polysorbate 80 1.0 g -Water- -q.s.- 00-mL
  • the compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient quantity of water is then added with stirring to provide 100 mL of the solution which is filtered and bottled.
  • the above ingredients are melted, mixed and filled into soft elastic capsules.
  • This example illustrates the preparation of a representative pharmaceutical formulation for parenteral administration containing a compound of the invention, or a pharmaceutically acceptable salt thereof:
  • Polyethylene glycol 400 20.0 g
  • the compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient quantity of 0.9% saline solution is then added with stirring to provide 100 mL of the I.V. solution which is filtered through a 0.2 m membrane filter and packaged under sterile conditions.
  • This example illustrates the preparation of a representative pharmaceutical composition in suppository form containing a compound of the invention, or a pharmaceutically acceptable salt thereof:
  • Polyethylene glycol 1000 74.5%
  • the ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.
  • This example illustrates the preparation of a representative pharmaceutical formulation for insufflation containing a compound of the invention, or a pharmaceutically acceptable salt thereof:
  • the ingredients are milled, mixed, and packaged in an insufflator equipped with a dosing pump.
  • This example illustrates the preparation of a representative pharmaceutical formulation in nebulized form containing a compound of the invention, or a pharmaceutically acceptable salt thereof:
  • the compound of the invention is dissolved in ethanol and blended with water.
  • the formulation is then packaged in a nebulizer equipped with a dosing pump.
  • EXAMPLE 12 This example illustrates the preparation of a representative pharmaceutical formulation in aerosol form containing a compound of the invention, or a pharmaceutically acceptable salt thereof: Ingredients % wt./wt.
  • the compound of the invention is dispersed in oleic acid and the propellants. The resulting mixture is then poured into an aerosol container fitted with a metering valve. * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * * *

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Vascular Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Biomedical Technology (AREA)
  • Oncology (AREA)
  • Neurosurgery (AREA)
  • Pulmonology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Quinoline Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

Compounds of formula (I), where m, n, R1, R2, R3, R4 and R6 are described herein, are useful as inhibitors of platelet adenosine diphosphate. Pharmaceutical compositions containing these compounds, methods of using these compounds as antithrombotic agents and processes for synthesizing these compounds are also described herein.

Description

2 - AMINOCARBONYL - QUINOLINE COMPOUNDS AS PLATELET ADENOSINE DIPHOSPHATE RECEPTOR ANTAGONISTS
This application claims priority to U.S. Provisional Application Serial No. 60/432,792 filed December 11 , 2002 the entirety of which is incorporated herein by reference.
Field of the Invention
The invention relates to quinoline derivatives, their use as platelet adenosine diphosphate receptor antagonists, compositions containing them and processes for their preparation.
Background of the Invention
Platelets interact with the coagulation and fibrinolysis systems in the maintenance of hemostasis and in the pathogenesis of thrombosis and thromboembolism. Platelets rapidly adhere to damaged vascular tissue, and release a variety of prothrombotic, chemotactic, and mitogenic factors, aimed at prompting hemostasis and wound healing. Platelets also play an important role in arterial thrombosis, a common cause of death and disability in patients with cardiovascular disease. Platelet inhibitors have been successfully used for secondary prevention of arterial thrombosis in patients with coronary, cerebral, and peripheral vascular disease. Platelets adhere to exposed subendothelium after vessel wall injury by binding to von
Willebrand factor (vWf) and collagen. This induces platelets to change shape from a disc shape to a round form with pseudopodia, which enforces platelet adhesion and aggregation. The final common pathway for platelet aggregation is the activation of the fibrinogen receptor (GPIIb-llla). As a result, dimeric fibrinogen molecules present in plasma can bind and link platelets together to form aggregates. .
Activated platelets secrete their granule contents, many of which act directly on blood cells, including platelets themselves, and endothelium. Platelets contain several kinds of secretory granules. The dense-granules contain adenosine diphosphate ("ADP"), adenosine triphosphate ("ATP") and serotonin. The α-granules contain several platelet-specific proteins (platelet factor 4 and β-thromboglobulin), growth factors (PDGF, TGF-β, EGF and ECGF) and coagulation factors (fibrinogen, Factor V and vWf). Platelets also secrete biologically active arachidonic acid products. Well known is TxA2 which is inhibited by aspirin through irreversible inactivation of the cyclooxygenase producing TxA2.
Many stimuli, such as thrombin, collagen, ADP and thromboxane A2 (TxA2), activate platelets by binding to their cell surface receptors. Most of these receptors are G-protein- coupled-reeeptors.- Activation-of-G-proteins-has been-shown to be-an-essential-event in- platelet activation. For example, platelets from Gq-/- mice do not aggregate in response to thrombin, collagen, ADP or TxA2 (Offermans, S. et al., Nature (1998), Vol. 389, No. 11, pp. 183-185). Many down-stream signaling events have been elucidated, including activation of phospholipase-C (PLC) and protein kinase C, increase in intracellular calcium concentration, decrease in cAMP level and tyrosine phosphorylation. ADP plays a pivotal role in platelet activation. ADP not only causes primary aggregation of platelets but is also responsible for the secondary aggregation following activation by other agonists such as thrombin and collagen. Contained at ver high concentrations in the platelet dense-granules, ADP is released when platelets are activated to reinforce platelet aggregation. ADP-induced platelet activation plays an important role in maintaining normal hemostasis. Several congenital bleeding disorders have been linked to the decreased number of platelet ADP receptors and deficiency of ADP-induced platelet aggregation. Patients having "storage pool disease", which is due to defects in the storage of nucleotides and/or their secretion from the platelet dense-granules, have impaired platelet aggregation in response to collagen and other stimuli due to the absence of the amplification effects by ADP.
ADP-induced platelet activation also plays a key role in the initiation and propagation of thrombosis. Administration of ADP has been shown to induce thrombus formation in rat and mice mesenteric venules. In contrast, ADP-removing enzymes have been shown to dramatically reduce platelet deposition on collagen and to inhibit laser-induced thrombosis in rat mesenteric arterioles and venules, supporting the theory that ADP plays a role in mediating platelet recruitment in thrombus formation. Several ADP-induced early signaling events in platelets have been described. These include a transient rise in free cytoplasmic calcium, an inhibition of adenylate cyclase through activation of Gj2, an increase in cytosolic pH by activating the Na+/H+-exchange, and exposure of the platelet binding sites for fibrinogen independent of protein kinase C. While these signaling events collectively contribute to platelet aggregation, the specific role of each remains the subject of on-going investigations.
The current model of ADP-induced platelet activation involves two G-protein coupled purinergic receptors, one of which is coupled to the activation of the phospholipase-C pathway (P2Y and the other is coupled to the inhibition of adenylate cyclase (P2YAC). P2YAc is the best target for a platelet ADP receptor antagonist for several reasons. First, P2YAc is predominately platelet specific. Secondly, it is required for ADP-induced aggregation. Thirdly, it plays an important role in sustaining thrombin or collagen-induced aggregation. Finally, it is the molecular target for anti-aggregatory drugs such as Clopidogrel and Ticlopidine. Both of these drugs have been shown to be efficacious in various thrombosis models. However, CldpidbgreTrTas Beerf shown to' be aήTrreversibleTiήhibitor όf'platelet aggregation" with a slow ~ ' onset of action. Similarly, the ATP analogues, AR-C67085 and AR-C69931 MX, which are potent antagonists for ADP-induced platelet aggregation, have also been shown to be effective in thrombosis models and are currently under clinical investigation. All these findings indicate that ADP is a critical mediator of arterial thrombus formation and hence an excellent target for antithrombotic intervention.
When the properties of current oral platelet inhibitors, such as aspirin, Clopidogrel and Ticlopidine are compared, it becomes clear that, while relatively safe, current oral platelet inhibitors are only modestly effective in preventing thrombotic complications in patients with underlying vascular disease. It is clear that there is a need in this field for a potent, selective, reversible, orally active platelet ADP receptor (P2YAc) inhibitor.
SUMMARY OF THE INVENTION
The compounds of the invention are antagonists of the platelet ADP receptor, P2YAC, and are therefore useful in treating disease-states characterized by thrombotic activity and in so doing are useful as antithrombotic agents in the treatment and prevention of thrombosis. Accordingly, in one aspect, the invention is directed to compounds selected from the group consisting of the following formula (I):
Figure imgf000004_0001
wherein: m and n are independently 1 to 4; R1 is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl; R2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl, aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl, alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl, carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl, aminocarbonylalkyl, aralkoxycarbonylaminoalkyl, __ alkoxycarbonyljalkylaminocaφonyja^
(alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl, (carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl; R3 is aryl or aryloxy each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; or R3 is aralkyl or aralkoxy, wherein the alkyl radical in the aralkyl or aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9), and wherein the aryl radical in the aralkyl or aralkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl,
-R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; each R5 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and each R9 is hydrogen, alkyl, aralkyl or haloalkyl; as a single stereoisomer, a mixture of individual stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt thereof. i In another aspect, this invention is compounds selected from the group consisting of the following formula (II):
Figure imgf000005_0001
wherein: m and n are independently 1 to 4; R1 is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl;
R2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl, aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl, alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl, carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl, aminocarbonylalkyl, aralkoxycarbonylaminoalkyl, alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl, (alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl, (carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl; R3 is heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7,
-R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; or R3 is heteroarylalkoxy, wherein the alkoxy radical in the heteroarylalkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2,
-R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9), and wherein the heteroaryl radical in the heteroarylalkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclyialkoxy; each R5 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl; R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; - - -— __ each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and each R9 is hydrogen, alkyl, aralkyl or haloalkyl; as a single stereoisomer, a mixture of individual stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt thereof. In another aspect, this invention is directed to pharmaceutical compositions useful in treating a mammal having a disease-state characterized by thrombotic activity, which composition comprises a pharmaceutically acceptable excipient and a compound of formula (I) or a compound of formula (II) as defined above.
In another aspect, this invention is directed to methods of treating disease-states characterized by thrombotic activity, which methods comprise administering to a mammal having a disease-state characterized by thrombotic activity a therapeutically effective amount of a compound of formula (I) or formula (II) as defined above.
Detailed Description of the Invention Definitions
As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:
"Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, π-propyl, 1-methylethyl (/so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (f-butyl), and the like. Unless stated otherwise specifically in the specification, it is understood that for radicals, as defined below, that contain a substituted alkyl group that the substitution can occur on any carbon of the alkyl group. "Alkylene chain" refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like.
"Alkylcarbonyl" refers to a radical of the formula -C(O)-Ra where Ra is an alkyl radical as defined above, e.g., acetyl, ethylcarbonyl, n-propylcarbonyl, and the like.
"Alkylcarbonylamino" refers to a radical of the formula -N(H)-C(O)-Ra where Ra is an alkyl radical as defined above, e.g., acetylamino, ethylcarbonylamino, n-propylcarbonylamino, and the like.
"Alkylthio" refers to a radical of the formula -S-Ra where Ra is an alkyl radical as defined above, e.g., methylthio, ethylthio, n-propylthio, and the like.
"Alkylsulfonylalkyl" refers to a radical of the formula -Ra-S(O)2-Ra where each Ra is independently an alkyl radical as defined above, e.g., methylsulfonylmethyl, - _ _ .
2-methylsulfonylethyl, 2-ethylsulfonylpropyl, and the like. "Alkoxy" refers to a radical of the formula -ORa where Ra is an alkyl radical as defined above, e.g., methoxy, ethoxy, n-propoxy, 1-methylethoxy (/so-propoxy), n-butoxy, n-pentoxy, 1,1-dimethylethoxy (f-butoxy), and the like.
"Alkoxycarbonyl" refers to a radical of the formula -C(O)ORa where Ra is an alkyl radical as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and the like.
"Alkoxycarbonylalkyl" refers to a radical of the formula -Ra-C(O)ORa where each Ra is independently an alkyl radical as defined above, e.g., methoxycarbonylmethyl, (1,1- dimethylethoxy)carbonylmethyl, 2-(methoxycarbonyl)ethyl, and the like.
"Alkoxycarbonylaminocarbonyl" refers to a radical of the formula -C(O)-N(H)-C(O)ORa where Ra is an alkyl radical as defined above, e.g., methoxycarbonylaminocarbonyl, ethoxycarbonylaminocarbonyl, n-propoxycarbonylaminocarbonyl, and the like.
"Alkoxyalkoxyalkylcarbonyl" refers to a radical of the formula -C(O)-Ra-O-Ra-O-Ra where each Ra is independently an alkyl radical as defined above, e.g., 2-(ethoxy)ethoxymethylcarbonyl, 3-(2-(n-butoxy)ethoxy)propylcarbonyl, and the like. "Alkoxycarbonylalkyl" refers to a radical of the formula -Ra-C(O)ORa where each Ra is independently an alkyl radical as defined above, e.g., methoxycarbonylmethyl, 2-(ethoxycarbonyl)ethyl, 2-(methoxycarbonyl)propyl, and the like.
"Alkoxycarbonylalkoxy" refers to a radical of the formula -O-Ra-C(O)ORa where each Ra is independently an alkyl radical as defined above, e.g., methoxycarbonylmethoxy, 2- (ethoxycarbonyl)ethoxy, 2-(methoxycarbonyl)propoxy, and the like.
"Alkoxycarbonylalkylcarbonyl" refers to a radical of the formula -C(O)-Ra-C(O)ORa where each Ra is independently an alkyl radical as defined above, e.g., methoxycarbonylmethylcarbonyl, 2-(ethoxycarbonyl)ethylcarbonyl, 2-(methoxycarbonyl)propylcarbonyl, and the like. "Alkoxycarbonylalkylaminocarbonylalkyl" refers to a radical of the formula
-Ra-C(O)-N(H)-Ra-C(O)ORa where each Ra is independently an alkyl radical as defined above, e.g. , methoxycarbonylmethyl, 2-(ethoxycarbonyl)ethylaminocarbonylmethyl, 2-(2-(methoxycarbonyl)propylaminocarbonyl)propyl, and the like.
"Alkoxycarbonylalkylthioalkyl" refers to a radical of the formula -Ra-S-Ra-C(O)ORa where each Ra is independently an alkyl radical as defined above, e.g., methoxycarbonylmethylthiomethyl, 2-(ethoxycarbonyl)ethylthiomethyl, 2-(2-(methoxycarbonyl)propylthio)propyl, and the like.
"Alkoxycarbonylalkoxycarbonylalkyl" refers to a radical of the formula -Ra-C(O)-O-Ra-C(O)ORa where each Ra is independently an alkyl radical as defined above, e.g., methoxycarbonylmethoxy, 2-(ethoxycarbonyl)ethoxycarbonylmethyl, „
3-(2-(methoxycarbonyl)propoxycarbonyl)propyl, and the like. "(AlkoxycarbonylaIkyl)(alkyl)aminocarbonylalkyl" refers to a radical of the formula -Ra-C(O)-N(Ra)-Ra-C(O)ORa where each Ra is independently an alkyl radical as defined above, e.g., (methoxycarbonyImethyl)(methyl)aminocarbonylmethyl, 2-((ethoxycarbonylmethyl)(methyl)aminocarbonyl)ethyI, and the like. "Amino" refers to the -NH2 radical.
"Aminoalkyl" refers to a radical of the formula -Ra-NH2, e.g., aminomethyl, 2-aminomethyl, 2-aminopropyl, and the like.
"Aminocarbonyl" refers to the -C(O)NH2 radical.
"Aminocarbonylalkoxy" refers to a radical of the formula -O-Ra-C(O)NH2, e.g., aminocarbonylmethoxy, 2-(aminocarbonyl)ethoxy, 2-(aminocarbonyl)propoxy, and the like.
"Aminocarbonylalkyl" refers to a radical of the formula -Ra-C(O)NH2, e.g., aminocarbonylmethyl, 2-(aminocarbonyl)ethyl, 2-(aminocarbonyl)propyl, and the like.
"Aryl" refers to a phenyl or naphthyl radical. Unless stated otherwise specifically in the specification, the term "aryl" or the prefix "ar-" (such as in "aralkyl") is meant to include aryl radicals optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, -R8-C[N(R7)2]-C(O)OR7, wherein each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl, each R8 is a bond or a straight or branched alkylene chain, and each R9 is hydrogen, alkyl, aralkyl or haloalkyl as defined herein.
"Aralkyl" refers to a radical of the formula -RaRb where Ra is an alkyl radical as defined above, substituted by Rb, an aryl radical, as defined above, e.g., benzyl. The Ra radical may be optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9, wherein each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl, each R8 is a bond or a straight or branched alkylene chain, and each R9 is hydrogen, alkyl, aralkyl or haloalkyl as defined herein. The Rb radical may be optionally substituted one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, -R8-C[N(R7)2]-C(O)OR7, wherein each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl, each R8 is a bond or a straight or branched alkylene chain, and each R9 is hydrogen, alkyl, aralkyl or haloalkyl as defined herein.
"Aryloxy" refers to a radical of the formula -ORb where Rb is an optionally substituted aryl radical as defined above, e.g., phenoxy. "Arylcarbonyl" refers to a radical of the formula -C(O)-Rb-where-Rb-is anjjptionally substituted aryl radical as defined above, e.g., phenylcarbonyl, (4-acetylaminophenyl)carbonyl, (2-methoxyphenyl)carbonyl, and the like. For R1, preferred arylcarbonyl radicals are those radicals wherein the Rb group is optionally substituted by by one or more substituents independently selected from the group consisting of acetylamino, carboxy, aminocarbonyl, alkoxycarbonyl, haloalkoxy, alkoxy, and alkyl. "Aryloxycarbonyl" refers to a radical of the formula -C(O)ORb where Rb is an optionally substituted aryl radical as defined above, e.g., phenoxycarbonyl.
"Aryloxyalkylcarbonyl" refers to a radical of the formula -C(O)ORbRa where Ra is an alkyl radical, as defined above, substituted by Rb, an optionally substituted aryl radical, as defined above, e.g., phenoxymethylcarbonyl, (2-phenoxyethyl)carbonyl, and the like. "Aralkoxy" refers to a radical of the formula -ORθ where Re is an optionally substituted aralkyl radical as defined above, e.g., benzyloxy, 3-phenylpropoxy, and the like.
"Aralkoxyalkyl" refers to a radical of the formula -Ra-ORe where Ra is an alkyl radical as defined above and Re is an optionally substituted aralkyl radical as defined above, e.g., benzyloxymethyl, 2-(benzyloxy)ethyl, 2-(benzyloxy)propyl, and the like. "Aralkoxycarbonyl" refers to a radical of the formula -C(O)ORe where Re is an optionally substituted aralkyl radical as defined above, e.g., benzyloxycarbonyl, and the like.
"Aralkoxycarbonylalkyl" refers to a radical of the formula -Ra-C(O)ORe where Ra is an alkyl radical as defined above and Re is an optionally substituted aralkyl radical as defined above, e.g., benzyloxycarbonylmethyl, 2-(benzyloxycarbonyl)ethyl, 3-((naphthalen-2- yl)oxy)carbonyl)propyl, and the like.
"Aralkoxycarbonylaminoalkyl" refers to a radical of the formula -Ra-N(H)-C(O)ORe where Ra is an alkyl radical as defined above and Re is an optionally substituted aralkyl radical as defined above, e.g., benzyloxycarbonylaminomethyl, 2-(benzyloxycarbonylamino)ethyl, 2- (benzyloxycarbonylamino)propyl, and the like. "Carboxy" refers to the -C(O)OH radical.
"Carboxyalkyl" refers to a radical of the formula -Ra-C(O)OH, where Ra is an alkyl radical as defined above, e.g., carboxymethyl, 2-carboxyethyl, 2-carboxypropyl and the like.
"Carboxyalkoxy" refers to a radical of the formula -O-Ra-C(O)OH, where Ra is an alkyl radical as defined above, e.g., carboxymethoxy, 2-carboxyethoxy, 2-carboxypropoxy, and the like. "Carboxyalkylcarbonyl" refers to a radical of the formula -C(O)-Ra-C(O)OH, where Ra is an alkyl radical as defined above, e.g., 2-carboxyethylcarbonyl, carboxymethylcarbonyl, 3-carboxypropylcarbonyl, and the like.
"Carboxyalkylamino" refers to a radical of the formula -N(H)-Ra-C(O)OH where Ra is an alkyl radical as defined above, e.g., carboxymethylamino, 2-carboxyethyiamino, 3- carboxypropylamino, and the like. "Carboxyalkylaminocarbonylalkyl" refers to a radical of the formula -Ra-C(O)-N(H)-Ra-C(O)OH where each Ra is independently an alkyl radical as defined above, e.g., carboxymethylaminocarbonylmethyl, 2-(carboxymethylaminocarbonyl)ethyl, 2-(2- carboxyethyl)aminocarbonyl)ethyl, 3-(2-carboxyethyl)aminocarbonyl)butyl, and the like. "Carboxyalkylthioalkyl" refers to a radical of the formula -Ra-S-Ra-C(O)OH were each Ra is independently an alkyl radical as defined above, e.g., carboxymethylthiomethyl, (1-carboxyethyl)thiomethyl, 2-((1-carboxypropyl)thio)ethyl, and the like.
"Carboxyalkoxyalkyl" refers to a radical of the formula -Ra-O-Ra-C(O)OH where each Ra is independently an alkyl radical as defined above, e.g., 2-(carboxymethoxy)ethyl, (2-carboxyethoxy)methyl, 3-(2-carboxypropoxy)propyl, and the like.
"Carboxyalkoxycarbonylalkyl" refers to a radical of the formula -Ra-C(O)-O-Ra-C(O)OH where each Ra is independently an alkyl radical as defined above, e.g., carboxymethoxycarbonylmethyT, 2-(carboxymethoxycarbonyl)ethyl, 2-((2- carboxyethoxy)carbonyl)propyl, and the like. "Cycloalkyl" refers to a stable 3- to 10-membered monocyclic or bicyclic radical which is saturated, and which consist solely of carbon and hydrogen atoms, e.g., cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, decalinyl and the like. Unless otherwise stated specifically in the specification, the term "cycloalkyl" is meant to include cycloalkyl radicals which are optionally substituted one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, -R8-C[N(R7)2]-C(O)OR7, wherein each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl, each R8 is a bond or a straight or branched alkylene chain, and each R9 is hydrogen, alkyl, aralkyl or haloalkyl as defined herein. "Cycloalkylcarbonyl" refers to a radical of the formula -C(O)-Rc where Rc is a cycloalkyl radical as defined above, e.g., cyclobutylcarbonyl, cyclopropylcarbonyl, and the like. For R1, a preferred cycloalkylcarbonyl radical is that radical wherein the Rc group is optionally substituted by a phenyl group.
"(Carboxy)(hydroxy)alkyl" refers to a radical of the formula -Ra(OH)-C(O)OH wherein Ra is an alkyl radical defined above substituted by an hydroxy radical and a carboxy radical, as defined herein, e.g., 1-carboxy-3-hydroxypropyl, 2-carboxy-4-hydroxybutyl, 1-carboxy-5- hydroxypent-2-yl, and the like.
"(Carboxyalkyl)(alkyl)aminocarbonylalkyl" refers to a radical of the formula -Ra-C(O)-N(Ra)-Ra-C(O)OH wherein each Ra is independently an alkyl radical as defined above, and wherein the nitrogen atom is substituted by the Ra group and the -Ra-C(O)OH group, e.g., (carboxyethyl)(ethyl)aminocarbonylmethylr2-((2 - - carboxyethyl)(methyl)aminocarbonyl)ethyl, and the like. "Cyano" refers to the -C^l radical.
"Dialkylamino" refers to a radical of the formula -N(Ra)-Ra where each Ra is independently an alkyl radical, e.g., dimethylamino, diethylamino, methylethylamino, and the like. "Dialkylaminocarbonyl" refers to a radical of the formula -C(O)-N(Ra)-Ra where each Ra is independently an alkyl radical, e.g., dimethylaminocarbonyl, diethylaminocarbonyl, methyl(ethyl)aminocarbonyl, and the like.
"Dialkylaminoalkyl" refers to a radical of the formula -Ra-N(Ra)-Ra where each Ra is independently an alkyl radical as defined above, e.g., dimethylaminomethyl, 2-(diethylamino)ethyl, 3-(methyl(ethyl)amino)propyl, and the like.
"Dialkylaminoalkoxy" refers to a radical of the formula -O-Ra-N(Ra)-Ra where each Ra is independently an alkyl radical as defined above, e.g., dimethylaminomethoxy, 2-(diethylamino)ethoxy, 3-(methyl(ethyl)amino)propoxy, and the like.
"Di(alkylcarbonyl)amino" refers to a radical of the formula -N(C(O)-Ra)-C(O)-Ra where each Ra is independently an alkyl radical as defined above, e.g., di(acetyl)amino, di(ethylcarbonyl)amino, and the like.
"Halo" refers to bromo, chloro, iodo or fluoro.
"Haloalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
"Haloalkylsulfonylaminoalkyl" refers to a radical of the formula -Ra-N(H)-S(O)2Rf where Ra is an alkyl radical as defined above and Rf is a haloalkyl radical as defined above, e.g., 2-(trifluoromethoxysulfonylamino)ethyl, 3-(trifluoromethoxysulfonylamino)propyl, and the like. "Haloalkoxy" refers to a radical of the formula -ORf where Rf is an haloalkyl radical as defined above, e.g., trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy, and the like.
"Haloalkenyloxy" refers to a radical of the formula -ORg where Rg is an haloalkenyl radical as defined above, as defined above, e.g., 1 ,2-difluoroethenyloxy, 3-bromo-2-fluoroprop- 1-enyloxy, 1 ,2-dibromoethenyloxy, and the like.
"Haloalkoxycarbonyl" refers to a radical of the formula -C(O)ORf where Rf is an haloalkyl radical as defined above, e.g., trifluoromethoxycarbonyl, difluoromethoxycarbonyl, trichloromethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 1-fluoromethyl-2-fluoroethoxycarbonyl, 3-bromo-2-fluoropropoxycarbonylτ 1-bromomethyl-2-bromoethoxycarbonyl,. and the like. _ _ .
"Hydroxy" refers to the -OH radical. "Hydroxyalkyl" refers to a alkyl radical as defined above that is substituted by a hydroxy radical, e.g., hydroxy methyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 3-hydroxybutyl, and the like.
"Heterocyclyl" refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For purposes of this invention, the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the heterocyclyl radical may be aromatic or partially or fully saturated. The heterocyclyl radical may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound. Examples of such heterocyclyl radicals include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl, carbazolyl, cinnolinyl, decahydroisoquinolyl, dioxolanyl, furanyl, furanonyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, indanyl, indolizinyl, isoxazolyl, isoxazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiazolidinyl, thiadiazolyl, triazolyl, tetrazolyl, tetrahydrofuryl, triazinyl, tetrahydropyranyl, thienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. Unless stated otherwise specifically in the specification, the term "heterocyclyl" is meant to include heterocyclyl radicals as defined above which are optionally substituted one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, -R8-C[N(R7)2]-C(O)OR7, wherein each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl, each R8 is a bond or a straight or branched alkylene chain, and each R9 is hydrogen, alkyl, aralkyl or haloalkyl as defined herein.
"Heteroaryl" refers to a heterocyclyl radical as defined above wherein the heterocyclyl radical is partially or fully aromatic.
"Heterocyclylalkyl" refers to a radical of the formula -Ra-Rh where Ra is an alkyl radical as defined above and Rh is an heterocyclyl radical as defined above, e.g., imidazol-3-yImethyl, - triazol-3-ylmethylr2-tetrazolylethyl, and the like.- For R2 preferred heterocyclylalkylradicals are MISSING UPON TIME OF PUBLICATION
which are available in most public and university libraries, as well as through on-line databases (the American Chemical Society, Washington, D.C. may be contacted for more details). Chemicals that are known but not commercially available in catalogs may be prepared by custom chemical synthesis houses, where many of the standard chemical supply houses (e.g., those listed above) provide custom synthesis services.
"Prodrugs" is meant to indicate a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound of the invention. Thus, the term "prodrug" refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need thereof, but is converted in vivo to an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to yield the parent compound of the invention, for example, by hydrolysis in blood. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., "Pro-drugs as Novel Delivery
Systems," A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
The term "prodrug" is also meant to include any covalently bonded carriers which release the active compound of the invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of the invention may be prepared by modifying functional groups present in the compound of the invention in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound of the invention. Prodrugs include compounds of the invention wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the invention and the like. "Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
"Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution. "Pharmaceutically acceptable salt" includes both acid and base addition salts.
"Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, giycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.
"Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but ire not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, Λ/-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine.
"Therapeutically effective amount" refers to that amount of a compound of the invention which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for a disease-state characterized by thrombotic activity. The amount of a compound of the invention which constitutes a "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
"Treating" or "treatment" as used herein covers the treatment of a disease-state in a mammal, preferably a human, which disease-stated is characterized by thrombotic activity, and includes:
(i) preventing the condition from occurring in a human, in particular, when such human is predisposed to the condition but has not -yet been diagnosed as having it;
(ii) inhibiting the condition, i.e., arresting its development; or (iii) relieving the condition, i.e., causing regression of the condition.
In the above definitions, the use of parentheses in a formula is used to conserve space. Accordingly, the use of parenthesis in a formula indicates that the group enclosed within the parentheses is attached directly to the atom preceding the parenthesis. For example, the term "(carboxy)(hydroxy)alkyl" is defined as a radical of the formula -Ra(OH)-C(O)OH. This formula can be drawn as follows:
Figure imgf000017_0001
It will also be appreciated that certain compounds of the invention or pharmaceutically acceptable salts thereof, may exist in, and be isolated in, isomeric forms, including tautomeric forms, cis- or /rans-isomers. In addition, certain compounds of the invention or pharmaceutically acceptable salts thereof may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, such as (R)- or (S)-. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (R)- and (S)- isomers may be prepared using chiral synthons or chiral reagents by methods known to those of ordinary skill in the art, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. The nomenclature used herein is a modified form of the I.U.P.A.C. nomenclature system wherein the compounds of the invention are named herein as derivatives of the quinoline moiety.
Figure imgf000017_0002
is named herein as 2-[1S-(4-(methoxycarbonyl)piperazin-1-yl)carbonyl-3- carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1-carboxy)methoxyquinoline. Unless otherwise indicated, compound names are intended to include any single stereoisomer, enantiomer, racemate or mixtures thereof.
Utility of the Compounds of the Invention
The compounds of the invention act as reversible, selective antagonists of the platelet ADP receptor, P2YAC. Accordingly, the compounds are useful in treating disease-states which are characterized as having thrombotic activity. In particular, the compounds are useful as inhibitors of platelet activation, aggregation and degranulation, anti-thrombotic agents or in the treatment or prophylaxis of unstable angina, coronary angioplasty (PTCA), myocardial infarction, perithrombolysis, primary arterial thrombotic I complications of atherosclerosis such as thrombotic or embolic stroke, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic disease such as angioplasty, endarterectomy, stent placement, coronary and other vascular graft surgery, thrombotic complications of surgical or mechanical damage such as tissue salvage following accidental or surgical trauma, reconstructive surgery including skin and muscle flaps, conditions with a diffuse thrombotic/platelet consumption component such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, thrombotic complications of septicernia, adult respiratory distress syndrome, anti-phospholipid syndrome, heparin-induced thrombocytopaenia and pre-eclampsia/eclampsia, or venous thrombosis such as deep vein thrombosis, venoocclusive disease, hematological conditions such as myeloproliferative disease, including thrombocythemia; or in the prevention of mechanically-induced platelet activation in vivo, such as cardiopulmonary bypass (prevention of microthromboembolism), mechanically- induced platelet activation in vitro, such as use in the preservation of blood products, e.g. platelet concentrates, or shunt occlusion such as in renal dialysis and plasmapheresis, thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and organ graft rejection, conditions such as migraine, Raynaud's phenomenon, atheromatous plaque formation/progression, vascular stenosis/restenosis and asthma, in which platelet-derived factors are implicated in the disease process.
The compounds of formula (I) are also useful as standard or reference compounds, for example, as a quality standard or control, in tests or assays involving the inhibition of the platelet ADP receptor, P2YAC. Such compounds may be provided in a commercial kit, for — example, for use in pharmaceutical research involving the platelet ADP- receptor, P2YAC. For_ example, a compound of formula (I) could be used as a reference in an assay to compare its known activity to a compound with an unknown activity. This would ensure that the experimenter that the assay was being performed properly and provide a basis for comparison, especially if the test compound was a derivative of the reference compound. When developing new assays or protocols, compounds of formula (I) could be used to test their effectiveness.
Testing of the Compounds of the Invention
The ability of the compounds to inhibit the platelet adenosine diphosphate receptor known as the P2YAC receptor, and its biological effects may be tested in a variety of in vitro , ex vivo and in vivo assays. For example, the ability of the compounds to bind to the P2YAC receptor may be measured by methods similar to those described in Gachet, C. et al., Br. J. Haemotol. (1995), Vol. 91, pp. 434-444 and Mills, D.C.B., Thromb. Haemost. (1996), Vol. 76, No. 6, pp. 835-856, and by the method described below in Example 4. The ability of the compounds to inhibit ADP-induced aggregation of platelets may be measured by methods similar to those described in R.G. Humphries, Br. J. Pharm. (1995), Vol. 115, pp. 1110-1116 and Methods in Enzymology, Vol. 169, p. 3 and by the method described below in Example 5. The ability of the compounds to inhibit thrombus formation in vivo or ex vivo may be measured by methods similar to those described in J.M. Herbert, Cardiovasc. Drug Reviews (1993), Vol. 11, No. 2, pp. 180-198 or J.D. Folts, Circulation (1976), Vol. 54, No. 3, p. 365, or by the methods described below in Example 6. The results of these assays clearly demonstrate that the compounds of the invention are functional antagonists of the platelet adenosine diphosphate receptor and are thereful useful in inhibiting platelet aggregation and thrombus formation.
Administration of the Compounds of the Invention Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally, topically, transdermally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Generally, depending on the intended mode of administrationτthe pharmaceutically ~ acceptable compositions will contain about 1 % to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. Preferably, the composition will be about 5% to 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical exdpients. The preferred route of administration is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of severity of the disease-state to be treated. For such oral administration, a pharmaceutically acceptable composition containing a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, is formed by the incorporation of any of the normally employed exdpients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharine, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
Preferably such compositions will take the form of capsule, caplet or tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.
The compounds of the invention, or their pharmaceutically acceptable salts, may also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).
Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a compound(s) of the invention (about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, ' butylated hydroxytoluene, etc.
Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pennsylvania, 1990). The composition to be administered will, in -any-event, contain-a therapeutically effective amount of a ompound of theτnvention, or a _ - pharmaceutically acceptable salt thereof, for treatment of a disease-state characterized by thrombotic activity in accordance with the teachings of this invention.
The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease-states; and the host undergoing therapy. Generally, a therapeutically effective daily dose is from about 0.14 mg to about 14.3 mg/kg of body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof; preferably, from about 0.7 mg to about 10 mg/kg of body weight per day; and most preferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day. For example, for administration to a 70 kg person, the dosage range would be from about 10 mg to about 1.0 gram per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably from about 50 mg to about 700 mg per day, and most preferably from about 100 mg to about 500 mg per day.
Preferred Embodiments
Of the compounds of the invention as set forth above in the Summary of the Invention, several groups of compounds are particularly preferred.
Of the compounds of formula (I) as set forth above in the Summary of the Invention, a preferred group of compounds is that group of compounds wherein: m is 1; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R3 is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2,
-R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R8-N(R7)C(O)OR9; each R4 is is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; R5 is hydrogen; -R- is hydrogen or alkyl; — - — each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and R9 is hydrogen, alkyl, aralkyl or haloalkyl.
Of this preferred group of compounds, a preferred subgroup of compounds is that subgroup of compounds wherein: m is 1 ; n is 1 or 2;
R1 is hydrogen or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R3 is aryl optionally substituted by one or more substituents selected from the group consisting of carboxy or alkoxycarbonyl; each R4 is is independently selected from the group consisting of hydrogen, alkyl, halo, or haloalkyl; R5 is hydrogen; and R6 is hydrogen. Of this preferred subgroup of compounds, a preferred compound is 2-[1 S-(4-
(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- carboxy)phenylquinoline in trifluoroacetic acid.
Another preferred group of compounds of formula (I) is that group of compounds wherein: m is 1 ; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R3 is aryloxy optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7,
-R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9,
-R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; R5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl; ^
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and
R9 is hydrogen, alkyl, aralkyl or haloalkyl.
Of this preferred group of compounds, a preferred subgroup of compounds is that subgroup of compounds wherein: m is 1 ; n is 1 or 2;
R1 is hydrogen or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R3 is aryloxy optionally substituted by one or more substituents selected from the group consisting of alkyl, tetrazolyl, -R8-C(O)OR7, -R8-N(R7)2, -R8-N(R7)-S(O)2-R7, and
-R8-C[N(R7)2]-C(O)OR7; each R4 is is independently selected from the group consisting of hydrogen, alkyl, halo, or haloalkyl; R5 is hydrogen; R6 is hydrogen; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and each R8 is a bond or a straight or branched alkylene chain.
Of this preferred subgroup of compounds, preferred compounds are selected from the group consisting of the following:
2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1 ,1-ethanediol; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1,1-ethanediol; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-amino-5- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1,1-ethanediol; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(4- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1,1-ethanediol; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- carboxymethy phenoxyquinoline in trifluoroacetic acid;
2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(1 - amino-1-carboxy)methyl)phenoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(2- amino-2-carboxy)ethyl)phenoxyquinoline in trifluoroacetic acid; -2-[1-S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-methyl- -
5-carboxy)phenoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yI)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5-carboxy-
2-diethylaminomethyl)phenoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyI)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-tetrazol-
5-yl)phenoxyquinoline in 2,2,2-trifluoro-1 ,1-ethanediol; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- trifluoromethylsulfonylamino)phenoxyquinoline in trifluoroacetic acid; and 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-
(3-carboxy)phenoxyquinoline in trifluoroacetic acid.
Another preferred group of compounds of formula (I) is that group of compounds wherein: m is 1 ; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R3 is aralkyl wherein the alkyl radical in the aralkyl substituent i optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7,
-R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and
-R9-N(R7)C(O)OR9), and wherein the aryl radical in the aralkyl substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7,
-R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9,
-R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; R5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and R9 is hydrogen, alkyl, aralkyl or haloalkyl. Another preferred-group of compounds-of formula (I) is-that group of compounds — wherein: m is 1; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R3 is aralkoxy wherein the alkyl radical in the aralkyl substituent is not optionally substituted and wherein the aryl radical in the aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;
R5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl; R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and R9 is hydrogen, alkyl, aralkyl or haloalkyl.
' Of this preferred group of compounds, a preferred subgroup of compounds is that subgroup of compounds wherein: m is 1; n is 1 or 2;
R is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R3 is aralkoxy wherein the aryl radical in the aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, and -R8-N(R7)2; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, or haloalkyl; R5 is hydrogen; R6 is hydrogen; each R7-is hydrogenralkyl, aryl,-aralkyl, or haloalkyl and - - — each R8 is a bond or a straight or branched alkylene chain. Of this preferred subgroup of compounds, preferred compounds are selected from the group consisting of the following:
2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-benzyloxyquinoline; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4- benzyloxyquinoline;
2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4- benzyloxyquinoline; 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4- benzyloxy-8-methoxyquinoline; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxy-
8-methoxyquinoline; 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4- methoxycarbonyl)benzyloxyquinoline; 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4- carboxy)benzyloxyquinoline;
2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3- methoxycarbonyl)benzyloxyquinoline; 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3- carboxy)benzyloxyquinoline; 2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-(1,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-4-benzyloxyquinoline; and 2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4- benzyloxyquinoline.
Another preferred group of compounds of formula (I) is that group of compounds wherein: m is 1; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R3 is aralkoxy wherein the alkyl radical in the aralkoxy substituent is substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7,
-R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and
-R9-N(R7)C(O)OR9), and wherein the aryl radical in the aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl,-cyano,-nitro, tetrazolyl, .R 0R7,^R1-C(0)0R!,_-R8-C(Q)N(R!)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and
-R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, 5 aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbony()amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; R5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, 10 alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and R9 is hydrogen, alkyl, aralkyl or haloalkyl. 15 Of this preferred group of compounds, a preferred subgroup of compounds is that subgroup of compounds wherein: m is 1 ; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl; 20 R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is aralkoxy wherein the alkyl radical in the aralkoxy substituent is substituted by
-R8-C(O)OR7, and wherein the aryl radical in the aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo and
-R8-OR7; 25 each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino; R5 is hydrogen; '
R6 is hydrogen; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and 30 each R8 is a bond or a straight or branched alkylene chain.
Of this preferred subgroup of compounds, preferred compounds are selected from the group consisting of the following: 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1 ,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(1 -phenyl-1 - -35- -methoxycarbonyl)methoxyquinoline; - - - — — — _ __ _ _ __ -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1-phenyl-
1-methoxycarbonyl)methoxyquinoline; -[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1 -phenyl-
1-carboxy)methoxyquinoline; -[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-
(1 -phenyl-1 -carboxy)methoxyquinoline; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(1- carboxy-1 -phenyl)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1-naphth-1-yl-1-carboxy)methoxyquinoline; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8- fluoro-4-(1-methoxycarbonyl-1-phenyl)methoxyquinoline in acetic acid; -[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8- fluoro-4-(1 -carboxy-1 -phenyl)methoxyquinoline in acetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -(2-fluoro)phenyl)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4- (1 -ethoxycarbonyl- 1 -phenyl)methoxyquinoline in trifluoroacetic acid; -[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-6-fluoro-7-methyl-4-(1- phenyl-1-carboxy)methoxyquinoline; - 1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -(4-chloro)phenyl)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -(3-methoxy)phenyl)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6,8-difluoro-
4-(1 -carboxy-1 -phenyl)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6- dimethylamino-4-(1 -phenyl-1 -carboxy)methoxyquinoline; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-6- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- chloro-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(1 , 1 -dimethylethoxycarbonyl)piperazin-1 -yl)carbonyl-3- methoxycarbonylpropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1- carboxy)methoxyquinoline; -[1 S-(4-(1 , 1 -dimethylethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl- 6-fluoro-7-methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline; -[1S-(4-(methoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; -[1 S-(4-(1 , 1 -dimethylethylaminocarbonyl)piperazin-1 -yl)carbonyl-3- carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1 -phenyl-1 - carboxy)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(furan-2-ylcarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; -[1 S-(4-(3-methylphenyl)piperazin-1 -yl)carbonyl-3-(1 , 1 - dimethylethoxycarbonyl)propyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1- carboxy)methoxyquinoline; -[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(phenyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-
6-fluoro-7-methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline; and 2-[1 S-(4-(phenyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-
(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid.
Of the compounds of formula (II) as set forth above in the Summary of the Invention, a preferred group of compounds is that group of compounds wherein: m is 1; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, and -R8-N(R7)2; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino; R5 is hydrogen; R6 is hydrogen; each R7 is~hydrogen alkylraryl,-aralkyl, or haloalkyl; and each R8 is a bond or a straight or branched alkylene chain. Of this preferred group of compounds, a preferred compound is 2-[1 S-(4- (ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1, 2,3,4- tetrahydroisoquinolin-2-yl)quinoline in trifluoroacetic acid.
Another preferred group of compounds of formula (II) is that group of compounds wherein: m is 1; n is 1 or 2;
R is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl; R3 is heteroarylalkoxy, wherein the alkoxy radical in the heteroarylalkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo and -R8-C(O)OR7, and wherein the heteroaryl radical in the heteroarylalkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, and -R8-N(R7)2; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino; R5 is hydrogen; R6 is hydrogen; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and each R8 is a bond or a straight or branched alkylene chain.
Of this preferred group of compounds, preferred compounds are selected from the group consisting of the following:
2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5- methylisoxaxol-3-yl)methoxyquinoline in trifluoroacetic acid;
2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2- methylthiazol-4-yl)methoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-methoxycarbonylpropyl]aminocarbonyl-4-(1 - phenyl-1 -ethoxycarbonyl-1 -chloro)methoxyquinoline; 2-[1 -(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -thien-3-yl)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-7- methyl-4-(5-methylisoxazol-3-yl)methbxyquinoline; and 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-7- methyl-4-(2-methylthiazol-4-yl)methoxyquinoline in rifluoroacetic acid. ._ Preparation of the Compounds of the Invention
The compounds of the invention are prepared according to the methods described below in the following Reaction Schemes. It is understood that those compounds of the invention which are not specifically prepared in the following Reaction Schemes may be prepared by similar synthetic processes with the appropriately substituted starting materials and reagents. It is also understood that during the preparation of the compounds of the invention, as described below, additional reactive groups (for example, hydroxy, amino or carboxy groups) on the intermediate compounds utilized in the preparation may be protected as needed by the appropriate protecting group by treating the intermediate compound prior to the desired reaction with the appropriate protecting group precursor by methods known to those of ordinary skill in the art. The protecting groups may then be removed as desired by methods known to those of ordinary skill in the art, for example, by acidic or basic hydrolysis. Such protecting groups and methods are described in detail in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis, 2nd Edition, 1991, John Wiley & Sons. Preferred nitrogen-protecting groups are "Boc" (f-butoxycarbonyl) and "CBZ" (benzyloxycarbonyl).
It will also be appreciated by those skilled in the art, although such protected derivatives of compounds of the invention as described above in the Summary of the Invention, may not possess pharmacological activity as such, they may be administered to a mammal having a disease-state characterized by thrombotic activity and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All prodrugs of compounds of the invention are included within the scope of the invention.
It is understood that in the following description, combinations of substituents and/or variables of the depicted formulae are permissible only if such conbinations result in stable compounds which can be isolated by methods known to those of ordinary skill in the art. Transient compounds are indicated by brackets.
For purposes of convenience, the preparation of compounds of formula (I) (where R3 is aryl, aralkyl, aryloxy or aralkoxy) are only described below. However, one of ordinary skill in the art would understand that in order to prepare the corresponding compounds of formula (II), all that one would need to do is replace the pertinent intermediates (such as compounds of formula (J)) with the appropriate compound (such as compounds of formula (J) where R3a is heteroarylalkyl) and to adjust the experimental parameters accordingly.
Ar Preparation of Compounds-of-formula (D) MISSING UPON TIME OF PUBLICATION
,1a which can then be treated to standard deprotecting procedures to remove the R nitrogen protecting group prior to being reacted with the compound of formula (B) to form compounds of formula (C) and (D) wherein R1 is as described above in the Summary of the Invention.
B. Preparation of Compounds of formula (H)
Compounds of formula (H) are intermediates in the preparation of compounds of formula (I) and are prepared as described below in Reaction Scheme 2a wherein n is as described as above in the Summary of the Invention; R4is as described above in the Summary of the Invention; and R10 is alkyl or aralkyl:
REACTION SCHEME 2a
R
Figure imgf000033_0001
Compounds of formulae (E), and (F) are commercially available, for example, from Aldrich, or may be prepared according to methods known to those of ordinary skill in the art. Compounds of formula (G) and formula (H) may alternatively be prepared by methods disclosed in Great Britain Patent No. 1 ,334,705.
In general, compounds of formula (H) are prepared by first treating a compound of formula (F) in a protic solvent, such as methanol, with an equimolar amount of a compound of formula (E) with stirring at ambient temperature for about 30 minutes to about an hour, preferably for about 30 minutes. The solvent is removed by evaporation to form a residue. To an aprotic polar solvent, such as diphenyl ether, heated to between about 200°C and about 250°C, preferably to about 250°C is then added the residue and the temperature of the reaction mixture is maintained at the high temperature for about 30 minutes to an hour, " preferably fδfabδϋt 30 mirTutesTat whicfrpoint the" reaction mixture is allowed to cool to- ambient temperature. The resulting precipitate is collected and washed with a aprotic polar MISSING UPON TIME OF PUBLICATION
REACTION SCHEME 2b
Figure imgf000035_0001
(Fa) (Fb)
Figure imgf000035_0002
(Gb)
Compounds of formula (Fa) and formula (E) are commercially available, or can prepared according to methods known to those of ordinary skill in the art.
In general, compounds of formula (Gb) are prepared by first treating a compound of formula (Fa) with a reducing agent, such as tin (II) chloride dihydrate, under standard chemical reduction conditions, such as in a protic solvent, to form the compound of formula (Fb), which is isolated from the reaction mixture by standard isolation techniques. The compound of formula (Fb) in a protic solvent, such as methanol, is then treated with a slightly excess molar amount of a compound of formula (E) at reflux temperatures for about 2 to about 4 hours, preferably for about 4 hours. The reaction mixture is then concentrated. An organic solvent is heated to a non-boiling point temperature of between about 240°C and about 260°C, and the concentrate is then added to the solvent. The temperature of the mixture is maintained at the non-boiling point temperature for about 10 to 20 minutes, preferably for about 20 minutes. The reaction mixture is then cooled slowly to ambient temperature and diluted with an organic solvent. The compound of formula (Ga) is isolated from the reaction mixture by standard isolation techniques, such as filtration. The compound of formula (Ga) is treated with a hydrolyzing agent under standard hydrolysis conditions and then treated under standard reducing conditions, such as hydrogen gas and palladium over carbon, to form a compound of formula (Gb).
Compounds of formula (Gb) may then be used instead of compounds of formula (H) in subsequent Reaction Schemes to prepare compounds of the invention.
C. Preparation of Compounds of Formula (la)
Compounds of formula (la) are compound of the invention and are prepared as described below in Reaction Scheme 3 wherein m, n, R1, R2, R4, R5, and R6 are as defined above in the Summary of the Invention, R3a is aryl or aralkyl, and X is halo:
REACTION SCHEME 3
Figure imgf000036_0001
Compounds of formulae (D) and (H) are prepared by methods disclosed herein. Compounds of formula (J) are commercially available, for example, from Aldrich Co., or can be prepared according to methods known to one of ordinary skill in the art.
In general, compounds of formula (la) are prepared by first treating a compound of formula (H) under standard Williamson synthesis conditions, such as in the presence of a base in an aprotic solvent, for example, cesium carbonate in Λ,Λ-dimethylformamide ("DMF"), with an equimolar amount of a compound of formula (J) at temperatures between about ambient temperature and about 100°C. The reaction mixture is stirred from about 2 hours to about 10 hours, preferably for about 10 hours, to yield the compound of formula (K), which is then treated under standard hydrolysis conditions to yield the compound of formula (L).
The compound of formula (L) in an aprotic solvent mixture, for example, methylene chloride and DMF or methylene chloride and triethylamine, is then treated with a slightly excess molar amount of a peptide coupling reaction additive, such as 1-hydroxybenzotriazole ("HOBT") and a slightly excess molar amount a coupling agent for amide formation, such as 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide ("EDCI") at ambient temperature. An equimolar amount of a compound of formula (D) in an aprotic solvent, such as methylene chloride, is then added to the reaction mixture. The reaction mixture is stirred at ambient temperature for about 4 to about 12 hours, preferably for about 12 hours. The compound of formula (la) is then isolated from the reaction mixture by standard isolation techniques, such as evaporation of the solvents, extraction and concentration.
If desired, compounds of formula (la) may be deprotected to yield the corresponding free acid or free amine derivatives. Furthermore, compounds of formula (la) wherein R1 is a nitrogen-protecting group, such as an alkyl carbonyl, can be hydrolyzed under standard acid hydrolysis conditions to yield the corresponding compound of formula (la) wherein R1 is hydrogen, which can then be treated with the appropriately substituted acid halide, carbamoyl halide or isocyanate to yield the appropriately substituted R1 compound of formula (la).
D. Preparation of Compounds of Formula (lb)
Compounds of formula (lb) are compounds of the invention and are prepared as described below in Reaction Scheme 4 wherein n, R1, R2, R4, R5 and R6 are as described above in the Summary of the Invention, R3a is aryl or aralkyl and X is halo: REACTION SCHEME 4
Figure imgf000038_0001
(D)
Figure imgf000038_0002
Compounds of formula (D) are prepared as described herein or may be prepared by methods known to one of ordinary skill in the art. Compounds of formula (H) are prepared as described herein or may be prepared by methods known to one of ordinary skill in the art, such as those found in Great Britain Patent No. 1 ,334,705.
In general, compounds of formula (lb) are prepared by first treating a suspension of a compound of formula (H) in an aprotic solvent mixture, such as methylene chloride and DMF, with a slightly excess molar amount of a peptide coupling reaction additive, such as 1- hydroxybenzotriazole ("HOBT") and a slightly excess molar amount a coupling agent for amide formation, such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ("EDCI") at ambient temperature. An equimolar amount of a compound of formula (D) in an aprotic solvent, such as methylene chloride, is then added to the reaction mixture. The reaction mixture is stirred at ~ ambient temperature for a period oftime of between-about 4 hours~and about 12 hours,- preferably for a period of time of between about 6 hours and about 12 hours. The compound of formula (M) is then isolated from the reaction mixture by standard isolation techniques, such as evaporation of the solvents, extraction and concentration.
The compound of formula (M) is then treated under standard Williamson synthesis conditions, such as in the presence of base in an aprotic solvent, for example, cesium carbonate in acetonitrile:DMF, with an an equimolar amount of a compound of formula (J) at a temperature of between about ambient temperature and 100°C. The reaction mixture is stirred for a period of time of between 30 minutes and about 10 hours, preferably for abou 30 minutes. The compound of formula (lb) is then isolated from the reaction mixture by standard isolation techniques, such as organic extraction and concentration. If desired, compounds of formula (lb) can be treated under standard hydrolysis conditions to yield the corresponding free amine or acid.
E. Preparation of Compounds of Formulae (lc), (Id) and (le)
Compounds of formulae (lc), (Id) and (le) are compounds of the invention and are prepared as described below in Reaction Scheme 5 wherein m, n, R1, R2, R4, R5 and R6 are as described above in the, Summary of the Invention, X is halo, R3b is aryl or aralkyl, and R3c is heteroaryl:
REACTION SCHEME 5
Figure imgf000040_0001
(le)
Compounds of formulae (H) and (D) are prepared as described herein or can be prepared according to methods known to one of ordinary skill in the art. Compounds of formulae (P), (Q) and (R) are commercially available, for example, from Aldrich Chemical Co., or can be prepared according to methods known to one of ordinary skill in the art.
In general, compounds of formulae (lc), (Id) and (le) are prepared by first treating a compound of formula (H) with a halogenating agent, such as phosphorus pentachloride or phosphorus oxychloride, under standard halogenating conditions. The compound of formula (N) is isolated from the reaction mixture by standard isolation techniques. The compound of formula (N) is then treated with a compound of formula (D) under standard peptide coupling conditions, as described herein, to yield a compound of formula (O), which is isolated from the reaction mixture by standard isolation techniques.
The compound of formula (O) in an polar aprotic solvent, such as DMSO, in the presence of a base, such as cesium carbonate, is then treated with a compound of formula (P). The resulting reaction mixture is heated to a temperature of between about 40°C and about 60°C, preferably at about 60°C for a period of time of between about 4 hours and about 16 hours, preferably for about 16 hours. The compound of formula (lc) is then isolated from the reaction mixture by standard isolation techniques, such as filtration and purification by preparative HPLC. If desired, the compound of formula (lc) can be treated under standard hydrolysis conditions to further yield the corresponding free acid or amine.
Alternatively, a mixture of a compound of formula (O) and a compound of formula (Q) in a polar aprotic solvent, such as DMSO, is heated to a temperature of between about 80°C and 105°C, preferably to about 100°C, for a period of time of between about 6 hours and 18 hours, preferably for about 18 hours. The compound of formula (Id) is then isolated from the reaction mixture by standard isolation techniques, such as purification by reverse phase HPLC. If desired, the compound of formula (Id) can be hydrolyzed under standard hydrolysis conditions to further yield the corresponding amine or acid.
Alternatively, a compound of formula (O) is treated with a compound of formula (R) under standard boronic acid/palladium coupling conditions to yield the corresponding compound of formula (le), which is isolated from the reaction mixture by standard isolation techniques. If desired, the compound of formula (le) can be hydrolyzed under standard hydrolysis conditions to further yield the corresponding amine or acid.
Alternatively, compounds of formula (Gb) may be used in the above Reaction Schemes in place of the compounds of formula (H).
All compounds of the invention as prepared above which exist in free base or acid form may be converted to their pharmaceutically acceptable salts by treatment with the appropriate inorganic or organic base or acid. Salts of the compounds prepared above may be converted to their free base or acid form by standard techniques.
* * * * *
The following specific preparations and examples are provided as a guide to assist in the practice of the invention, and are not intended as a limitation on the scope of the invention.
PREPARATION 1 -Compounds of-formula-(D)- A. To a solution of W-benzyloxycarbonyl-L-glutamic acid H-butyl ester (24.4 g, 72.3 mmol) in tetrahydrofuran ("THF") (400 mL) and CH2CI2(100 mL) was added 1- hydroxybenzotriazole ("HOBT") (10.7 g, 79.5 mmol) and 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide ("EDCI") (15.3 g, 79.5 mmol). After 5 minutes, 1-ethoxycarbonylpiperazine (11.7 mL, 79.5 mmol) was added and the reaction was stirred overnight. The reaction mixture was evaporated in vacuo to afford an oil, which was dissolved in ethyl acetate, and washed with saturated NaHCO3, 1 M HaHSO and brine. The organic layer was evaporated in vacuo to 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (40.7 g), as an oil that was used without further purification. To 4-ethoxycarbonyl-1-(1- (benzyloxycarbonyl)amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine in MeOH (100 mL) was added 10% Pd/C (1 g) and the mixture was shaken under 50 psi H2 overnight. The reaction was filtered and stripped to 4-ethoxycarbonyl-1-(1-amino-3-(1,1- dimethylethoxycarbonyl)propyl)carbonylpiperazine (25 g, 99%) and used without further purification; NMR (CDCI3) 1.25 (t, 3), 1.43 (s, 9), 2.55 (m, 1), 1.90 (m, 1), 2.37 (m, 1), 2.55 (m, 1), 3.40-3.70 (m, 8), 3.80 (m, 1), 4.18 (q, 2) ppm. %
B. In a similar manner, other compounds of formula (D) were prepared. 4-ethoxycarbonyl-1-(aminomethyl)carbonylpiperazine;
4-ethoxycarbonyl-1 -(1 -amino-3-carboxypropyl)carbonylpiperazine;
4-ethoxycarbonyl-2-methyl-1-(aminomethyl)carbonylpiperazine; 4-ethoxycarbonyl-3-methyl-1 -(aminomethyl)carbonylpiperazine;
4-ethoxycarbonyl-1-(1-amino-5-((2-chlorobenzyloxy)carbonylamino)pentyl)carbonylpiperazine;
4-ethoxycarbonyl-1-(1-amino-2-(benzyloxycarbonyl)ethyl)carbonylpiperazine;
4-ethoxycarbonyl-1 -(1 -amino-2-phenylethyl)carbonylpiperazine;
4-ethoxycarbonyl-1 -(1 -amino-2-methylpropyl)carbonylpiperazine; 4-ethoxycarbonyl-1 -(1 -amino-2-carboxyethyl)carbonylpiperazine; and
4-ethoxycarbonyl-1-(1,5-diaminopentyl)carbonylpiperazine.
C. Alternatively, Λ/-benzyloxycarbonyl-L-glutamic acid -f-butyl ester (34 g, 100 mmol) and EDCI (22 g, 110 mmol), HOBT (15 g, 110 mmol) were combined in 800 mL CH2CI2 with triethylamine (24 mL, 172 mmol). The resulting reaction mixture was stirred at ambient temperature for 20 minutes, then 1-ethoxycarbonylpiperazine (18 g, 120 mmol) was added. The resulting mixture was stirred at ambient temperature for 15 hours. The reaction mixture was then washed with water, 2N NaHSO4, and brine, then concentrated in vacuo to afford an oil, which was purified by flash column chromatography on silica gel (acetate/hexane=1/1) to afford 4-ethoxycarbonyl-1-(1-(benzyloxycarbonyl)amino-3-(1 ,1- — dimethylethoxycarbonyl)propyl)carbonylpiperazine (40 g). _4-ethoxycarbonyl-1-(-1~
(benzyloxycarbonyl)amino-3-(1 ,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (40g) was dissolved in 200 mL of MeOH, 2 g Pd/C(10%) was added and hydrogenated at 50 psi for 1 hour. Regular work up afforded 4-ethoxycarbonyl-1-(1-amino-3-(1 ,1- dimethylethoxycarbonyl)propyI)carbonylpiperazine (25 g).
PREPARATION 2
Compounds of formula (G)
A. To a solution of m-toludine (20.0 g, 0.186 mol) in methanol (300 mL), dimethyl acetylenedicarboxylate (26.42 g, 0.186 mol) was added drop-wise and the reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed by evaporation and the residue was added to stirred diphenyl ether (150 ml), which has been preheated to 250°C. After 30 minutes, the mixture was cooled to ambient temperture and the resulting precipitate was collected and washed with hot petroleum ether (1.5 L) to give a mixture (27.0 g) of 5-methyl-4-hydroxy-2-methoxycarbonylquinoline and 7-methyl-4-hydroxy-2- methoxycarbonylquinoline. The mixture was dissolved in boiling methanol (1.3 L) and kept at ambient temperature for two days to afford (6.45 g, 16%) of 7-methyl-4-hydroxy-2- methoxycarbonylquinoline, NMR (DMSO-d6) 2.40 (s, 3), 3.92 (s, 3), 6.56 (s, 1), 7.16 (d, 1), 7.68 (s, 1), 7.94 (d, 1) ppm.
B. In a similar manner, other compounds of formula (G) were prepared as follows: 8-methoxy-4-hydroxy-2-methoxycarbonylquinoline; 5-amino-4-hydroxy-2-methoxycarbonylquinoline;
5-nitro-4-hydroxy-2-methoxycarbonylquinoline;
5-carboxymethylamino-4-hydroxy-2-methoxycarbonylquinoline;
7-chloro-4-hydroxy-2-methoxycarbonylquinoline;
5-di(acetyl)amino-4-hydroxy-2-methoxycarbonylquinoline; 5-acetylamino-4-hydroxy-2-methoxycarbonylquinoline;
5,7-dichloro-4-hydroxy-2-methoxycarbonylquinoline;
6-chloro-4-hydroxy-2-methoxycarbonylquinoline;
6-nitro-4-hydroxy-2-methoxycarbonylquinoline;
6-amino-4-hydroxy-2-methoxycarbonylquinoline; 7-benzyloxy-4-hydroxy-2-methoxycarbonylquinoline;
4,7-dihydroxy-2-methoxycarbonylquinoline;
7-prop-1-oxy-4-hydroxy-2-methoxycarbonylquinoline;
7-carboxymethoxy-4-hydroxy-2-methoxycarbonylquinoline;
7-diethylaminoethoxy-4-hydroxy-2-methoxycarbonylquinoline; -7-methoxy-4-hydroxy-2-methoxycarbonylquinoline; -
7-(2-(4-hydroxy-2-carboxypyrrolidinyl)ethoxy)-4-hydroxy-2-methoxycarbonylquinoline; -methyl-4-hydroxy-2-methoxycarbonylquinoline; -diethylaminomethyl-4-hydroxy-2-methoxycarbonylquinoline; -benzyloxy-4-hydroxy-2-methoxycarbonylquinoline; ,6-dihydoxy-2-methoxycarbonyIquinoline; -carboxymethoxy-4-hydroxy-2-methoxycarbonylquinoline; -ethoxy-4-hydroxy-2-methoxycarbonylquinoline; -methoxy-4-hydroxy-2-methoxycarbonylquinoline; -prop-2-oxy-4-hydroxy-2-methoxycarbonylquinoline; -fluoro-4-hydroxy-2-methoxycarbonylquinoline; -trifluoromethyl-4-hydroxy-2-methoxycarbonylquinoline; -hydroxymethyl-4-hydroxy-2-methoxycarbonylquinoline; -cyano-4-hydroxy-2-methoxycarbonylquinoline; -nitro-4-hydroxy-2-methoxycarbonylquinoline; -carboxy-4-hydroxy-2-methoxycarbonylquinoline; -trifluoromethoxy-4-hydroxy-2-methoxycarbonylquinoline; -trifluoromethoxy-4-hydroxy-2-methoxycarbonylquinoline; -acetyl-4-hydroxy-2-methoxycarbonylquinoline; -ethoxycarbonyl-4-hydroxy-2-methoxycarbonylquinoline; -ethyl-4-hydroxy-2-methoxycarbonylquinoline; -carboxy-4-hydroxy-2-methoxycarbonylquinoline; -aminocarbonyl-4-hydroxy-2-methoxycarbonylquinoline; ,7-dimethoxy-4-hydroxy-2-methoxycarbonylquinoline; -chloro-7-methyl-4-hydroxy-2-methoxycarbonylquinoline; -fluoro-7-methyl-4-hydroxy-2-methoxycarbonylquinoline; -fluoro-4-hydroxy-2-methoxycarbonylquinoline; -fluoro-7-chloro-4-hydroxy-2-methoxycarbonylquiήoline; -bromo-4-hydroxy-2-methoxycarbonylquinoline; ,7-dimethyl-4-hydroxy-2-methoxycarbonylquinoline; -methoxy-7-methyl-4-hydroxy-2-methoxycarbonylquinoline; -methoxy-7-chloro-4-hydroxy-2-methoxycarbonylquinoline; -chloro-8-fluoro-4-hydroxy-2-methoxycarbonylquinoline; ,7-dichloro-4-hydroxy-2-methoxycarbonylquinoline; ,8-difluoro-4-hydroxy-2-methoxycarbonylquinoline; ,7-difluoro-4-hydroxy-2-methoxycarbonylquinoline; -dimethylamino-4-hydroxy-2-methoxycarbonylquinoline; -fluoro-6-methyl-4-hydroxy-2-methoxycarbonylquinoline; 6-methyl-7-chloro-4-hydroxy-2-methoxycarbonylquinoiine;
6-acetyl-4-hydroxy-2-methoxycarbonylquinoline;
6-methylthio-4-hydroxy-2-methoxycarbonylquinoline;
4,5-dihydroxy-2-methoxycarbonylquinoline;
7-ethyl-4-hydroxy-2-methoxycarbonylquinoline;
5-methyl-4-hydroxy-2-methoxycarbonylquinoline;
5-hydroxymethoxy-4-hydroxy-2-methoxycarbonylquinoline;
5-(3-ethoxycarbonylpropoxy)-4-hydroxy-2-methoxycarbonylquinoline; and
5-(3-carboxypropoxy)-4-hydroxy-2-methoxycarbonylquinoline.
PREPARATION 3 Compounds of Formula (H)
A. 7-methyl-4-hydroxy-2-methoxycarbonylquinoline (6.45 g, 30.14 mmol) was suspended in MeOH (150 mL) and water (100 mL), and LiOH (3.08 g, 75.5 mmol) was added and stirred at ambient temperature for 2 hours. The methanol was evaporated in vacuo and residue was crystallized by addition of 2N hydrochloric acid. The resulting solid was filtered, washed with water and dried to afford 7-methyl-4-hydroxy-2-carboxyquinoline (6.0 g, 98%), NMR (DMSO-d6) 2.40 (s, 3), 6.68 (s, 1), 7.22 (d, 1), 7.68 (s, 1), 7.96 (d, 1).
B. In a similar manner, the following compounds of formula (H) were prepared: 8-methoxy-4-hydroxy-2-carboxyquinoline;
5-amino-4-hydroxy-2-carboxyquinoline;
5-nitro-4-hydroxy-2-carboxyquinoline;
5-carboxymethylamino-4-hydroxy-2-carboxyquinoline;
7-chloro-4-hydroxy-2-carboxyquinoline; 5-di(acetyl)amino-4-hydroxy-2-carboxyquinoline;
5-acetylamino-4-hydroxy-2-carboxyquinoline;
5,7-dichloro-4-hydroxy-2-carboxyquinoline;
6-chloro-4-hydroxy-2-carboxyquinoline;
6-nitro-4-hydroxy-2-carboxyquinoline; 6-amino-4-hydroxy-2-carboxyquinoline;
7-benzyloxy-4-hydroxy-2-carboxyquinoline;
4,7-dihydroxy-2-carboxyquinoline;
7-prop-1-oxy-4-hydroxy-2-carboxyquinoline;
7-carboxymethoxy-4-hydroxy-2-carboxyquinoline; 7-diethylaminoethoxy-4~-hydroxy-2-carboxyquinoline;
7-methoxy-4-hydroxy-2-carboxyquinoline; 7-(2-(4-hydroxy-2-carboxypyrrolidinyl)ethoxy)-4-hydroxy-2-carboxyquinoline;
8-methyl-4-hydroxy-2-carboxyquinoline;
6-diethylaminomethyl-4-hydroxy-2-carboxyquinoline;
3-methyl-4-hydroxy-2-carboxyquinoline; 6-benzyloxy-4-hydroxy-2-carboxyquinoline;
4,6-dihydoxy-2-carboxyquinoline;
6-carboxymethoxy-4-hydroxy-2-carboxyquinoline;
6-ethoxy-4-hydroxy-2-carboxyquinoline;
6-methoxy-4-hydroxy-2-carboxyquinoline; 6-prop-2-oxy-4-hydroxy-2-carboxyquinoline;
7-fluoro-4-hydroxy-2-carboxyquinoline;
7-trifluoromethyl-4-hydroxy-2-carboxyquinoline;
7-hydroxymethyl-4-hydroxy-2-carboxyquinoline;
7-cyano-4-hydroxy-2-carboxyquinoline; 7-nitro-4-hydroxy-2-carboxyquinoline;
2,6-dicarboxy-4-hydroxyquinoline;
7-trifluoromethoxy-4-hydroxy-2-carboxyquinoline;
6-trifluoromethoxy-4-hydroxy-2-carboxyquinoline;
7-acetyl-4-hydroxy-2-carboxyquinoline; 5-ethoxycarbonyl-4-hydroxy-2-carboxyquinoline;
6-ethyl-4-hydroxy-2-carboxyquinoline;
2,7-dicarboxy-4-hydroxyquinoline;
6-aminocarbonyl-4-hydroxy-2-carboxyquinoline;
6,7-dimethoxy-4-hydroxy-2-carboxyquinoline; 6-methyl-7-chloro-4-hydroxy-2-carboxyquinoline;
6-chloro-7-methyl-4-hydroxy-2-carboxyquinoline;
6-fluoro-7-methyl-4-hydroxy-2-carboxyquinoline;
6-fluoro-4-hydroxy-2-carboxyquinoline;
6-fluoro-7-chloro-4-hydroxy-2-carboxyquinoline; 7-bromo-4-hydroxy-2-carboxyquinoline;
6,7-dimethyl-4-hydroxy-2-carboxyquinoline;
6-methoxy-7-methyl-4-hydroxy-2-carboxyquinoline;
6-methoxy-7-chloro-4-hydroxy-2-carboxyquinoline;
6-chloro-8-fluoro-4-hydroxy-2-carboxyquinoline; -6,7--dichloro=4τhy.droxy-2 carboxyquinoline;_
6,8-difluoro-4-hydroxy-2-carboxyquinoline; 6,7-difluoro-4-hydroxy-2-carboxyquinoline; 6-dimethylamino-4-hydroxy-2-carboxyquinoIine; 5-fluoro-6-methyl-4-hydroxy-2-carboxyquinoline; 6-acetyl-4-hydroxy-2-carboxyquinoline; 6-methylthio-4-hydroxy-2-carboxyquinoline; 4,5-dihydroxy-2-carboxyquinoline; 5-hydroxymethoxy-4-hydroxy-2-carboxyquinoline; 7-methyl-4-hydroxy-2-carboxyquinoline; 5-methyl-4-hydroxy-2-carboxyquinoline; 5-(3-ethoxycarbonylpropoxy)-4-hydroxy-2-carboxyquinoline; and 5-(3-carboxypropoxy)-4-hydroxy-2-carboxyquinoline.
PREPARATION 4 Compounds of formulae (Fb), (Ga) and (Gb) A. To a solution of SnCI2.H2O (140 g, 0.62 mol) in ethanol (350 mL) was added a solution of 2,6-dichloro-3-nitrotoluene (25 g, 0.12 mol) in ethanol (50 mL). The reaction mixture was refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water (100 mL), pH was adjusted to approximately pH 12 with 1N NaOH solution and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over sodium sulfate, and concentrated to afford 2,6-dichloro-3-aminotoluene (21 g, 98%); NMR (CDCI3) 2.42 (s, 3), 6.62 (d, 1), 7.14 (d, 1) ppm.
B. To a solution of 2,6-dichloro-3-aminotoluene (20.5 g, 0.11 mol) in methanol (300 mL) was added dimethyl acetylenedicarboxylate (15 mL, 0.12 mol) and the reaction mixture was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure to a yellow solid. Diphenyl ether (350 mL) was heated to 230-240°C, and the yellow solid was added to it. The temperature was maintained at 230-240°C for 20 minutes and the reaction mixture was cooled slowly to ambient temperature and diluted with petroleum ether (1L). The solid was filtered and washed with hot ethyl acetate to afford a brown solid, 2- (methoxycarbonyl)-4-oxo-6,8-dichloro-7-methylquinoline (28.5 g, 85%); NMR (CDCI3) 2.62 (s, 3), 4.04 (s, 3), 7.02 (s, 1 ), 8.24 (s, 1 ) ppm.
C. 2-(Methoxycarbonyl)-4-oxo-6,8-dichloro-7-methylquinoline (28.5 g, 99.6 mmol) was suspended in methanol (1 L) and a solution of LiOH.H2O (20.5 g, 0.5 mol) in water (200 mL) was added to the solution. The resulting reaction mixture was stirred at ambient temperature for 0.5 hours. Pd/C (5.8 g) was added to the reaction mixture and the resulting reaction mixture-was-shaken-under 50 Psi hydrogen overnight.^The reaction-mixture-was- filtered, concentrated under reduced pressure to remove methanol, diluted with water (300 mL) and the pH was adjusted to between pH 3 and pH 4 by 2N HCl. The precipitate was collected by filtration, washed with water and dried to afford a white solid, 2-carboxy-4-oxo-7- methylquinoline (20 g, 90%); NMR (DMSO-d6) 2.40 (s, 3), 6.60 (s, 1), 7.20 (d, 1), 7.68 (s, 1), 7.96 (d, 1) ppm. D. Alternatively, to a solution of 4-chloro-3-methyl aniline (20.0 g, 0.141 mol) in
MeOH (400 mL) was added drop-wise dimethyl acetylenedicarboxylate (21.07 g, 0.148 mol). The reaction mixture was stirred at ambient temperature for 30 minutes. The solvent was removed by evaporation and the residue was added to stirred diphenyl ether (300 mL), which has been preheated to 250°C. After 30 minutes, the mixture was cooled to ambient temperature and the resulting precipitate was collected and washed with 1L of hot petroleum ether to give a mixture (29.0 g) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline and 2- methoxycarbonyl-6-chloro-5-methyl-4-oxoquinoline as a gray solid. The mixture was dissolved in boiling methanol (1 L) and filtered hot. The collected solids were boiled in 1.2 L of methanol and filtered hot to afford (6.45 g, 16%) of 2-methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoline: 1H NMR (DMSO-d6) 2.41 (s, 3), 3.92 (s, 3), 6.58 (s, 1), 7.86 (s, 1), 7.96(s, 1) ppm.
E. 2-Methoxycarbonyl-6-chloro-7-methyl-4-oxoquinoiine (7.00 g, 28.00 mmol) was suspended in 300 mL of MeOH and 100 mL of water. Lithium hydroxide (3.40 g, 90 mmol) was added and the reaction was stirred at room temp for 2 hours. The methanol was evaporated in vacuo and the product was crystallized by addition of 2N hydrochloric acid. The solid was filtered, washed with water and dried to afford 5.9 g (88%) of 2-carboxy-6-chloro-7-methyl-4- oxoquinoline: H NMR (DMSO-d6) 2.40 (s, 3), 6.60 (s, 1), 7.84 (s, 1), 7.98 (s, 1) ppm.
PREPARATION 5 Compounds of Formulae (K) and (L) A. 2-carboxy-4-hydroxyquinoline (5 g, 1.0 eq) was dissolved in 50 mL DMF.
Cesium carbonate (20 g, 2.3 eq) was added to the solution and the resulting reaction mixture was heated at 50°C for 20 minutes. Benzyl bromide (10g, 2.1eq) was added. The resulting reaction mixture was stirred at 50°C for 1 hour. Then the reaction mixture was poured into 500 mLice-water, the precipitate was collected by filtration, and dried in vacuo to afford 2- benzyloxycarbonyl-4-benzyloxyquinoline (9.1 g). 2-benzyloxycarbonyl-4-benzyloxyquinoline (9.0 g) was dissolved in 50 mL THF, and 2 N LiOH solution (20 mL) was added, and the resulting reaction mixture was stirred at ambient temperature for 2 hours. The solvent was then removed in vacuo, and the residue acidified by the addition of 2N NaHSO4 to pH 3-4. The white precipitate was collected to afford 2-carboxy-4-benzyloxyquinoline (7.2 g), which was ™ used without furtherpurificationr
B. In a similar manner, other compounds of formula (K) and (L) were prepared. PREPARATION 6 Compounds of Formula (M)
A. To a suspension of 2-carboxy-6-chloro-7-methyl-4-oxoquinoline (7.5 g, 31.69 mmol) in dichloromethane: DMF (350 mL, 2.5:1) was added HOBT (5.13 g, 38 mmol) and EDCI (7.25 g, 38 mmol) and the reaction mixture was stirred for 10 minutes. A solution of
4-ethoxycarbonyl-1-(1-amino-3-(1 ,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (10.8 g, 31.64 mmol) in 50 mL dichloromethane was added. The reaction was stirred at ambient temperature for 6 hours. The solvent was evaporated in vacuo and the residue was partitioned in ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine and concentrated to afford an off-white foam that was purified by flash chromatography (2% methanol in dichloromethane ) to afford 2-[1 S-(4- (ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl- 7-methyl-6-chloro-4-hydroxyquinoline as a white foam, (14.4 g, 80%).
B. In a similar manner, other compounds of formula (M) were prepared. C. Alternatively, 2-carboxy-4-hydroxyoxoquinoline (640 mg, 3.2 mmol), EDCI (674 mg, 3.5 mmol), and HOBT (525 mg, 3.5 mmol) were combined in 20 mL CH2CI2 with triethylamine (0.67 mL, 4.8 mmol). The resulting reaction mixture was stirred at ambient temperature for 10 minutes, then 4-ethoxycarbonyl-1-(1-amino-3-(1,1- dimethylethoxycarbonyl)propyl)-carbonylpiperazine (1.1 g, 3.3 mmol) was added. The resulting mixture was stirred at ambient temperature for 2 hours. The reaction mixture was washed with water, 2N NaHSO4, and brine, then concentrated in vacuo to afford an oil, which was purified by flash column chromatography on silica gel to afford 2-[1S-(4-(ethoxycarbonyl)piperazin-1- yl)carbonyl-3-(1 ,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-4-hydroxyquinoline (1.28 g). D. Alternatively, to a solution of 2-carboxy-6-chloro-8-fluoro-4-hydroxyquinoline (1.0 g ,4.14 mmol) in DMF (50 mL) was added diisopropylethyl amine (3.0 eq., 2.2 L). The mixture was stirred at ambient temperature for 30 minutes. EDCI (1.2 eq., 969 mg ) and HOBT (1.1 eq., 628 mg) were added, followed by the addition of 4-ethoxycarbonyl-1-(1-amino- 3-(1 ,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (1.493 g, 1.05 eq.) and the mixture was stirred overnight at ambient temperature. The solvent, DMF, was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1 M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%-3% MeOH in CH2CI2 afforded the coupling product, 2-[1S-(4-(ethoxycarbonyl)piperazin-1- yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-6-chloro-8-fluoro-4- hydroxyquinoline in acetic acid, (2.01 g).
PREPARATION 7 Compounds of Formula (N)
A. To 20 mL POCI3 was added 2-carboxy-7-methyl-4-hydroxyquinoline (2.5 g, 12.3 mmol) and PCI5 (11.5 g, 55 mmol). The mixture was heated to 130°C for 3 hours. The reaction mixture was cooled and poured onto ice. The solution was neutralized with solid
5 NaOH and adjusted to pH 11 with solid KOH. The tan precipitate was filtered, slurried in 250 mL water and adjusted to pH 2 with concentrated HCl. The resultant solid was filtered and dried to afford 2-carboxy-7-methyl-4-chloroquinoline (1.34 g, 50%).
B. In a similar manner, other compounds of formula (N) were prepared:
10 PREPARATION S
Compounds of Formula (O)
A. A solution of 4-ethoxycarbonyl-1 -(1 -amino-3-(methoxycarbonyl)propyl)- carbonylpiperazine (0.97 g, 3.23 mmol), 4-chloro-2-carboxyquinoline (0.67 g, 3.23 mmol), EDCI (0.68 g, 3.55 mmol) and HOBT (0.48 g, 3.55 mmol) was combined in 30 mL of THF. The
15 reaction mixture was stirred overnight at ambient temperature.? The reaction was diluted with ethyl acetate and washed with water. The organic layer was concentrated to give a dark oil (0.87 g) that was purified by flash chromotography through silica gel with 2:1 ethyl acetate- hexanes to provide 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3- (methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline, (0.46 g).
20 B. A solution of 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-
(methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline (0.15 g, 0.313 mmol) was dissolved in 5 mL THF and LiOH (0.25 M, 1.9 mL, 0.47 mmol) was added. The reaction was stirred for 2 hours. The reaction was concentrated to an oil, acidified with 10% HCl, extracted into ethyl acetate, and concentrated to provide pure 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-
25 carboxypropyl]aminocarbonyl-4-chlorcquinoline (167 mg): H NMR 1.20 (t, 3), 1.90 (m, 1),
2.05 (m, 1), 2.35 (m, 2), 3.35-3.60 (m, 8), 3.65 (m, 2), 4.05 (q, 2), 5.07 (m, 1), 7.95 (m, 1), 8.02 (m, 1), 8.23 (s, 1), 8.30 (m, 1), 8.98 (m, 1) ppm.
C. Alternatively, to a solution of 2-carboxy-7-methyl-4-chloroquinoline (1.3 g, 5.9 mmol) in THF (50 mL) at 0°C was added W-methylmorpholine (1.7 mL, 14.7 mmol) followed by
30 iso-butylchioroformate (0.84 mL, 6.45 mmol). The reaction was stirred for 0.5 hours, then 4- ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (2.0 g, 5.9 mmol) was added and the reaction was warmed to ambient temperature. Aqueous work-up afforded a crude product. The sample was purified by flash chromatography through silica gel (3:2 ethyl acetate:hexanes) to afford 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-
Figure imgf000050_0001
D. In a similar manner, other compounds of formula (O) were prepared: EXAMPLE 1 Compounds of Formula (la)
A. 2-Carboxy-4-benzyloxyquinoline (800 mg, 1.0 eq) and EDCI (680 mg, 1.1 eq), HOBT (520 mg, 1.1 eq) were combined in 25 mL methylene chloride with triethylamine (1.0 mL,
3.2 eq). The resulting reaction mixture was stirred at ambient temperature for 10 minutes, and then 4-ethoxycarbonyl-1-(1-amino-3-(benzyloxycarbonyl)propyl)carbonylpiperazine was added (1.0 g, 1.25 eq). The resulting reaction mixture was stirred at ambient temperature for 12 hours. The reaction mixture was then washed with water, 2N NaHSO4, and brine, then concentrated in vacuo to afford an oil, which was purified by flash column chromatography on silica gel to afford 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4- benzyloxyquinoline (1.6 g). Then 50 mg of 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3- benzyloxycarbonylpropyl]aminocarbonyl-4-benzyloxyquinoline was dissolved in 2 mL MeOH and 1 mL water, and lithium hydroxide added (10 mg), and the resulting mixture was stirred at ambient temperature for 2 hours. Standard work-up afforded 2-[1 S-(4-
(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxyquinoline (30 mg).
B. In a similar manner, the following compounds of formula (la) were prepared: 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-benzyloxyquinoline; 2-[(4-(ethoxycarbonyl)piperazin-1 -yl)carbonylmethyl]aminocarbonyl-6-fluoro-7-methyl-4-(1 - phenyl-1 -carboxy)methoxyquinoline; 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4- benzyloxy-8-methoxyquinoline; and 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxy- 8-methoxyquinoline.
EXAMPLE 2 Compounds of Formula (lb) A. Methyl σ-bromophenylacetate (0.22 g, 1 mmol) was added to a solution of 2- [1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-(1 ,1 -dimethylethoxycarbonyl)propyl]- aminocarbonyl-7-methyl-6-chloro-4-hydroxyquinoline (0.42 g, 0.74mmol) and cesium carbonate (0.48 g, 1.48 mmol) in 10 mL CH3CN/DMF (4:1) and stirred at40°C for 30 minutes. The reaction mixture was filtered, evaporated, dissolved in ethyl acetate, washed with water, brine and concentrated to afford 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1- methoxycarbonyl)methoxyquinoline as a reddish oil (0.55 g). The crude material was carried on to the next step. B. A solution of 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-(1 , 1 - dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1- methoxycarbonyl)methoxyquinoline (0.55 g, ) in MeOH (5 mL) was saponified by reaction with LiOH (3mL, 0.25 M) for 40 minutes. The solvent was evaporated and the residue was purified
5 by preparative HPLC to afford 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-(1 , 1 - dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1- carboxy)methoxyquinoline as two pure diastereomers (A) and (B) as white solids (A 180 mg, B 190 mg): 1H NMR of B (DMSO-d6) 1.18 (t, 3), 1.20 (s, 9), 1.82 (m, 1), 2.0 (m, 1), 2.22 (m, 2), 2.54 (s, 3), 3.46 (m, 8), 4.04 (q, 2), 5.00 (m, 1), 6.38 (s, 1), 7.2 (m, 3), 7.45 (s, 1), 7.62 (m, 2), 10 8.04 (s, 1), 8.10 (s, 1), 8.86 (d, 1) ppm.
C. A solution of 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1 ,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-6-chloro-4-(1-phenyl-1- carboxy)methoxyquinoline (190 mg, 0.23 mmol) in 50% TFA-dichloromethane (6 mL) was stirred at ambient temperature for 1 hour. The solvent was evaporated and purified by
15 preparative HPLC to afford 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3- carboxypropyl]aminocarbonyl-7-methyl-6-chloro-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; as a white solid (116 mg, 66%) as a TFA salt: 1H NMR (DMSO-d6) 1.12 (t„ 3), 1.85 (m, 1), 2.05 (m, 1), 2.30 (m, 2), 2.55 (s, 3), 3.45 (m, 6), 3.65 (m, 2), 4.05 (q. 2), 5.02 (m, 1), 6.39 (s, 1), 7.45 (m, 3), 7.56 (s, 1), 7.69 (d, 2), 8.10 (s, 1), 8.20 (s, 1) 8.88 (d, 1) ppm.
20 D. Alternatively, 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-4-hydroxyquinoline (100 mg, 1.0 eq) and cesium carbonate (190 mg, 3.0 eq.) were combined in 5 mL of DMF, and methyl ff-bromophenylacetate (66 mg, 1.5 e q) was added. The resulting reaction mixture was stirred at 50°C for 1 hour. Then the mixture was poured into 50 mL ice-water, extracted with 2x50ml
25 ethyl acetate, and the organic phase was washed with 3x30ml water, and then brine. The crude product was purified by flash column chromatography (acetate/gexane = 1/1) to provide 2-[1 S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1 ,1 -dimethylethoxycarbonyl)propyl]- aminocarbonyl-4-(1 -phenyl-1 -methoxycarbonyl)methoxyquinoline (120 mg), which was dissolved in 2 mL of trifluoroacetic acid. The resulting reaction mixture was stirred at ambient
30 temperature for 20 minutes, and then concentrated in vacuo. The residual oil was dissolved in 30 mL ethyl acetate, washed with saturated NaHCO3, brine, and dried in vacuo to afford (90 mg). 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyI-3-carboxypropyl]aminocarbonyl-4-(1 - phenyl-1 -methoxycarbonyl)methoxyquinoline (60 mg) in 3 mL MeOH was added to a solution of 15 mg (3 eq.) LiOH in 2 L water. The resulting reaction mixture was stirred at ambient
• 35 — temperature-for 2
Figure imgf000052_0001
to pH 3-4 with 2 N NaHSO2, and extracted by 2X20 mL acetate to afford a white solid, 2-[1S- (4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1 -phenyl-1 - carboxy)methoxyquino!ine (40 mg).
E.. In a similar manner, the following compounds of formula (lb) were prepared: 2-[1 S-(4-(3-methylphenyI)piperazin-1-yl)carbonyl-3-(1 ,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-4-benzyloxyq uinoline;
2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4- benzyloxyquinoline; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-rηethyl-4-
(1 -phenyl-1 -carboxy)methoxyquinoline; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(1 - carboxy-1 -phenyl)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1-naphth-1-yl-1-carboxy)methoxyquinoline;
2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -(2-fluoro)phenyl)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-
(1-ethoxycarbonyl-1-phenyl)methoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5- methylisoxaxol-3-yl)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2- methylthiazol-4-yl)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-methoxycarbonylpropyl]aminocarbonyl-4-(1- phenyl-1 -ethoxycarbonyl-1 -chloro)methoxyquinoline;
2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6,8-difluoro-
4-(1 -carboxy-1 -phenyl)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-6- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; 2-[1 -(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropylJaminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -thien-3-yl)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-7- methyl-4-(5-methylisoxazol-3-yl)methoxyquinoline; 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-7- - . methyl-4-(2-methylthiazol-4-yl)methoxyquinoline-in trifluoroacetic acid 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -(4-chloro)phenyl)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -(3-methoxy)phenyl)methoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-6- dimethylamino-4-(1-phenyl-1-carboxy)methoxyquinoline; 2-[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-
6-fluoro-7-methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline; -[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-6-fluoro-7-methyl-4-(1- phenyl-1 -carboxy)methoxyquinoline; -[1 S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-(1 ,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1- carboxy)methoxyquinoline; -[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3- methoxycarbonylpropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1- carboxy)methoxyquinoline; -[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl- 6-fluoro-7-methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline;
2-[1S-(4-(furan-2-ylcarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(methoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(1 ,1-dimethylethylaminocarbonyl)piperazin-1-yl)carbonyl-3- carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1 -phenyl-1 - carboxy)methoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(phenyl)piperazin-1 -yl)carbonyl-3-(1 , 1 -dimethylethoxycarbonyl)propyl]aminocarbonyl-
6-fluoro-7-methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline; and 2-[1S-(4-(phenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-
(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid.
E. Alternatively, 2-[(4-(ethoxycarbonyl)piperazin-1- yl)carbonylmethyl]aminocarbonyl-4-hydroxyquinoline (100 mg, 1.0 eq) and cesium carbonate (300 mg, 2.5 eq) were combined in 10 mL of DMF. Methyl 4-(bromomethyl)benzoate (65 mg, 1.-1-eq) was added-to-the solution-and the resulting-mixture-was stirred at 50-C for 30 minutes^ The reaction mixture was poured into 200 mL of ice water, extracted with 2x100 mL ethyl acetate, and the organic phase was washed with 3x100 mL water, followed by a brine wash. The crude mixture was purified by flash column chromatography to provide 2-[(4- (ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4- methoxycarbonyl)benzyloxyquinoline (107 mg). To a solution of 2-[(4- 5 (ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4- methoxycarbonyl)benzyloxyquinoline (78 mg) in 4 mL THF was added a solution of 16 mg LiOH in 3 mL of water. The resulting reaction mixture was stirred at ambient temperature for 2 hours, followed by standard work-up to provided 65 mg of 2-[(4-(ethoxycarbonyl)piperazin-1- yl)carbonylmethyl]aminocarbonyl-4-(4-carboxy)benzyloxyquinoline.
10 F. In a similar manner, the following compounds of formula (lb) were prepared:
2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3- methoxycarbonyl)benzyloxyquinoline; and 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3- carboxy)benzyloxyquinoline.
15 G. Alternatively, to a suspension of NaH (53.0 mg, 2.20 mmol), DMF (8 mL) was added a solution of 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-6-chloro-8-fluoro-4-hydroxyquinoline ( 500mg, 0.88 mmol) in DMF ( 2 mL). The reaction mixture was stirred at ambient temperature for 30 minutes. A solution of methyl σ-bromophenylacetate (4 eq., 831 mg ) in DMF (3 mL) was
20 added dropwise and the reaction mixture was heated at 50°C overnight. The solvent, DMF, was evaporated in vacuo. The residue was treated with ethyl acetate, washed with water (2X) and brine, followed by evaporation and flash column chromatography with 1-2% MeOH in DCM to afford 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1 ,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-methoxycarbonyl-1-
25 phenyl)methoxyquinoline (324mg ). 2-[1 S-(4-(Ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-(1 , 1 - dimethylethoxycarbonyl)propyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-methoxycarbonyl-1- phenyl)methoxyquinoline (324 mg, 0.45 mmol) was then treated with TFA: DCM (1:1, 1.8 mL) at ambient temperature for 4 hours. Evaporation, dilution with DCM, and repeated evaporation gave a crude product. Flash column chromatography with 100% ethyl acetate and 3-5%
30 MeOH (with 0.1 % acetic acid) in ethyl acetate afforded 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 - yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-methoxycarbonyl-1- phenyl)methoxyquinoline in acetic acid; (233 mg ): NMR (CD3OD) 1.25 (t, 3),1.99 (m, 1), 2.2 (m, 1), 2.45 (m, 2 ), 3.4-3.8 (m, 11), 4.16 (q, 2), 5.25 (m, 1), 6.38 (s, 1), 7.45 (m, 3), 7.68 (m, 4), 8.10 (s, 1), 9.05 (m, 1) ppm.
_35 _ _ „ H. 2-[-1S-(4-(Ethoxycarbonyl)piperazιn-1-yl)carbonyl-3- carboxypropyl]aminocarbonyl-6-chloro-8-fluoro-4-(1-methoxycarbonyl-1- phenyl)methoxyquinoline (154 mg, 0.233 mmol ) was added to a mixture of THF:H2O, 3:1, 6.0 mL) and LiOH (4 eq.). The mixtutre was stirred at ambient temperature for 1.5 hours . The pH value was adjusted to 3.0 with 1 N HCl solution, followed by extraction with ethyl acetate and evaporation of solvent to give a crude product. Flash column chromatography with 100% ethyl acetate and 5-10% MeOH (with 0.1% AcOH ) in ethyl acetate afforded 2-[1S-(4- (ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8-fluoro-4-(1- carboxy-1-phenyl)methoxyquinoline in acetic acid (30 mg): NMR (CD3OD) 1.25 (t, 3), 1.99 (m, 1), 2.2 (m, 1), 2.45 (m, 2 ), 3.4-3.9 (m, 8), 4.16 (q, 2), 5.20 (m, 1), 6.35 (s, 1), 7.45-7.75 (m, 7), 8.05 (s, 1), 9.02 (m, 1) ppm.
EXAMPLE 3 Compounds of formulae (lc), (Id) and (le)
A. To a mixture of 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-chloroquinoline (475 mg, 0.87 mmol) and CsCO3 (1.13 g, 4 mmol) in 20 mL DMSO was added methyl 3-hydroxybenzoate (160 mg, 1 mmol). The reaction was heated at 60°C overnight. The reaction was filtered and purified by preparative HPLC to afford 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-(3-methoxycarbonyl)- phenoxyquinoline (200 mg, 35%). B. 2-[1S-(4-(Ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-(3- methoxycarbonyl)phenoxyquinoline (200 mg, 0.3 mmol) was dissolved in a mixture of methylene chloride and trifluoroacetic acid (5 mL, 4:1 mixture) and stirred for 3 hours. The solution was evaporated to an oil and dissolved in MeOH (10 mL). Lithium hydroxide (3 mL, 0.25 M) was added and the solution was stirred overnight. The reaction was evaporated, adjusted to pH <7 with TFA and purified by preparative HPLC to afford 2-[1 S-(4- (ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-(3- carboxy)phenoxyquinoline in trifluoroacetic acid, (25 mg, 15%). 1H NMR: (DMSO-d6) 1.15 (t, 3), 1.80 (m, 1), 2.00 (m, 1), 2.55 (s, 3), 3.30-3.60 (m, 8), 4.05 (q, ), 4.95 (m, 1), 7.05 (s, 1), 7.61 (m, 2), 7.65 (d, 1), 7.75 (s, 1), 8.25 (d. 1), 8.91 (d, 2) ppm.
C. In a similar manner, the following compounds of formula (lc) were prepared: 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1 ,1-ethanediol; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2- -carboxy)phenoxyquinoline in-2;272-trifluoro-1,1 -ethanediol;- - 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-amino-5- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1 ,1-ethanediol; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(4- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1,1-ethanediol; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- carboxymethyl)phenoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(1 - amino-1-carboxy)methyl)phenoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(2- amino-2-carboxy)ethyl)phenoxyquinoline in trifluoroacetic acid;
2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-methyl-
5-carboxy)phenoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5-carboxy-
2-diethylaminomethyl)phenoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-tetrazol-
5-yl)phenoxyquinoline in 2,2,2-trifluoro-1,1-ethanediol; and 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- trifluoromethylsulfonylamino)phenoxyquinoline in trifluoroacetic acid.
D. A solution of 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3- (methoxycarbonyl)propyl]aminocarbonyl-4-chloroquinoline (0.15 g, 0.313 mmol) and 1,2,3,4- tetrahydroisoquinoline (0.15 mmol) was mixed in 3 mL of DMSO and heated to 100°C for 18 hours. The reaction was purified by reversed-phase HPLC. The product was dissolved in 0.25 M LiOH solution and stirred for 6 hours. Purification by reversed-phase HPLC afforded. 2-[1 S- (4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1 ,2,3,4- tetrahydroisoquinolin-2-yl)quinoline in trifluoroacetic acid, to form a compound of formula (Id).
E. In a similar manner, other compounds of formula (Id) were prepared. F.. A solution of 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-7-methyl-4-bromoquinoline (10 mg, 0.17 mmol), 3-carboxyphenylboronic acid (0.26 mmol), Pd(PPh3) (40 mg), and 2 M sodium carbonate (217 μl) was combined in 10 mL of toluene-ethanol and heated at 80°C overnight. The reaction was purified by reversed-phase HPLC. The product was dissolved in 10 mL of 1/1 TFA- methylene chloride solution and stirred for 2 hours. The product was concentrated in vacuo to afford 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- carboxy)phenylquinoline in trifluoroacetic acid. — G-. In a-similar-manner^-other-compounds of formula-(le)-were-prepared. EXAMPLE 4 Receptor Binding Studies
The ability of the compounds of the invention to bind to the platelet adenosine diphosphate ("ADP") receptor was tested using human washed platelets and rat washed platelets by displacement assays. Methods:
One day old platelet concentrates were purchased from a local blood bank. The platelet concentrates were spun at 680 g for 10 minutes and the resulting pellets were resuspended in modified Tyrode's buffer ( 135 mM NaCI, 3.6 mL KCI, 1.8 mM MgCI2, 9 mM HEPES, 0.18 mg/mL BSA, 4.5 mM glucose, pH 6.6) supplemented by 2% acid citrate dextrose (ACD). This platelet suspension was spun at 680 g for 10 minutes and the final pellet was resuspended in platelet binding buffer (20mM Tris buffer, pH 7.5, 140 mM NaCI, 4 mM KCI, 2 mM MgCI2ι 1 mM EDTA, 0.1% BSA, 5 mM glucose, 2 g/mL aprotinin, and 2 g/mL leupeptin). Platelets were isolated from rat whole blood as described in Example 13 with the final pellet resuspended in platelet binding buffer. The platelet number for binding to rat platelets (5 x 106 per well) was normalized to the number of platelets for binding to human platelet (4-6 x 106 per well).
Binding reactions were initiated by mixing [33P]-2-methylthio-ADP (0.3-0.5 nM), test compounds and washed platelets in 96-well plates. The reactions were kept at ambient temperature for 60 minutes under constant shaking and were stopped by fast-filtration onto 96-well, glass-fiber (GFC) filter plates followed by washing 5 times with ice-cold 50 mM Tris buffer (pH 7.5). The amount of [33P]-2-methylthio-ADP bound to the filters was measured by scintillation counting. Non-specific binding was determined in the presence of 10 μM unlabelled 2-methylthio-ADP. Competition studies were done using a single concentration of [33P]-2-methylthio-ADP (0.3 nM) and varying concentrations of test compounds. Results:
The compounds of the invention, when tested in this assay, demonstrated their ability to inhibitor the binding of [33P]-2-methylthio-ADP binding to the human platelet ADP receptor and the rat platelet ADP receptor. EXAMPLE 5
ADP-induced Aggregation In Vitro Studies The compounds of the invention were evaluated as functional antagonists of the platelet ADP receptor using both human and rat washed platelets. Methods: " Human venous-blood-was collected froπrhealthy; drug=free volunteers-into-1/6-volume -
3.2% acid/citrate/dextrose. Whole blood from Nembutal-anesthetized rats was collected from the abdominal aorta into 1/10 volume 3.8% acid/citrate/dextrose. Platelet rich plasma (PRP) was prepared by centrifugation at 800 g for 3-4 successive 1.5-minute intervals, with removal of the PRP after each spin. Alternatively, some PRP preps were performed by centrifugation at 100 g for 15 minutes. Washed platelets were prepared from the PRP by centrifugation at 680 g for 15 minutes and the platelet pellet resuspended in Tyrode's buffer (137 mM NaCI, 2.7 mM KCI, 12 mM NaHCO2, 0.42 mM NaH2PO, 1 mM MgCI2, 2 M CaCI2, 0.35% BSA, 5.5 mM glucose, 5 mM HEPES, pH 7.35 supplemented with f.c. 10% ACD solution. The platelets were washed a total of two times under these acidic conditions and the platelet pellet collected by centrifugation at 680 g for 15 minutes at ambient temperature. The final platelet pellet was resuspended at 2 X 108 platelets/mL in Tyrode's buffer containing 0.02 units/mL apyrase. This platelet suspension was kept at 37°C for at least 30 minutes prior to studies.
Inhibition of ADP-induced aggregation was measured at 37°C in a 4-channel aggregometer. The platelet suspension (0.5 mL) was stirred at 1200 rpm. Human fibrinogen (400 μg) was added at time zero for 1 minute followed by 2 minute pre-incubation in the presence or absence of antagonist. Platelet aggregation was induced with the addition of 10 or 31.6 μM ADP (submaximal response) in human platelets or 3 or 10 μM ADP (submaximal response) in rat and monitored for 5 minutes. ADP-induced aggregation was quantified by measuring increase in light transmission (%T) compared to Tyrode's buffer control. IC50 values were determined using the 4-parameter equation. Results:
The compounds of the invention, when tested in this assay, demonstrated the ability to inhibit ADP-induced platelet aggregation in vitro in human and rat washed platelets.
EXAMPLE 6 Efficacy Assay Inhibition of thrombus formation by compounds of the invention was evaluated in the rat arterio-venous (A-V) shunt model. Methods:
Male Sprague-Dawley rats (350-400 g, 10-18 per group) were anesthetized with Nembutal (65 mg/kg, i.p). The left carotid artery and the right jugular vein were each cannulated with a piece of PE-50 tubing (8 cm, siliconized). Fifty minutes after anesthesia, the arterial and venous catheters were connected (A-V shunt) by a piece of shunt tubing (Tygon S- 50-HL, 6 cm) that contained a silk thread (6-0 silk suture, 10 cm) coated with collagen (Horm, 100 μg/ml). Blood was allowed to flow through the A-V shunt for 10 minutes. The amount of thrombus deposited on the silk thread was measured as dry weight (24 hours at ambient temperature )r- A compound of- the invention-^ r3 and 10 mg/kg)-(as-the-appropriate salt form) or vehicle (15% DMSO in saline, 1 mlJkg) was injected via the jugular vein catheter 5 minutes before the A-V shunt. Blood samples (1 mL) were taken immediately before the dosing and at the end of the A-V shunt for measurements of ex vivo platelet aggregation and plasma levels of the compound of the invention. Results:
When tested in this assay, compounds of the invention demonstrated the ability to dose- dependently inhibit platelet aggregation and thrombus formation in the rat A-V shunt model. Both the inhibition of platelet aggregation and thrombus formation were also parallel in relation to the changes in plasma drug concentrations. Thus, the inhibition of thrombus formation is correlated with the inhibition of platelet aggregation induced by the compound of the invention.
EXAMPLE 7
This example illustrates the preparation of representative pharmaceutical compositions for oral administration containing a compound of the invention, or a pharmaceutically acceptable salt thereof: A. Ingredients % wt./wt.
Compound of the invention 20.0%
Lactose 79.5%
Magnesium stearate 0.5%
The above ingredients are mixed and dispensed into hard-shell gelatin capsules containing 100 mg each, one capsule would approximate a total daily dosage. B. Ingredients % wt./wt.
Compound of the invention 20.0%
Magnesium stearate 0.9%
Starch 8.6% Lactose 69.6%
PVP (polyvinylpyrrolidine) 0.9%
The above ingredients with the exception of the magnesium stearate are combined and granulated using water as a granulating liquid. The formulation is then dried, mixed with the magnesium stearate and formed into tablets with an appropriate tableting machine. C. Ingredients
Compound of the invention 0.1 g
Propylene glycol 20.0 g
Polyethylene glycol 400 20.0 g
Polysorbate 80 1.0 g -Water- -q.s.- 00-mL,
The compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient quantity of water is then added with stirring to provide 100 mL of the solution which is filtered and bottled.
D. Ingredients % wt./wt.
Compound of the invention 20.0%
Peanut Oil 78.0%
Span 60 2.0%
The above ingredients are melted, mixed and filled into soft elastic capsules.
Ingredients % wt./wt.
10 Compound of the invention 1.0%
Methyl or carboxymethyl cellulose 2.0%
0.9% saline q.s. 100 mL
The compound of the invention is dissolved in the cellulose/saline solution, filtered and bottled for use. 15 EXAMPLE 8
This example illustrates the preparation of a representative pharmaceutical formulation for parenteral administration containing a compound of the invention, or a pharmaceutically acceptable salt thereof:
Ingredients 20 Compound of the invention 0.02 g
Propylene glycol 20.0 g
Polyethylene glycol 400 20.0 g
Polysorbate 80 1.0 g
0.9% Saline solution q.s. 100 mL
25 The compound of the invention is dissolved in propylene glycol, polyethylene glycol 400 and polysorbate 80. A sufficient quantity of 0.9% saline solution is then added with stirring to provide 100 mL of the I.V. solution which is filtered through a 0.2 m membrane filter and packaged under sterile conditions.
30 EXAMPLE 9
This example illustrates the preparation of a representative pharmaceutical composition in suppository form containing a compound of the invention, or a pharmaceutically acceptable salt thereof:
Ingredients % wt./wt.
-35- -Gompound-of-the invention- -1-0%
Polyethylene glycol 1000 74.5% Polyethylene glycol 4000 24.5%
The ingredients are melted together and mixed on a steam bath, and poured into molds containing 2.5 g total weight.
EXAMPLE 10
This example illustrates the preparation of a representative pharmaceutical formulation for insufflation containing a compound of the invention, or a pharmaceutically acceptable salt thereof:
Ingredients % wt./wt. Micronized compound of the invention 1.0%
Micronized lactose 99.0%
The ingredients are milled, mixed, and packaged in an insufflator equipped with a dosing pump.
EXAMPLE 11
This example illustrates the preparation of a representative pharmaceutical formulation in nebulized form containing a compound of the invention, or a pharmaceutically acceptable salt thereof:
Ingredients % wt./wt. Compound of the invention 0.005%
Water 89.995%
Ethanol 10.000%
The compound of the invention is dissolved in ethanol and blended with water. The formulation is then packaged in a nebulizer equipped with a dosing pump.
EXAMPLE 12 This example illustrates the preparation of a representative pharmaceutical formulation in aerosol form containing a compound of the invention, or a pharmaceutically acceptable salt thereof: Ingredients % wt./wt.
Compound of the invention 0.10%
Propellant 11/12 98.90%
Oleic acid 1.00%
The compound of the invention is dispersed in oleic acid and the propellants. The resulting mixture is then poured into an aerosol container fitted with a metering valve. * * * * *
While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

What is claimed is:
A compound of formula (I):
Figure imgf000064_0001
wherein: m and n are independently 1 to 4;
R1 is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl;
R2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl, aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl, alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl, carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl, aminocarbonylalkyl, aralkoxycarbonylaminoalkyl, alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl, (alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl, (carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl;
R3 is aryl or aryloxy each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -Rδ-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; or R3 is aralkyl or aralkoxy, wherein the alkyl radical in the aralkyl or aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9), and wherein the aryl radical in the aralkyl or aralkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7,-R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7) ,_-_R8 N(R7)_C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; each R5 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and each R9 is hydrogen, alkyl, aralkyl or haloalkyl; as a single stereoisomer, a mixture of individual stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt thereof.
2. The compound of Claim 1 wherein: m is 1 ; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R8-N(R7)C(O)OR9; each R4 is is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;
R5 is hydrogen;
R6 is hydrogen or alkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and
R-is-hydrogen,-alkyl,-aralkyLor haloalkyl.-
3. The compound of Claim 2 wherein: m is 1; n is 1 or 2;
R1 is hydrogen or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is aryl optionally substituted by one or more substituents selected from the group consisting of carboxy or alkoxycarbonyl; each R4 is is independently selected from the group consisting of hydrogen, alkyl, halo, or haloalkyl; R5 is hydrogen; and R6 is hydrogen.
4. The compound of Claim 4, namely, 2-[1 S-(4-(ethoxycarbonyl)piperazin-1- yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-carboxy)phenylquinoline in trifluoroacetic acid. f
5. The compound of Claim 1 wherein: m is 1; n is 1 or 2;
R is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is aryloxy optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;
R5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a~bond or a-straight or branched-alkylene chain;-and-
R9 is hydrogen, alkyl, aralkyl or haloalkyl.
6. The compound of Claim 5 wherein: m is 1; n is 1 or 2;
R1 is hydrogen or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is aryloxy optionally substituted by one or more substituents selected from the group consisting of alkyl, tetrazolyl, -R8-C(O)OR7, -R8-N(R7)2, -R8-N(R7)-S(O)2-R7, and
-R8-C[N(R7)2]-C(O)OR7; each R4 is is independently selected from the group consisting of hydrogen, alkyl, halo, or haloalkyl; R5 is hydrogen; R6 is hydrogen; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and each R8 is a bond or a straight or branched alkylene chain.
7. The compound of Claim 6 selected from the group consisting of the following: 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1,1-ethanediol; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1,1-ethanediol; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-amino-5- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1,1-ethanediol; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(4- carboxy)phenoxyquinoline in 2,2,2-trifluoro-1,1-ethanediol; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- carboxymethyl)phenoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(1- amino-1-carboxy)methyl)phenoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-(2- amino-2-carboxy)ethyl)phenoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2-methyl-
5-carboxy)phenoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5-carboxy-
2-diethylaminomethyl)phenoxyquinoline-in-trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3-tetrazol-
5-yl)phenoxyquinoline in 2,2,2-trifluoro-1,1-ethanediol; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(3- trifluoromethylsulfonylamino)phenoxyquinoline in trifluoroacetic acid; and 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-
(3-carboxy)phenoxyquinoline in trifluoroacetic acid.
8. The compound of Claim 1 wherein m is 1; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is aralkyl wherein the alkyl radical in the aralkyl substituent is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9), and wherein the aryl radical in the aralkyl substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;
R5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and
R9 is hydrogen, alkyl, aralkyl or haloalkyl.
9. The compound of Claim 1 wherein: m s 1 ; n is 1 or 2; R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R -,2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R 33 is aralkoxy wherein the alkyl radical in the aralkyl substituent is not optionally substituted and wherein the aryl radical in the aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;
R5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and
R9 is hydrogen, alkyl, aralkyl or haloalkyl.
10. The compound of Claim 9 wherein: m is 1; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is aralkoxy wherein the aryl radical in the aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl,
-R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, and -R8-N(R7)2; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, or haloalkyl; R5 is hydrogen; R6 is hydrogen; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and each R8 is a bond or a straight or branched alkylene chain.
11. The compound of Claim 10 selected from the group consisting of the following: 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-benzyloxyquinoline; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4- benzyloxyquinoline; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4- benzyloxyquinoline; 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-benzyloxycarbonylpropyl]aminocarbonyl-4- benzyloxy-8-methoxyquinoline; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-benzyloxy-
8-methoxyquinoline; 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4- methoxycarbonyl)benzyloxyquinoline; 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(4- carboxy)benzyloxyquinoline; 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3- methoxycarbonyl)benzyloxyquinoline; 2-[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-4-(3- carboxy)benzyloxyquinoline; 2-[1 S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-(1 ,1- dimethylethoxycarbonyl)propyl]aminocarbonyl-4-benzyloxyquinoline; and 2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4- benzyloxyquinoline.
12. The compound of Claim 1 wherein: m is 1 ; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is aralkoxy wherein the alkyl radical in the aralkoxy substituent is substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9), and wherein the aryl radical in the aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and ~-Ra e[H(Rz)fre(0)QRl; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy;
R5 is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and
R9 is hydrogen, alkyl, aralkyl or haloalkyl.
13. The compound of Claim 12 wherein: m is 1; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is aralkoxy wherein the alkyl radical in the aralkoxy substituent is substituted by
-R8-C(O)OR7, and wherein the aryl radical in the aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo and
-R8-OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino; R5 is hydrogen; R6 is hydrogen; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and each R8 is a bond or a straight or branched alkylene chain.
14. The compound of Claim 13 selected from the group consisting of the following: 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-(1 , 1 - dimethylethoxycarbonyl)propyl]aminocarbonyl-4-(1 -phenyl-1 - methoxycarbonyl)methoxyquinoline; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1-phenyl- 1-methoxycarbonyl)methoxyquinoline; -[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1 -phenyl-
1-carboxy)methoxyquinoline; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-
(1 -phenyl-1 -carboxy)methoxyquinoline; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1-phenyl-1-carboxy)methoxyquinoline; -[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(1 • carboxy-1 -phenyl)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -naphth-1 -yl-1 -carboxy)methoxyquinoline; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8- fluoro-4-(1-methoxycarbonyl-1-phenyl)methoxyquinoline in acetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-8- fluoro-4-(1 -carboxy-1 -phenyl)methoxyquinoline in acetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -(2-fluoro)phenyl)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-4-
(1-ethoxycarbonyl-1-phenyl)methoxyquinoline in trifluoroacetic acid; -[(4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl]aminocarbonyl-6-fluoro-7-methyl-4-(1- phenyl-1-carboxy)methoxyquinoline; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -(4-chloro)phenyl)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1 -carboxy-1 -(3-methoxy)phenyl)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6,8-difluoro-
4-(1 -carboxy-1 -phenyl)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6- dimethylamino-4-(1 -phenyl-1 -carboxy)methoxyquinoline; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-6- methyl-4-(1-phenyl-1-carboxy)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- chloro-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; -[1S-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)carbonyl-3- methoxycarbonylpropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1 -phenyl-1 - carboxy)methoxyquinoline; 2-[1 S-(4-(1 , 1 -dimethylethoxycarbonyl)piperazin-1 -yl)carbonyl-3-carboxypropyl]aminocarbonyl-
6-fluoro-7-methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline; 2-[1S-(4-(methoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(1 , 1 -dimethylethylaminocarbonyl)piperazin-1 -yl)carbonyl-3- carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-(1 -phenyl-1 - carboxy)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(furan-2-ylcarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(3-methylphenyl)piperazin-1 -yl)carbonyl-3-(1 , 1 - dimethylethoxycarbonyl)propyl]aminocarbonyl-6-fluoro-7-methyl-4-(1-phenyl-1- carboxy)methoxyquinoline; 2-[1S-(4-(3-methylphenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7- methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(phenyl)piperazin-1 -yl)carbonyl-3-(1 , 1 -dimethylethoxycarbonyl)propyl]aminocarbonyl-
6-fluoro-7-methyl-4-(1 -phenyl-1 -carboxy)methoxyquinoline; and 2-[1S-(4-(phenyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-fluoro-7-methyl-4-
(1 -phenyl-1 -carboxy)methoxyquinoline in trifluoroacetic acid.
15. A pharmaceutical composition useful in treating a mammal having a disease- state characterized by thrombotic activity, which composition comprises a pharmaceutically acceptable excipient and a compound of formula (I):
Figure imgf000073_0001
wherein: m and n are independently 1 to 4;
R1 is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, -alkoxycar.bonylaminocarbonyl,_or heterocyclylcarbonyl;. R2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl, aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl, alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl, carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl, aminocarbonylalkyl, aralkoxycarbonylaminoalkyl, alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl, (alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl, (carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl;
R3 is aryl or aryloxy each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2J-C(O)OR7; or R3 is aralkyl or aralkoxy, wherein the alkyl radical in the aralkyl or aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9), and wherein the aryl radical in the aralkyl or aralkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; each R5 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and each R9 is hydrogen, alkyl, aralkyl or haloalkyl; as a single stereoisomer, a mixture of individual stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt thereof.
16. A method of treating a disease-state characterized by thrombotic activity, which method comprises administering to a mammal having a disease-state characterized by thrombotic activity a therapeutically effective amount of a compound of formula (I):
Figure imgf000075_0001
wherein: m and n are independently 1 to 4;
R1 is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl;
R2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl, aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl, alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl, carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl, aminocarbonylalkyl, aralkoxycarbonylaminoalkyl, alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl, (alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl, (carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl;
R3 is aryl or aryloxy each independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; or R3 is aralkyl or aralkoxy, wherein the alkyl radical in the aralkyl or aralkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9), and wherein the aryl radical in the aralkyl or aralkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl,
Figure imgf000075_0002
-R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; each R5 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and each R9 is hydrogen, alkyl, aralkyl or haloalkyl; as a single stereoisomer, a mixture of individual stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt thereof.
17. A compound of formula (II):
Figure imgf000076_0001
wherein: m and n are independently 1 to 4;
R1 is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl;
R2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl, aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl, alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl, carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl, .aminocarbonylalkyl,.aralkoxycarbonylaminpalkyl,_ alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl, (alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl, (carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl;
R3 is heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; or R3 is heteroarylalkoxy, wherein the alkoxy radical in the heteroarylalkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9), and wherein the heteroaryl radical in the heteroarylalkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; each R5 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl. aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and each R9 is hydrogen, alkyl, aralkyl or haloalkyl; as a single stereoisomer, a mixture of individual stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt thereof.
18. The compound of Claim 17 wherein: m is 1 ; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl; R? is-hydrogen, carboxyalkyl.-alkoxycarbonylalkyl-or-aralkoxycarbonylalkyl - R3 is heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, and -R8-N(R7)2; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino;
R5 is hydrogen;
R6 is hydrogen; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and each R8 is a bond or a straight or branched alkylene chain.
19. The compound of Claim 18, namely, 2-[1S-(4-(ethoxycarbonyl)piperazin-1- yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)quinoline in trifluoroacetic acid.
20. The compound of Claim 17 wherein: m is 1 ; n is 1 or 2;
R1 is hydrogen, aryl, aralkyl, or alkoxycarbonyl;
R2 is hydrogen, carboxyalkyl, alkoxycarbonylalkyl or aralkoxycarbonylalkyl;
R3 is heteroarylalkoxy, wherein the alkoxy radical in the heteroarylalkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo and -R8-C(O)OR7, and wherein the heteroaryl radical in the heteroarylalkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, and -R8-N(R7)2; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino, or dialkylamino;
R5 is hydrogen;
R6 is hydrogen; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; and each R8 is a bond or a straight or branched alkylene chain.
21. The compound of Claim 20 selected from the group consisting of the following: 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(5-
^methylisoxaxoI-3=-yl)methoxyquinoline in-trifluoroacetic-acid 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(2- methylthiazol-4-yl)methoxyquinoline in trifluoroacetic acid; 2-[1 S-(4-(ethoxycarbonyl)piperazin-1 -yl)carbonyl-3-methoxycarbonylpropyl]aminocarbonyl-4-(1 - phenyl-1 -ethoxycarbonyl-1 -chloro)methoxyquinoline; 2-[1-(4-(ethoxycarbonyl)piperazin-1-yi)carbonyl-3-carboxypropyl]aminocarbonyl-7-methyl-6- fluoro-4-(1-carboxy-1-thien-3-yl)methoxyquinoline in trifluoroacetic acid; 2-[1S-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-7- methyl-4-(5-methylisoxazol-3-yl)methoxyquinoline; and 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-6-chloro-7- methyl-4-(2-methylthiazol-4-yl)methoxyquinoline in trifluoroacetic acid.
22. A pharmaceutical composition useful in treating a mammal having a disease- state characterized by thrombotic activity, which composition comprises a pharmaceutically acceptable excipient and a compound of formula (II):
Figure imgf000079_0001
wherein: m and n are independently 1 to 4;
R1 is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl;
R2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl, aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl, alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl, carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl, aminocarbonylalkyl, aralkoxycarbonylaminoalkyl, alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl, (alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl, (carboxyalkyl)(alkyl)aminocarbonylalkyl, OTjιelerocyclyJaiky|;„
R3 is heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; or R3 is heteroarylalkoxy, wherein the alkoxy radical in the heteroarylalkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9), and wherein the heteroaryl radical in the heteroarylalkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; each R5 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R6 is hydrogen, alkyl, carboxyalkyl, or alkoxycarbonylalkyl; each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and each R9 is hydrogen, alkyl, aralkyl or haloalkyl; as a single stereoisomer, a mixture of individual stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt thereof.
23. A method of treating a disease-state characterized by thrombotic activity, which method comprises administering to a mammal having a disease-state characterized by thrombotic activity a therapeutically effective amount of a compound of formula (II):
Figure imgf000080_0001
wherein: m and n are independently 1 to 4; R1 is hydrogen, alkyl, carboxyalkyl, aryl, aralkyl, alkylcarbonyl, aryloxyalkylcarbonyl, carboxyalkylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylalkyl, alkoxycarbonyl, arylcarbonyl, aryloxycarbonyl, aralkoxycarbonyl, cycloalkylcarbonyl, haloalkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, alkoxycarbonylaminocarbonyl, or heterocyclylcarbonyl;
R2 is hydrogen, alkyl, aryl, aralkyl, alkylsulfonylalkyl, aralkoxyalkyl, hydroxyalkyl, aminoalkyl, haloalkylsulfonylaminoalkyl, carboxyalkylthioalkyl, alkoxycarbonylalkylthioalkyl, carboxyalkyl, (carboxy)(hydroxy)alkyl, carboxyalkoxyalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, carboxyalkoxycarbonylalkyl, alkoxycarbonylalkoxycarbonylalkyl, aminocarbonylalkyl, aralkoxycarbonylaminoalkyl, alkoxycarbonylalkylaminocarbonylalkyl, carboxyalkylaminocarbonylalkyl, (alkoxycarbonylalkyl)(alkyl)aminocarbonylalkyl, (carboxyalkyl)(alkyl)aminocarbonylalkyl, or heterocyclylalkyl;
R3 is heteroaryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; or R3 is heteroarylalkoxy, wherein the alkoxy radical in the heteroarylalkoxy substituent is optionally substituted by one or more substituents selected from the group consisting of halo, cyano, nitro, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, and -R9-N(R7)C(O)OR9), and wherein the heteroaryl radical in the heteroarylalkoxy substituent is independently optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, cyano, nitro, tetrazolyl, -R8-OR7, -R8-C(O)OR7, -R8-C(O)N(R7)2, -R8-C(O)R7, -R8-N(R7)2, -R8-N(R7)C(O)R7, -R8-N(R7)C(O)OR9, -R8-N(R7)-S(O)2-R7, and -R8-C[N(R7)2]-C(O)OR7; each R4 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, aralkoxy, halo, haloalkyl, haloalkoxy, hydroxy, cyano, alkylthio, carboxy, alkoxycarbonyl, aminocarbonyl, alkylcarbonyl, nitro, amino, monoalkylamino, dialkylamino, carboxyalkylamino, alkylcarbonylamino, di(alkylcarbonyl)amino, hydroxyalkyl, dialkylaminoalkyl, carboxyalkoxy, alkoxycarbonylalkoxy, dialkylaminoalkoxy, and heterocyclylalkoxy; each R5 is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aralkyl, carboxy, alkoxycarbonyl, aralkoxycarbonyl, carboxyalkyl, and alkoxycarbonylalkyl;
R- is hydrogen, -alkyl.-carboxyalkylror-alkoxycarbonylalkyl;- each R7 is hydrogen, alkyl, aryl, aralkyl, or haloalkyl; each R8 is a bond or a straight or branched alkylene chain; and each R9 is hydrogen, alkyl, aralkyl or haloalkyl; as a single stereoisomer, a mixture of individual stereoisomers, or a racemic mixture; or a pharmaceutically acceptable salt thereof.
PCT/US2003/039079 2002-12-11 2003-12-09 2-aminocarbonyl-quinoline compounds as platelet adenosine diphosphate receptor antagonists WO2004052366A1 (en)

Priority Applications (14)

Application Number Priority Date Filing Date Title
CA2507657A CA2507657C (en) 2002-12-11 2003-12-09 2-aminocarbonyl-quinoline compounds as platelet adenosine diphosphate receptor antagonists
JP2004558607A JP4662777B2 (en) 2002-12-11 2003-12-09 2-Aminocarbonylquinoline compounds as platelet adenosine diphosphate receptor antagonists
EA200500899A EA200500899A1 (en) 2002-12-11 2003-12-09 ANTAGONISTS OF ADDROSE DIPHOSPHATE PLATELET RECEPTOR
UAA200506729A UA83648C2 (en) 2002-12-11 2003-12-09 Platelet adenosine diphosphate receptor antagonists
AT03796831T ATE477800T1 (en) 2002-12-11 2003-12-09 2-AMINOCARBONLYL-QUINOLINE COMPOUNDS AS ADENOSINE DIPHOSPHATE PLATELE RECEPTOR ANTAGONISTS
EP03796831A EP1578423B1 (en) 2002-12-11 2003-12-09 2-aminocarbonyl-quinoline compounds as platelet adenosine diphosphate receptor antagonists
MXPA05006302A MXPA05006302A (en) 2002-12-11 2003-12-09 2-aminocarbonyl-quinoline compounds as platelet adenosine diphosphate receptor antagonists.
AU2003297763A AU2003297763A1 (en) 2002-12-11 2003-12-09 2-aminocarbonyl-quinoline compounds as platelet adenosine diphosphate receptor antagonists
AP2005003363A AP2005003363A0 (en) 2002-12-11 2003-12-09 2-Aminocarbonyl-quinoline componds as platelet ad enosine diphosphate receptor antagonists.
NZ540872A NZ540872A (en) 2002-12-11 2003-12-09 2-Aminocarbonyl-quinoline compounds as platelet adenosine diphosphate receptor antagonists
YUP-2005/0450A RS20050450A (en) 2002-12-11 2003-12-09 2-aminocarbonyl-quinoline compounds as platelet adenosine diphosphate receptor antagonists
DE60333866T DE60333866D1 (en) 2002-12-11 2003-12-09 2-AMINOCARBONLYL-CHINOLINE COMPOUNDS AS ADENOSINE DIPHOSPHATE PLATEN RECEPTOR ANTAGONISTS
BR0317222-8A BR0317222A (en) 2002-12-11 2003-12-09 2-Aminocarbonyl-quinoline Compounds as Platelet Adenisine Diphosphate Receptor Antagonists
NO20053335A NO20053335L (en) 2002-12-11 2005-07-08 2-aminocarbonylquinoline compounds as platelet adenosine diphosphate receptors.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US43279202P 2002-12-11 2002-12-11
US60/432,792 2002-12-11

Publications (2)

Publication Number Publication Date
WO2004052366A1 true WO2004052366A1 (en) 2004-06-24
WO2004052366A9 WO2004052366A9 (en) 2005-06-23

Family

ID=32507994

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2003/039079 WO2004052366A1 (en) 2002-12-11 2003-12-09 2-aminocarbonyl-quinoline compounds as platelet adenosine diphosphate receptor antagonists

Country Status (23)

Country Link
US (2) US7056923B2 (en)
EP (1) EP1578423B1 (en)
JP (1) JP4662777B2 (en)
KR (1) KR20050085580A (en)
CN (1) CN1747732A (en)
AP (1) AP2005003363A0 (en)
AT (1) ATE477800T1 (en)
AU (1) AU2003297763A1 (en)
BR (1) BR0317222A (en)
CA (1) CA2507657C (en)
DE (1) DE60333866D1 (en)
EA (1) EA200500899A1 (en)
EC (1) ECSP055912A (en)
ES (1) ES2348942T3 (en)
MX (1) MXPA05006302A (en)
NO (1) NO20053335L (en)
NZ (1) NZ540872A (en)
OA (1) OA12970A (en)
PL (1) PL377053A1 (en)
RS (1) RS20050450A (en)
UA (1) UA83648C2 (en)
WO (1) WO2004052366A1 (en)
ZA (1) ZA200505492B (en)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007022241A3 (en) * 2005-08-17 2007-09-27 Schering Corp Novel high affinity quinoline-based kinase ligands
WO2008044217A2 (en) 2006-10-13 2008-04-17 Actelion Pharmaceuticals Ltd 2-aminocarbonyl-pyridine derivatives
WO2008128647A1 (en) * 2007-04-23 2008-10-30 Sanofi-Aventis Quinoline-carboxamide derivatives as p2y12 antagonists
JP2008539224A (en) * 2005-04-28 2008-11-13 アクテリオン ファーマシューティカルズ リミテッド Pyrimidine derivatives
WO2009125366A1 (en) 2008-04-11 2009-10-15 Actelion Pharmaceuticals Ltd Substituted 2-phenyl-pyridine derivatives
JP2010507646A (en) * 2006-10-25 2010-03-11 アクテリオン ファーマシューティカルズ リミテッド 2-Phenyl-6-aminocarbonyl-pyrimidine derivatives and their use as P2Y12 receptor antagonists
WO2010116328A3 (en) * 2009-04-08 2011-01-13 Actelion Pharmaceuticals Ltd 6-(3-aza-bicyclo[3.1.0]hex-3-yl)-2-phenyl-pyrimidines as adp receptor antagonists
US7910576B2 (en) 2007-06-18 2011-03-22 Sanofi-Aventis Pyrrole derivatives as P2Y12 antagonists
CN102304108A (en) * 2011-06-28 2012-01-04 中国药科大学 Five-membered heterocyclic dicarbonyl derivative and application thereof on multi-drug resistant bacteria
US8466156B2 (en) 2008-04-11 2013-06-18 Actelion Pharmaceuticals Ltd. 2-phenyl-4-cyclopropyl-pyrimidine derivatives
US8518912B2 (en) 2007-11-29 2013-08-27 Actelion Pharmaceuticals Ltd. Phosphonic acid derivates and their use as P2Y12 receptor antagonists
US8664203B2 (en) 2009-04-22 2014-03-04 Actelion Pharmaceuticals Ltd. Thiazole derivatives and their use as P2Y12 receptor antagonists
US10730896B2 (en) 2016-09-22 2020-08-04 Idorsia Pharmaceuticals Ltd Crystalline forms
US11179390B2 (en) 2017-03-15 2021-11-23 Idorsia Pharmaceuticals Ltd Subcutaneous administration of a P2Y12 receptor antagonist

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7335648B2 (en) * 2003-10-21 2008-02-26 Inspire Pharmaceuticals, Inc. Non-nucleotide composition and method for inhibiting platelet aggregation
ATE469157T1 (en) * 2003-10-21 2010-06-15 Inspire Pharmaceuticals Inc TETRAHYDROFUROÄ3,4-DIOXOL COMPOUNDS AND COMPOSITIONS AND METHODS FOR INHIBITING TROMBOCYTE AGGREGATION
DE102006020385A1 (en) * 2006-04-28 2007-10-31 Dade Behring Marburg Gmbh Method and device for determining platelet function under flow conditions
CN104151235B (en) * 2014-08-07 2016-01-20 南阳师范学院 A kind of quinoline preparation method
CN112062687B (en) * 2020-09-02 2023-11-21 上海信谊万象药业股份有限公司 Synthesis method of azasetron hydrochloride intermediate 3-amino-5-chloro-2-hydroxybenzoic acid methyl ester
CN112920181A (en) * 2021-01-29 2021-06-08 中国医科大学 N- (5-phenyl-1, 3, 4-thiadiazole-2-yl) benzamide compound

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4258192A (en) * 1977-12-16 1981-03-24 Mitsubishi Chemical Industries Limited N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
WO1994018185A1 (en) * 1993-02-10 1994-08-18 Pentapharm Ag Piperazides of substituted phenylalanine derivates as thrombin inhibitors
US5346907A (en) * 1988-04-05 1994-09-13 Abbott Laboratories Amino acid analog CCK antagonists
EP0739886A2 (en) * 1995-04-28 1996-10-30 LG Chemical Limited Selective thrombin inhibitors
WO2002098856A2 (en) * 2001-06-06 2002-12-12 Schering Aktiengesellschaft Piperazine oxyquinoline (naphthaline) platelet adenosine diphosphate receptor antagonists

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US60474A (en) * 1866-12-18 Pbtee chick
GB1334705A (en) 1970-06-19 1973-10-24 Ici Ltd Pharmaceutical compositions containing kynurenic acid derivatives
WO1992008709A1 (en) 1990-11-15 1992-05-29 Pentapharm Ag Meta-substituted phenyl alanine derivatives
US6207665B1 (en) 1997-06-12 2001-03-27 Schering Aktiengesellschaft Piperazine derivatives and their use as anti-inflammatory agents

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4258192A (en) * 1977-12-16 1981-03-24 Mitsubishi Chemical Industries Limited N2 -Arylsulfonyl-L-argininamides and the pharmaceutically acceptable salts thereof
US5346907A (en) * 1988-04-05 1994-09-13 Abbott Laboratories Amino acid analog CCK antagonists
WO1994018185A1 (en) * 1993-02-10 1994-08-18 Pentapharm Ag Piperazides of substituted phenylalanine derivates as thrombin inhibitors
EP0739886A2 (en) * 1995-04-28 1996-10-30 LG Chemical Limited Selective thrombin inhibitors
WO2002098856A2 (en) * 2001-06-06 2002-12-12 Schering Aktiengesellschaft Piperazine oxyquinoline (naphthaline) platelet adenosine diphosphate receptor antagonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KAMM W ET AL: "TRANSPORT OF PEPTIDOMIMETIC THROMBIN INHIBITORS WITH A 3-AMIDINO-PHENYLALANINE STRUCTURE: PERMEABILITY AND EFFLUX MECHANISM IN MONOLAYERS OF A HUMAN INTESTINAL CELL LINE (CACO-2)", PHARMACEUTICAL RESEARCH, NEW YORK, NY, US, vol. 18, no. 8, 2001, pages 1110 - 1118, XP009003114, ISSN: 0724-8741 *
PIERCE A C ET AL: "Estimation of Binding Affinities for Selective Thrombin Inhibitors via Monte Carlo Simulations", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY. WASHINGTON, US, vol. 44, no. 7, 2001, pages 1043 - 1050, XP002226501, ISSN: 0022-2623 *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008539224A (en) * 2005-04-28 2008-11-13 アクテリオン ファーマシューティカルズ リミテッド Pyrimidine derivatives
US8048881B2 (en) 2005-04-28 2011-11-01 Actelion Pharmaceuticals Ltd. Pyrimidine derivatives and their use as P2Y12 receptor antagonists
WO2007022241A3 (en) * 2005-08-17 2007-09-27 Schering Corp Novel high affinity quinoline-based kinase ligands
JP2009504753A (en) * 2005-08-17 2009-02-05 シェーリング コーポレイション A novel high affinity quinoline-based kinase ligand
KR101525260B1 (en) * 2006-10-13 2015-06-02 액테리온 파마슈티칼 리미티드 2-aminocarbonyl-pyridine derivative
WO2008044217A3 (en) * 2006-10-13 2008-06-19 Actelion Pharmaceuticals Ltd 2-aminocarbonyl-pyridine derivatives
US8093250B2 (en) 2006-10-13 2012-01-10 Actelion Pharmaceuticals Ltd. 2-aminocarbonyl-pyridine derivatives
WO2008044217A2 (en) 2006-10-13 2008-04-17 Actelion Pharmaceuticals Ltd 2-aminocarbonyl-pyridine derivatives
JP2010507646A (en) * 2006-10-25 2010-03-11 アクテリオン ファーマシューティカルズ リミテッド 2-Phenyl-6-aminocarbonyl-pyrimidine derivatives and their use as P2Y12 receptor antagonists
US8044055B2 (en) 2006-10-25 2011-10-25 Actelion Pharmaceuticals Ltd. 2-phenyl-6-aminocarbonyl-pyrimidine derivatives and their use as P2Y12 receptor
WO2008128647A1 (en) * 2007-04-23 2008-10-30 Sanofi-Aventis Quinoline-carboxamide derivatives as p2y12 antagonists
JP2010524984A (en) * 2007-04-23 2010-07-22 サノフィ−アベンティス Quinoline-carboxamide derivatives as P2Y12 antagonists
US8669266B2 (en) 2007-04-23 2014-03-11 Sanofi Quinoline-carboxamide derivatives as P2Y12 antagonists
US7910576B2 (en) 2007-06-18 2011-03-22 Sanofi-Aventis Pyrrole derivatives as P2Y12 antagonists
US8518912B2 (en) 2007-11-29 2013-08-27 Actelion Pharmaceuticals Ltd. Phosphonic acid derivates and their use as P2Y12 receptor antagonists
WO2009125366A1 (en) 2008-04-11 2009-10-15 Actelion Pharmaceuticals Ltd Substituted 2-phenyl-pyridine derivatives
US8466156B2 (en) 2008-04-11 2013-06-18 Actelion Pharmaceuticals Ltd. 2-phenyl-4-cyclopropyl-pyrimidine derivatives
US8058263B2 (en) 2008-04-11 2011-11-15 Actelion Pharmaceuticals Ltd Substituted 2-phenyl-pyridine derivatives
CN101998961A (en) * 2008-04-11 2011-03-30 埃科特莱茵药品有限公司 Substituted 2-phenyl-pyridine derivatives
US8288385B2 (en) 2009-04-08 2012-10-16 Actelion Pharmaceuticals Ltd. 6-(3-aza-bicyclo[3.1.0]hex-3-yl)-2-phenyl-pyrimidines
WO2010116328A3 (en) * 2009-04-08 2011-01-13 Actelion Pharmaceuticals Ltd 6-(3-aza-bicyclo[3.1.0]hex-3-yl)-2-phenyl-pyrimidines as adp receptor antagonists
US8664203B2 (en) 2009-04-22 2014-03-04 Actelion Pharmaceuticals Ltd. Thiazole derivatives and their use as P2Y12 receptor antagonists
CN102304108A (en) * 2011-06-28 2012-01-04 中国药科大学 Five-membered heterocyclic dicarbonyl derivative and application thereof on multi-drug resistant bacteria
US10730896B2 (en) 2016-09-22 2020-08-04 Idorsia Pharmaceuticals Ltd Crystalline forms
US11365209B2 (en) 2016-09-22 2022-06-21 Idorsia Pharmaceuticals Ltd Crystalline forms
US11179390B2 (en) 2017-03-15 2021-11-23 Idorsia Pharmaceuticals Ltd Subcutaneous administration of a P2Y12 receptor antagonist

Also Published As

Publication number Publication date
UA83648C2 (en) 2008-08-11
PL377053A1 (en) 2006-01-23
ZA200505492B (en) 2006-03-29
KR20050085580A (en) 2005-08-29
ATE477800T1 (en) 2010-09-15
CA2507657A1 (en) 2004-06-24
DE60333866D1 (en) 2010-09-30
EA200500899A1 (en) 2006-02-24
AP2005003363A0 (en) 2005-09-30
EP1578423A1 (en) 2005-09-28
MXPA05006302A (en) 2005-08-29
CA2507657C (en) 2011-05-31
NO20053335L (en) 2005-09-07
WO2004052366A9 (en) 2005-06-23
BR0317222A (en) 2005-11-01
OA12970A (en) 2006-10-13
US20060122188A1 (en) 2006-06-08
AU2003297763A1 (en) 2004-06-30
CN1747732A (en) 2006-03-15
NZ540872A (en) 2007-08-31
NO20053335D0 (en) 2005-07-08
US7084142B2 (en) 2006-08-01
JP4662777B2 (en) 2011-03-30
ES2348942T3 (en) 2010-12-17
US20040138229A1 (en) 2004-07-15
EP1578423B1 (en) 2010-08-18
US7056923B2 (en) 2006-06-06
JP2006511519A (en) 2006-04-06
ECSP055912A (en) 2005-11-22
RS20050450A (en) 2007-08-03

Similar Documents

Publication Publication Date Title
US7084142B2 (en) Platelet adenosine diphosphate receptor antagonists
US7026323B2 (en) Platelet adenosine diphosphate receptor antagonists
CA2395772C (en) Sulfonamide-containing heterocyclic compounds
WO2004078114A2 (en) Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-ii receptor antagonists.
US20110059981A9 (en) New Pyridine Analogues V
AU2007225693A1 (en) Novel 1,2,3,4-tetrahydroquinoxaline derivative having glucocorticoid receptor binding activity
CZ158098A3 (en) Quiinoline-4-carboxamide derivatives, process of their preparation pharmaceutical preparation and their use as antagonists of neurokinin 3(nk-3) and 2(nk-2) receptors
CA2668596A1 (en) Novel 1,2-dihydroquinoline derivative having substituted phenylamino lower alkyl group and ester-introduced phenyl group as substituents
JP2007522142A (en) Benzimidazole-substituted thiophene derivatives having activity against IKK3
JP2006501210A (en) Aminobenzothiazole compounds having NOS inhibitory activity
CA3201443A1 (en) Tetrahydroquinoline derivative and medicinal use thereof
AU2008264999B8 (en) Sulfonyl-quinoline derivatives
KR20060065662A (en) Aminoquinoline derivatives and their use as adenosine a3 ligands
WO2010073078A2 (en) Heterocyclic compounds as hdac inhibitors
EA010392B1 (en) Imidazole derivatives, the production thereof, and the use of the same as a medicament
NZ272258A (en) Substituted quinolone derivatives and pharmaceutical compositions

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: P-2005/0450

Country of ref document: YU

AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 168786

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2507657

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2373/DELNP/2005

Country of ref document: IN

WWE Wipo information: entry into national phase

Ref document number: 2004558607

Country of ref document: JP

WWE Wipo information: entry into national phase

Ref document number: PA/a/2005/006302

Country of ref document: MX

Ref document number: 377053

Country of ref document: PL

Ref document number: 2003297763

Country of ref document: AU

Ref document number: 1020057010688

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 540872

Country of ref document: NZ

COP Corrected version of pamphlet

Free format text: PAGES 13, 31 AND 33, DESCRIPTION, REPLACED BY CORRECT PAGES 13, 31 AND 33; DUE TO LATE TRANSMITTAL BY THE RECEIVING OFFICE

WWE Wipo information: entry into national phase

Ref document number: CR2005-007885

Country of ref document: CR

WWE Wipo information: entry into national phase

Ref document number: 200500899

Country of ref document: EA

WWE Wipo information: entry into national phase

Ref document number: 2003796831

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2005/05492

Country of ref document: ZA

Ref document number: 200505492

Country of ref document: ZA

WWE Wipo information: entry into national phase

Ref document number: 05067344

Country of ref document: CO

WWE Wipo information: entry into national phase

Ref document number: 20038A96637

Country of ref document: CN

WWP Wipo information: published in national office

Ref document number: 1020057010688

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 1-2005-501103

Country of ref document: PH

WWP Wipo information: published in national office

Ref document number: 2003796831

Country of ref document: EP

ENP Entry into the national phase

Ref document number: PI0317222

Country of ref document: BR