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WO1992012708A1 - Proprietes anticoagulantes de composes macrocycliques et procede de traitement - Google Patents

Proprietes anticoagulantes de composes macrocycliques et procede de traitement Download PDF

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Publication number
WO1992012708A1
WO1992012708A1 PCT/US1992/000501 US9200501W WO9212708A1 WO 1992012708 A1 WO1992012708 A1 WO 1992012708A1 US 9200501 W US9200501 W US 9200501W WO 9212708 A1 WO9212708 A1 WO 9212708A1
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WIPO (PCT)
Prior art keywords
acid
compound
subunits
composition
group
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PCT/US1992/000501
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English (en)
Inventor
Kou M. Hwang
You M. Qi
Su-Ying Liu
Thomas C. Lee
William Choy
Jen Chen
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Genelabs Technologies, Inc.
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Publication date
Priority claimed from US07/647,469 external-priority patent/US5166173A/en
Priority claimed from US07/647,720 external-priority patent/US5196452A/en
Application filed by Genelabs Technologies, Inc. filed Critical Genelabs Technologies, Inc.
Priority to AU12645/92A priority Critical patent/AU657308B2/en
Priority to KR1019930702267A priority patent/KR930702967A/ko
Priority to JP4505406A priority patent/JPH06505477A/ja
Publication of WO1992012708A1 publication Critical patent/WO1992012708A1/fr

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    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • C07C309/09—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton containing etherified hydroxy groups bound to the carbon skeleton
    • C07C309/11—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing oxygen atoms bound to the carbon skeleton containing etherified hydroxy groups bound to the carbon skeleton with the oxygen atom of at least one of the etherified hydroxy groups further bound to a carbon atom of a six-membered aromatic ring
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    • C07C309/41—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton
    • C07C309/42—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
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    • C07C309/43—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing singly-bound oxygen atoms bound to the carbon skeleton having at least one of the sulfo groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
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    • C07C309/45—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/49—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
    • C07C309/50—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms having at least one of the sulfo groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
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    • C07C309/57—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
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    • C07C309/57—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton
    • C07C309/60—Sulfonic acids having sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing carboxyl groups bound to the carbon skeleton the carbon skeleton being further substituted by singly-bound oxygen atoms
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/37—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/10—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C323/18—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton
    • C07C323/21—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and singly-bound oxygen atoms bound to the same carbon skeleton having the sulfur atom of at least one of the thio groups bound to a carbon atom of a six-membered aromatic ring of the carbon skeleton with the sulfur atom of the thio group bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system
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    • C07C65/01—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups
    • C07C65/105—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing hydroxy or O-metal groups polycyclic
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3834—Aromatic acids (P-C aromatic linkage)
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3882—Arylalkanephosphonic acids

Definitions

  • the present invention relates to macrocyclic
  • Blood coagulation or clotting is the result of a complex series of biochemical reactions.
  • hemostasis and the associated process of blood coagulation prevent undue loss of blood from an injured blood vessel.
  • inappropriate coagulation of blood may occur within the circulatory system in pathological states such as atheroschlerosis or in response to a variety of insults, including surgery and implantation of medical devices. This can lead to occlusion of a vessel and/or thromboembolism, in which all or part of a blood clot breaks loose and becomes lodged as an embolus in another region of the circulatory system.
  • emboli are, in some cases, life-threatening, especially when they cause obstruction of the pulmonary or cerebrovascular circulatory system.
  • Coagulation of blood can be stimulated by either of two different, but interconnected pathways - the
  • the intrinsic pathway is so called, because,
  • Factor IXa is a protease which converts inactive Factor X to active Factor Xa. This conversion is
  • Factor II prothrombin
  • Factor Ila thrombin
  • Factor Va can be released by stimulated platelets.
  • Thrombin is a protease which cleaves the high molecular weight fibrinogen to fibrin monomers. These monomers form a gel, to which red blood cells adhere to form a blood clot. The strength of the clot is increased by the fibrin monomer interchain transglutamination reactions, catalyzed by factor XIIIa.
  • clots are broken down ("dissolved") by an endogenous fibrinolytic system.
  • the active protease plasmin is formed from inactive plasminogen by enzymatic cleavage catalyzed in vivo by one or more of a number of
  • tissue plasminogen activator t-PA
  • Streptokinase, a bacterial product, or urokinase, isolated from human cells, are also capable of activating plasminogen, as shown in figure 14. Plasmin non-specifically cleaves fibrin and other plasma
  • Tissue Factor is a lipoprotein present on surfaces of non-circulatory cells, such as fibroblasts, or activated monocytes or endothelial cells to which the blood may be exposed in certain pathological states.
  • Factor VIIa in the presence of calcium, effects the conversion of Factor IX to Factor IXa as well as the conversion of Factor X to Factor Xa.
  • Factor VII itself has about 1/100 the proteolytic
  • agents which affect blood hemostasis fall into three categories: agents which interfere with platelet activation and aggregation, agents which
  • Aspirin, dipyridamole and ticlopidine are examples of anti-platelet drugs.
  • anti-clotting agents Their utilities as anti-clotting agents are generally limited to prophylaxis against atherosclerotic disease, repeat myocardial infarction, transient ischemic attack, and alone or in association with anticoagulants in certain cardiac valvular disorders. They are not
  • clotting events such as venous thrombosis, nor is there considered to be a mechanistic basis for their use in such disorders.
  • tissue plasminogen agents which promote disintegration of blood clots.
  • fibrinogen agents which promote disintegration of blood clots.
  • tissue plasminogen agents which promote disintegration of blood clots.
  • anticoagulant drugs are limited to the heparin-like compounds, which are active only when given intravenously, and to the oral coumarin
  • Heparin is an endogenous
  • glycosaminoglycan which serves as a catalyst for the reaction between antithrombin and various activated factors in the coagulation cascade (Factors IXa, Xa, XIa, Xlla, kallikrein and thrombin). This reaction results in inhibition of these factors, and thus inhibition of coagulation.
  • Heparin is not well absorbed orally and has a relatively short half-life in the bloodstream. Side effects of long term heparin therapy can include
  • thrombocytopenia with associated paradoxical arterial thrombosis, and, rarely, osteoporosis.
  • Overdosage with heparin can be antagonized by injection of protamine sulfate.
  • Oral anti-coagulants including warfarin and other coumarin derivatives, produce their effects on blood coagulation by indirect means. These compounds inhibit regeneration of vitamin K in the liver. Vitamin K is a precursor to several of the coagulation pathway factors, including Factors II (prothrombin), VII, IX, and X;
  • the coumarin drugs have a relatively long onset of therapeutic activity, since their effectiveness is dependent upon depletion of endogenous depots of active vitamin K.
  • Coumarin therapy requires careful management, due to a number of drug and nutritional interactions which serve increase or decrease effective dosage levels. Treatment with coumarin derivatives is also associated with several serious side effects
  • the prothrombin time assay (PT) is measures the extrinsic system of coagulation and is therefore used to detect deficiencies in factors II, V, VII, and X. PT is also used to monitor therapy in patients receiving coumarin anti-coagulants, since factors II and VII are among those which are dependent upon vitamin K.
  • the activated partial thromboplastin time assay (APTT) measures coagulation factors present in the intrinsic system of coagulation, with the exception of platelets and factor XIII. It is generally used to monitor heparin therapy. Plasma clotting time is another measurement of the intrinsic coagulation pathway, and is also useful in monitoring heparin therapy.
  • heparin As described above, current anti-coagulant regimens include treatment with various forms of heparin, or coumarin drugs. Of the two, the heparin drugs are by far the better tolerated and are easier to titrate. However, the usefulness of these compounds is limited by their currently obligatory intravenous route of administration. Although formulations of these compounds have been administered enterally, anticoagulant activity has been observed only after intraduodenal administration
  • Coumarin drugs such as warfarin can be given orally; however, the usefulness of these drugs is limited by their relatively long onset time, difficulty in
  • the present invention provides a method for
  • the method involves administering to a subject a macrocyclic compound
  • aryl ring subunits composed of aryl ring subunits connected one to another by ring-attached bridge linkages which form a continuous chain of connected backbone atoms.
  • the subunits have sulfonic acid-derived substituents on non-backbone atoms of the aryl subunit rings.
  • the ring subunits preferably include naphthalene subunits with sulfonic-acid derived substituents at the 3 and 6 ring positions, phenyl subunits with sulfonic acid-derived substituents at the 4 ring position, where the bridge linkages in the macrocycle are between the 2 ring-carbon position of one naphthalene or phenyl group, and the 7 ring-carbon group of an adjacent naphthalene group or 6 ring-carbon position of an adjacent phenyl group.
  • the compound preferably includes 4-8 such subunits.
  • the sulfonic acid-derived substituent is preferably sulfonic acid, a sulfonate salt, sulfinic acid, a sulfinate salt, a sulfone, or a sulfonamide.
  • the macrocyclic compound includes at least 4 naphthalene subunits, each having sulfonic acid-derived substituents at 3 and 6 ring-carbon positions , polar groups at 1 and 8 ring positions, and bridge linkages between the 2 ring-carbon position of one subunit and the 7 ring-carbon position of an adjacent subunit.
  • One preferred compound of this type has the general structure:
  • R 2 is sulfonic acid, sulfonate salt, sulfinic acid, a sulfinate salt, an alkyl sulfone, or a polar
  • the macrocyclic compound includes at least 4 phenyl subunits with para-position sulfonic acid derived substituents, bridge linkages between the 2 ring-carbon position of one subunit and the 6 ring-carbon position of an adjacent subunit.
  • One preferred compound of this type has the general structure:
  • n, R 1 , R 2 and R 4 are as above.
  • the compound may be administered orally or parenterally.
  • Such treatment method may further include administering to the subject a dose of protamine sufficient to reverse anti-coagulant effects of the compound.
  • the invention includes a method of inhibiting blood coagulation by administering to the subject a therapeutically effective dose of a macrocyclic biocompatible polymer composed having at least six regularly spaced sulfonic-acid derived substituents selected from the group consisting of an alkyl sulfone, and a polar sulfonamide of the form SO 2 NHR, where NHR is NH 2 , NHOH, or an amino acid.
  • a macrocyclic biocompatible polymer composed having at least six regularly spaced sulfonic-acid derived substituents selected from the group consisting of an alkyl sulfone, and a polar sulfonamide of the form SO 2 NHR, where NHR is NH 2 , NHOH, or an amino acid.
  • the polymer is a
  • macrocyclic compound composed or aryl ring subunits which are connected by ring-attached bridge linkages which form a continuous chain of connected atoms making up the backbone of the macrocycle, and which contain the
  • R 2 is sulfonic acid, sulfonate salt, sulfinic acid, sulfinate salt, a sulfone, or a sulfonamide
  • R 1 O, and -OH, an alkyl or aryl ether, ester, or acid, or a mixture thereof
  • Figure 1 shows the general structure of a
  • FIGS. 2A and 2B show non-oxidized (2A)
  • Figures 3A and 3B illustrate two general methods of synthesis of a macrocyclic compound like the one shown in Figure 2A;
  • Figures 4A and 4B show an unoxidized (4A) and partially oxidized (4B) macrocycle with mixed phenyl and sulfonated naphthalene subunits;
  • Figure 5 illustrates reaction methods for converting the sulfonic acid substituents of macrocyclic chromotropic acid to glycyl sulfonamide and sulfonamide groups
  • Figure 6 illustrates a reaction method for
  • Figure 7 shows the general structure of a
  • macrocyclic compound composed of phenyl groups with para-position sulfonic acid-derived substitutents, for use in the present invention
  • Figures 9A and 9B illustrate general methods of synthesis of non-oxidized and partially oxidized forms of the Figure 8 compound
  • Figure 10 shows a reaction scheme for replacing the ring hydroxyl groups in the Figure-8 compound with acetyl groups
  • Figure 11 shows a reaction for converting sulfonic acid substituents to a glycyl sulfonamide group in a phenyl-subunit macrocyclic compound
  • Figure 12 shows a reaction scheme for producing a macrocylic compound like that shown in Figure 8 but with carboxylic acid-containing bridge linkages
  • Figure 13 shows a reaction scheme for replacing hydroxyl groups in the Figure-8 compound with carboxylic acid groups.
  • Figure 14 shows a schematic of the cascade of biochemical events which occur in the coagulation process in mammalian blood
  • Figure 15 shows a plot of prothrombin time in seconds (PT) as a function of concentration of KY-1, Y-1, and Y-49;
  • Figure 16 shows a plot of activated partial
  • thromboplastin time in seconds as a function of concentration of KY-1, Y-1, and Y-49;
  • Figure 17 shows a plot of APTT determined at various times after intravenous injection of 2.5 mg/kg (X) or 5.0 mg/kg ( ⁇ ) Y-1 in mice, where APTT is expressed as percent untreated control sample value run in parallel;
  • Figure 18 shows a plot of percent control APTT as a function of i.v. injected dose of Y-1 in rats, where APTT is expressed as percent untreated control value run in parallel;
  • Figure 19 shows a plot of thrombin time (TT) as a function of concentration of KY-1, Y-1, and Y-49;
  • Figure 20 shows a plot of atroxin time (AT) as a function of concentration of KY-1, Y-1, and Y-49;
  • Figures 21 show traces of change in optical density as a function of time in a platelet aggregation assay in which platelet aggregation was measured in the presence of collagen (A), collagen plus 24 (B) or 48 ⁇ g/ml (C) Y-49, collagen plus 24 (D) or 48 (E) ⁇ g/ml Y-1, collagen plus 24 (F) or 48 (G) ⁇ g/ml KY-1;
  • Figures 22 show plots of effects of varying concentrations of Y-1 (A), KY-1 and heparin (B) on plasmin activity;
  • Figure 23 A shows a composite plot of varying concentrations of KY-1 on clotting times measured as PT, TT, APTT, and AT;
  • Figure 23B shows a composite plot of varying
  • Figures 24A and 24B show plots of TT and APTT as a function of concentration of KY-1 (24A) or heparin (24B) concentration in plasma. Detailed Description of the Invention
  • Anticoagulant activity refers to the inhibition of the normal blood coagulation or clotting process
  • An "aryl ring” subunit is single ring or fused ring structure containing at least one aromatic ring, i.e., a 5- or 6-membered ring with the 6 pi electrons necessary for aromaticity.
  • aromatic ring i.e., a 5- or 6-membered ring with the 6 pi electrons necessary for aromaticity.
  • Examples include benzene, naphthalene, mixed aromatic and non-aromatic fused ring structures, such as tetralin, and heterocyclic structures, including fused-ring structures, such as quinoline, isoquinoline, and indole.
  • a "macrocyclic compound composed of aryl ring subunits” is a cyclic compound formed by linking ring atoms in aryl ring subunits to form a cyclic chain.
  • a "ring-attached bridge linkage” is a linkage between a ring atom of one aryl subunit to a ring atom of an adjacent aryl subunit in a macrocyclic compound
  • the chain is formed by the bridge linkages (R 4 ) to positions 2 and 7 of the naphthalene rings and the 5 ring atoms in naphthalene between positions 2 and 7.
  • the chain is formed by the bridge linkages (R 4 ) to positions 2 and 6 of the benzene rings and the 3 ring atoms in benzene between positions 2 and 6.
  • the non-chain atoms include the 5 naphthalene ring atoms from ring positions 3-6; in the Figure-7 compound, the 3 ring atoms from positions 3-5.
  • a "sulfonic acid-derived substituent” includes sulfonic acid, a sulfonic acid salt, sulfinic acid, sulfinate salts, alkyl and aryl sulfones, sulfonamides of the form SO 2 NHR, where R is H or a substituent having an OH, ether, ester, ketone, or acid moiety.
  • the first type is composed of naphthalene subunits with sulfonic acid-derived substituents, described in
  • subsection A The second general type is composed of phenyl subunits having para-position sulfonic acid-derived substituents, described in subsection B. From the synthetic routes given in the two sections, it will be apparent how macrocycles composed of mixed subunits, e.g., both naphthalene and phenyl subunits can be
  • the synthetic methods are also generally applicable to macrocycles composed of heterocyclic subunits with sulfonic acid-derived substituents.
  • Figure 1 shows the general structural formula of a macrocyclic compound composed of substituted naphthalene subunits, for use in the present invention.
  • exemplary compound of this type is shown in non-oxidized (I) and partially oxidized (II) form in Figures 2A and 2B, respectively.
  • the compound is a tetramer of
  • chromotropic acid (1,8-dihydroxy, 3,6-disulfonic acid naphthalene) subunits linked by methyl or methylene (>CH 2 or ⁇ CH) bridges (R 4 ).
  • R 4 methyl or methylene (>CH 2 or ⁇ CH) bridges
  • R 2 is a sulfonic acid-derived substituent which may be sulfonic acid, as shown in Figure 2, a sulfonate salt, sulfinic acid (-SO 2 H), and sulfinate salts, sulfones, and sulfonamides.
  • R 3 is H or Br or other halogen.
  • the R 4 bridge linking the chromotropic acid derivative subunits is preferably of the form >CHR or ⁇ CR (indicating
  • R unsaturated bridges in the partially oxidized form
  • R is H or a small carbon-containing group, such as lower alkyl, alkenyl, ketone, or carboxylic acid group, or aryl group.
  • the bridge may also be of the form - CH 2 NR'CH 2 -, where R' is similarly H or a small carbon containing group, such as a lower alkyl group.
  • the bridges in the macrocycle may be ring structures, including aryl ring structures, such as in the dimeric macrocycle shown in Figure 4, or analogous structures formed by bridging through heterocyclic rings, such as pyrole or furan rings.
  • the number of subunits may vary from 4 to 8, with macrocycles containing 4, 6, and 8 subunits being
  • R 1 , R j 2 R 3 , and R 4 substituents in Table 1 below are identified by their R 1 , R j 2 R 3 , and R 4 substituents in Table 1 below.
  • the KY and Y number in the lefthand column in the table refers to the analog designation of the
  • the method illustrated in Figure 3A involves cyclization of a chromotropic acid derivative (including chromotropic acid itself) with an aldehyde (RCHO) to form a macrocyclic compound, such as the tetramer shown Figure 2, in which the chromotropic acid subunits are linked by R-substituted methylene groups, i.e., in which R 4 is >CHR (including >CR).
  • RCHO aldehyde
  • chromotropic acid (III) is reacted with formaldehyde.
  • Example 1A for the synthesis of KY-1.
  • KY-42 is prepared by cyclization with glyoxylic acid (Example 1C); KY-48, in the presence of glyceraldehyde; KY-85, in the presence of benzaldehyde; KY-97, in the presence of acrolein; and KY-110, in the presence of pyruvic aldehyde.
  • glyoxylic acid Example 1C
  • KY-48 in the presence of glyceraldehyde
  • KY-85 in the presence of benzaldehyde
  • KY-97 in the presence of acrolein
  • KY-110 in the presence of pyruvic aldehyde.
  • the R bridge group may be further modified after the cyclization reaction.
  • KY-193 may be prepared by bromination of the KY-97 compound.
  • cyclization of the chromotropic acid derivatives (III) is carried out by reaction with hexamethylenetetramine, to form a 3-atom chain bridge of the type -CH 2 N(CH 3 )CH 2 - (V).
  • Example 1J cyclization reaction for the synthesis of KY-346 is given in Example 1J.
  • the -CH 2 N(CH 3 )CH 2 - bridge may be modified, after the cyclization reaction, to form a variety of N- substituted bridges of the -CH 2 N(R')CH 2 -, where R' is one of a variety of small carbon-containing groups, according to known synthetic methods.
  • Some of the bridges in the partially oxidized structure will have the form
  • FIG. 4A and 4B show the non-oxidized (VI) and partially oxidized (VIII) forms of the compound.
  • the chromotropic acid derivative is modified after cyclization so that the cyclized product will either contain the selected R 1 , R 2 , and R 3 substituent, or contain a substituent which can be readily modified to the selected substituent.
  • This approach is illustrated by the synthesis of KY-3, which has an SO 2 NH 2 R 2 substituent, as detailed in Example 1B.
  • cyclized chromotropic acid (VIII) is reacted first with chlorosulfonic acid, to form the corresponding R 2 - SO 2 Cl derivative (IX, Figure 5).
  • Figure 6 illustrates the conversion of sulfonyl groups of cyclized chromotropic acid to sulfinyl (XII) and alkyl sulfone or methyl sulfinyl ester (XIV).
  • the first stage of the reaction involves the formation of the
  • macrocyclic compounds with a variety of R- substituents may be prepared by modification of
  • chromotropic acid after cyclization.
  • cyclized chromotropic acid is first converted to the diether of hexanoic acid by initial reaction of cyclized chromotropic acid with 6-bromohexan- oic acid under basic reaction conditions.
  • chromotropic acid is reacted with an acid chloride of the form RCOCl, under basic conditions, as detailed in
  • the selected substituent is formed on the subunit naphthalene rings by derivatiza- tion of the naphthalene subunit, with subsequent subunit cyclization to form the desired macrocycle.
  • Example IH Reaction details are given in Example IH. Among other examples of this approach are KY-123 (Example 1G) and KY-147 (Example 1E).
  • the synthetic method for forming selected-substituent macrocyclic compounds may include both prior derivatization of chromotropic acid and subsequent derivatization of the subunits after cyclization.
  • chromotropic acid subunits are first reacted at the R 1 positions, to form the methyl ether derivative as described above.
  • formaldehyde the compound is further derivatized at the R 2 position, also as described above, to convert the SO 3 Na group to the desired SO 2 NH 2 substituent.
  • the KY compounds described above can be converted readily to a variety of sulfonic acid or sulfonate salts, by reaction in acid or in the presence of a suitable salt, according to well known methods.
  • a suitable salt such as ammonium chloride.
  • the macrocyclic compound shown in Table 1 are ammonium salts formed by cation exchange of protons in the presence of an ammonium salt, such as ammonium chloride.
  • exposure of the macrocyclic compound to a variety of metal cations such as the cations of Ca, Ba, Pt, Cu, Bi, Ge, Zn, La, Nd, Ni, Hf, or Pb, may produce both a metal salt and a metal chelate of the macrocyclic compound in which the metal is chelated at interior polar pocket in the compound.
  • Figure 7 shows the general structural formula of a macrocyclic compound composed of substituted phenol subunits, for use in the present invention.
  • Figure 8 is a tetramer of phenol para-sulfonic acid subunits linked by methylene bridges (XV).
  • XV methylene bridges
  • Figure 9A illustrates a general method for forming macrocyclic compounds of this type.
  • the macrocyclic precursor shown at the left (XVI) is a class of compounds known generally as tert-butyl calix(n)arenes, where n is the number of phenolic subunits (with para-position t- butyl substituents) in the macrocycle, and the bridge connections are methylene groups, t-butyl calixarenes with 4, 6, and 8, subunits are commercially available.
  • a t-butyl calixarene with a selected subunit number is treated with concentrated sulfuric acid, typically for about 4 to 5 hours at 75-85°C to effect substantially complete displacement of the 4-position t-butyl group by a sulfonic acid group.
  • concentrated sulfuric acid typically for about 4 to 5 hours at 75-85°C.
  • a similar method is used for preparing a sulfonated calixarene with partially oxidized 1-position OH groups, as shown at 9B.
  • the t-butyl calixarene starting material is treated with cone, sulfuric acid at a temperature above 100°C, preferably between 150-170°C.
  • the reaction is effective to sulfonate the subunit rings and to partially oxidize the interior OH groups.
  • partial oxidation can lead to a conjugated macrocyclic structure (XVIII) in which bridge contributes delocalized electrons. This conjugated structure is colored, and the development of a colored product can be used to monitor the course of the
  • the desired macrocycle can also be formed directly by reacting para-sulfonic acid phenol (or precursors thereof) under suitable bridging conditions, such as described above for producing
  • naphthalene-subunit macrocycles This is illustrated by the reaction shown in Figure 12, for production of a macrocyle having carboxylic acid-containing bridge groups.
  • phenol para-sulfonic acid is reacted with glyoxylic acid, under conditions similar to those described in Example 2C, to form the cyclized structure shown (XXII).
  • the macrocyclic compounds formed as above can be modified, according to general procedures outlined in Section IIA above, to achieve selected R 1 groups,
  • FIGS 10, 11, and 13 illustrate various reaction methods for modifying the R, group of an already formed macrocycle.
  • the sulfonated structure shown in Figure 8 is treated with acetic anhydride, to form an O-acetyl R 1 group. Details of the reaction are given in Example 2C. Since this structure would be expected to undergo hydrolysis in the presence of serum esterases, differences in the activity of the ester compound and the free OH compound would be expected to occur after intravenous (IV) administration.
  • Example 2G describes a similar reaction scheme for forming a toluene sulfonic acid ester at the R 1 position.
  • Figure 11 illustrates a general method for forming sulfonamides, such as glycylsulfonamide (XXI) of the
  • Example 2E for the synthesis of the glycyl sulfonamide compound.
  • the R 4 bridge linking the chromotropic acid derivative subunits is preferably of the form >CHR or ⁇ CR, where R is H or a small carbon-containing group, such as lower alkyl, alkenyl, ketone, or carboxylic acid group, or aryl group, as noted above, or of the form -CH 2 NR'CH 2 -, where R' is similarly H or a small carbon containing group, such as a lower alkyl group.
  • the bridges in the macrocycle may be ring structures, including aryl ring structures, analogous to the dimeric macrocycle shown in Figure 4.
  • the number of subunits may vary from 4 (e.g., Figure-4 structure) to 8, with macrocycles
  • the macrocycle formed may include mixtures of compounds with different subunit numbers (n)
  • n 4 structure (4 subunits) plus additional structures containing 5-8 subunits.
  • Assays which are used in assessing anticoagulant activity and, to some degree, mechanism of anticoagulant activity include, but are not limited to the activated partial thromboplastin time (APTT) assay, the prothrombin time (PT) assay, the thrombin time (TT) assay, the fibrinogen assay, the reptilase (atroxin time, AT) assay, and the plasma clotting (recalcification) time assay.
  • APTT activated partial thromboplastin time
  • PT prothrombin time
  • TT thrombin time
  • fibrinogen assay the reptilase (atroxin time, AT) assay
  • plasma clotting (recalcification) time assay Such assays and specific methods for carrying them out are known generally in the art and are described by Brown (1988).
  • the blood used to test compounds in such assays may be from a variety of vertebrate sources, although mammalian, and particularly human sources are preferred.
  • venous blood samples are obtained using clean venipuncture procedures, in order to prevent contamination of the sample by exogenous cells.
  • Blood samples employed in the screening compounds useful in the method of the invention may be collected in any of a number of standard collection tubes holding a calcium binding or chelating agent. Plastic tubes are preferred; however, glass-walled VACUTAINER TM tubes containing sodium citrate as a calcium binding agent are adequate in practicing most experiments supporting the invention.
  • Freshly drawn samples are stored at ice temperature for up to 2-4 hours prior to further processing, and are checked for the presence of clots or hemolysis; any tubes containing clots are discarded.
  • Plasma is obtained from the samples, using centrifugation procedures described in Example 4A. Plasma samples showing evidence of hemolysis are discarded, since hemolysis is known to shorten clotting time. Ideally, plasma samples are stored on ice and tested within 8 hours of collection. Alternatively, the samples may be frozen at -20° for testing within 1 week of collection. General methods used in collecting and processing blood samples for experiments in support of the invention are found in Example 4A.
  • Tests for anticoagulant activity may be carried out in vitro, wherein compound is added to an isolated plasma or blood sample, and effects on clotting time are measured. Anticoagulant activity may also be measured following administration of a compound to a whole animal. Such in vivo assessment of compound effects indicates the degree to which a drug is absorbed, distributed or biotransformed in the whole animal, and gives a measure of bioavailability.
  • Plasma clotting or recalcification time measures the integrity of intrinsic coagulation system. A deficiency or inhibition of any of the factors of the intrinsic system results in prolongation of plasma clotting time. Both heparin and coumarin anticoagulants prolong plasma clotting time.
  • plasma is mixed with calcium chloride at 37°, mixed and observed for clot formation.
  • Phenylic macrocyclic compounds KY225 and Y-47 exhibited the highest anti-coagulant activity in this assay. Concentrations of 12.5 ⁇ g of each of these compounds produced anticoagulant activity equivalent to 7.54 and 5.68 ⁇ g of heparin, respectively. Phenylic derivatives Y-48, Y-77, Y-78, Y-100 and Y-1 and napthylic derivatives Y-20, KY-42, KY-1, KY-357 and KYY-19 were approximately equipotent in the assay, exhibiting activities about 1/10-1/20 that of heparin on a mass basis.
  • Anticoagulation activity is to high to be measured in the assay.
  • mice The effects of Y-1 on clotting time following oral administration were studied in mice, as described in Example 13.
  • Table 4 shows the results of a study in which two doses of 500 or 625 mg/kg each of Y-1 were administered to female Swiss-Webster mice at 30 minute intervals by gastric gavage. Blood samples were
  • Y-1-treated animals showed increased clotting time, at both doses tested.
  • Y-1 (12 or 20 ⁇ g/ml) was also added directly to plasma samples from control animals, and plasma clotting times obtained were within the range of the times reported after oral administration of the compound.
  • Prothrombin time assesses the patency of the extrinsic coagulation pathway, and measures the presence of factors II, V, VII, and X. This assay also serves as an indicator of levels of fibrinogen less than about 80 mg/dL.
  • Prothrombin time is therefore useful in assessing therapy by coumarin anticoagulants, which inhibit production of factors II, VII, IX, and X.
  • the presence of relatively high concentrations of heparin in blood samples also prolongs prothrombin time measurements.
  • Example 4B Methods used in determining PT can be found in Example 4B. Briefly, the assay involves the addition of a tissue factor, such as thromboplastin-calcium reagent (Dade® Thromboplastin»C, Becton Dickinson) to a plasma sample. The duration of time from the time of addition until visible clot formation is observed is the PT.
  • a tissue factor such as thromboplastin-calcium reagent (Dade® Thromboplastin»C, Becton Dickinson)
  • Macrocyclic compounds KY-1, Y-1 and Y-49 were tested in a PT assay using human blood, as described in Example 6.
  • Human plasma samples containing varying amounts of test compound (0-250 ⁇ g/ml, final concentrations) were tested clotting time subsequent to mixing with thromboplastin-calcium reagent.
  • Macrocyclic compounds of the invention were given intravenously to rats at doses of 5 and 10 mg/kg (2 rats/dose). Subsequently (5 hours following
  • venous blood samples were tested for PT, APTT, and fibrinogen.
  • Table 5 shows the percent change in PT observed, as compared to the PT of blood plasma from saline-treated controls. Moderate increases in PT were observed for several of the compounds tested, most notably KY-225 and KY-226, partially oxidized macrocyclic compounds having 4 and 8 phenyl subunits, respectively.
  • Y-1 was administered at oral (p.o.) doses of 300 and 450 mg/kg to rats. Blood samples were taken and PT determinations made at times from 0.5 to 24 hours following administration, as
  • the APTT assay is employed as a measure of the integrity of the intrinsic blood coagulation pathway, described above. It measures the presence of all coagulation factors in the intrinsic system except platelets and factor XIII, and is commonly used to monitor heparin therapy, since heparin binds to several of the factors of the intrinsic pathway (XIa, IXa, Xa, thrombin).
  • Detailed methods used in carrying out this assay can b found in Example 4C. Briefly, the plasma sample is mixed with activated thromboplastin, such as Actin® Activated Cephaloplastin Reagent (Becton Dickinson). The tube containing the mixture is placed in a 37° water bath for 3 minutes, prior to addition of calcium chloride. The sample is then observed for fibrin web formation.
  • activated thromboplastin such as Actin® Activated Cephaloplastin Reagent (Becton Dickinson).
  • the tube containing the mixture is placed in a 37° water bath for 3 minutes, prior
  • Platelet poor plasma (human) was used to test the effects of KY-1, Y-1 and Y-49 on APTT, as described in Example 7.
  • Figure 16 shows the results of these
  • APTT prolongation of APTT was further examined, using rats as test animals.
  • compound Y-1 was given intravenously to animals at a doses of 2.-5 and 5 mg/kg, and blood samples were drawn from four different animals at various times following administration.
  • APTT induced an immediate prolongation of APTT to approximately 300% of normal or higher, with the anti-coagulant effect persisting up to 4-6 hours after the 2.5 mg/kg dose and remaining approximately 20% abve normal at 12 hours after the 5 mg/kg dose.
  • Data are expressed as percent of control values for each set of animals to normalize values obtained in different
  • Figure 18 illustrates the APTT dose-response
  • Murine plasma was tested for clotting time subsequent to oral administration of compound Y-1, as described in Example 13, and shown above in Table 4.
  • protamine sulfate was added to plasma samples from Y-1 treated animals at a concentration of 10.4 ⁇ g/ml. Addition of protamine sulfate to the samples resulted in reversal of the Y-1-induced prolongation of clotting times.
  • Fibrinogen is the polymeric precursor of fibrin monomers, which spontaneously polymerize to initiate clot formation.
  • fibrinogen is converted to fibrin by the proteolytic action of thrombin.
  • Fibrinogen content of blood may be affected by a number of insults. Lack of fibrinogen reduces clot formation.
  • the presence of relatively high concentrations of heparin in samples can result in an artificially low value for fibrinogen content as determined by the thrombin time assay (see following section), due to inhibition by heparin of endogenous and added thrombin.
  • Fibrinogen content of blood can be measured by adding an excess of thrombin to a dilute plasma sample and recording clotting time, as described in Example 4E.
  • Fibrinogen contents of plasma samples taken from rats previously given intravenous doses of various macrocyclic compounds are shown in Table 5, above. At higher doses, it is apparent that KY225, KY226, and, to a lesser degree, Y-48 treatment resulted in a decrease in
  • Thrombin time is another measure of the conversion of fibrinogen to fibrin, catalyzed in the blood by the enzyme thrombin. Prolonged thrombin times can be caused by a number of factors, including low fibrinogen levels, heparin, and other thrombin inhibitors such as fibrin degradation products.
  • the assay is carried out by adding a stock quantity of purified thrombin to platelet poor plasma samples, as described in Example 4G and recording the amount of time required for clot formation in the plasma.
  • Example 8 are shown in Figure 19, where it is seen that the presence of KY-1 in the plasma sample markedly increased thrombin time, whereas Y-49 showed no activity at the concentrations tested. 6. Reptilase Assay (Atroxin Time)
  • Reptilase an enzyme isolated from snake (Bothrops atrox) venom, which converts fibrinogen to fibrin, is not affected by heparin. It is therefore useful in testing for fibrinogen content of the blood of patients receiving heparin therapy. Blood from patients receiving a
  • fibrinolytic agent such as streptokinase
  • Integrity of platelet aggregation in a blood sample can be measured by a characteristic change in optical density of a platelet rich plasma sample in response to platelet aggregation promoting factors, such as ADP or collagen, as described in Example 4H.
  • platelet aggregation promoting factors such as ADP or collagen
  • KY-1 and Y-1 serve as prototype napthyl and phenyl macrocyclic compounds in analyzing the effects of these classes of compounds on blood coagulation.
  • Y-1 also prolonged PT, APTT, TT and AT. In contrast to KY-1, the effect of Y-1 on AT was minimal, with no
  • Y-1 exhibited anti-platelet activity.
  • Y-1 and KY-1 were shown to be active in vivo, when administered either parenterally or orally. Peak effects after oral administration were dose dependent and were observed between about 0.5 and 4 hours following oral administration of 450 mg/kg Y-1, as assessed by APTT (Table 6).
  • an aryl macrocyclic compound of the type described in Section II is administered to the bloodstream of a patient at risk for developing thromboembolism.
  • the compounds of the invention appear to have direct effects on a factor or factors present in the coagulation
  • the main routes of drug delivery are intravenous and oral, with the preferred route being oral.
  • Other drug- administration methods such as intra-arterial,
  • subcutaneous, or nasal insufflation which are effective to deliver the drug into the bloodstream, are also contemplated.
  • the dosage which is administered is a pharmaceutically effective dose, defined as a dose effective to prolong coagulation time of blood in a patient.
  • a pharmaceutically effective dose defined as a dose effective to prolong coagulation time of blood in a patient.
  • compound concentrations in the range of 10-100 ⁇ g/ml are generally effective to inhibit coagulation, as assessed by plasma recalcification time, APTT or PT, in vitro.
  • an effective dose would be one which produces a concentration of compound in this range in the blood.
  • aryl macrocyclic compounds produce anti-coagulant effects for 4 hours or longer in a dose-related manner following intravenous administration.
  • the crude chloride product was dissolved in 100 ml of 25% ammonium water solution and allowed to react for 2 hours at room temperature. The mixture was concentrated in vacuo and the remaining oil was dissolved in a small amount of water and filtered. The product was precipitated by adding acetonitrile to the filtrate and collected by filtration and washing with acetonitrile.
  • the compound was characterized as follows: Melting point (M.P.)> 300°C;
  • UV (H 2 O) 246 nm
  • Chromotropic acid, disodium (10mM) in 50 ml water was mixed with glyoxylic acid (10.0 mM, in 5 ml water) and 10 ml of 37% hydrogen chloride at room temperature. The mixture was boiled for 8 hours and the color of the solution turned to dark red. The resultant solution was added to 50 ml of water and filtered. The filtrate was concentrated and ethanol was added to precipitate the product of KY-42. The yield was 87%.
  • the compound was characterized as follows:
  • KY-1 (2mM) was treated with 5 ml chlorosulfonic acid and the mixture was stirred at 50°C for one-half hour. The resultant mixture was added to 50 g of crushed ice to precipitate the product which was collected by filtration and then washed with ether.
  • the crude sulfonyl chloride product was treated with sodium sulfite (20 mM) in 4 ml water.
  • the reaction mixture was kept slightly alkaline by addition at intervals of small portions of 50% NaOH for 2 days.
  • ethanol was added to precipitate the product, which was acidified by addition of 50% H 2 SO 4 , followed by addition of ethanol to precipitate sodium sulfate.
  • the ethanol phase was mixed with ether (1:2, v/v) to precipitate the desired product.
  • N-methyl chromotropic acid chloride was formed by reacting chromotropic acid (disodium salt) with
  • KY-1 (50mM) was dissolved in 80 ml of NaOH water solution (0.2M NaOH) and heated to 50°C, dimethylsulfate (0.2M) was added slowly for 1 hour. The mixture was continuously stirred for another 2 hours and left at room temperature for 2 days. Saturated NaCl solution (100 ml) was added to the resultant substance and filtered. The precipitate was washed with ethanol, acetonitrile and ether sequentially. The dry substance was dissolved in 100 ml of methanol and filtered. The filtrate was concentrated and ether was added to precipitate the methyl ether of KT-1.
  • KY-1 from Example 1A was first treated with thionyl chloride to produce chromotropic acid sulfonyl chloride. This compound was reduced by excess sodium sulfite in the presence of sodium bicarbonate to produce the correspond- ing sodium sulfonate salt of cyclized chromotropic acid (R 2 - SO 2 Na). The sulfonate salt was treated with
  • Chromotropic acid was first treated with thionyl chloride to produce chromotropic acid sulfonyl chloride.
  • Chromotropic acid disodium salt was dissolved in 80 ml of water at a concentration of 50 mM with stirring at 50°C until the solution turned to clear, hexamethylenetetramine (50 mM) was then added to above solution with continuous stirring at the same temperature for additional two hours. At this time, the color of this mixture converted to dark blue. The mixture was allowed to stir at room temperature for 2 days. The resultant dark blue solution was filtered and the filtrate was concentrated, evaporated by flask, which was subsequently treated with 200 ml methanol to precipitate the product KY-346. The yield of KY-346 was 85%.
  • the compound was characterized as follows:
  • 4-tert-butylcalix(4)arene (10 g) was treated with 200 ml of concentrated H 2 SO 4 at room temperature for 0.5 hour and then at 75-85°C oil bath for another 4 hours. The reaction was completed when no water-insoluble material was detected. The resultant oil was dropped into 500 g of crushed ice and the solution was filtered by reduced pressure. After the water removed away from the
  • 4-tert-Butylcalix(4)arene (1 g) was treated with 10 ml of 95-98% sulfuric acid at room temperature for 0.5 hours then at 160°C for 5 minutes. After the resultant mixture was cool, the mixture was poured slowly into 100 ml of crushed ice and filtrated. The solution was evaporated and the residual was added with 300 ml acetonitrile to produce great amount of precipitate which was collected by filtration and washed with acetonitrile. The crude product was dissolved in 20 ml methanol and the product was precipitated by addition of diethyl ether. Yield was 84%.
  • Y-1 (1 g) is heated at 60-70°C with chlorosulfonic acid (20 ml) for 1 hour. After cooling to room temperature, the oily material is poured into ice water, and the precipitate is filtered. After washing the precipitate with cold water, the crude product is dissolved in 100 ml of 25% ammonium water solution and allowed to react for 2 hours at room temperature. The mixture is concentrated in vacuo and the remaining oil is dissolved in a small amount of water and filtered. The product is precipitated by adding acetonitrile to the filtrate and collected by filtration and washing with acetonitrile.
  • Y-1 (1 g) is heated at 60-70°C-with chlorosulfonic acid (20 ml) for 1 hour. After cooling to room temperature, the oily material is poured into ice water, and the precipitate is filtered. After washing the precipitate with cold water, the material is added to 50 ml of solution containing 5.7 g glycine and 2.1 g NaOH, and stirred for 2 hours at room temperature. After removal of all solvent from the resultant substance, the residue is dissolved in a 200 ml of cold methanol and filtered. The filtrate is added with acetonitrile to precipitate the product.
  • trifluoromethanesulfonic anhydride (1.0 ml) is added to ice cold dry dichloromethane solution (10 ml) of 2,6, di-tert-butyl-4-methylpyridine (1.25 g) and 4-tert-butylcalix[4]arene (0.65 g). After overnight stirring at room temperature, the mixture is diluted with pentane (10 ml) and filtered. The filtrate is extracted with ice cold 1N aqueous NaOH solution, ice cold 1N aqueous HCl solution, then saturated aqueous NaCl
  • Chromotropic acid, disodium (10 g) in 55 ml of water was treated with 22 ml of 30 ml 37% HCl. To this
  • Venous blood samples were taken using clean
  • Samples were collected in collection tubes (VACUTAINER TM ) containing sodium citrate such that 9 parts of blood were added to 1 part of 3.8% sodium citrate, and placed in an icebath. Prior to centrifugation, blood samples were checked for the presence of clots, and any tubes containing clots were discarded.
  • VACUTAINER TM collection tubes
  • Plasma samples were then placed in an icebath for testing within 8 hours of collection, or were
  • Plasma samples collected as described in Example 4A were pre-warmed to 37° in a waterbath, then 0.1 ml aliquots above were forcibly added to tubes containing 0.2 ml thromboplastin-calcium reagent (Dade®
  • Thromboplastin ⁇ C Becton Dickinson
  • Thromboplastin ⁇ C Becton Dickinson
  • APTT Activated Partial Thromboplastin Time
  • Plasma samples were collected as described in Example 4A and stored in an icebath until testing. 0.1 ml of plasma sample was mixed with 0.1 ml of partial
  • thromboplastin Actin® Activated Cephaloplastin Reagent; Becton Dickinson
  • thromboplastin Actin® Activated Cephaloplastin Reagent; Becton Dickinson
  • the tube containing the mixture was placed in a 37° water bath for 3 minutes, prior to addition of 0.2 ml of pre-warmed (37°) 0.025 M calcium chloride).
  • the tube was then tilted gently at 5 second intervals, for a total of 20 seconds at 37°, then removed from the water bath and the periodic tilting continued as the sample was observed for fibrin web formation. All samples were assayed in duplicate.
  • Clotting time was determined after addition of thrombin reagent (Data-Fi® Thrombin Reagent, Baxter Healthcare Corp., Miami, FL; reconstituted according to
  • Plasma samples were centrifuged to produce platelet poor plasma (1500 ⁇ g, 15 min.), as described in Example 4A. Plasma samples (0.2 ml) were incubated at 37° for 5 minutes. ATROXIN® (Sigma Chemical Co., St. Louis, MO), prewarmed to 37°, was added as a 0.1 ml aliquot to each sample tube with mixing to initiate the reaction. Time to clotting was recorded as Atroxin time. G. Thrombin Time Assay (TT)
  • Thrombin solution was prepared by diluting concentrated stock human a-thrombin (4270 u/ml) into barbital buffered saline, pH 7.35 to achieve a 10X concentrated working stock. The final concentration of thrombin to be used in standard assays was determined by testing serial
  • Platelet poor plasma was prepared as described in Example 4A, and prewarmed at 37° in 0.18 ml aliquots. Test compounds or saline were added to the plasma samples to produce a final volume of 0.2 ml. The reaction was initiated by addition of 10 ⁇ l of 10-fold concentrated stock purified human a-thrombin to each sample. Incubation was
  • Plasma samples were drawn with a plastic syringe and transferred to plastic test tubes containing a sufficient volume of sodium citrate to produce a final concentration of 0.011 M sodium citrate in the sample.
  • Samples of platelet rich plasma (PRP) and platelet poor plasma (PPP) were prepared from each sample by first centrifuging the sample at 150 ⁇ g for 5 minutes at room temperature and collecting the red blood cell free supernatant (PRP), then centrifuging the remaining blood at 1500 ⁇ g for 15 minutes to obtain the PPP supernatant.
  • PRP platelet rich plasma
  • PPP platelet poor plasma
  • a control 0.5 ml sample of PPP was transferred to an aggregometer cuvette. Several 0.45 ml samples of room temperature PRP were transferred to separate cuvettes. A baseline reading of the PPP sample was obtained by placing the PPP in the aggregometer and incubating at 37° according to aggregometer manufacturer's instructions. A PRP sample was then placed in the aggregometer and allowed to equilibrate for 2 minutes, prior to addition of test reagent contained in 0.05 ml saline. Percent aggregation values were obtained for each sample.
  • Plasmin chromogenic assays were carried out using a standard clinical protocol, at the Stanford University Blood Bank.
  • Venous blood samples were collected from rat tail vein into tubes containing sodium citrate (8%), and plasma was prepared, using procedures described in Example 1A.
  • KY-1, Y-1 and Y-49 were tested in a PT assay using platelet poor plasma prepared from human blood, similar to that described in Example 4B.
  • plasma samples 0.1 ml
  • 10 ⁇ l saline containing varying amounts of test compound (0-250 ⁇ g/ml, final concentrations).
  • the resulting mixed aliquots were forcibly added to tubes containing 0.2 ml pre-warmed (37°) Thromboplastin-calcium reagent (Dade®
  • Thromboplastin ⁇ C Baxter Healthcare Corp., Hayward, CA.
  • Each tube was timed individually for clot formation while subjected to gentle mixing, using the manual tilt tube method. Time to clot formation was recorded as PT for each sample.
  • Example 4C Effect of KY-1, Y-49 and Y-1 on APTT KY-1, Y-1 and Y-49 were tested in an APTT assay using platelet poor plasma prepared from human blood, similar to that described in Example 4C.
  • Plasma samples were collected as described in Example 4A. Plasma samples (0.1 ml) were pre-mixed with 0-364 ⁇ g of test compound in 10 ⁇ l saline. The mixed samples were added to 0.1 ml of APTT reagent (Automated APTT®, Organon Teknika Corp., Durham, NC), prior to addition of 0.2 ml 0.025 M calcium chloride, pre-warmed to 37° on a fibrometer plate. The sample was timed for formation of fibrin web.
  • APTT reagent Automated APTT®, Organon Teknika Corp., Durham, NC
  • TT Thrombin Time
  • reaction was initiated by addition of 10 ⁇ l (42u/ml) purified human a-thrombin (amount calibrated to give a TT of 20 sec. in untreated human platelet poor plasma). Time to clot formation was recorded for all samples.
  • Samples of human platelet poor plasma (0.2 ml) were incubated at 37° with 10 ⁇ l aliquots of saline containing test compound (final concentration, 0-900 ⁇ g/ml) for 5 minutes.
  • ATROXIN® (Sigma Chemical Co., St. Louis, MO), prewarmed to 37°, was added as a 0.1 ml aliquot to each sample tube to initiate the reaction. Time to clotting was recorded as Atroxin time.
  • KY-1 and Y-1 were tested for effects on plasmin chromogenic activity.
  • KY-1 was tested at concentrations of 20.3, 40.6, and 81.1 ⁇ g/ml final concentration
  • Y-1 was tested at final concentrations of 9.4 and 18.8 ⁇ g/ml.
  • heparin was tested at a final concentration of 0.41 ⁇ g/ml. Results are shown in Figures 22 A-C.
  • Macrocyclic compounds at various concentrations were dissolved in phosphate buffered saline (pH 7.4) and administered to rats at 2.5, .5, or 25 mg/kg,
  • Example 4A a blood sample was taken from each rat, plasma prepared, as described in Example 4A, and determinations of PT, APTT, and fibrinogen content made, as described in Examples 4B, 4C and 4E, respectively.
  • mice Female Swiss-Webster mice (27-28 g each) were each given 2 doses (500 or 625 mg/kg) of compound or saline (PBS) at 30 minute intervals by gastric gavage. Blood samples were collected into 8% citrate via retro-orbital venipuncture 2.5 hours following the initial dosing.
  • PBS saline
  • Example 14 Blood plasma was obtained, processed as described in Example 4A, and assayed for plasma clotting time as described in Example 4C. For comparison, Y-1 (12 or 20 ⁇ g/ml) was added to plasma samples from saline treated control animals, and samples were tested for clotting time as described in Example 5. Results of this assay are shown in Table 4.
  • Example 14
  • Rats were given Y-1 at a dose of 450 mg/kg by gastric gavage.
  • Arterial blood samples were withdrawn at 0.5, 4, 8, 16, and 24 hours through a cannula inserted in the left carotid artery, with tip extending to the descending aorta.
  • Plasma samples were prepared as described in Example 4A, and tested for PT and APTT, as described in Examples 4B and 4C.
  • An additional dose of 225 mg/kg was administered to a subgroup of animals 23 hours after the initial dosing, and plasma from these animals was also tested at 24 hours. Results are shown in Table 6.
  • Example 4A (4/time period) were bled through a cannula inserted in the cartoid artery to the descending aorta, and the blood was processed to obtain plasma, as described in Example 4A. An APTT assay was carried out on each plasma sample.
  • Example 41 General platelet aggregation assay procedures were used as described in Example 41. Collagen dose was titrated to give maximal response to platelet aggregation using citrated platelet-rich plasma. KY-1 and Y-49 at 24 ⁇ g/ml and 48 ⁇ g/ml concentrations had no effect on collagen-induced aggregation (0.47 ⁇ g/ml). Y-1 at 24 ⁇ g/ml had a slight inhibitory effect while at 48 ⁇ g/ml showed

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Abstract

Composition pharmaceutique destinée à être utilisée pour inhiber la coagulation sanguine chez un patient. Cette composition comprend un composé macrocyclique constitué de sous-unités de structures cycliques aryle reliées les unes aux autres par des liaisons à pont fixées sur les structures cycliques et renfermant des substituants provenant d'acide sulfonique fixés sur des atomes ne servant pas de pont des sous-unités, qui sont incorporées dans un support pharmaceutical acceptable. Cette invention concerne également de nouveaux composés macrocycliques.
PCT/US1992/000501 1991-01-29 1992-01-21 Proprietes anticoagulantes de composes macrocycliques et procede de traitement WO1992012708A1 (fr)

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AU12645/92A AU657308B2 (en) 1991-01-29 1992-01-21 Anti-coagulant properties of macrocyclic compounds and method of treatment
KR1019930702267A KR930702967A (ko) 1991-01-29 1992-01-21 마크로고리 화합물의 항응고 특성 및 그것을 이용한 치료방법
JP4505406A JPH06505477A (ja) 1991-01-29 1992-01-21 高環状化合物の抗血液凝固剤及び治療方法

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US07/647,720 US5196452A (en) 1991-01-29 1991-01-29 Macrocyclic anti-viral compound and method
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WO1994003165A1 (fr) * 1992-08-06 1994-02-17 Genelabs Technologies, Inc. Composes a base de calix(n)arene pour traitement antithrombotique
WO1997049677A1 (fr) * 1996-06-26 1997-12-31 Transdiffusia S.A. PROCEDE DE DESALKYLATION ET DE SULFONATION DES CALIXARENES p-ALKYL
US7432371B2 (en) 2002-02-07 2008-10-07 Covalent Partners, Llc Nanofilm and membrane compositions
US7595368B2 (en) 2002-09-17 2009-09-29 Covalent Partners, Llc Nanofilm compositions with polymeric components
US7767810B2 (en) 2002-02-07 2010-08-03 Covalent Partners, Llc Macrocyclic modules comprising linked cyclic synthon units for use in the formation of selectively permeable membranes
US8182695B2 (en) 2003-08-06 2012-05-22 Whiteford Jeffery A Bridged macrocyclic module compositions

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KR100707163B1 (ko) 2005-10-12 2007-04-13 삼성에스디아이 주식회사 고체산, 이를 포함하는 고분자 전해질막 및 이를 채용한연료전지
KR101264331B1 (ko) 2006-02-25 2013-05-14 삼성에스디아이 주식회사 고분자 전해질막, 이의 제조 방법 및 이를 구비한 연료전지
DE102006036326A1 (de) * 2006-08-03 2008-02-07 Charité - Universitätsmedizin Berlin Dendritische Polyglycerolsulfate und -sulfonate und deren Verwendung bei entzündlichen Erkrankungen
JP5700269B1 (ja) * 2013-07-19 2015-04-15 Dic株式会社 フェノール性水酸基含有化合物、感光性組成物、レジスト用組成物、レジスト塗膜、硬化性組成物、レジスト下層膜用組成物、及びレジスト下層膜

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994003165A1 (fr) * 1992-08-06 1994-02-17 Genelabs Technologies, Inc. Composes a base de calix(n)arene pour traitement antithrombotique
WO1997049677A1 (fr) * 1996-06-26 1997-12-31 Transdiffusia S.A. PROCEDE DE DESALKYLATION ET DE SULFONATION DES CALIXARENES p-ALKYL
US5952526A (en) * 1996-06-26 1999-09-14 Transdiffusia S.A. Process for the dealkylating sulfonation of p-alkyl calixarenes
US7432371B2 (en) 2002-02-07 2008-10-07 Covalent Partners, Llc Nanofilm and membrane compositions
US7767810B2 (en) 2002-02-07 2010-08-03 Covalent Partners, Llc Macrocyclic modules comprising linked cyclic synthon units for use in the formation of selectively permeable membranes
US8110679B2 (en) 2002-02-07 2012-02-07 Covalent Partners Llc Nanofilm and membrane compositions
US7595368B2 (en) 2002-09-17 2009-09-29 Covalent Partners, Llc Nanofilm compositions with polymeric components
US8182695B2 (en) 2003-08-06 2012-05-22 Whiteford Jeffery A Bridged macrocyclic module compositions

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