JP2002517466A - Novel potassium channel drugs and their uses - Google Patents

Abstract

(57) Abstract The present invention relates to novel multi-binding compounds that bind to potassium (K ⁺ ) channels and regulate their activity. The compounds of the present invention comprise from 2 to 10 K ⁺ channel ligands covalently linked by a linker, wherein the ligands, in the monovalent (ie, unlinked) state, have one or more To the K ⁺ channel. The manner in which these ligands are linked together is such that the multi-binding agent so formed has a higher biological effect as compared to the same number of unlinked ligands that are provided to bind to K ⁺ channels. And / or show a therapeutic effect. The present invention also relates to methods of using such compounds and methods of preparing them. The compounds of the present invention are particularly useful for treating mammalian diseases and conditions mediated by K ⁺ channels. Accordingly, the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of the present invention.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001] This application is related to US patent application Ser. No. 60 / 088,46, filed on Jun. 8, 1998.
No. 5, No. 60 / 093,068, filed Jul. 16, 1998.
No. 60/113, filed Dec. 24, 1998,
No. 864, which is hereby incorporated by reference in its entirety.

BACKGROUND FIELD OF THE INVENTION [0002] The present invention relates to novel multi-binding compounds that bind to and regulate the activity of potassium (K ⁺ ) channels. The compounds of the present invention may have two to two covalently linked by a linker.
Includes 10 K ⁺ channel ligands, where these ligands are monovalent (
That is, in the uncoupled state, it binds to one or more types of K ⁺ channels. The manner in which these ligands are linked together is such that the multi-binding agent so formed has a higher biological effect and a greater number of unlinked ligands than are available to bind to K ⁺ channels. And / or to show a therapeutic effect. The present invention also relates to methods of using such compounds and methods of preparing them.

The compounds of the present invention are particularly useful for treating mammalian diseases and conditions mediated by K ⁺ channels. Accordingly, the present invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of a compound of the present invention.

REFERENCES The following publications are cited herein as superscripts:

[0005]

[Table 1] The entire disclosure of each of the above publications is incorporated herein by reference, to the same extent, as if the contents of each individual publication were specifically and individually incorporated by reference herein. Has been incorporated.

(State of the art) Voltage-gated potassium channels respond to changes in membrane potential by causing K ^+
28 to mediate the outflow. The voltage-gated K ⁺ channel, in its open state, typically transitions to an inactive state and must regain its ability to respond to external stimuli during the recovery period. Inwardly rectifying voltage-gated potassium channels in the heart muscle are also activated by acetylcholine (ie, they are gated by more than one form of stimulation) ¹⁸ . Calcium activated K ⁺
The channel has been described ¹⁶ . Potassium channels, which serve a variety of important cellular functions, These include irritability, setting the quiescent potential and maintenance activities repolarization potential, transmembrane transport, volume adjustment, ²⁸ such as a signal conversion and the like. They have been implicated in various pathophysiological disorders, including hypertension, cardiac arrhythmias, insulin-dependent diabetes, non-insulin-dependent diabetes, diabetic neuropathy, stroke,
Tachycardia, ischemic heart disease, heart failure, angina, myocardial infarction, transplant rejection, autoimmune disease, sickle cell anemia, muscular dystrophy, gastrointestinal disease, mental disorder, sleep disorder, anxiety disorder, neurosis, alcoholism, Inflammation, cerebrovascular ischemia, CNS disease, epilepsy, Parkinson's disease, asthma, incontinence, urinary dysfunction, dysuria, irritable bowel syndrome, restenosis, subarachnoid hemorrhage, Alzheimer's disease, , ⁴⁵ which mediate transmission of pain impact.

FIG. 1 illustrates in cross-section the transmembrane domain / subunit organization of various transporter molecules, as currently understood by researchers in the field of transport physiology. It should be understood that other subunits that may be involved in or required for transporter activity have been omitted from this figure for simplicity purposes.

Referring to FIG. 1, voltage-gated ion channels and related proteins are tetrameric structures, which are formed by noncovalent association of individual subunits (1), (2). Or the interaction of homologous domains (3) of the monomeric protein. These channels also differ in the number of transmembrane segments per subunit or per domain. The inward rectifier K ⁺ channel and the P _2x purinergic channel have two transmembrane segments in each subunit, while the shaker K ⁺ channel has six transmembrane segments per subunit. Segment and the Na ⁺ and Ca ⁺⁺ channels have 1
There are six transmembrane segments per domain. Neurotransmitter-gated ion channels (eg, as shown at (4)) are organized as pentamers, each of which has four transmembrane segments / domains. Activation gate for the potassium channel has not been confirmed, the trap door (trap door) mechanism has been proposed ^{81, 120.}

[0009] Potassium channels are structurally is similar to the sodium and calcium ion channels, tetrameric structure of smaller than those and a simple ^98, K ⁺ channels, the four polypeptides, ^3. Formed. However, potassium channels are representative of various types of ion channels ^18. Although homotetramers can form, there is evidence that heterotetramers may be functionally related in vivo ¹⁰ . The X-ray structure of the bacterial K ⁺ channel, which is homologous to the mammalian K ⁺ channel, has been disclosed ²¹ . K ⁺ channel prokaryotic animals were found to have the same structure as K ⁺ channels of eukaryotes ^104. This channel has an inverted tee with a large hydrophobic cavity.
pee) structure. This cavity (10 °) is centered on the cytoplasmic side of the channel, and appears to grow as the channel opens ²¹ , ⁸² , ¹¹⁰ , ¹¹⁴ . Voltage-gated cardiac potassium channel gene ¹⁰ as cDNA, but are cloned, ^{113, 116.} The variability of these potassium channel genes can be associated with disease states ¹⁴ , ⁴⁸ , ⁵⁰ , ⁷⁰ .

[0010] Drug binding sites for tetraethylammonium, quinidine and 4-aminopyridine are found in the inner vestibule of the K ⁺ channel, and the involved amino acid side chains are localized in the S6 helix . Binding studies using mutagenesis, show similarities to the local anesthetic (LA) coupled to the sodium channel, sodium channel inhibitors, in the cavity, ^{72, 88} deeper bonds.

There appear to be two types of potassium channel inactivation (N-type and C-type), which can occur simultaneously in shaker-type potassium channels. Both are partially linked to activation and, once activation is complete, they are usually insensitive to voltage. N-type inactivation in a shaker-type B channel depends on a group of amino acids at the N-terminus that bind to this activated channel and block the intracellular opening of the channel. No sequence similarity has been found between the N-termini of the N-type inactivated channels. N-type inactivation, at a positive potential, is insensitive to voltage and competes with binding agents on the intracellular surface of this channel. C-type inactivation is not well understood but occurs during sustained depolarization due to obstruction of the external port of this channel. C-type inactivation is voltage-insensitive at the potential at which activation is completed, whereas recovery from C-type inactivation is voltage-sensitive. Inactivation of both C-type and N-type is activated and linked or partially linked, both, it is necessary to comparable activation proceeds ^40.

[0012] Not surprisingly, potassium channels are important targets for drug therapy.
Be recognized. For example, potassium channels have been targeted by certain antidiabetic, antihypertensive, and antiarrhythmic drugs.

[0013] Potassium channel antagonists have been used to treat arrhythmias. Antiarrhythmic drugs are classified into four classes in the Vaughan Williams taxonomy: Class I (sodium channel blockers); Class II (β-blockers); Class III (potassium channel blockers); IV (calcium channel blocker). As shown in Table 1, antiarrhythmic drugs may have activity ⁸⁹ , ⁹² , ^{101 in} several channels and / or with several receptors. Newer drugs are more selective for particular K ⁺ channels, as shown in Table 2.
Properties of some known K ⁺ channel blockers are shown in Table 3. Table 5 shows the major K ⁺ currents and some agents that block them ⁴⁵ . Most of the drugs in development are I _Kr blocker ^{87, 103, 112.} Some drugs appear to be cation open channel blockers ¹¹⁵ , ¹¹⁸ , ¹¹⁹ .

[0014] Two separate drug (e.g., little or potassium channel openers totally ineffective and class III antiarrhythmic compound against the cardiac action potential) combination therapy with is disclosed ^75.

The clinical disadvantages of currently used drugs cannot be ignored. The most common adverse side effects include headache, hypotension, nausea, vomiting, dizziness and the like. Other side effects include photophobia, corneal microdeposits, neuropathy, fatigue ³⁵ , ³⁹ , ⁴¹ , ⁵⁶ , ⁶¹ , interstitial pneumonia,
Hepatotoxicity, Pro arrhythmia (proarrhythmic) effect ⁴⁶ may include thyroid abnormalities and bradycardia. Reverse use dependency
nce) is capable of causing torsades de pointes (induced arrhythmia), a little or major problem of all known class III agents ^{42, 43, 47, 96, 117.}
Further, there may be no survival benefit associated with the use of these reagents ^67. With a few exceptions, currently used drugs have a short duration of action and must be administered frequently to achieve a sustained effect.

[0016] Therefore, there is a continuing need for new compounds with even higher tissue selectivity, high efficacy, low side effects and more favorable duration of action.

SUMMARY OF THE INVENTION The present invention relates to novel multi-binding compounds that bind to K ⁺ channels in mammalian tissues to treat diseases and conditions mediated by such channels. Can be used.

The present invention also relates to general synthetic methods for generating large libraries of diverse multimeric compounds, which are candidates that possess multibinding properties for potassium channels. The various multimeric compound libraries provided by the present invention are synthesized by combining a linker with a ligand to provide a library of multimeric compounds, wherein the linker and the ligand each enable covalent bonding. Having complementary functional groups. The library of linkers preferably has diverse properties (eg, valency, linker length, linker geometry and rigidity, hydrophilic or hydrophobic, amphiphilic, acidic, basic and polar). Is selected. This library of ligands is preferably selected to have various points of attachment on the same ligand, different functional groups otherwise at the same site on the same ligand, and the like.

The present invention also relates to libraries of various multimeric compounds, which are candidates for possessing multibinding properties. These libraries are prepared by the methods described above and allow for a rapid and efficient assessment of which molecular constraints confer polybinding to ligands or ligand types targeting potassium channels.

Thus, the present invention in one aspect of its composition aspect relates to multi-binding compounds and salts thereof, which contain from 2 to 10 ligands, which may be the same or different, which are the same or different. Covalently linked to the resulting linker, each of these ligands contains a ligand domain that can bind to a K ⁺ channel.

The multibinding compounds according to the invention are preferably represented by the formula I: (L) _p (X) _q I wherein each L is in each case a ligand which may be the same or different;
In each case, are may be the same or different linker; p is an integer from 2 to 10; and q is 1 to 20 integer; wherein each of these ligands, the K ⁺ channel Contains a ligand domain that can bind. Preferably,
q is smaller than p.

Preferably, when the multibinding compound binds to a K ⁺ channel in a mammal,
Regulates diseases and conditions mediated by this K ⁺ channel.

In another aspect of the composition aspect, the present invention provides a pharmaceutically acceptable excipient and
A therapeutically effective amount of one or more multi-binding compounds, which can be the same or different from two to one
Contains 0 ligands, which are covalently linked to linkers which may be the same or different
And each of these ligands is responsible for the cellular K ⁺ Contains a ligand domain that can bind to the channel, thereby
Or a condition thereof) or a pharmaceutically acceptable salt thereof.
About.

[0024] In yet another aspect of the composition aspect, the present invention provides a pharmaceutically acceptable excipient and a therapeutically effective amount of one or more polybinding compounds of Formula I or a pharmaceutically acceptable compound thereof. For pharmaceutical compositions containing possible salts: (L) _p (X) _q I wherein each L is in each case a ligand which may be the same or different; X
Are in each case the same or different linkers; p is an integer from 2 to 10; and q is an integer from 1 to 20; wherein each of these ligands is a mammalian disease Or it contains a ligand domain that can bind to the K ⁺ channel of the cell that mediates the condition, thereby regulating this disease or condition. Preferably, q is less than p.

The present invention, in one aspect of its method aspects, relates to a method of modulating the activity of a K ⁺ channel in a biological tissue, wherein the method comprises conditions sufficient to cause a change in the activity of this channel in the tissue. Below, contacting the tissue with the K ⁺ channel with a multi-binding compound (or a pharmaceutically acceptable salt thereof), wherein the multi-binding compound comprises two Containing 10 to 10 ligands, which are covalently linked to linkers which may be the same or different, each of these ligands
Contains a ligand domain that can bind to K ⁺ channels.

In another aspect of the method aspect, the present invention relates to a method of treating a disease or condition in a mammal resulting from the activity of a K ⁺ channel, the method comprising:
Administering a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable excipient and one or more multi-binding compounds (or pharmaceutically acceptable salts thereof). The binding compound contains two to ten ligands, which may be the same or different, and these are covalently linked to linkers, which may be the same or different, each of which binds to the K of a cell that mediates a disease or condition in a mammal. ⁺ Contains a ligand domain that can bind to the channel.

[0027] The present invention, in yet another aspect of its method aspects, relates to a method of treating a disease or condition in a mammal that results from the activity of a K ⁺ channel, wherein the method is pharmaceutically acceptable. Administering a therapeutically effective amount of a pharmaceutical composition comprising a novel excipient and one or more polybinding compounds represented by Formula I or a pharmaceutically acceptable salt thereof: (L) _p (X) _q I where each L is in each case a ligand which may be the same or different;
Are in each case the same or different linkers; p is an integer from 2 to 10; and q is an integer from 1 to 20; wherein each of these ligands is a mammalian disease Or it contains a ligand domain that can bind to the K ⁺ channel of the cell that mediates the condition. Preferably, q is less than p.

In a further aspect, the present invention provides a process for preparing a multibinding reagent of Formula I. This is accomplished by combining the ligand with the linker under conditions that form a covalent bond between the p appropriately functionalized ligands and the q complementary functionalized linkers. Alternatively, to prepare these compounds, linking a portion of the p appropriately functionalized ligands with q complementary functionalized linkers, followed by subsequent steps Thus, completing the synthesis of these ligands can be performed. Another method that can be used involves linking p appropriately functionalized ligands with a portion of the linker, and then, in a subsequent step, completing the synthesis of the ligand. Coupling one or more appropriately functionalized ligands with a complementary functionalized linker followed by one or more additional ligands to prepare the claimed compounds Coupling with a linker can be performed. Coupling as above, where the coupling of different linkers appropriately functionalized occurs simultaneously, may also be used.

The present invention, in one aspect of its method aspects, relates to a method for identifying a multimeric binding ligand compound that possesses multiple binding to a potassium channel, the method comprising: (a) a ligand Or identifying a mixture of ligands, wherein each ligand contains at least one reactive functional group; (b) identifying a library of linkers, wherein the library Wherein each linker contains at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; (c) a ligand or mixture of ligands identified in (a) At least two stoichiometric equivalents of the linker and the library of linkers identified in (b) are reacted with the complementary functional group to reduce the amount of the linker and the ligand. Preparing a multimeric ligand compound library by combining at least under conditions that form a covalent bond between the two; and (d) assaying the multimeric ligand compound produced in (c) above. To identify multimeric ligand compounds possessing multiple binding properties.

In another aspect of the method aspect, the present invention relates to a method for identifying a multimeric ligand compound possessing multiple binding to a potassium channel, the method comprising: (a) a ligand Wherein each ligand contains at least one reactive functional group; (b) identifying a linker or mixture of linkers, wherein each linker Contains at least two functional groups that are complementary to at least one of the reactive functional groups of the ligand; (c) the complementary functional groups react to react with the linker and the ligands At least two stoichiometric equivalents of the library of ligands identified in (a) and a linker identified in (b) under conditions that form a covalent bond with at least two of Preparing a multimeric ligand compound library by combining the multimeric ligand compound and a mixture of the linkers; and (d) assaying the multimeric ligand compound produced in (c) above to obtain a multimer having multi-binding properties. Identify ligand compounds.

The preparation of the multimeric ligand compound library is achieved by either sequential or simultaneous combination of two or more stoichiometric equivalents of the ligand identified in (a) and the linker identified in (b). You. Sequential addition is preferred when ensuring the preparation of heterodimeric or multimeric compounds using a mixture of different ligands. Simultaneous addition occurs when at least a portion of the multimeric compound being prepared is a homomultimeric compound.

The assay protocol listed in (d) can be performed on the multimeric ligand compound library generated in (c) above, or preferably, each member of the library is a liquid chromatographic separation. Chromatography mass spectrum (LCM
S).

The present invention, in one aspect of its composition aspect, relates to a library of multimeric ligand compounds that can possess multivalency for potassium channels, wherein the library is prepared by a method comprising: (A) identifying a ligand or mixture of ligands, wherein each ligand contains at least one reactive functional group; (b) identifying a library of linkers, Wherein each linker in the library contains at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand; and (c) the complementary functional group Reacts to form a covalent bond between the linker and at least two of these ligands, under the conditions wherein Preparing a multimeric ligand compound library by combining at least two stoichiometric equivalents of a mixture of the linkers with the library of linkers identified in (b).

The present invention, in another aspect of its composition aspect, relates to a library of multimeric ligand compounds that can possess multipotency for potassium channels, wherein the library comprises:
Prepared by methods that include: (a) identifying a library of ligands, wherein each ligand contains at least one reactive functional group; (b) a linker or linker Wherein each linker contains at least two functional groups that have complementary reactivity to at least one of the reactive functional groups of the ligand; and (c) And b.) At least two stoichiometric equivalents of the library of ligands identified in (a) under conditions in which the complementary functional groups react to form a covalent bond between the linker and at least two of the ligands. Preparing a multimeric ligand compound library by combining the above and the linker or mixture of linkers identified in (b).

In a preferred embodiment, the library of linkers used in any of these method or library aspects of the invention comprises a flexible linker, a rigid linker, a hydrophobic linker, a hydrophilic linker, a linker of different geometry, It is selected from the group consisting of an acidic linker, a basic linker, a linker of different polarization and an amphipathic linker. For example, in one embodiment, each of the linkers in the linker library may contain linkers of different chain lengths and / or linkers with different complementary reactive groups. The length of such a linker is preferably about 2-100 °.
Range.

In another preferred embodiment, the potassium channel ligand or ligand mixture has reactive functional groups at different sites on the multimeric ligand compound such that the ligand on the multimeric ligand compound has a range of orientations. Selected to have. Such reactive functional groups include, for example, carboxylic acids, carboxylic acid halides, carboxylic esters, amines, halides, isocyanates, vinyl unsaturated, ketones, aldehydes, thiols, alcohols, aldehydes, and precursors thereof. Body. Of course, the reactive functional group on the ligand is selected to be complementary to at least one of the reactive groups on the linker such that a covalent bond can be formed between the linker and the ligand. I understand.

In another embodiment, the multimeric ligand compound is a homomer
ic) (ie, each of these ligands can bind at a different moiety but are identical) or heterodimeric (ie, at least one of these ligands is different from the other ligand) ).

[0038] In addition to the combination methods described herein, the present invention provides a rational molecular constraint that confers multiple binding to a class of multimeric compounds or ligands that target a receptor. Provide an iterative process to evaluate Specifically, this method aspect relates to a method for identifying a multimeric ligand compound that possesses multiple binding properties for potassium channels, comprising: (a) a first collection of multimeric compounds. Or to prepare a repeat,
The first collection or repeat is prepared by contacting at least two stoichiometric equivalents of a ligand or mixture of ligands targeting a receptor with a linker or mixture of linkers, wherein the ligand or mixture of ligands comprises at least The linker or linker mixture contains at least two functional groups having a complementary reactivity to at least one of the reactive functional groups of the ligand, wherein the contact comprises one reactive functional group. (B) assaying a first collection or repeat of the multimeric compound, wherein the complementary functional groups react to form a covalent bond between the linker and at least two of the ligands; Assessing whether the multimeric compound possesses multiple binding properties; (c) at least Repeating the above processes (a) and (b) until it is found that the multimeric compound has multi-binding properties; (d) any molecular constraints listed above in (a)-(c) Assessing whether the multimeric compound found in the first iteration has conferred multiple binding properties; (e) creating a second collection or repeat of the multimeric compound,
This second collection or repeat creates specific molecular constraints that confer multi-binding properties on the multimeric compound found in the first repeat above; (f) which molecular constraints correspond to the first Assessing whether the multimeric compounds found in the two collections or repetitions confer enhanced multibinding properties; and (g) optionally, repeating steps (e) and (f) , To create more molecular constraints.

Preferably, steps (e) and (f) are performed at least twice, more preferably 2 to 50 times, even more preferably 3 to 50 times, even more preferably at least 5 to 50 times Repeated.

DETAILED DESCRIPTION OF THE INVENTION Biological systems are generally controlled by molecular interactions between bioactive ligands and their receptors, where the receptors are molecules or portions thereof (ie, ligands). Domain) to produce a biological effect. K ⁺ channels are considered pharmacological receptors: they have specific binding sites for ligands with agonist and antagonist activity; binding of ligands to such sites Modulate the K ⁺ flux through a channel; its channel properties (ie gating and ion selectivity)
Is adjustable. Thus, diseases or conditions involving or mediated by K ⁺ channels can be treated with pharmacologically active ligands that interact with such channels to initiate, modulate or block transporter activity.

The interaction between K ⁺ channels and K ⁺ channel binding ligands can be described in terms of “affinity” and “specificity”. The “affinity” and “specificity” of any given ligand-K ⁺ channel interaction is determined by the complementarity of the molecular binding surface and the energy loss of complexation (ie, the freedom between the bound and free states). (Net difference in energy). Affinity can be quantified by the equilibrium constant of complex formation, the ratio of on / off rate constants, and / or the free energy of complex formation. Specificity is related to the difference in binding affinity of the ligand for different receptors.

The net free energy of the interaction of such a ligand with the K ⁺ channel is the energy gain (enthalpy gained by molecular complementarity and entropy gained by hydrophobic effects) and energy loss (decrease of solvation) And the enthalpy lost due to reduced translational, rotational and conformational degrees of freedom).

The compounds of the present invention contain from 2 to 10 K ⁺ channel binding ligands, which are covalently linked together and can act as multiple binding agents. Without wishing to be bound by theory, it is believed that the high activity of these compounds results, at least in part, from their ability to bind to multiple ligand binding sites on the K ⁺ channel in a multivalent fashion. , Which results in a more favorable net binding free energy. Multivalent interactions differ from collections of individual monovalent interactions by being able to confer enhanced biological and / or therapeutic effects. Multivalent binding can amplify binding affinities and differences in binding affinities, resulting in high binding specificities and affinities.

Definitions As used herein: The term “alkyl,” unless otherwise indicated, refers to a monoradical of a branched or unbranched saturated hydrocarbon chain. Which preferably has 1 to 40 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms (e.g. methyl, Ethyl, n-propyl, isopropyl, n-butyl, secondary butyl, tertiary butyl, n
-Hexyl, n-octyl, n-decyl, n-dodecyl, 2-ethyldodecyl,
Tetradecyl).

The term “substituted alkyl” means an alkyl group as defined above having one to five substituents selected from the group consisting of: alkoxy, substituted alkoxy, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thiohetero Aryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl,
Heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO- alkyl, -SO- aryl, -SO- heteroaryl, -SO ₂ - alkyl, -SO ₂ - aryl, -SO ₂ -heteroaryl, and -NR ^a R ^b, wherein R ^a and R ^b can be the same or different and are hydrogen,
Selected from optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic).

The term “alkylene” means a diradical of a branched or unbranched saturated hydrocarbon chain, which preferably has 1 to 40 carbon atoms, preferably 1 It has from 10 to 10 carbon atoms, more preferably from 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (-CH ₂ -), ethylene (-CH ₂ CH ₂ -), the propylene isomers (e.g., -CH ₂ CH ₂ CH ₂ - and _{-CH (CH 3) CH 2 -} )
Examples are given by groups such as

The term “substituted alkylene” means: (1) an alkylene group as defined above having one to five substituents selected from the group consisting of: alkoxy, substituted alkoxy, Cycloalkyl, substituted cycloalkyl, cycloalkenyl,
Substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyacylamino, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryl oxy, thioaryloxy, heteroaryl, heteroaryloxy, thioheteroaryloxy, heterocyclic, heterocyclooxy, thioheterocyclooxy, nitro, and -NR _a R _b (where, R _a and R _b, And may be the same or different and are selected from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. Further, two or more substituents on the alkylene group are fused to such a substituted alkylene group, and one or more cycloalkyl groups, substituted cycloalkyl groups, cycloalkenyl groups, substituted cycloalkenyl group, an aryl group, and the like to form a heterocyclic or heteroaryl group; (2) oxygen, sulfur and NR _a - is interrupted by 1 to 20 atoms independently selected from Wherein R _a is hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic; Selected from carbonyl), carboxyester, carboxamide and sulfonyl. Is the group; and one to five of which is interrupted by 1 to 20 atoms as defined having and above a substituent, an alkylene group as defined above as defined above (3). Examples of substituted alkylenes are chloromethylene (-CH (Cl) -), aminoethylene _{(-CH (NH 2) CH 2} -), 2- carboxyethyl the propylene isomers (
—CH ₂ CH (CO ₂ H) CH ₂ —), ethoxyethyl (—CH ₂ CH ₂ O—CH ₂ C)
H ₂ -), ethyl methyl aminoethyl _{(-CH 2 CH 2 N (CH} 3) CH 2 CH 2 -)
, 1-ethoxy-2- (2-ethoxy - ethoxy) ethane (-CH ₂ CH ₂ O-C
_{H 2 CH 2 -OCH 2 CH 2} -OCH 2 CH 2 -) and the like.

The term “alkaryl” or “aralkyl” means an -alkylene-aryl group and a -substituted alkylene-aryl group, where alkylene and aryl are as defined herein. . Such an alkaryl group is
Exemplified by benzyl, phenethyl and the like.

The term “alkoxy” refers to an alkyl-O-, alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O- group, where Alkyl, alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein. Preferred alkoxy groups are alkyl-O-, which include, for example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy. , 1,2-dimethylbutoxy and the like.

The term “substituted alkoxy” refers to a substituted alkyl-O— group, a substituted alkenyl-O
-Group, substituted cycloalkyl-O- group, substituted cycloalkenyl-O- group, and substituted alkynyl-O- group, wherein substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are , As defined herein.

The term “alkylalkoxy” refers to an -alkylene-O-alkyl group, an alkyl
Len-O-substituted alkyl group, substituted alkylene-O-alkyl group and substituted alkyl
A ren-O-substituted alkyl group, wherein alkyl, substituted alkyl, alkyl
Ren and substituted alkylene are as defined herein. like this
Examples of groups include methylenemethoxy (-CH_TwoOCH_Three), Ethylene methoxy (-CH _Two CH_TwoOCH_Three), N-propylene-iso-propoxy (-CH_TwoCH_TwoCH_TwoOC
H (CH_Three)_Two), Methylene-t-butoxy (-CH_Two-OC (CH_Three)_Three)Such
There is.

The term “alkylthioalkoxy” means an -alkylene-S-alkyl group, an alkylene-S-substituted alkyl group, a substituted alkylene-S-alkyl group and a substituted alkylene-S-substituted alkyl group, wherein , Alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylthioalkoxy group, has alkylene -S- alkyl, which, by way of example, methylene thio methoxy (-CH ₂ SCH _3), ethylene thiomethoxide _{(-CH 2 CH 2 SCH 3)} , n- propylene - iso - thiopropoxy (-CH ₂ C
_{H 2 CH 2 SCH (CH 3} ) 2), methylene -t- thiobutoxy (-CH ₂ SC (C
H ₃ ) ₃ ).

“Alkenyl” means a branched or unbranched unsaturated hydrocarbon monoradical, which is preferably 2 to 40 carbon atoms, preferably
It has 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and preferably has 1 to 6 double bonds. This term is further exemplified by groups such as vinyl, prop-2-enyl, pent-3-enyl, hexa-5-enyl, 5-ethyldode-3,6-dienyl and the like.

The term “substituted alkenyl” means an alkenyl group as defined above having one to five substituents selected from the group consisting of: alkoxy, substituted alkoxy, acyl, acylamino, acyloxy , Amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, hydroxyl,
Keto, thioketo, carboxyl, carboxylalkyl, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, aryloxy, thioaryloxy, heteroaryloxy, thioheteroaryloxy, heterocyclooxy, thioheterocyclo Oxy, nitro, -SO-alkyl,
-SO- substituted alkyl, -SO- aryl, -SO- heteroaryl, -SO ₂
- alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl, -SO ₂ - heteroaryl, and -NR ^a R ^b (where, R ^a and R ^b may be the same or different, hydrogen, optionally Substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic).

“Alkenylene” means an unsaturated hydrocarbon diradical, which is preferably 2 to 40 carbon atoms, preferably 2 to 10 carbon atoms, more preferably It has from 2 to 6 carbon atoms and preferably has from 1 to 6 double bonds. The term further includes 1,2-ethenyl, 1,3-prop-
2-enyl, 1,5-pent-3-enyl, 1,4-hex-5-enyl, 5-
Exemplified by groups such as ethyl-1,12-dodec-3,6-dienyl.

The term “substituted alkenylene” refers to one to five selected from the group consisting of
Means an alkenylene group as defined above with the substituents: alkoxy, substituted
Alkoxy, acyl, acylamino, acyloxy, amino, aminoacyl, a
Minoacyloxy, oxyacylamino, azide, cyano, halogen, hydroxy
Sil, keto, thioketo, carboxyl, carboxylalkyl, thiol, thio
Alkoxy, substituted thioalkoxy, aryl, aryloxy, thioaryl
Xy, heteroaryl, heteroaryloxy, thioheteroaryloxy, multiple
Cyclic, heterocyclooxy, thioheterocyclooxy, nitro, and -NR ^a R^b(Where R^aAnd R^bMay be the same or different, hydrogen, optionally substituted
Alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,
Selected from aryl, heteroaryl and heterocyclic). Furthermore, like this
Is substituted with two substituents on the alkenylene group,
One or more cycloalkyl groups substituted with an alkenylene group;
Group, cycloalkenyl group, substituted cycloalkenyl group, aryl group, heterocyclic group
Or those forming a heteroaryl group are exemplified.

“Alkynyl” means an unsaturated hydrocarbon monoradical, which is preferably 2 to 40 carbon atoms, preferably 2 to 10 carbon atoms, more preferably It has from 2 to 6 carbon atoms and preferably has from 1 to 6 triple bonds. The term further includes acetylenyl, prop-2-ynyl,
Exemplified by groups such as pent-3-ynyl, hexa-5-ynyl, 5-ethyldode-3,6-diynyl and the like.

The term “substituted alkynyl” refers to one to five selected from the group consisting of:
Means an alkynyl group as defined above having a substituent: alkoxy, substituted alkynyl
Coxy, acyl, acylamino, acyloxy, amino, aminoacyl, amino
Acyloxy, oxyacylamino, azide, cyano, halogen, hydroxyl
, Keto, thioketo, carboxyl, carboxylalkyl, thiol, thioal
Coxy, substituted thioalkoxy, aryl, aryloxy, thioaryloxy
, Heteroaryl, heteroaryloxy, thioheteroaryloxy, heterocyclic
Formula, heterocyclooxy, thioheterocyclooxy, nitro, -SO-alkyl
, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO _Two -Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Aryl, -SO_Two-Heteroa
Reel, SO_Two-Heterocyclic, and -NR^aR^b(Where R^aAnd R^bAre the same
Or different, hydrogen, optionally substituted alkyl, cycloalkyl, alky!
Kenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and hetero
Selected from cyclic).

“Alkynylene” means a diradical of an unsaturated hydrocarbon group, which is preferably 2 to 40 carbon atoms, preferably 2 to 10 carbon atoms, more preferably It has from 2 to 6 carbon atoms and preferably has from 1 to 6 triple bonds. The term further includes 1,3-prop-2-ynyl, 1,
5-pent-3-ynyl, 1,4-hex-5-ynyl, 5-ethyl-1,12
-Dode-3,6-diynyl and the like.

The term “acyl” refers to the group —CHO, alkyl-C (O) —, substituted alkyl-C (O) —, cycloalkyl-C (O) —, substituted cycloalkyl-C ( O
)-Group, cycloalkenyl-C (O)-group, substituted cycloalkenyl-C (O)-
Groups, aryl-C (O)-groups, heteroaryl-C (O)-groups and heterocyclic-
Refers to the group C (O)-, where alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl and heterocyclic are as defined herein. It is.

The term “acylamino” refers to a —C (O) NRR group, wherein each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic. Or both R groups are joined to form a heterocyclic group (eg, morpholine), wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are referred to herein. As defined.

The term “aminoacyl” refers to the group —NRC (O) R, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic. Where the alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “aminoacyloxy” refers to the group —NRC (O) OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic. Where the alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

The term “acyloxy” refers to an alkyl-C (O) O— group, a substituted alkyl-C
(O) O- group, cycloalkyl-C (O) O- group, substituted cycloalkyl-C (O
) O-, aryl-C (O) O-, heteroaryl-C (O) O-, and heterocyclic-C (O) O- groups, where alkyl, substituted alkyl, Cycloalkyl, substituted cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “aryl” refers to an unsaturated aromatic carbocyclic ring of 6 to 20 carbon atoms having a single ring (eg, phenyl) or multiple condensed (fused) rings (eg, naphthyl or anthryl). Means a formula group.

Unless otherwise restricted by the definition for this aryl substituent,
The aryl group may have 1 to 5 substituents selected from the group consisting of
Substituents can be substituted with: acyloxy, hydroxy, thiol, acyl, alkyl,
Alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,
Substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloa
Alkyl, substituted cycloalkenyl, amino, aminoacyl, acylamino, alka
Reel, aryl, aryloxy, azide, carboxyl, carboxyl al
Kill, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocycle
Formula, heterocyclooxy, aminoacyloxy, oxyacylamino, thioal
Coxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy
, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-hete
Lower aryl, -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO_Two-Aryl
, -SO_Two-Heteroaryl, trihalomethyl, NR^aR^b(Where R^aAnd R ^b Can be the same or different and are hydrogen, optionally substituted alkyl, cycloal
Kill, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl
And heterocyclics). Preferred aryl substituents include alkyl, a
Lucoxy, halo, cyano, nitro, trihalomethyl and thioalkoxy
Can be

The term “aryloxy” means an aryl-O— group in which the aryl group is as previously described, including an optionally substituted aryl group ( This is also defined above).

The term “arylene” means a diradical derived from an aryl or substituted aryl as defined above and includes 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,2 -Exemplified by naphthylene and the like.

The term “amino” refers to the group —NH ₂ .

The term “substituted amino” refers to the group —NRR, where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, alkynyl, substituted alkynyl , Aryl, heteroaryl and heterocyclic, provided that R is not both hydrogen.

The term “carboxyalkyl” refers to a “—C (O) O-alkyl” group, “—C
(O) O-substituted alkyl "group," -C (O) O-cycloalkyl "group," -C (
O) O-substituted cycloalkyl "group," -C (O) O-alkenyl "group," -C (
O) O-substituted alkenyl "," -C (O) O-alkynyl "and" -C (
O) O-substituted alkynyl "group, wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl are as defined herein.

The term “cycloalkyl” means a cyclic alkyl group having 3 to 20 carbon atoms, which has a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, a single ring structure (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, etc.) or a multiple ring structure (eg, adamantanyl, etc.).

The term “substituted cycloalkyl” refers to one to five selected from the group consisting of
Means a cycloalkyl group having three substituents: alkoxy, substituted alkoxy, cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide, cyano, halogen, Hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, Heterocyclooxy, hydroxyamino, alkoxyamino, nitro,-
SO- alkyl, -SO- substituted alkyl, -SO- aryl, -SO- heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl, -
SO ₂ -heteroaryl, and —NR ^a R ^b, where R ^a and R ^b can be the same or different and are hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, Selected from heteroaryl and heterocyclic).

The term “cycloalkenyl” refers to a cyclic alkenyl group of 4 to 20 carbon atoms that has a single cyclic or fused ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for example, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.

The term “substituted cycloalkenyl” refers to one or more selected from the group consisting of:
Means a cycloalkenyl group having 5 substituents: alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azide , Cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy , Heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO- Roariru, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl, -SO ₂ - heteroaryl, and -NR ^a R ^b (where,
R ^a and R ^b can be the same or different and are hydrogen, optionally substituted alkyl,
Selected from cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic).

The term “halo” or “halogen” refers to fluoro, chloro, bromo and iodo.

“Haloalkyl” refers to an alkyl as defined above (eg, 3-fluorododecyl, 12,12) substituted by one to four halo groups, as defined above, which may be the same or different. , 12-trifluorododecyl, 2-bromooctyl, 3
-Bromo-6-chloroheptyl and the like).

The term “heteroaryl” refers to 1 to 15 carbon atoms and 1 to 4 heteroatoms (at least one ring, if more than one ring is present).
This means an aromatic group having (selected from oxygen, nitrogen and sulfur).

Unless otherwise restricted by the definition for this heteroaryl substituent,
A heteroaryl group such as is optionally selected from the group consisting of
Can be substituted with from 1 to 5 substituents: acyloxy, hydroxy, thiol, acyl
, Alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloa
Alkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl,
Substituted cycloalkyl, substituted cycloalkenyl, amino, aminoacyl, acyla
Mino, alkaryl, aryl, aryloxy, azide, carboxyl, car
Boxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryl
Xy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamido
, Thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroa
Reeloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl,
-SO-heteroaryl, -SO_Two-Alkyl, -SO_Two-Substituted alkyl, -SO _Two -Aryl, -SO_Two-Heteroaryl, trihalomethyl, mono- and di-
Alkylamino, and mono- and NR^aR^b(Where R^aAnd R^bAre the same
Or different, hydrogen, optionally substituted alkyl, cycloalkyl, alky!
Kenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and hetero
Selected from cyclic). Preferred heteroaryls include pyridyl, pyrrolyl and
And frills.

The term “heteroaryloxy” means a heteroaryl-O— group.

The term “heteroarylene” refers to a diradical radical derived from a heteroaryl or substituted heteroaryl as defined above, and includes 2,6-pyridylene, 2,4-pyridylene, 1,2-quinolinylene , 1,8-quinolinylene, 1,4
-Benzofuranylylene, 2,5-pyridinylene, 1,3-morpholinylene, 2,
Exemplified by groups such as 5-indolenyl.

The term “heterocycle” or “heterocyclic” refers to 1 to 40 carbon atoms and 1 to 10 heteroatoms, preferably 1 to 4 heteroatoms, in the ring. A monoradical saturated or unsaturated group having a single ring or multiple condensed rings with atoms, which is selected from nitrogen, sulfur, phosphorus and / or oxygen, is meant.

Unless otherwise restricted by the definition for this heterocyclic substituent, such heterocyclic groups may optionally comprise 1-5, preferably from the group consisting of: Which can be substituted with one to three substituents: alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, Halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, hetero Cyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-
Heteroaryl, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - aryl, -SO ₂ - heteroaryl, and -NR ^a R ^b (where, R ^a and R ^b are the same or different , Hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic). Such heterocyclic groups can have a single ring or multiple condensed rings.

Examples of nitrogen heterocycles and heteroaryls include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthylpyridine , Quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indolin, morpholino, piperidinyl tetrahydron And the like, as well as N-alkoxy-nitrogen containing heterocycles.

A preferred class of heterocyclic compounds includes “crown compounds”, which are specific types of heterocycles having one or more repeat units of the formula [— (CH ₂ —) _m Y—]. Means a cyclic compound, wherein m is greater than or equal to 2 and Y can be O, N, S or P in each individual case. Examples of crown compounds, by way of example _{only, [- (CH 2) 3} -NH-] 3, [- ((CH 2) 2 -O
) ₄ -((CH ₂ ) ₂ —NH) ₂ ] and the like. Typically, such crown compounds can have from 4 to 10 heteroatoms and from 8 to 40 carbon atoms.

The term “heterocyclooxy” means a heterocyclic —O— group.

The term “thioheterocyclooxy” means a heterocyclic —S— group.

The term “heterocyclene” means a diradical group derived from a heterocycle as defined herein, and is exemplified by groups such as 2,6-morpholino, 2,5-morpholino, and the like. .

The term “oxyacylamino” refers to the group —OC (O) NRR, where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl or heterocyclic. Wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

The term “thiol” refers to the group —SH.

The term “thioalkoxy” refers to the group —S-alkyl.

The term “substituted thioalkoxy” refers to the group —S-substituted alkyl.

The term “thioaryloxy” means an aryl-S— group in which the aryl group is as previously described, including an optionally substituted aryl group. (Also defined above).

The term “thioheteroaryloxy” means a heteroaryl-S— group in which the heteroaryl group is as previously described, optionally as defined above. And substituted aryl groups as defined in

With respect to any of the above groups containing one or more substituents, of course, such groups contain sterically impractical and / or synthetically unrealizable substitutions or substitution patterns. It turns out that it does not. In addition, the compounds of the present invention include all stereochemical isomers resulting from the substitution of these compounds.

“Alkyl optionally interrupted by 1 to 5 atoms selected from O, S or N” means that the carbon chain is interrupted by O, S or N. Means defined alkyl. Within that range, ethers, sulfides and amines (eg, 1-methoxydecyl, 1-pentyloxynonane, 1- (2-
Isopropoxyethoxy) -4-methylnonane, 1- (2-ethoxyethoxy)
Dodecyl, 2- (t-butoxy) heptyl, 1-pentylsulfanylnonane,
Nonylpentylamine, etc.).

“Heteroarylalkyl” means a heteroaryl as defined above linked to an alkyl as defined above (eg, pyrid-2-ylmethyl, 8-quinolinylpropyl, and the like).

“Optional” or “as needed” means that the subsequently described event or circumstance may or may not occur, and that this statement indicates that the event or circumstance occurs and This includes cases where the event does not occur. For example,
An optionally substituted alkyl means that the alkyl can be substituted or unsubstituted by the groups recited in the definition of substituted alkyl.

The term “pharmaceutically acceptable salt” refers to salts that retain the biological effectiveness and properties of the multibinding compounds of the present invention, which are not biologically or otherwise undesirable. Not a salt. In many cases, the multi-binding compounds of the present invention may be modified by the presence of amino and / or carboxyl groups or similar groups.
Acid and / or base salts can be formed.

[0100] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines such as: alkyl amines, dialkyl amines, trialkyl amines, substituted Alkylamine, di (substituted alkyl)
Amine, tri (substituted alkyl) amine, alkenylamine, dialkenylamine, trialkenylamine, substituted alkenylamine, di (substituted alkenyl) amine, tri (substituted alkenyl) amine, cycloalkylamine, di (cycloalkyl) amine, tri ( (Cycloalkyl) amine, substituted cycloalkylamine, disubstituted cycloalkylamine, trisubstituted cycloalkylamine, cycloalkenylamine, di (cycloalkenyl) amine, tri (cycloalkenyl) amine, substituted cycloalkenylamine, disubstituted cycloalkenyl Amine, trisubstituted cycloalkenylamine, arylamine, diarylamine, triarylamine, heteroarylamine, diheteroarylamine, triheteroarylamine, heterocyclic amine, diheterocyclic amine Emissions, tri heterocyclic amines, mixed di- - and triamines (
In this case, at least two of the substituents on the amine are different and include alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic Selected from the group consisting of: Also included are amines whose two or three substituents together with the amino nitrogen form a heterocyclic or heteroaryl group.

Examples of suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri (isopropyl) amine, tri (n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine , Histidine, caffeine, procaine, hydravamine (hyd
rabamine), choline, betaine, ethylenediamine, glucosamine, N
-Alkylglucamines, theobromine, purine, piperazine, piperidine, morpholine, N-ethylpiperidine and the like. It should also be understood that other carboxylic acid derivatives (eg, carboxylic acid amides (including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, etc.)) will be useful in practicing the present invention.

[0102] Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids that induce salts include acetic, propionic, glycolic, pyruvic, oxalic, malic, malonic, succinic, maleic, fumaric, tartaric, citric, benzoic, cinnamic, Mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

The term “protecting group” or “blocking group” refers to a compound that, when attached to one or more hydroxyl, thiol, amino or carboxyl groups of these compounds, prevents a reaction from taking place at these groups. And protecting groups can be removed by conventional chemical or enzymatic steps to restore the hydroxyl, thiol, amino or carboxyl groups. Generally, T. W. Greene
& P. G. FIG. M. Wuts, Protective Groups in O
rgnic Synthesis (2nd edition, 1991, John Wiley)
and Sons, N.M. Y. See).

The particular removable blocking group used is not critical, and preferred removable hydroxyl blocking groups include the usual substituents as follows:
Allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine,
Phenacyl, t-butyl-diphenylsilyl and any other groups, which can be chemically introduced onto the hydroxyl function and later, under mild conditions compatible with the nature and compatibility of the product, Or can be selectively removed by either enzymatic methods).

Preferred removable amino blocking groups include the usual substituents such as:
Which can be removed by the usual conditions compatible with the properties of the product.
: T-butoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ)
), Fluorenylmethoxycarbonyl (FMOC), allyloxycarbonyl (
ALOC).

Preferred carboxyl protecting groups include esters (eg, methyl, ethyl, propyl, t-butyl, etc.), which can be removed by mild hydrolysis conditions compatible with the nature of the product. .

As used herein, the term “inert organic solvent” or “inert solvent” refers to
Means solvents which are inert under the reaction conditions described in connection therewith [for example, benzene, toluene, acetonitrile, tetrahydrofuran ("TH
F "), dimethylformamide (" DMF "), chloroform (" CHCl ₃ "
), Methylene chloride (i.e. dichloromethane or "CH ₂ Cl _2"), diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert- butanol, dioxane,
Pyridine and the like]. The solvent used in the reaction of the present invention is an inert solvent, unless otherwise specified.

The term “K ⁺ channel” is composed of an integral membrane protein that functions to allow K ⁺ to equilibrate across a membrane at a diffusion limited rate according to its electrochemical gradient. Means the structure.

As used herein, “ligand” refers to a compound that is a binding partner for a K ⁺ channel receptor, for example, a compound bound thereto by complementation. The specific region of the ligand molecule that is recognized by the ligand binding site of the K ⁺ channel receptor is called the “ligand domain”. A ligand can either be receptor bound by itself, or it can require the presence of one or more non-ligand components for binding (eg, ions, lipid molecules, solvent molecules, etc.).

The ligands useful in the present invention include K⁺Channel modulators include:
Quinidine^6,94, Glibenclamide, procaine, tetraethylammonium²⁰,
Clofilium¹⁰², Melperon⁸, Pinacidil, WAY-123,398⁹¹,
Lomacarim²⁶, Propoful, thiopentone (thiope)
ntone)³², Risotide, almocarrant (al
mokarant)³⁶, Bretylium³⁸, N-acetylprocainamide, tac
Phosphorus, UK66,914, RP58866, 4-aminopyridine, RP4935
6⁴⁵, Affinidine⁴⁹, Chromanol 293B⁵⁷, L-
768,673 and its analog⁵³, Betanidine⁵⁴, Disopyramide^{twenty three}, Dececi
Luamiodarone¹, NE-10064^9,84, Artilide¹¹
, Dofetilide^{19,73,74,90,99}, E-4031^{24,99, 109} , Sematilide^106,107, Ambasilide, azimilide^{Five, 80,86,93,100,108} , Tedisamil, drondarone (dro
nedarone)⁷⁹, Ibutilide^78,111, Sotalol⁸⁵, Benzodiazepine
Nalog^76,77And amiodarone^{55,65,83,95,105}. Various potassium channels
See Table 4 for Gand structures.

Although many currently known potassium channel ligands are expected to be usable in preparing the multibinding compounds of the present invention (Table 2), portions of the ligand structure that are not essential for molecular recognition and avidity ( That is, the portion that is not its ligand domain) can be substantially altered, replaced with unrelated structures, and in some cases omitted altogether, without affecting its binding interaction. Should be able to understand. Thus, a ligand that exhibits minimal activity or lacks useful activity as a monomer can be very active as a multi-binding compound due to the biological benefits afforded by polyvalency. It should be understood that the term “ligand” is not to be construed as limited to compounds known to be useful as K ⁺ channel receptor binding compounds (eg, known agents). A key requirement for a ligand as defined herein is that it has a ligand domain, as defined above, which can be used to bind to a recognition site on a K ⁺ channel. is there.

For the purposes of the present invention, the term “ligand” includes racemic ligands, as well as the individual stereoisomers of these ligands, including pure enantiomers and non-racemic mixtures thereof. Is interpreted as The scope of the invention as described and claimed,
Includes the racemic forms of these ligands, as well as the individual enantiomers and their non-racemic mixtures.

As used herein, the term “ligand binding site” refers to a site on a K ⁺ channel receptor that recognizes a ligand domain and provides a binding partner for the ligand. The ligand binding site can be defined by monomeric and multimeric structures. This interaction may produce a unique biological effect (eg, agonism, antagonism, regulation) or may maintain an ongoing biological event or the like.

It should be recognized that the ligand binding sites of the K ⁺ channel receptors involved in biological multivalent binding interactions are, to varying degrees, restricted by their intra- and inter-molecular associations. is there. For example, the K ⁺ channel ligand binding site can be covalently linked in a single structure, non-covalently associated in one or more multimeric structures, embedded in a membrane or biopolymer matrix, and the like. Thus, the same site may have less translation and rotational freedom than if it were present in solution as a monomer.

The terms “agonism” and “antagonism” are well-known in the art. As used herein, the term “agonist” refers to a ligand that, when bound to a K ⁺ channel, stimulates its activity. The term “antagonist” refers to a ligand that, when bound to a K ⁺ channel, inhibits its activity. Blocking or activating a channel, rather than occupying the pore of that channel,
It may result from an allosteric effect of the ligand binding to this channel. These allosteric effects can result in changes in the conformation of the protein, which affects the K ⁺ binding site, the gating mechanism and / or the pore area (ie, ion penetration).

Potassium channels can exist in several modes: C (closed dormant state); C ^* (activated and closed state); O (open state); and I (inactive state). ⁴⁴ . The likelihood that a channel is present in one of these four states changes with voltage. Certain ligands can have different binding affinities for different states and can produce agonist or antagonist activity.

The term “modulating effect” is taken to mean the ability of a ligand to alter the activity of a K ⁺ channel by binding it.

A “multi-binding agent” or “multi-binding compound” is defined herein as having two as defined herein, covalently linked to one or more linkers, which may be the same or different. 10 to 10 K ⁺ channel ligands, which may be the same or different
A compound having the general formula (1), which can have polyvalency as defined below.

Multi-binding compounds provide an improved biological and / or therapeutic effect as compared to the same number of unlinked ligands available to bind to the ligand binding site on the K ⁺ channel. Examples of improved “biological and / or therapeutic effects” include increased ligand-receptor binding interactions (eg, increased affinity, increased ability to elicit a functional change at the target, response, Increased speed), increased selectivity for the target, increased potency, increased potency, decreased toxicity, increased therapeutic index, improved duration of action, improved bioavailability, improved biokinetics, improved activity spectrum, etc. Is mentioned. The multibinding compounds of the present invention exhibit at least one (preferably more than one) of the above effects.

As used herein, “monovalent” means a single binding interaction between one ligand and one ligand binding site as defined herein. It should be noted that compounds having multiple copies of one ligand (or multiple ligands) are monovalent when only one ligand of the compound interacts with the ligand binding site. Examples of monovalent interactions are shown below.

[0121]

Embedded image As used herein, "multivalent" refers to two to ten linked ligands, which can be the same or different, and two or more corresponding ligand binding sites (
These may be the same or different) simultaneously. An example of a trivalent bond is shown below for illustrative purposes.

[0122]

Embedded image Not all compounds containing multiple copies of the ligand attached to the linker necessarily show the phenomenon of multivalency, i.e. the biological and / or therapeutic effect of this multi-binding agent depends on the presence of these ligands. It should be understood that the effect is greater than the same number of unlinked ligands available to bind to the binding site. In order for multivalent binding to occur, the ligand domains of the ligands that are linked together are, in a particular manner, linked to their ligands in a specific manner to elicit the desired ligand orientation result and produce a multibinding interaction. Must be presented at the ligand binding site of origin.

[0123] The term "library" is, at least three, preferably, 10 ² to 10 ^9,
More preferably, it means 10 ² to 10 ⁴ multimeric compounds. Preferably, these compounds are in a single solution or reaction mixture that can facilitate their synthesis,
Prepared as a number of compounds. In one embodiment, the library of multimeric compounds can be directly assayed for multibinding properties. In another embodiment, each member of the library of multimeric compounds is first isolated and optionally characterized. This member is then assayed for multibinding properties.

The term “collection” refers to a set of multimeric compounds that are prepared either sequentially or simultaneously (eg, in combination). The collection comprises at least 2 members, preferably 2 to 10 ⁹ members, more preferably 10 to 10 ⁴ members.

The term “multimeric compound” refers to a compound containing 2 to 10 ligands covalently linked via at least one linker, wherein the compound has multiple binding properties (as described herein). (As defined in this document).

The term “pseudohalide” refers to a functional group that reacts in a similar manner with a halogen in a substitution reaction. Such functional groups include, by way of example, mesyl, tosyl, azide and cyano groups.

The term “linker” refers to two to ten ligands (as defined above), in place, identified in place by the symbol X, but in a manner that provides a compound that may have multivalency. It means a group to be covalently bonded. The linker is a ligand directing material that allows it to bind multiple copies of the ligand, which may be the same or different.

The term “linker” refers to anything that is not considered part of this ligand, for example, ancillary groups (eg, solubilizing groups, lipophilic groups), pharmacodynamics or pharmacokinetics. Groups that improve the diffusivity of the multi-binding compound, spacers that link the ligand to the linker (eg, by imparting flexibility or rigidity to the linker, in whole or in part). And) a group that assists the ligand orientation function of the linker. The term "linker", however, does not include solid inert supports (eg, beads, glass particles, rods, etc.), but the multi-binding compounds of the present invention can be used, if desired, eg,
It should be understood that it can be attached to a solid support for use in separation and purification steps and for similar applications.

In the present invention, the degree to which the activity of the multibinding compound is increased as described above depends on the efficiency of the linker binding the ligand to the array of ligand binding sites. In addition to presenting these ligands for multivalent interactions with the ligand binding site, the linker spatially constrains these interactions to occur within the dimensions defined by the linker.

The linker used in the present invention may be any desired ligand binding site of the K ⁺ channel (such a site may be located inside the cell membrane, inside the channel (ie, within the channel / translocation pore), To allow for the multivalent binding of the ligand to both the interior and the perimeter, at the interface between the lipid bilayer and the channel, or at any intermediate location thereof. Selected. Preferred linker lengths include the distance between adjacent ligand binding sites, and the geometry of the linker,
Varies depending on flexibility and composition. The length of the linker preferably ranges from about 2 ° to about 100 °, more preferably, from about 2 ° to about 50 °, and even more preferably, from about 5 ° to about 20 °.

The ligands are covalently attached to the linker using conventional chemical methods. Reaction chemistries that result in such linkages are well known in the art, and involve the use of reactive functional groups present on the linker and ligand. Preferably, the reactive functional groups on the linker are selected in relation to the functional groups available for coupling on the ligand, or in relation to the functional groups that can be introduced into the ligand for this purpose. Again, such reactive functional groups are well known in the art. For example, the reaction between a carboxylic acid of any of the linkers or ligands and a primary or secondary amine of the ligand or linker in the presence of a suitable well-known activating agent causes the reaction of the ligand or the linker with the primary or secondary amine. To form an amide bond covalently linking to the linker; the reaction between the amine group of either the linker or the ligand and the sulfonyl halide of the ligand or the linker is
A sulfonamide bond is formed which covalently attaches the ligand to the linker; and the reaction between the alcohol or phenol group of either the linker or the ligand and the alkyl or aryl halide of the ligand or linker is: An ether bond is formed that covalently attaches this ligand to the linker. The table below and FIG. 6 illustrate a number of reactive functional groups and the bonds formed in the reaction between them. In the absence of functional groups, they are described in J. March, A
advanced Organic Chemistry, 4th edition (Wiley-
Interscience, N.M. Y. , 1992) by appropriate chemical reactions described in standard organic chemistry textbooks.

[0132]

[Table 2] The linker is attached to the ligand at a position that retains the ligand domain-ligand binding site interaction, specifically at a position where the ligand domain of the ligand can orient itself and bind to the ligand binding site. Such a position,
And synthetic protocols for ligation are well known in the art. The term linker includes everything that is not considered part of this ligand.

The relative orientation of the ligand domain depends on the particular point of attachment of the ligand to the linker, and the geometry of its backbone. The determination of where acceptable substitutions can be made on a ligand is typically determined by prior knowledge of the structure-activity relationship of the ligand and / or the like and / or information about the ligand-receptor complex (eg, X-ray crystallography, NMR, etc.). Such locations and conjugation protocols for conjugation are well known in the art and can be determined by one of skill in the art (eg, “Methods of Making”, Examples 1-2).
9 and FIGS. Following attachment of the ligand to the linker or a critical portion thereof (eg, 2-10 atoms of the linker), the linker-ligand conjugate is tested for retention of activity in the relevant assay system. (See "Uses and Testing" below for representative assays.)

At present, this multi-binding compound can be a divalent compound (where two ligands are covalently attached) or a trivalent compound (where three ligands are covalently attached). Preferably, there is. The design of the linker is discussed further under the heading "Methods of Preparation".

“Efficacy” as used herein refers to the minimum concentration at which a ligand can achieve a desired biological or therapeutic effect. The potency of a ligand is typically proportional to its affinity for its receptor. In some cases, this potency may correlate non-linearly with its affinity. In comparing the efficacy of two agents (eg, aggregates of a multi-binding agent and its unlinked ligand), each dose-response curve was analyzed using the same test conditions (eg, in vitro or in vivo assays, appropriate animal models (eg, For example, in a human patient)). The conclusion that the multi-binding agent produces an equivalent biological or therapeutic effect at a lower concentration (eg, on a weight, molar or single ligand basis) than the unbound ligand aggregate is: It shows an increase in potency.

“Selectivity” or “specificity” is a measure of the binding preference of a ligand for different receptors. The selectivity of a ligand for its target receptor relative to other receptors is determined by the ratio of the respective K _d values (ie, the dissociation constant of each ligand-receptor complex) or at a lower value than the K _d. If is found, it is indicated by the ratio of the respective EC ₅₀ or IC ₅₀ (ie, the concentration that produces 50% of the maximal response to the ligand that interacts with two distinct receptors).

The term “treatment” refers to the treatment of any disease or condition in a mammal, especially a human, and includes the following: (i) may be susceptible to the condition Preventing the disease or condition from occurring in a subject who has not been diagnosed as suffering from, so that this treatment constitutes a prophylactic treatment of the disease condition; (ii) Inhibiting the disease or condition (ie, preventing its progress); (iii) reducing the disease or condition (ie, causing a regression of the disease or condition); or (iv) intrinsic. Reducing the symptoms resulting from the disease or condition without addressing the disease or condition (eg, reducing the symptoms of angina or other ischemic conditions, but reducing the underlying etiology ( Example, atherosclerosis or hypertension) is not removed).

The phrase “disease or condition modulated by treatment with a multi-binding K ⁺ channel ligand” refers to any art-recognized disease that is generally effectively treated with a ligand for a K ⁺ channel. Conditions and / or conditions, and these disease states and / or conditions, include those that are known to be effectively treated by certain multi-binding compounds of the invention (ie, compounds of Formula I).
Such disease states include, by way of example only, hypertension, cerebral ischemia, cardiac arrhythmias (especially,
Arrhythmias arising from potassium-related changes in membrane potential and conductivity), cardiac hypertrophy due to the weight burden of systole or diastole, congestive heart failure, and the like.

The term “therapeutically effective amount” means the amount of a multibinding compound, when administered to a mammal in need of such treatment and as defined above, sufficient to effect such treatment. The therapeutically effective amount will vary depending on the subject being treated and the disease condition, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can be readily determined by one skilled in the art.

The term “pharmaceutically acceptable excipient” is understood to include vehicles and carriers that can be administered with a multi-binding compound in order to facilitate its intended functioning performance. The use of such media for pharmaceutically active substances is well-known in the art. Examples of such vehicles and carriers include solutions, solvents, dispersion media, retarders, emulsions and the like. Any other conventional carrier suitable for use with the multi-binding compound also falls within the scope of the invention.

Methods of Making Linker The linker, when covalently attached to multiple copies of these ligands, results in a biocompatible, substantially non-immunogenic, multi-binding compound. The biological activity of the multi-bound K ⁺ channel compound depends on the geometry, composition, size, length, flexibility or rigidity of the linker, the presence or absence of anionic or cationic charges, relative hydrophobicity / hydrophilicity. Very sensitive to, and similar properties. Thus, the linker is preferably selected to maximize the biological activity of the compound. The linker can be biologically "neutral", i.e., does not itself contribute any additional biological activity to the multi-binding compound, or may further enhance the biological activity of the compound. Can be selected. In general, the linker may be selected from any organic molecular structure that orients more than one ligand binding to its receptor to allow for multivalency. In this regard, the linker can be viewed as a "backbone" on which the ligand is placed to elicit the desired ligand orientation result to produce a multi-binding compound.

For example, different orientations of the ligand can be achieved by using monocyclic or polycyclic groups (eg, aryl and / or heteroaryl groups) or by incorporating one or more carbon-carbon multiple bonds. By using different structures (alkenyl, alkenylene, alkynyl or alkynylene), this can be achieved by changing the geometry of this backbone (linker). The optimal geometry and composition of the backbone (linker) used in the multibinding compounds of the present invention is based on the properties of the receptor for which they are intended. For example, when a rigid cyclic group (eg, aryl, heteroaryl) or a non-rigid cyclic group (eg, cycloalkyl or crown group) may be required to achieve a strongly coupled bond, It is preferred to use such groups in order to reduce the entropy of

The different hydrophobic / hydrophilic nature of this linker, as well as the presence or absence of a charged moiety, can be easily controlled by one skilled in the art. For example, hexamethylenediamine (H ₂ N
The hydrophobicity of a linker derived from (CH ₂ ) ₆ NH ₂ ) or a related polyamine is such that the alkylene group can be converted to a poly (oxyalkylene) group (eg, commercially available “Jeffam”).
Ines "(as found in surfactants) can be modified to be substantially more hydrophilic.

Different scaffolds can be designed to give preferred orientation of these ligands.
Identification of the appropriate backbone geometry for ligand domain presentation is an important first step in the construction of multibinding agents with enhanced activity. A systematic spatial survey strategy can be used to help identify preferred scaffolds by iterative methods. FIG. 2 illustrates a useful method for determining the optimal backbone orientation for a ligand domain, which can be used to prepare the bivalent compounds of the present invention. What is described here can be substituted by various methods known to those skilled in molecular design.

As shown in FIG. 2, these ligands, which are shown as filled circles, have a central core structure (eg, phenyldiacetylene (panel A)
) Or cyclohexanedicarboxylic acid (panel B)). These ligands are spaced from this core by variable length (m and n) binding moieties. If the ligand has multiple binding sites (see discussion below), the orientation of the ligand on the binding site may also vary. The position of the display vector around these central core structures changes, thereby resulting in a collection of compounds. Assaying each individual compound of the resulting collection as described results in a subset of compounds having the desired high activity (eg, potency, selectivity). Ensemble Molecular Dyn
Analysis of this subset by techniques such as amics suggests a skeletal orientation that provides the desired properties.

In this process, it may be necessary to use multiple copies of the same central core structure or a combination of different types of display cores. It should be noted that core structures other than those shown here can be used to determine the optimal backbone display orientation of these ligands. The above techniques can be extended to trivalent compounds and higher order compounds.

[0147] A wide variety of linkers are commercially available (Chem Sources USA and Chem Sources International; the ACD).
Electronic databases; and Chemical Abstracts). Many of the linkers suitable for use in the present invention fall into this category. Others can be readily synthesized by methods known in the art, as described below. Examples of linkers include an aliphatic moiety, an aromatic moiety, a steroidal moiety, a peptide, and the like. Specific examples include peptides or polyamides, hydrocarbons, aromatics, heterocycles,
There are ethers, lipids, cationic or anionic groups, or combinations thereof.

Examples are shown below and in FIG. 3, but it will be understood that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. Should be. For example, the properties of the linker include the solubility (in water, fat, lipids, biological fluids, etc.) of the multi-binding compound, hydrophobicity, hydrophilicity, flexibility of the linker,
In order to change antigenicity, stability, and the like, denaturation can be achieved by adding or inserting an auxiliary group to the linker. For example, the introduction of one or more poly (ethylene glycol) (PEG) groups into the linker increases the hydrophilicity and water solubility of the multibond compound, increases both molecular weight and molecular size, and is not PEGylated. Depending on the nature of the linker, in vivo retention times may be longer. In addition, PEG can reduce antigenicity and can increase the overall rigidity of the linker.

Auxiliary groups that increase the water solubility / hydrophilicity of the linker (and thus the resulting multi-bonded compound) are useful in practicing the present invention. Therefore, in order to increase the water solubility and / or hydrophilicity of the multi-binding compound of the present invention, an auxiliary group (for example, ethylene glycol, alcohol, polyol (for example, glycerin, glycerol propoxylate, saccharide (monosaccharide, oligosaccharide) It is within the scope of the present invention to use small repeat units (eg, including), carboxylate (eg, small repeat unit such as glutamic acid, acrylic acid), amines (eg, tetraethylenepentamine). . In a preferred embodiment, the auxiliary group used to improve water solubility / hydrophilicity is a polyether. In a particularly preferred embodiment, the auxiliary group contains a small number of repeating ethylene oxide (-CH ₂ CH ₂ O-) units.

It is also within the scope of the present invention to incorporate lipophilic auxiliary groups within the structure of the linker to increase the lipophilicity and / or hydrophobicity of the compounds of formula I. Lipophilic groups useful with the linker of the present invention include, but are not limited to, lower alkyl groups, aromatic groups and polycyclic aromatic groups. These aromatic groups can be either substituted or unsubstituted with other groups, but are at least substituted with groups that allow covalent attachment to the linker. The term “aromatic group” as used herein includes both aromatic hydrocarbons and heteroaromatics. Other lipophilic groups useful with the linkers of the present invention include fatty acid derivatives that may or may not form micelles in aqueous media, and the interaction between the multi-binding compound and biological membranes And other specific lipophilic groups that regulate.

It is also within the scope of the present invention to use auxiliary groups that incorporate the compound of Formula I into vesicles (eg, liposomes) or micelles. The term "lipid" is any fatty acid derivative capable of forming a bilayer or micelle, wherein the hydrophilic portion of the lipid material is oriented toward its aqueous phase while the hydrophobic portion is oriented toward the bilayer. What is oriented is meant. Hydrophilicity is derived from the presence of phosphato, carboxylic acid, sulfato, amino, sulfhydryl, nitro, and other similar groups well known in the art. Hydrophobicity can be imparted by including the following groups: including but not limited to long chain saturated and unsaturated aliphatic hydrocarbon groups having up to 20 carbon atoms. However, such groups are substituted by one or more aryl, heteroaryl, cycloalkyl and / or heterocyclic groups. Preferred lipids include phosphoglycerides and sphingolipids, representative examples of which include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyl oil.
oyl) phosphatidylcholine, lysophosphatidylcholine, lysophosphatidyl-ethanolamine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoylphosphatidylcholine and dilinoleoylphosphatidylcholine. Other compounds lacking phosphorus (eg,
Sphingolipids and glycosphingolipids) also fall into a group called lipids. In addition, the amphiphilic lipids can be mixed with other lipids, including triglycerides and sterols.

The flexibility of the linker can be manipulated by including bulky and / or rigid auxiliary groups. The presence of bulky or rigid groups can hinder free rotation about the bond in the linker, or between the linker and the auxiliary group, or between the linker and the functional group. Rigid groups include, for example, groups whose conformational freedom is restricted by the presence of rings and / or π bonds (eg, aryl, heteroaryl, and heterocyclic groups). Other groups that can provide rigidity include polypeptide groups (eg, oligo- or polyproline chains).

[0153] Stiffness can also be provided electrostatically. Therefore, if these auxiliary groups are charged either positively or negatively, the similarly charged auxiliary groups will force this linker to have the maximum distance between each of the same charges. Configuration. The energy loss that brings these same charged groups closer together is
The square of the distance between these groups is inversely related, and the linker tends to hold in a configuration that maintains separation between similarly charged auxiliary groups. In addition, oppositely charged auxiliary groups tend to be attracted to their oppositely charged counterparts, which can result in both intermolecular and intramolecular ionic bonds. This non-covalent mechanism tends to hold the linker in a conformation that allows binding between oppositely charged groups. A charged auxiliary group, or a protecting group with a latent charge (this is followed by deprotection, pH change,
Oxidation, reduction, or other mechanisms known to those skilled in the art) are within the scope of the invention.

The bulky group includes, for example, a large atom, an ion (for example, iodine, sulfur, or a metal ion), a group containing a large atom, or a polycyclic group (an aromatic group or a non-aromatic group). And structures incorporating one or more carbon-carbon π bonds (ie, alkenes and alkynes). The bulky groups also
Mention may be made of oligomers and polymers which are branched or linear. Branched species are expected to increase the rigidity of this structure per unit molecular weight gain over linear species.

In a preferred embodiment, rigidity (entropy control) is provided by the presence of cycloaliphatic (eg, cycloalkyl), aromatic and heterocyclic groups. In another preferred embodiment, it contains one or more 6-membered rings. In further preferred embodiments, the ring is an aryl group (eg, phenyl or naphthyl) or a macrocyclic ring (eg, a crown compound).

In view of the above, it is clear that the proper selection of a linker group that will provide the proper orientation, entropy and physicochemical properties is entirely within the skill of the art.

[0157] Eliminating or reducing the antigenicity of the multibinding compounds described herein is also within the scope of the present invention. In some cases, the antigenicity of the multibinding compound may be eliminated or reduced, for example, by using a group such as poly (ethylene glycol).

Compounds of Formula I As described above, the multi-binding compounds described herein contain 2-10 ligands covalently linked to a linker, wherein the linker comprises a K Ligand is linked in a manner that allows multivalent binding to the ligand binding site of the ⁺ channel. The linker spatially constrains interactions from taking place within the dimensions defined by the linker. This factor and other factors enhance the biological and / or therapeutic effect of the multi-binding compound as compared to the same number of ligands used in a single binding mode.

The compounds of the present invention are preferably represented by the empirical formula (L) _p (X) _q , where L, X, p and q are as defined above. This is interpreted to include several ways in which these ligands can be ligated together to achieve the purpose of multivalency, and a more detailed description is provided below.

As mentioned above, the linker may be considered as the backbone to which the ligand is attached. Therefore, these ligands can be placed at any suitable position on the scaffold (eg,
It should be understood that the bond can be at the end of the linear chain or at any intermediate position thereof.

The simplest and most preferred multi-binding compounds are divalent compounds, which can be represented as LXL, wherein L is a ligand and are the same or different and X is a linker . Trivalent compounds can also be represented in a linear fashion, ie, as a sequence of repeating units LXLXL, where L is a ligand and, like X, At the same or different. However, trivalent compounds can also contain three ligands attached to the central core, and therefore (
L) ₃ X, wherein the linker X can contain, for example, an aryl or cycloalkyl group. The tetravalent compound may be a linear array: LXLXLXL, or a branched array:

[0162]

Embedded image That is, it can be represented by a branched structure similar to isomers of butane (n-butyl, iso-butyl, sec-butyl and t-butyl). Alternatively, it is an aryl or cycloalkyl derivative as described above,
It can be represented as having four ligands attached to its core linker.

The same requirement applies to higher multi-binding compounds of the invention containing 5 to 10 ligands. However, for a multiple binding agent attached to a central linker such as an aryl, cycloalkyl or heterocyclic group or crown compound, there will be sufficient attachment sites on this linker to accommodate the number of ligands present. There are obvious constraints that must be taken; for example, a benzene ring cannot accommodate more than six ligands, whereas a polycyclic linker (eg, biphenyl) can accommodate more ligands.

Formula (L) _p (X) _q is also taken to represent a cyclic compound of formula (-LX-) _n , where n is 2-10.

All of the above changes are construed as falling within the scope of the invention as defined by formula (L) _p (X) _q . Examples of divalent and higher valent compounds of the invention are shown in FIG. 4A.
４4D.

In view of the foregoing, a preferred linker may be represented by the formula: -X'-Z- (Y'-Z) _m -Y "-ZX'- where m is X ′ is an integer from 0 to 20; X ′ is in each individual case —O—, −
S-, -S (O)-, -S (O) _2- , -NR-, -N ⁺ RR'-, -C (O)-
, -C (O) O-, -C (O) NH-, -C (S), -C (S) O-, -C (S
A) NH— or a covalent bond, wherein R and R ′ are in each individual case
R is as defined below for R ′ and R ″; Z is, in each individual case, alkylene, substituted alkylene, alkylalkoxy, cycloalkylene, substituted cycloalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenyl, Selected from alkenylene, substituted cycloalkenylene, arylene, substituted arylene, heteroarylene, heterocyclene, substituted heterocyclene, crown compound or covalent bond; Y ′ and Y ″ are, in each individual case,
Selected from the group consisting of:

[0167]

Embedded image -S-S- or a covalent bond; wherein n is 0, 1 or 2;
And R ″ are in each individual case selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl or heterocyclic.

Further, the linker moiety may optionally be selected at any atom therein.
It can be substituted by one or more alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl or heterocyclic groups.

As indicated above, the simplest (and preferred) structure is a divalent compound that can be represented as LXL, where L is the same or different K in each case ⁺ Is a channel ligand and X is a linker. Thus, an example of the preparation of a divalent ligand is given below as an illustration of the manner in which the multi-bound compounds of Formula I are obtained.

The following reaction scheme is used to link potassium channel modulators of phenylmethanesulfonamides (dofetilide, ibtilide, sematilide, sotalol and E-4031) and benzofurans (amiodarone, decylamiodarone, NE-10064). A preferred connection method will be described. These methods are
Similarly, any K ⁺ channel ligand that contains or can be functionalized with groups compatible with the chosen linker (eg, azimilide and tedisamil) is to be construed as being true.

As mentioned above, the linker can be attached at different positions on the ligand molecule to obtain different orientations of the ligand domain and promote multivalency. For example, locations that may be available to link benzofurans such as amiodarone are indicated by arrows in the structure shown in FIG.

Preferred binding positions suggested by known SARs are illustrated in the reaction schemes of FIGS. Examples of ligands are shown in Table 4.

Certain K ⁺ channel ligands are chiral and may exhibit stereoselectivity.
The most active enantiomer is preferably used as a ligand in the multibinding compounds of the present invention. Chiral resolution of enantiomers is achieved by conventional separation of diastereomeric derivatives or salts, followed by conventional separation by chromatography or fractional crystallization (eg, Bossert et al., Angew, Ch.).
em. Int. Ed. 20: 762-769 (1981) and U.S. Pat.
, 571,827 and references cited therein). They can also be obtained by asymmetric synthesis.

[0174] These ligands are covalently attached to the linker using conventional chemical methods. Reaction chemistries that result in such linkages are well known in the art and involve the coupling of reactive functional groups present on the linker and ligand. In some cases, it may be necessary to protect portions of the ligand that are not involved in the ligation reaction. Protecting groups for this purpose are well known in the art and are generally designated in these reaction schemes by the symbols PG and PG '.

Preferably, the reactive functional group on the linker is selected in relation to a functional group available for coupling on the ligand or which can be introduced on the ligand for this purpose. . In one embodiment, the linker is coupled to a ligand precursor and ligand synthesis is completed in a subsequent step.
In the absence of functional groups, they are described in J. March, Advanced Organ
ic Chemistry, 4th Edition (Wiley-Interscience,
N. Y. , 1992) by appropriate chemical reactions described in standard organic chemistry textbooks. An example of a chemical reaction for linking a ligand by a linker is shown in FIG. 6, where R ¹ and R ² represent a ligand and / or a linking group. One skilled in the art understands that the reactions exemplified herein can be substituted with synthetically equivalent coupling reactions.

The linker to which these ligands or ligand precursors bind contains a “core” molecule having two or more functional groups with reactivity complementary to that of the functional groups on the ligand. FIG. 3 shows the size, shape, length, orientation, rigidity,
Various "cores" are illustrated that are useful for varying acidity / basicity, hydrophobicity / hydrophilicity, hydrogen bonding properties, and the number of linked ligands. This pictorial description is to be construed as merely illustrative of the invention, and not as limiting the scope of the invention to the structures illustrated. In these figures and the subsequent reaction schemes, the solid circle is generally used to represent the core molecule, which in the examples is "L
Ink ". This black circle corresponds to the linker as defined above after the reaction.

Preferred compounds of the formula I are divalent. Thus, for purposes of brevity, most of the figures and reaction schemes below illustrate the synthesis of divalent K ⁺ channel modulators. It should be noted, however, that the same method can be used to generate higher order multi-bond compounds (ie, compounds of the invention where p is 3-10) (see, eg, FIGS. 15 and 20). ).

Reactions performed under standard amide coupling conditions are sterically hindered (hind
ed) in an inert polar solvent (eg, DMF, DMA) in the presence of a base (eg, TEA, DIPEA) and a standard amide coupling reagent (eg, DPPA, PyBOP, HATU, DCC). Will be

Several methods for preparing divalent benzofuran (BF) compounds as exemplified herein with amiodarone and structurally similar molecules are described in the reaction scheme for amiodarone and dronedarone shown in FIG. Described. These are described in detail in Examples 1-3.

Some methods for preparing divalent phenylmethanesulfonamide (PMS) compounds, as exemplified by dofetilide, ibutilide, sematilide and sotalol, as well as structurally similar molecules, are shown in FIGS. In the reaction scheme,
Described. These will be described in detail in Examples 4 to 11.

Some methods for preparing divalent azimilide and tedisamil compounds are shown in FIG.
This is illustrated in the reaction schemes shown in FIGS. These are described in Examples 12 to 14.
This will be described in detail.

The methods for preparing compounds of Formula I described above involve coupling the ligand directly to a homobifunctional core. Another method for preparing both divalent and higher order multi-binding compounds, which can be used with all ligands, is to introduce a "spacer" before coupling to the central core. is there. Such spacers can themselves be selected from the same set of available core compounds. An example of this coupling method using the starting material prepared as described above is shown in FIG. 14, where the spacer is represented by a solid circle. As defined herein, the linker is
Contains this spacer + core. These are described in detail in Examples 15-17.

Higher order valences (ie, p> 2) of compounds of formula I can be prepared by simply extending the above methods. As shown in FIG. 15, the compound is prepared by coupling a ligand to a central core having multiple functional groups. The reaction conditions are the same as described above for the preparation of the divalent compound, but with appropriate adjustments in the molar amounts of ligand and reagent. These are described in detail in Examples 18-21.

FIGS. 16 and 17 show ligands coupled to the polypeptide core with side chain spacers. Solid phase peptide synthesis can be used to generate a wide variety of peptide core molecules. Techniques well known to those skilled in the art (including combinations) are used to alter the distance between the ligand binding sites on the core molecule, the number of binding sites available for coupling, and the chemical properties of the core molecule. You. To selectively protect the functional groups on the core molecule, orthogonal protecting groups are used, whereby an auxiliary group is inserted into the linker of the multi-binding compound and / or the "heterovalomer (heterov)".
alomers) (ie, multi-binding compounds with non-identical ligands).

All of the above synthetic methods use the step of symmetrically linking a ligand, either attached or not attached to a spacer, to a functionally equivalent moiety on the central core. Compounds of formula I also have an asymmetric linear approach.
ear approach). This method is preferred when linking two or more ligands at different junctions (see, eg, FIG. 18) or when preparing heterobaromers (eg, see FIG. 19). These are described in detail in Examples 22-25.

Compound Isolation and Purification Isolation and purification of the compounds and intermediates described herein can be carried out by any suitable separation or purification, if desired (eg, filtration, extraction, crystallization, Such as column chromatography, thin-layer chromatography, thick-layer chromatography, low-pressure or high-pressure liquid chromatography for separation or a combination of these procedures)
Can be performed. The characterization is preferably by NMR
And by mass spectrometry.

Uses and Tests The multibinding compounds of the present invention can be used to modulate potassium channels in various tissues including heart, muscle and nerve. These typically include mammalian diseases and conditions in which K ⁺ channels are involved or mediated by them (
For example, it is used to treat hypertension, cardiac arrhythmias, cerebral ischemia, congestive heart failure, etc.).

The multibinding compounds of the present invention are tested in well-known and reliable assays, and their activity is compared to that of the corresponding unlinked (ie, monovalent) ligand.

(Binding Affinity for Potassium Channel) This binding affinity is determined by a radioligand competition inhibition assay ²³ .
The ability of the compounds of the invention to compete with [ ³ H] dofetilide or similar radioligand in binding to the high and low affinity binding sites of guinea pig ventricular myocytes is measured in vitro. This binding affinity is calculated from the competition curve,
It is compared to that of a monovalent ligand and / or a monovalent linker-ligand conjugate.

[0190] antiarrhythmic effect of (antiarrhythmic effect) the compounds of the present invention, myocardial infarction at the induction and dogs can reproducibly induce ventricular tachycardia or ventricular fibrillation, can be determined in vivo ^{1, 22.} The suppression of induced arrhythmias is measured.

The anti-fibrillatory and anti-arrhythmic effects of the compounds of the present invention can be determined in vivo using a canine model of sudden death ⁷ . The reduction in the incidence of programmed electrical stimulation (PES) -induced ventricular tachycardia and protection against ischemia-induced ventricular fibrillation are measured.

The antiarrhythmic effects of the compounds of the present invention can be determined in vivo using a mouse chloroform model ⁸ . The proportion of animals exhibiting normal sinus rhythm is measured.

The antiarrhythmic effects of the compounds of the present invention can be determined in vivo using a rat coronary artery ligation model ⁸ . Ventricular extrasystoles occurring over a 30 minute period following this procedure are counted.

The antiarrhythmic effects of the compounds of the present invention can be determined in vitro or in vivo using a rat coronary artery ligation / reperfusion model ⁸ . In the in vitro model, the excised rat heart is reverse-perfused with a solution of the compound to be tested, then the coronary arteries are ligated, followed by reperfusion. In its in vivo evaluation, the compound is administered intraperitoneally, then the coronary arteries are ligated, followed by reperfusion. In both models, the incidence and time to onset of premature ventricular contractions, tachyarrhythmias and fibrillation during reperfusion are measured.

The antiarrhythmic effects of the compounds of the present invention can be determined in vivo using an anesthetized rat model with ventricular arrhythmias ⁹ . The time to onset of ventricular extrasystole is measured.

The antiarrhythmic effects of the compounds of the invention can be determined in vivo using a canine myocardial infarction model, where the compounds are treated 24 hours after ligation of the left anterior descending coronary artery.
¹¹ to be administered. Effective refractory period of right ventricle, duration of monophasic action potential, and P
The reduction in ES-induced ventricular tachycardia and ventricular fibrillation is measured.

The ability of the compounds of the present invention to extend the action potential (delay the onset of active block) and recover faster from block can be determined in vitro using rabbit ventricular myocytes ^13,30 . The occurrence and recovery from blockage in the long depolarizing clamp is measured.

The ability of the compounds of the present invention to inhibit repolarization arrhythmias can be determined in vitro using canine epicardial intermediate myocardium and endocardium and canine cardiac Purkinje fibers, and can also be performed in anesthetized rabbits. ^26,58,62 .

The ability of the compounds of the present invention to inhibit arrhythmias is shown in cat feline coronary artery occlusion and left stellate ganglion stimulation model, transient ischemia conscious dog model during exercise with healed myocardial infarction (MI) ^{52 and 59} can be determined in vivo using a conscious dog model of complete occlusion after a new MI.

[0200] Performance of a compound to extend the duration of action potential of the present invention, by using the guinea pig heart, can be determined in vivo and in vitro ^57, also using cardiac Purkinje fibers cattle, in vitro ⁶³ can be determined.

[0201] Performance of the compounds of the invention to prevent atrial fibrillation (AF), using the canine model of sustained vagal tone AF, ⁶⁸ to be determined. Prevention of AF induction is measured. Reverse use dependence can also be determined.

Effects on Tachycardia The effects of the compounds of the present invention on tachycardia can be determined in vitro using rabbit right atrial tone samples ² . The microelectrode method is used to measure the ability to prolong the refractory period and prevent the onset of tachycardia.

[0203] Effect of the compounds of this invention for tachyarrhythmia using the right ventricular papillary muscle of the guinea pig may be determined in vitro ^27. The duration of the action potential at different extracellular potassium concentrations is measured.

Effects on Potassium Current The effects of compounds of the present invention on repolarization currents I _K and I _TO were determined using whole cell recordings in papillary muscle cells from cat ventricular myocytes and ovariectomized rabbit hearts. do it,
^4,31 can be determined in vitro.

The effect of the compounds of the present invention on various specific potassium currents is
Ventricular and sinoatrial node cells, human atrial myocytes, canine ventricular muscle and Purkin
D fiber, guinea pig papillary muscle, single voltage-fixed guinea pig ventricular myocytes and
Can be determined in vitro using human ventricular endocardial myocardium^{6,12,17,25,29,32 , 33,37,51,66,69,71} .

[0206] Performance of the compounds of the invention to inhibit potassium currents in non-cardiac specimen ⁶⁰ using the taste receptor cells of the rat can be determined.

Selectivity and / or Specificity The ability of the compounds of the present invention to modulate KATP channels can be determined using the ⁸⁶ Rb efflux assay ^15,64 . Therefore, this is a potency assay.

[0208] selectivity and / or specificity of the compounds of the present invention uses a CHO cell line expressing a particular recombinant potassium channel subtypes can be determined ^34.

The selectivity of the compounds of the invention for various potassium channel currents can be determined in vitro using cloned K channels expressed in cells or ventricular myocytes ^12,34 .

The selectivity of the compounds of the present invention for various receptors can be determined in vitro using rat synaptosome membranes. (Pong et al., "Binding
profile of NE-10064, a novel Class I
II anti-arrhythmic agent to rat brai
n receptors ", Phaseb J. et al. , 7: A474 (1993)).

Anti-vasoconstrictor activity Anti-vasoconstrictor activity is the concentration of compound required to produce 50% vasorelaxation in rabbit thoracic aortic strips contracted with KCl in the presence of calcium. As
Determined as described in Brittain et al., Physilogist, 28: 325 (1985). Alternatively, in guinea pig Langendorff heart preparations, the concentration of the compound required to inhibit the coronary vasoconstriction induced by the thromboxane analog (U-46619, ie, 9,11-methanoepoxy-PGH ₂ ) is: Eltze et al., Chirality, 2: 233-240 (1
990) as described.

Antihypertensive Activity Antihypertensive activity is determined in spontaneously hypertensive male rats by measurement of mean arterial blood pressure (Rovnyak et al., J. Med. Chem., 35: 325).
4-3263 (1992)).

Tissue Selectivity Selectivity for vascular smooth muscle as compared to myocardium inhibits the concentration of multi-binding compounds that cause a 50% increase in coronary blood flow in isolated guinea pig hearts and myocardial contractility It can be evaluated by comparing with the concentration required for the measurement. For example, Osterrie
der, W.C. And Holck, M .; , J. et al. Cardiovasc. Pharm
. , 13: 754-9 (1989); and Cremers et al. Card
iovasc. Pharm. , 29: 692-696 (1997).

Combinatorial Libraries The methods described above lend themselves to combinatorial approaches to identify multimeric compounds with multibinding properties for potassium channels.

Specifically, factors such as the correct juxtaposition of individual ligands of a multi-binding compound with respect to an associated array of binding sites on a target may be important in optimizing the interaction of a multi-binding compound with its target. It is also important to maximize the biological benefits of multivalency. One approach involves identifying a library of candidate multiple binding compounds with properties that span multiple binding parameters relevant to a particular target. These parameters include: (1) the nature of the ligand, (2)
Ligand orientation, (3) valency of the structure, (4) linker length, (5) linker geometry, (6) linker physical properties, and (7) linker chemical functionality.

A library of multimeric compounds that may have multiple binding properties (ie, candidate multiple binding compounds) comprising multiple such variables is prepared, and these libraries are then: Evaluated by conventional assays corresponding to the selected ligand and the desired multibinding parameters. The requirements associated with each of these variables are set forth below: (Ligand Selection) A single ligand or set of ligands can be used to create a library of candidate multiple binding compounds whose library is directed against a particular biological target. Selected for incorporation. The only requirement for the ligands chosen is that they be able to interact with the chosen target. Thus, the ligand may be a known drug, an improved version of a known drug, a substrate of a known drug or an improved substrate of a known drug, which are capable of interacting with this target, or other compounds. . The ligand is
Preferably, the selection is based on known advantageous properties, which can be devised to carry over or be enhanced in a multi-bond form. Advantageous properties include proven safety and efficacy in human patients, appropriate PK / ADME profiles, synthetic availability, and desirable physical properties (eg, solubility,
LogP). It is important to note, however, that ligands with disadvantageous properties from the preceding list may still have more favorable properties through the multi-binding compound formation process; On the basis, some ligands should not necessarily be excluded. For example, a ligand that is not sufficiently potent at a particular target to be effective in a human patient can be very potent and effective when presented in a multi-bound form. Ligands that are potent and effective but have no mechanistic toxic side effects can have a high therapeutic index (high potency compared to toxicity) as a multi-binding compound. Compounds that exhibit short in vivo half-lives may have long half-lives as multi-binding compounds. The physical properties that limit the usefulness of the ligand (eg, poor bioavailability due to low solubility, hydrophobicity, hydrophilicity) can be rationally modulated in a multi-bound form, and can be tailored to the desired application. A compound having the characteristic properties is obtained.

(Orientation: Selection of Ligand Binding Point and Ligation Chemistry) For each ligand, several points are selected that bind this ligand to the linker. The point of attachment selected on the ligand / linker is functionalized to contain a complementary reactive functional group. This allows for scrutiny of the effect of presenting ligands to their receptors in multiple relative orientations (important multibinding design parameters). The only requirement to select a connection point is that at least one of these points
Sometimes binding to an individual does not interfere with the activity of the ligand. Such attachment points can be identified by structural information (when available). For example,
Examination of the eutectic structure of the protease inhibitor bound to its target can identify one or more sites where the linker bond does not interfere with the enzyme (inhibitor interactions). Alternatively, assessing ligand / target binding by nuclear magnetic resonance can identify sites that are not essential for ligand / target binding. See, for example, Fesik et al., US Pat.
See No. 91,643. When such structural information is not available, the use of a structure-activity relationship (SAR) to the ligand suggests where substantial structural changes are and are not possible. Structural information and SAR
In the absence of both information, the library can simply select at multiple points of attachment that can present the ligand in multiple different orientations. Subsequent evaluation of this library will reveal which positions are appropriate for binding.

The binding sites that interfere with the activity of the monomeric ligand may also be defined in the library, provided that such compounds have at least one ligand attached in a manner that does not interfere with the intrinsic activity. It is important to emphasize that inclusion in a candidate multibinding compound may be advantageous. This selection is derived, for example, from heterobivalent interactions associated with a single target molecule. For example, consider a receptor antagonist ligand bound to its target receptor, and then determine the antagonist binding site (which is an element of the receptor that is not part of the formal antagonist binding site and / or an element of the matrix surrounding the receptor ( For example, membrane)
By linking a second copy of the same ligand to it using a linker that interacts with the same receptor molecule at a site adjacent to
Consider modifying this ligand. At this time, the orientation most favorable for the interaction of the second ligand molecule with the receptor / matrix is to place the second ligand molecule with the linker at a position that prevents the activity of the ligand at the formal antagonist binding site. It can be achieved by combining. Another way to take this into account is that the SAR of an individual ligand associated with a multi-binding structure often differs from the SAR of the same ligand in monomeric form.

The foregoing discussion suggests that two copies of the same ligand bound to a single linker via different points of attachment, one of which can interfere with the binding / activity of this monomeric ligand. The focus was on the bivalent interactions of the dimeric compounds. It should be appreciated that the bivalent advantage can also be achieved with heterodimeric structures having two different ligands that bind to a common target or different targets. For example, 5HT ₄
Receptor antagonists and bladder selective muscarinic M ₃ antagonists,
Linkers can be attached via a point of attachment that does not interfere with the binding affinity of the monomeric ligand for their respective receptor sites. The dimeric compounds, 5HT ₄ ligand and M ₃ favorable interactions between elements close to the official M ₃ antagonist binding site of the receptor, and M ₃ formal of ligand and 5HT ₄ receptor 5
Because of the favorable interaction between the proximate the HT ₄ antagonist binding site element to achieve a high affinity for both receptors. Therefore, this dimeric compound is a more potent and selective antagonist of irritable bladder and may be an excellent therapy for urinary urge incontinence.

[0220] Once the ligand binding points have been selected, the possible chemical bond types at these binding points are identified. The most preferred forms of chemical bonding include those that are readily and generally compatible with the overall structure of the ligand (or protected form of the ligand), and that are typical of chemical and physiological conditions. Are stable, essentially non-toxic and compatible with the large number of available linkers. Amide bond, ether,
Amines, carbamates, ureas and sulfonamides are just a few examples of preferred linkages.

Linker: Valence, linker length, linker geometry, stiffness, physical properties and related multi-binding parameters that extend across the selection of chemical functional groups. Used to generate libraries of candidate multi-binding compounds. For a library of linkers, the choice of linker used in this library of linkers takes into account the following factors: (valency) In most cases, this library of linkers is started with a bivalent linker . By choosing the ligand and the correct juxtaposition of the two ligands for its binding site, such molecules can have target binding affinities and specificities higher than sufficient to confer a biological advantage. It is possible to show. Further, the bivalent linker or structure is also typically of a suitable size to retain the desired biodistribution properties of the small molecule.

(Length of Linker) The linker is selected to have a length that can measure the range of the distance between ligands (including the preferable distance for a predetermined bivalent interaction). In some cases, the preferred distance can be approximated somewhat accurately from the precise structural information of the target (typically, enzyme and soluble receptor targets). In other cases where precise structural information is not available (e.g., 7TM G-protein coupled receptor), approximate the maximum distance between binding sites either on adjacent receptors or at different locations on the same receptor. To make a simple model available. In situations where the two binding sites are on the same target (or target subunit for multiple subunit targets), the preferred linker distance is 2-20 °, and a more preferred linker distance is 3-12 °. is there. In situations where the two binding sites are on separate (eg, protein) target sites, the preferred linker distance is between 20 and
100 °, and a more preferable distance is 30 to 70 °.

Linker Geometry and Stiffness The combination of ligand binding site, linker length, linker geometry and linker stiffness can be presented at the binding site by displaying the ligand of the candidate multibinding compound in three dimensions. Determine a viable method. Linker geometry and stiffness are nominally determined by chemical composition and bonding pattern,
Other features that can be controlled and spanning functions in multi-coupling arrays
on) and can be systematically changed. For example, the geometry of the linker can be achieved by attaching two ligands to the ortho, meta and para positions of the benzene ring, or by a 1,1-position vs. a 1,2-position vs. 1,3 around a cyclohexane core.
-At position 1,4-position, in the cis or trans configuration, or in the cis or trans configuration at the point of ethylenic unsaturation. The stiffness of the linker can be varied by controlling the number and relative energy of the different conformational states possible for the linker. For example, a bivalent compound having two ligands linked by a 1,8-octyl linker is one in which the two ligands are 4,4'-
It has much more freedom than a compound attached to a position and is therefore less rigid.

Physical Properties of the Linker The physical properties of the linker are nominally determined by the chemical structure and bonding pattern of the linker, and the physical properties of the linker are determined by the overall physical properties of the candidate multi-binding compound containing it. Affect the mechanical properties. The range of linker composition is typically selected to provide a range of physical properties (hydrophobic, hydrophilic, amphiphilic, polar, acidic and basic) in the candidate multi-binding compound. . The particular choice of the physical properties of the linker is made in relation to the physical properties of the ligand to which they bind, preferably
The goal is to generate molecules with advantageous PK / ADME properties. For example, the linker may be selected such that it is not too hydrophilic or hydrophobic to be easily absorbed and / or distributed in vivo.

Chemical Function of the Linker The chemical function of the linker is a chemistry selected to provide a range of physical properties sufficient to connect the linker to the ligand and extend the initial inspection of this parameter. Is selected to match

Combinatorial Synthesis Choosing a set of n ligands (where n is determined by the sum of the number of different points of attachment for each selected ligand) and m linkers by the method outlined above, A library of (n!) M candidate bivalent multibinding compounds is prepared,
This extends to the relevant multi-binding design parameters for a particular target. For example, two ligands bound in all possible combinations (one could have two points of attachment (A1,
A2) and one generated from three attachment points (B1, B2, B3)) gives at least 15 possible combinations of multiple binding compounds:

[0227]

Embedded image When each of these combinations is joined by 10 different linkers, a library of 150 candidate multibinding compounds is obtained.

Given the nature of this library combination, a common chemistry is preferably to link reactive functional groups on these ligands with complementary reactive functional groups on these linkers. ,used. Thus, this library lends itself to the implementation of efficient parallel synthesis methods. This combinatorial library can use solid phase synthesis reactions well known in the art, where the ligand and / or linker is attached to a solid support. Alternatively and preferably, the combinatorial library is prepared in the solution phase. After synthesis, the candidate multibinding compounds are optionally assayed, eg, by chromatographic methods (eg, HPLC), prior to assaying for activity.
Purified.

Analysis of Arrays by Biochemical, Analytical, Pharmacological and Combinatorial Methods The properties and activities of candidate multiple binding compounds in this library to determine which compounds possess multiple binding Various methods are used to characterize
Physical constants such as solubility under various solvent conditions and logD / clogD values can be determined. A combination of NMR spectroscopy and computational methods are used to determine the low energy conformation of a candidate multibond compound in a fluid medium. The ability of members of this library to bind desired and other targets is determined by various standard methods, including radioligand displacement assays for receptor and ion channel targets, and kinetic for many enzyme targets. Inhibition assays. In vitro efficacy (eg, against receptor agonists and antagonists, ion channel blockers, and antimicrobial activity) can also be determined.
Pharmacological data (oral absorption, inverted gut penetration
(including other pharmacodynamic parameters) and efficacy data can be determined with appropriate models. In this way, important structure-activity relationships are obtained for the multi-bond design parameters, which are then used for future studies.

[0230] Of the members of this library, those that exhibit multibinding as defined herein can be readily determined by conventional methods. First, members exhibiting multiple binding (both in vitro and in vivo) are identified by conventional methods described above, including conventional assays.

Second, identifying the structure of a compound that exhibits multiple binding can be accomplished by art-recognized procedures. For example, each member of the library can be encrypted or labeled with the appropriate information so that at a later point the structure of the associated member can be determined. See, for example, Dower et al., International Patent Application Publication No. WO 93/06.
No. 121; Brenner et al., Proc. Natl. Acad. Sci. , US
A, 89: 5181 (1992); Gallop et al., US Pat. No. 5,846,8.
See No. 39; each of these in their entirety is incorporated herein by reference. Alternatively, the structure of the relevant polyvalent compound can also be determined by methods known in the art (eg, Hindsgaul et al., Canadian Patent Application No. 2,240,325, which was published on July 11, 1998). Can be determined from a soluble, unlabeled library of candidate polyvalent compounds. Such methods combine frontal affinity chromatography with mass spectroscopy to determine both the structure of the candidate multibinding compound and its relative binding affinity to the receptor.

The process set forth above for dimeric candidate multibinding compounds can, of course, be extended to trimeric candidate compounds and higher analogs thereof.

Follow-Up Synthesis and Analysis of Additional Arrays Based on the information obtained from the analysis of the initial library, any elements of this process include specific relative ligand orientations, linker lengths, linker One or more promising multi-bond “lead” compounds may be identified, such as defined by geometry. Then, around these leads, additional libraries can be generated,
Provides further information on the relationship between structure and activity. These arrays are typically provided with a linker structure to further optimize target affinity and / or activity at the target (antagonism, partial agonism, etc.) and / or to alter physical properties. With more concentrated changes. Iterative redesign using novel principles of multi-bond design with classic medicinal chemistry, biochemistry and pharmacology approaches /
The analysis allows for the preparation and confirmation of optimal multi-binding compounds with biological benefits to their targets and as therapeutic agents.

To further refine this procedure, suitable divalent linkers include, by way of example only, those derived from: dicarboxylic acids, disulfonyl halides,
Dialdehydes, diketones, dihalides, diisocyanates, diamines, diols, mixtures of carboxylic acids, sulfonyl halides, aldehydes, ketones, halides, isocyanates, amines and diols. In each case, the carboxylic acid, sulfonyl halide, aldehyde, ketone, halide, isocyanate,
The amine and diol functional groups are reacted with complementary functional groups on the ligand to form covalent bonds. Such complementary functional groups are well known in the art, as exemplified in the following table:

[0235]

[Table 3] Representative linkers include the following linkers identified as X-1 to X-418 as shown below:

[0236]

[Table 4] Representative ligands for use in the present invention include, by way of example, L-1 through L-4. The L-1 ligand is a benzofuran compound (for example, 7A-1, 7B-1 or 7C-1 in Examples 1 to 3). The phenylmethanesulfonamide structure has an L-2 ligand (for example, 8A-1, 8B-1, 8C- of Examples 4 to 11).
1, 9A-1, 9B-1, 10A-1, 10B-1 or 11-1). The L-3 ligand is an azimilide compound (for example, one of Examples 12 to 13).
2-1 and 12-3). The L-4 ligand is a tedisamil compound (eg, 13-1 in Example 14).

The combinations of the ligand (L) with the linker (X) according to the invention include, by way of example only, homo- and heterodimers, wherein the first ligand is the above-mentioned L-1
~ L-4, and the second ligand and linker are selected from:

[0238]

[Table 5] Pharmaceutical Formulations The compounds of formula I, when used as medicaments, are usually administered in the form of a pharmaceutical composition. The present invention therefore provides a pharmaceutical composition comprising: as active ingredient one or more compounds of the above formula I or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable salts Excipients, carriers, diluents, penetration enhancers, solubilizers and adjuvants. These compounds may be administered alone or in combination with other therapeutic agents (eg, other antihypertensives, diuretics, etc.). Such compositions are prepared in a manner well known in the pharmaceutical art (eg, Remington's).
s Pharm. Sci. , Mack Publishing Co .; , Phi
ladelphia, PA, 17th edition (1985) and "Modern Ph.
arm. ", Marcel Dekker, Inc. , 3rd edition (GS Ban)
ker & C. T. Rhodes)).

The compounds of formula I may be administered by any of the appropriate modes of administration for agents having similar utilities, for example, oral, parenteral, rectal, sublingual, intranasal or transdermal routes. The most suitable route will depend on the nature and severity of the condition being treated. Oral administration is a preferred route for the compounds of the present invention. In preparing the compositions of the present invention, the active ingredient is usually diluted with an excipient or enclosed in a carrier such as a capsule, flavoring bag, paper or other container. . When the excipient is provided as a diluent, it can be a solid, semi-solid or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. . Thus, these compositions may be used as tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid medium or liquid). In vehicles), ointments (containing, for example, up to 10% by weight of active compound), soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders. Pharmaceutically acceptable salts of this active agent can be prepared by standard procedures known to those skilled in synthetic organic chemistry (see
This is described, for example, in J.A. March, Advanced Organic
Chem. Reactions, Mechanisms and Struct
ure, 4th edition (NY: Wiley-Interscience, 1992)
)) Can be prepared.

Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum arabic, calcium phosphate,
Alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. These formulations may further contain: lubricants (eg, talc, magnesium stearate and mineral oil); wetting agents; emulsifiers and suspending agents; preservatives (eg, methyl and propyl hydroxybenzoate); Fees;
And fragrances.

The compositions of the present invention can be administered to a patient using procedures known in the art,
It can be formulated so as to give quick, sustained or delayed release of the active ingredient. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems, which contain a polymer coated reservoir or a drug-polymer matrix formulation. Examples of controlled release systems are described in U.S. Patent Nos. 3,845,770;
Nos. 525; 4,902,514; and 5,616,345. Another preferred formulation for use in the method of the present invention is a transdermal delivery device (
"Patch"). Such transdermal patches may be used for continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for dispensing pharmaceutical agents is well-known in the art. For example, U.S. Patent Nos. 5,023,252; 4,992,445 and 5,001,
See No. 139. Such patches may be configured for continuous, pulsatile or on demand distribution of pharmaceutical agents.

[0242] These compositions are preferably formulated in a unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as a single dosage for human subjects and other mammals, each unit comprising a suitable pharmaceutical excipient ( (Eg, tablets, capsules, ampoules) containing a predetermined amount of active substance calculated to produce the desired therapeutic effect. The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. Preferably, for oral administration, each dosage unit contains 1 to 250 mg of the compound of the formula I, and for parenteral administration, preferably 0.1 to 60 mg of the compound of the formula I or a pharmaceutically acceptable salt thereof. Contains an acceptable salt. However, the amount of compound that is actually administered will depend on the relevant situation, including, for example, the condition to be treated, the route of administration selected, the actual compound to be administered and its relative activities, the age, weight, and weight of the individual patient. And responsiveness, severity of the patient's symptoms, etc.).

To prepare a solid composition such as a tablet, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition, which is a compound of the present invention. (Containing a homogeneous mixture). When referring to these preformulated compositions as homogeneous, the active ingredient is dispersed throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms (eg, tablets, pills, and capsules) Means uniformly distributed over the

The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can contain an inner dosage and an outer dosage component, the latter being in the form of an overlying mantle. These two components are provided by an enteric layer, which is provided to resist disintegration in the stomach and pass its internal components intact through the duodenum or delay release. Can be separated. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol and cellulose acetate. Is mentioned.

The liquid forms in which the novel compositions of the present invention can be incorporated for oral administration or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and edible oils such as corn oil. , Cottonseed oil, sesame oil, coconut oil or peanut oil) and elixirs and similar pharmaceutical vehicles.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described above. Preferably, these compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferred pharmaceutically acceptable solvents can be nebulized by using an inert gas. The nebulized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure respirator. The solution, suspension or powder composition may be preferably administered orally or nasally from devices which deliver the formulation in an appropriate manner.

The following formulation examples illustrate representative formulation compositions of the present invention.

Formulation Example 1 A hard gelatin capsule is prepared containing the following ingredients: Amount Ingredient (mg / capsule) Active Ingredient 30.0 Starch 305.0 Magnesium Stearate 5.0 Combine the above ingredients and 340 mg And filled into hard gelatin capsules.

Formulation Example 2 A tablet formulation is prepared using the following ingredients: Amount Ingredient (mg / Tablet) Active Ingredient 25.0 Microcrystalline Cellulose 200.0 Colloidal Silicon Dioxide 10.0 Stearic Acid 5 0.0 These ingredients are mixed, compressed and tablets (each weighing 240 mg)
To form

Formulation Example 3 A dry powder inhaler formulation containing the following ingredients is prepared: Ingredient% by weight Active ingredient 5 Lactose 95 This active ingredient is mixed with this lactose and the mixture is dried powder inhaler To be added.

Formulation Example 4 Tablets (each containing 30 mg of active ingredient) are prepared as follows: Amount ingredient (mg / tablet) Active ingredient 30.0 Starch 45.0 Microcrystalline cellulose 35 4.0 Polyvinylpyrrolidone (as a 10% solution in sterile water) 4.0 Sodium carboxymethyl starch 4.5 Magnesium stearate 0.5 Talc 1.0 Total 120.0 The active ingredient, starch and cellulose were 20 mesh U.S. S. Pass through sieve and mix well. To the resulting powder was mixed a solution of polyvinylpyrrolidone, which was then mixed with a 16 mesh U.S.A. S. Pass through sieve. The granules so formed are dried at 50 ° C to 60 ° C and dried at 16 mesh U.S.A. S. Pass through sieve. The granules were then given No. 30 mesh U.S. S. Add sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a sieve, mix and compress on a tablet machine to give tablets (each weighing 120 mg).

Formulation Example 5 Capsules (each containing 40 mg of drug) are prepared as follows: Amount Ingredient (mg / capsule) Active Ingredient 40.0 Starch 109.0 Magnesium Stearate 1 0.0 total amount 150.0 This active ingredient, starch and magnesium stearate were mixed, and 2
0 mesh U.S. S. Pass through a sieve and fill into hard gelatin capsules in an amount of 150 mg.

Formulation Example 6 Suppositories (each containing 25 mg of active ingredient) are prepared as follows: Component Amount Active ingredient 25.0 mg Saturated fatty acid glyceride Up to 2,000.0 mg.

This active ingredient was designated as No. 60 mesh U.S. S. Pass through a sieve and suspend in the pre-melted saturated fatty acid glyceride using the minimum heat required. This mixture is
It is then poured into a 2.0 g apparent volume suppository mold and allowed to cool.

Formulation Example 7 Suspensions (each containing 50 mg of drug per 5.0 mL dose) are prepared as follows: Ingredient Amount Active Ingredient 50.0 mg Xanthan Gum 4.0 mg Sodium carboxymethylcellulose (11%) Microcrystalline cellulose (89%) 50.0 mg Sucrose 1.75 g Sodium benzoate 10.0 mg Flavors and dyes Optional Pure water up to 5.0 ml.

Mix this active ingredient, sucrose and xanthan gum, 10 mesh U.S. S. Pass through a sieve and then mix with the pre-made aqueous solution of the microcrystalline cellulose and sodium carboxymethylcellulose. The sodium benzoate, flavor and dye are diluted with some of the water and added with stirring. Then enough water is added to produce the required volume.

Formulation Example 8 Amount Ingredient (mg / capsule) Active ingredient 15.0 mg Starch 407.0 mg Magnesium stearate 3.0 mg Total amount 425.0 mg.

Mix this active ingredient, starch and magnesium stearate, 2
0 mesh U.S. S. Pass through a sieve and fill into hard gelatin capsules in an amount of 425.0 mg.

Formulation Example 9 A subcutaneous formulation may be prepared as follows: Ingredient Amount Active Ingredient 5.0 mg Corn oil 1.0 mL.

It is often desirable or necessary to introduce the pharmaceutical composition into the brain, either directly or indirectly. Direct methods usually involve placing a drug delivery catheter in the host's ventricular system to bypass the blood-brain barrier. One such implantable delivery system for use in delivering biological agents to specific anatomical regions of the body is described in US Pat. No. 5,011,472, the contents of which are incorporated herein by reference. Is incorporated herein by reference.

Indirect methods, which are generally preferred, generally involve formulating the composition to provide drug lamination by converting hydrophilic drugs into lipid-soluble drugs. including. Latination generally blocks the hydroxyl, carbonyl, sulfate, and primary amine groups present on the drug, making it more lipid soluble and undergoing transport across the blood-brain barrier. Achieved by making it easier. Alternatively, delivery of a hydrophilic drug can be enhanced by intra-arterial infusion of a hypertonic solution that can temporarily open the blood-brain barrier.

(Synthesis Example) (Example 1 (FIG. 7A)) N, N′-dimethyl-N, N′-di- [2- [4- [2-butyl-3-benzofuranylcarbonyl] -2) , 6-Diiodophenoxy] ethyl] hexane (7A-
2, where n = 1 and Link is (CH ₂ ) ₆ . 3-[(2-bromoethoxy) -3,5-diiodobenzoyl (diod
obenzoyl)]-2-butylbenzofuran (7A-1, which is described in Eur.
J. Med. Chem. , 1974, 19-25 and Belgian Patent No. 9001.
(2 mmol), diisopropylethylamine (5 mmol) and 1,6-di- (methylamino) hexane (1 mmol).
A solution of l) in acetonitrile (25 mL) is maintained at room temperature and the reaction is monitored by thin layer chromatography (tic). The reaction was complete, the solution was added to water and extracted with CH ₂ Cl _2. The extract is dried and evaporated and the residue is chromatographed to give the title compound 7A-2.

B. In a similar manner, in A above, as described herein, 1,6-di-
By using different diamines instead of (methylamino) hexane, different compounds of formula 7A-2 are obtained.

C. In a similar manner, using a different bromo compound of Formula 7A-1 as described herein above in A, gives a different compound of Formula 7A-2.

Example 2 (FIG. 7B) 1,8-di- [2- [4- [2-butylbenzofuran-3-ylcarbonyl]-
2,6-diiodophenoxy] ethyl] methylamino] -3,5-dioxaoctane (7B-2, where n is 1 and Link is (CH ₂ ) ₂ (O
Preparation of (CH ₂ ) ₂ ) ₂ A. N-methyl 2- [4- [2-butylbenzofuran-3-ylcarbonyl]
-2,6-diiodophenoxy] -ethylamine (7B-1) (this is Eur
. J. Med. Chem. , 1974, 19-25) (5 mmol), 1,8-dibromo-3,5-dioxaoctane (2.5 mmol).
mmol) and diisopropylethylamine (2 mL) in EtOH (25 mL)
) Keep the solution at room temperature. The progress of this reaction is followed by tlc. The reaction was complete, pour the mixture into water and extracted with CH ₂ Cl _2. The extract is dried and evaporated and the residue is chromatographed to give the title compound 7B-2 (where n is 1 and Link is (CH ₂ ) ₂ (O
Obtaining (CH _{2) 2)} is _2).

B. In a similar manner, using different compounds 7B-1 as described herein provides different linking compounds of formula 7B-2.

C. In a similar manner, instead of 1,8-dibromo-3,5-dioxaoctane,
By using different linking compounds as described herein, Formula 7B
-2 different linking compounds are obtained.

Example 3 (FIG. 7C) 1,10-di- [2-butyl- [3- [4- (3-dibutylaminopropoxy)
Benzoyl] benzofuran-5-yl] aminosulfonyl] decane (7C-2,
Here, Link is ((CH ₂ ) ₂ ) ₁₀ ). 5-amino-2-butyl-3- [4- (3-dibutylaminopropoxy)
Benzoyl] benzofuran (7C-1) (which, as described in EP No. 0,471,609, prepared) (1 mmol) and 1,10-di (chlorosulfonyl) decane (0.5 mmol), CH ₂ Cl Heat in ₂ (20 mL) at reflux. The progress of this reaction is followed by tlc. When this reaction is completed,
This solution is added to dilute Na ₂ CO ₃ . The organic phase was separated, dried and evaporated and the residue was chromatographed to give the title compound 7C-2
Get.

B. In a similar manner, using different di- (chlorosulfonyl) linking compounds, as described herein, gives different linking compounds of formula 7C-2.

Example 4 (FIG. 8A) 1,6-di [4- [2- [2- [4- (methylsulfonylamino) phenoxy]
Ethylmethylamino] ethyl] phenylaminosulfonyl] hexane (8A-2
, Where Link is (CH ₂ ) ₄ ) 2- [4- (methylsulfonylamino) phenoxy] ethyl bromide (21-
1) (10 mmol) and N-methyl 2- (4-nitrophenyl) ethylamine (21-2) (10 mmol) (both are J. Med. Chem., 199).
(Prepared as described in US Pat. No. 0,1151) in MeCN (100 mL) containing K ₂ CO ₃ (3 g) and KI (0.2 g) at reflux under heating I do. The reaction is monitored by tlc. When the reaction is completed, the solution is added to water and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed on N-methyl N-
(4-Nitrophenylethyl) 2- [4- (methylsulfonylamino) phenoxy] ethylamine (21-3) is obtained.

B. The above compound (3 mmol) was dissolved in EtOH (50 mL) and Ra
New nickel (1 g) is added. The mixture is stirred under a hydrogen atmosphere. The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is filtered and then evaporated. The residue was chromatographed to give N-
Methyl N- (4-aminophenylethyl) 2- [4- (methylsulfonylamino) phenoxy] ethylamine (8A-1) is obtained.

C. Hexane-1,6-chloride (1 mmol), dry CH ₂ Cl ₂ (25mL) solution of diisopropylethylamine (1 mL) and 8A-1 (0.5mmol), maintained at room temperature. The progress of the reaction is monitored by tlc. The reaction was complete, the solvent was removed under reduced pressure and the residue chromatographed to give the title compound 8A-2 (here, Link is, (CH ₂₎ a ₄₎ is obtained.

D. In a similar manner, at C above, by using different di (chlorosulfonyl) linking compounds as described herein, the different linking compounds 8A-2
Is prepared.

Example 5 (FIG. 8B) 1,4-di [4- [2-methyl-2- [4- (methylsulfonylamino) phenyl] ethylamino] ethoxy] phenyl] aminosulfonylmethyl] benzene (
8B-2, where, Link is _{p-CH 2 C 6 H 4} CH 2) Preparation A. 2- (4-nitrophenoxy) ethyl bromide (21-4) (10 mmol)
And 2- (4-methylsulfonylaminophenyl) N-methylethylamine (
21-5) (10 mmol) in MeCN (50 mL) (K ₂ CO ₃ (2
g) is heated under reflux. The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is added to water and EtOA
Extract with c. The extract is dried and evaporated and the residue is chromatographed on N-methyl N- (4- (methylsulfonyl-amino)
(Phenylethyl) 2- (4-aminophenoxy) ethylamine (8B-1) is obtained.

B. The above compound (8B-1) (1 mmol) and 1,4-di- (chlorosulfonylmethyl) benzene (0.5 mmol) are dissolved in CH ₂ Cl ₂ (50 mL). The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is washed with dilute Na ₂ CO ₃ , then dried and evaporated. The residue was chromatographed, 8B-2 (here, Link is, p-CH ₂
C ₆ H ₄ CH ₂ ).

C. In a similar manner, using a different di (sulfonyl chloride) linking compound, as described herein above in B above, provides a different linking compound 8B-
Prepare 2.

Example 6 (FIG. 8C) 1,10-di- [2- [4- (methylsulfonylaminophenoxy) ethyl] 2
-[4- [methylsulfonylaminophenyl] ethyl] amino] decane (8C-
2. Where Link is (CH ₂ ) ₁₀ ) N-benzyl 2- [4- (methylsulfonylaminophenyl)] ethylamine (21-7, which was prepared as described in EP 338793) (10 mmol), 2- [4- (bromide) Methylsulfonylaminophenoxy)]
Ethyl 21-8 (10 mmol) and K ₂ CO ₃ to (1g), MeCN (50m
In L), heat at reflux. The progress of the reaction is monitored by tlc.
When the reaction is completed, the solution is added to water and extracted with EtOAc.
The extract is dried and evaporated and the residue is chromatographed on N-benzyl N-2- (4-methylsulfonylaminophenoxy) ethyl 2- (4-methylsulfonylaminophenyl) ethylamine (21-9). Get)

B. Compound 21-9 (1 mmol) is dissolved in EtOH (20 mL) and ammonium formate (100 mg) and 10% Pd / C (50 mg) are added. The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is filtered, then added to water and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed on N-
[2- (4-Methylsulfonylaminophenoxy) ethyl] 2- (4-methylsulfonylaminophenyl) -ethylamine (8C-1) is obtained.

C. The above compound (1 mmol), 1,10-dibromodecane (0.5 mmol)
), K ₂ CO ₃ (1 g) and KI (0.05 g) are heated at reflux in MeCN. The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is added to water and extracted with EtOAc. Drying this extract,
And evaporate. The residue is chromatographed to give the title compound 8C-2, where Link is (CH ₂ ) ₁₀ .

D. In a similar manner, using a different dialkylating agent, as described herein, in place of 1,10-dibromodecane at C above, gives the compound of formula 8C-
Two different compounds are obtained.

Example 7 (FIG. 9A) 1,8-di- [4- [4- (ethylheptylamino) -1-hydroxybutyl]
Phenylamino-sulfonyl] octane (9A-2, where Link is (C
Preparation of H ₂ ) ₆ A. 4-nitrophenyl-4-oxobutanoic acid (21-10, which is Gaz
z. Chim. Ital. , 1967, 97, 654 and US Patent 5,40.
(10 mmol), 1-hydroxybenztriazole (10 mmol) and dicyclohexylcarbodiimide (10 mmol), dissolved as described in US Pat. No. 5,851, are dissolved in DMF (50 mL). To this solution is added ethylheptylamine (10 mmol). The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is added to water and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed to give N-ethyl N-heptyl 4- (4-nitrophenyl) -4-oxobutanamide (21-11).

B. The above prepared compound (2 mmol) is dissolved in dry diglyme (20 mL) and MeOH (1 mL). Lithium borohydride (25 mmol) is added and the solution is heated to reflux. The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is added to water and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed to give 4- [1-hydroxy-4 (ethylheptylamino) butyl] aniline (9A-1).

C. Compound 9A-1 (1 mmol) and octane-1,8-disulfonyl chloride (0.5 mmol) are dissolved in CH ₂ Cl ₂ . The progress of this reaction is tlc
Monitor with. When the reaction is completed, the solution is added to dilute Na ₂ CO ₃ and then extracted with EtOAc. The extract is dried and evaporated,
The residue is chromatographed to give the title compound 9A-2 (where Lin
k is (CH ₂ ) ₆ ).

D. In a similar manner, using different disulfonyl chlorides as described herein at C above gives different compounds of formula 9A-2.

Example 8 (FIG. 9B) 1,6-Di- [4- [4-hydroxy-4- (methylsulfonylaminophenyl)
) Butyl] -ethylamino] hexane (9B-2, where Link is (CH _Two )₆Preparation of A. 4- (4-aminophenyl) -4-oxobutanoic acid (21-12) (5 m
mol) with dicyclohexylcarbodiimide (5 mmol) and ethylamido
(5 mmol) in THF (50 mL). After 12 hours, this mixture
Add the product to water and extract with EtOAc. Wash the extract with diluted NaOH
And then dried and evaporated. Chromatography of the residue
To N-ethyl 4- (4-aminophenyl) -4-oxobutanamide (
21-13).

B. The product from A above (3 mmol) is dissolved in THF (25 mL) and to this solution is added diisopropylethylamine (5 mmol) and methanesulfonyl chloride (3 mmol). The reaction is monitored by tlc. When the reaction is completed, the solution is added to water and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed to give N-ethyl 4- (4-methylsulfonylaminophenyl) -4-oxobutanamide (21-14).

C. Dissolve the above compound (1 mmol) in ether (50 mL); cool the solution to 0 ° C. and add lithium aluminum hydride (5 mmol) to it. The reaction is monitored by tlc. When this reaction is completed, the excess hydride is decomposed by the addition of aqueous potassium sodium tartrate solution. The organic phase is separated, dried and evaporated down and the residue is chromatographed to give N-ethyl 4- (4-methylsulfonylaminophenyl) -4-hydroxybutylamine (9B-1).

D. Compound 9B-1 (1 mmol), diisopropylethylamine (2 mmol)
1) and 1,6-dibromohexane (0.5 mmol) in MeCN (25 m
L). The progress of the reaction is monitored by tlc. When the reaction is completed, the mixture is added to dilute Na ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The extract was dried and evaporated and the residue was chromatographed (where, Link is (CH ₂₎ a ₆₎ The title compound 9B-2 obtained.

E. In a similar manner, using a different dialkylating agent, as described herein, instead of 1,6-dibromohexane, gives different compounds of formula 9B-2.

Example 9 (FIG. 10A) 1,8-di- [4- [2- [diethylaminoethyl] aminocarbonyl] phenylaminosulfonyl] octane (10A-2, where Link is (CH ₂ ) Preparation of ₆ ) A. Procainamide (10A-1) (10 mmol) was added to MeCN (50 mL).
) And 1,8-di (chlorosulfonyl) octane (5 mmol) is added. The progress of the reaction is monitored by tlc. When this reaction is completed,
This solution is added to dilute Na ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The extract was dried and evaporated, (wherein, Link is (CH ₂₎ a ₆₎ the title compound 10A-2 obtained.

B. In a similar manner, using different disulfonyl chlorides, as described herein, provides different compounds of formula 10A-2.

Example 10 (FIG. 10B) 1,8-di- [N-ethylN ′-[2- [4- [methylsulfonylamino] benzoylaminoethyl] -amino] 3,5-dioxaoctane Preparation of (10B-2, where Link is (CH ₂ ) ₂ (O (CH ₂ ) ₂ ) ₂ ) N-ethyl N '-(4-methylsulfonylaminobenzoyl) ethylenediamine (10B-1) (this is described in J. Med. Chem., 1987, 30, 7).
55), diisopropylethylamine (5 mmol) and 1,8-dibromo-3,5-dioxaoctane (2.
5 mmol) is dissolved in MeCN (25 mL). The progress of this reaction is tlc
Monitor with. When the reaction is completed, the solution is added to dilute Na ₂ CO ₃ and extracted with CH ₂ Cl ₂ . The solution is dried and evaporated and the residue is chromatographed to give the title compound 10B-2 (where Link
Gives (CH ₂ ) ₂ (which is O (CH ₂ ) ₂ ) ₂ .

B. In a similar manner, using different dialkylating agents, as described herein, gives different compounds of formula 10B-2.

Example 11 (FIG. 11) 1,10-di- [2-hydroxy-2- [4-methylsulfonylaminophenyl] ethylamino] -decane (11-2, wherein Link is ( Preparation of CH ₂ ) ₁₀ A. 1,10-dibromodecane (5 mmol), 2-hydroxy-2- (4-
Methylsulfonylaminophenyl) -ethylamine (11-1) (10 mmol
) (Which, as described in EP 338 793, was prepared), potassium iodide (0.1 g) and K ₂ CO ₃ (1 g), it is stirred in MeCN (50 mL). The reaction is monitored by tlc. The reaction was complete, the mixture was added to water and extracted with CH ₂ Cl _2. The extract is dried and evaporated and the residue is chromatographed to give the title compound 11-2.
(Where Link is (CH ₂ ) ₁₀ ).

B. In a similar manner, using different alkylating agents, as described herein, gives different compounds of formula 11-2.

Example 12 (FIG. 12) 1,6-Di [4- [1-[[5- (4-chlorophenyl) -2-furanylmethylene] amino] -imidazolidin-2,4-dione 3-yl] butyl methylamino] hexane (12-2, where, Link is, (CH ₂₎ a ₆₎ A. preparation of 1-benzylamino-3- (4-iodobutyl) imidazolidine-2,4
-Dione (12-5), which was prepared as described in WO 93/04061, (5 mmol) was treated with methylamine (2 g) in MeOH (40 mL).
Add to the solution. The progress of the reaction is monitored by tlc. The reaction was complete, the mixture was added to water and extracted with CH ₂ Cl _2. The extract is dried and evaporated and the residue is chromatographed to give 1-benzylamino-3- (4-methylaminobutyl) imidazoline-2,4-dione (12-6).

B. The latter compound 12-6 (2 mmol) is added to EtOH (25 mL), which contains 10% Pd / C (50 mg) and ammonium formate (0.5 g). The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is filtered and added to water. The aqueous solution is extracted with EtOAc. The extract is dried and evaporated. The residue is chromatographed to give 1-amino-3- (4-methylaminobutyl) imidazolidine-2,4-dione (12-7).

C. The above compound (1 mmol) is dissolved in EtOH (20 mL). To this solution was added 5- (4-chlorophenyl) furan-2-carboxaldehyde (12-
8) (1 mmol) and p-toluenesulfonic acid (10 mg) are added. The progress of the reaction is monitored by tlc. The reaction was complete, the mixture was added to water and extracted with CH ₂ Cl _2. The extract is dried and evaporated to give 1- [5- (4-chlorophenyl) -2-furanylmethyleneamino] -3- [4- (methylamino) butyl] imidazolidin-2,4-dione (1
2-1) is obtained.

D. Compound 12-1 (1 mmol), 1,6-di- (p-toluenesulfonyloxy) hexane (0.5 mmol) and diisopropylethylamine (3 m
mol) in CH ₂ Cl ₂ (50 mL) is heated at reflux. The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is cooled and added to water. The aqueous solution was extracted with CH ₂ Cl _2, the extract was dried and evaporated. The residue was chromatographed to give the title compound 12
2 (where, Link is, (CH ₂₎ a ₆₎ is obtained.

E. In a similar manner, using other dialkylating agents, as described herein, gives different compounds of formula 12-2.

Example 13 (FIG. 12) 1,4-di [4- [1-[[5- (4-chlorophenyl) -2-furanylmethylene] amino] imidazolidin-2,4-dione- 3- yl] 4-butyl (piperazin-1-yl) butane (12-4, where, Link is (CH _{2) 4)}
Preparation of A. 1-benzylamino-3- (4-iodobutyl) imidazolidine-2,4
-Dione (12-5) (prepared as described in WO 93/04061) (5 mmol), diisopropylethylamine (10 mmol) and N-benzyloxycarbonylpiperazine (5 mmol) in MeCN (5
0 mL). The progress of the reaction is monitored by tlc. The reaction was complete, the mixture was added to water and extracted with CH ₂ Cl _2. The extract is dried and evaporated and the residue is chromatographed on 1
-Benzylamino-3- [4- (4-benzyloxycarbonylpiperazinyl)
[Butyl] -imidazoline-2,4-dione (12-9).

B. The above compound (2 mmol) is dissolved in EtOH (25 mL) and to this solution is added 5% Pd / C (100 mg) and ammonium formate (250 mg). The progress of the reaction is monitored by tlc. When the reaction is completed, the mixture is filtered and added to water, then extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed,
1-amino-3- [4- (piperazin-1-yl) butyl] imidazoline-2,
4-Dione (12-10) is obtained.

C. The above compound (1 mmol) is dissolved in EtOH (20 mL). To this solution was added 5- (4-chlorophenyl) furan-2-carboxaldehyde (12-
8) (1 mmol) and p-toluenesulfonic acid (10 mg) are added. The progress of this reaction is followed by tlc. The reaction was complete, the mixture was added to water and extracted with CH ₂ Cl _2. The extract is dried and evaporated to give 1- [5- (4-chlorophenyl) -2-furanylmethyleneamino]-
3- [4- (Piperazin-1-yl) butyl] imidazolidine-2,4-dione (12-3) is obtained.

D. 1,4-dibromobutane (0.5 mmol) and compound 12-3 (1 m
mol) in EtOH at room temperature, during which the progress of the reaction is
Monitor with. When the reaction is completed, the mixture is evaporated to dryness under reduced pressure and the residue is chromatographed to give compound 12-4.
(Where Link is (CH ₂ ) ₄ ).

E. In a similar manner, in Part D above, using different dialkylating agents, as described herein, provides different compounds of Formula 12-4.

Example 14 (FIG. 13) 1,10-di- (3-cyclopropylmethyl-9,9-tetramethylene-3,7
-Diazabicyclo [3.3.1] non-7-yl) decane (13-2, wherein
Link is (CH ₂ ) ₁₀ ). 3-benzyl-7-cyclopropylmethyl-9,9-tetramethylene-3
, 7-Diazabicyclo [3.3.1] nonane (20-1, where R ₁ is benzyl) (the preparation of which is described in EP 461574 (Table 1, compound 22)). ) (5 mmol) in MeOH (20 mL) (5% Pd
/ C (50 mg) and formic acid (0.5 mL). The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is filtered,
The solvent is removed under reduced pressure. The residue is chromatographed on 3
-Cyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [
3.3.1] Nonane (20-1, where R ₁ is H).

B. 1,10-Dibromodecane (0.5 mmol) was prepared using compound 20-1 (where R ₁ is H, which was prepared as described above) (1 mmol).
And diisopropylethylamine (0.5 mL) in DMF (10 mL). The progress of the reaction is monitored by tlc. When this reaction is completed,
This solution is added to dilute Na ₂ CO ₃ and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed,
(Where, Link is, (CH _{2) 10)} The title compound 13-2 obtained.

C. In a similar manner, using different dialkylating agents, as described herein, gives different compounds of structure 13-2.

Example 15 (FIG. 14) 1,4-di- [2- [2- [4- (2-butylbenzofuran-3-yl) carbonyl-2,6-diiodophenoxyethyl] methylamino ] acetylamino] butane (14-2, where, n is 1, Link is, (CH ₂₎ a ₄₎ A. preparation of Compound 7B-1 (this is described in Eur. J. Med. Chem., 1974,
According to the procedure described in 19-25 was prepared) and (5 mmol), diisopropylethylamine (5 mmol) and ethyl bromoacetate (5 mmol), CH ₂
Dissolved in Cl _2. The reaction is monitored by tlc. When the reaction is completed, the mixture is added to water and extracted with EtOAc. The extract is dried and evaporated; the residue is chromatographed on ethyl N-methyl 2- [4- [2-butylbenzofuran-3-ylcarbonyl] -2,6-diiodophenoxy] ethylaminoacetate. (14-1, where R is ethyl).

B. The above compound (1 mmol) is dissolved in THF (10 mL) and water (
3 mL) and lithium hydride monohydrate (1.25 mmol) are added. The reaction is monitored by tlc. Upon completion of the reaction, acetic acid (2 mmol) is added and the solvent is removed under reduced pressure. The residue is chromatographed to give N-methyl 2- [4- [2-butylbenzofuran-3-ylcarbonyl].
-2,6-diiodophenoxy] ethylaminoacetic acid (14-1, where R is
H).

C. Dissolve the compound prepared above (1 mmol) in DMF (20 mL) and add dicyclohexylcarbodiimide (1 mmol) and 1,4-diaminobutane (0.5 mmol). The reaction is monitored by tlc. When the reaction is completed, the mixture is added to water and extracted with EtOAc. The extract is dried and evaporated; the residue is chromatographed to give the title compound 14-2 (where n is 1 and Link is (
CH ₂ ) ₄ ).

D. In a similar manner, using different diamines, as described herein, gives different compounds of formula 14-2.

Example 16 (FIG. 14) 1,4-di- [3- [4- [2- [4- (methylsulfonylamino) phenoxy] ethyl] aminoethyl] phenylaminosulfonyl] propylmethylamino]
Butane (14-7, where, Link is, (CH ₂₎ a ₄₎ A. Preparation of N-methyl N- (4-aminophenylethyl) 2- [4- (methylsulfonylamino) phenoxy] ethylamine (14-3, which is prepared as described in Examples 3A and 3B) (5 mmol ) With CH ₂ Cl ₂ (25 mL)
) And add 3-azidopropylsulfonyl chloride (5 mmol). The reaction is monitored by tlc. When the reaction is completed, the mixture is added to water and extracted with EtOAc. The extract is dried and evaporated; the residue is chromatographed to give N-methyl N- [4
-(3-Azidopropylsulfonyl) aminophenylethyl] 2- [4- (methylsulfonylamino) phenoxy] -ethylamine (14-5) is obtained.

B. The compound prepared above (1 mmol) is dissolved in MeOH (20 mL) and 5% Pd / C (50 mg) is added. The mixture is stirred under a hydrogen atmosphere. The progress of the reaction is monitored by tlc. When the reaction is completed, the solution is filtered and the solvent is removed under reduced pressure. The residue was washed with MeOH (20 mL)
And add paraformaldehyde (1 mmol) and sodium cyanoborohydride (1 mmol). The reaction is monitored by tlc.
When the reaction is completed, the mixture is added to water and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed for N-methyl N- [4- (3-methylaminopropylsulfonyl) -aminophenylethyl] -2- [4- (methylsulfonylamino) [Phenoxy] ethylamine (14-6) is obtained.

C. 1,4-dibromobutane and (0.5 mmol) was dissolved in MeCN, and the addition of K ₂ CO ₃ (0.5g) and compound 14-6 (0.25 mmol).
The reaction is monitored by tlc. When the reaction is completed, the mixture is added to water and extracted with EtOAc. The extract was dried and evaporated and the residue chromatographed to give the title compound 14-7 (here, Link is, (CH ₂₎ a ₄₎ is obtained.

D. In a similar manner, using different dialkylating agents, as described herein, in Step C, above, provides different compounds of Formula 14-7.

Example 17 (FIG. 14) 1,8-di-[[N- [2- (4-methylsulfonylaminophenoxy) ethyl] N-2- (4-methylsulfonylaminophenyl) ethyl] 2 Preparation of [-Aminoethoxy] octane (14-10, where Link is (CH ₂ ) ₈ ) N-2- (4-methylsulfonylaminophenoxy) ethyl 2- (4-methylsulfonylaminophenyl) ethylamine (14-8, the preparation of which is described above in Examples 6A and 6B) (1 mmol) EtOH (20 mL)
And 2-bromoethanol (1 mmol) and diisopropylethylamine (5 mmol) are added to this solution. The reaction is monitored by tlc. When the reaction is completed, the mixture is added to water and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed on N- (2-hydroxyethyl) N- [2- (4-methylsulfonylaminophenoxy) ethyl] 2- (4-methylsulfonylamino Phenyl)
Ethylamine (14-9) is obtained.

B. Compound 14-9 (1 mmol) is dissolved in DMSO (10 mL) and KOH (10 mmol) and 1,8-dibromooctane (0.5 mmol) are added. The progress of the reaction is monitored by tlc. When this reaction is completed,
This mixture is added to water and extracted with EtOAc. Drying this extract,
After evaporation, the residue was chromatographed to give the title compound 1
4-10 (where Link is (CH ₂ ) ₈ ).

C. In a similar manner, different compounds of Formulas 14-10 can be obtained by using different dihalo compounds instead of 1,8-dibromooctane.

Example 18 (FIG. 15) 1,4,8,12-Tetra- [2- (4-methylsulfonylaminophenoxy)
Preparation of Ethyl] -1,4,8,12-tetraazacyclohexadecane (15-3, wherein X is O) 2- (4-methylsulfonylamino) phenoxyethyl bromide (15-1,
Where X is O and its preparation is described in Med. Chem. , 1990, 1
551) (1 mmol) and 1,4,8,12-tetraazacyclohexadecane (15-2) (1 mmol) are dissolved in MeCN (25 mL). The progress of the reaction is monitored by tlc. When the reaction is completed, the mixture is added to water and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed to give the title compound 15
-3 (where X is O).

B. In a similar manner, 2- (4-methylsulfonylaminophenyl) ethylamine (15-1, where X is a direct bond, the preparation of which is described in J. Med. Ch.
em. , 1990, 1551).
, 8,12-Tetra- [2- (4-methylsulfonylaminophenyl) ethyl]
Obtain -1,4,8,12-tetraazacyclohexadecane (15-3, where X is a direct bond).

Example 19 (FIG. 15) 1,3,5-tri [N-methyl 2- [2,6-diiodo-4- [2-butyl-3]
-Benzofuranylcarbonyl] phenoxy] ethyl] aminomethyl] benzene (
Preparation of 15-6) N-methyl 2- [4- [2-butylbenzofuran-3-ylcarbonyl] -2
, 6-Diiodophenoxy] ethylamine (15-4, which is described in Eur. JM
ed. Chem. , 1974, 19-25) (prepared according to the procedure described in
The 3 mmol) was dissolved in MeCN (30 mL), and added 1,3,5-tri (bromomethyl) benzene (1 mmol) and K ₂ CO ₃ (0.5g). The progress of the reaction is monitored by tlc. When the reaction is completed, the mixture is added to water and extracted with EtOAc. The extract is dried and evaporated, and the residue is chromatographed to give the title compound 15-6.

Example 20 (FIG. 15) Preparation of Trimeric Amide 15-9 A. N-methyl 2- [4- [2-butylbenzofuran-3-ylcarbonyl]
-2,6-diiodophenoxy] ethylamine (15-4, which is described in Eur.
. Med. Chem. , 1974, 19-25) (5 mmol) was dissolved in EtOH (25 mL) and ethyl bromoacetate (
5 mmol) and diisopropylethylamine (10 mmol) are added.
The progress of the reaction is monitored by tlc. When the reaction is completed, the reaction is added to water and extracted with EtOAc. Washing the extract with dilute HCl,
Dry and evaporate the solvent under reduced pressure. The residue was washed with THF (15 m
L) and add LiOH.H ₂ O (5 mmol). The progress of the reaction is monitored by tlc. When the reaction is complete, the pH is raised to dilute HCl
Is adjusted to 7 by the addition of The solvent was removed under reduced pressure and the residue was chromatographed to give N-methyl N- [2- [4- [2-butylbenzofuran-3-ylcarbonyl] -2,6-diiodophenoxy (diodophen).
oxy)] ethyl] glycine (15-7).

B. Compound 15-7 (3 mmol) is dissolved in DMF (25 mL) and dicyclohexylcarbodiimide (3 mmol) and tris (2-aminoethyl) amine (1 mmol) are added. The progress of the reaction is monitored by tlc. When the reaction is completed, the mixture is added to water and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed to give the triamide product 15-9.

Example 21 (FIG. 15) 1,4-Di- [N-methyl 2- (4-methylsulfonylaminophenoxy) -ethylamino] butane (15-12, where X is O And R is methyl and Link is (CH ₂ ) ₄ . 2- (4-methylsulfonylaminophenoxy) ethyl bromide (15-10
Where X is O) (2 mmol) and 1,4-di (methylamino)
Butane (15-11) (1 mmol) was added to MeCN (20 mL) (K ₂
Dissolved in CO ₃ (containing 0.5 g). The progress of the reaction is monitored by tlc. When the reaction is completed, the reaction is added to water and EtOAc
Extract with The extract is dried and evaporated, and the residue is chromatographed to give the title compound 15-12.

B. In a similar manner, in A above, by using 2- (4-methylsulfonylaminophenyl) ethyl bromide, the corresponding product, 1,4-di- [N-
Methyl 2- (4-methylsulfonylaminophenyl) -ethylamino] butane (
15-12, wherein X is a direct bond, R is methyl, and Li
nk is (CH ₂ ) ₄ ).

C. In a similar manner, using the different diamines 15-11 as described herein in A and B above, the corresponding diamine products 15-1
Get 2.

Example 22 (FIG. 18) Asymmetrically linked aminosulfonamides 18-4 (where Link is (C
Preparation of H ₂ ) ₂ A. N-methyl N- (4-aminophenylethyl) 2- [4- (methylsulfonylamino) phenoxy] ethylamine (18-1, the preparation of which is described in Example 4 above)
A and 4B) (2 mmol) in anhydrous CH ₂ Cl ₂ (25 mL)
); Diisopropylethylamine (10 mmol) and 3-bromopropanesulfonyl chloride (2 mmol) are added. The progress of this reaction is t
Track at lc. When the reaction is complete, the reaction is added to water and Et.
Extract with OAc. The extract is washed, dried and the solvent is evaporated off under reduced pressure. The residue was chromatographed to give 1-bromo-3- [4
- [N-methyl-2- [2- [4-methylsulfonyl amino] phenoxy] ethylamino] phenylaminosulfonyl] propane (18-2, where, Link is, (CH ₂₎ a ₂₎ is obtained.

B. N2- (4-Aminophenyl) ethyl 2- [4-methylsulfonylaminophenoxy] ethylamine (18-3, prepared using the method described in EP 338793) (1 mmol) and compound 18- 2 (1 mmol
) Is dissolved in CH ₂ Cl ₂ (25 mL) and to this solution is added diisopropylethylamine (10 mmol). The progress of the reaction is monitored by tlc. When the reaction is completed, the mixture is added to water and extracted with EtOAc.
The extract was dried and evaporated and the residue chromatographed to give the title compound 18-4 (here, Link is, (CH ₂₎ a ₂₎ is obtained.

C. In a similar manner, using different bromosulfonyl chlorides as described herein provides the corresponding compounds of formula 18-4.

Example 23 (FIG. 19) Preparation of Dimeric Heterobaromer 19-4, wherein Link is (CH ₂ ) ₅ . Using the procedure described in Example 22A, but substituting 6-bromohexanesulfonyl chloride for 3-bromopropanesulfonyl chloride, 1-
Bromo-6- [4- [N-methyl 2- [2- [4-methylsulfonylamino] phenoxy] ethylamino] phenylaminosulfonyl] hexane (19-2, where Link is (CH ₂ ) ₅ Is prepared).

B. The above compound (2 mmol) and N-ethyl 2- [4- [2-butylbenzofuran-3-ylcarbonyl] -2,6-diiodophenoxy] ethylamine (19-3, which is described in Eur. J. Med. Chem. , 1974, 19-25
Is prepared in MeCN (25 mL). The progress of the reaction is monitored by tlc. When the reaction is completed, the mixture is added to dilute NaHCO ₃ and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed to give the title compound 19
4 (where, Link is, (CH ₂₎ a ₅₎ is obtained.

C. In a similar manner, using different bromo compounds 19-2 gives the corresponding heterobaromers 19-4.

Example 24 (FIG. 19) Preparation of Dimeric Heterobaromer 19-8, wherein Link is (CH ₂ ) ₅ A. N- [4-[[2- (6-Methyl-2-pyridinyl) ethyl] -4-piperidinyl] carbonyl] phenylmethanesulfonamide (E-4031, Table 4,
This is described in J.A. Med. Chem. (Prepared as described in Chem., 1990, 903) (10 mmol) is dissolved in 48% HBr in AcOH (50 mL). The solution is heated to 60 ° C. and the progress of the reaction is monitored by tlc. When the reaction is completed, the mixture is cooled and the solvent is removed under reduced pressure.
The residue is dissolved in water and the solution is basified with aqueous NaOH. This aqueous solution is
Extract with H ₂ Cl ₂ , dry the extract and evaporate. The residue was chromatographed to give 6- [2- [4- [4-aminobenzoyl-1-).
Piperidyl] ethyl] -2-methylpyridine (19-5) is obtained.

B. The above compound 19-5 (2 mmol) was dissolved in CH ₂ Cl ₂ (35 mL),
To this solution is added diisopropylethylamine (5 mmol) and 6-bromohexanesulfonyl chloride (2 mmol). The progress of this reaction is tlc
Monitor with. When the reaction is completed, the mixture is added to dilute NaHCO ₃ and extracted with EtOAc. The extract is dried and evaporated,
The residue was chromatographed, compound 19-6 (here, Link is, (CH ₂₎ a ₅₎ is obtained.

C. To a solution of the above compound (1 mmol) in CH ₂ Cl ₂ (20 mL) was added N- [2-
(4-Methylsulfonylaminophenoxy) ethyl] 2- (4-methylsulfonylaminophenyl) -ethylamine (19-7, the preparation of which is described in Examples 6A and 6B) (1 mmol) is added. The progress of this reaction is tlc
Monitor with. When the reaction is completed, the mixture is added to dilute NaHCO ₃ and extracted with EtOAc. The extract is dried and evaporated,
The residue is chromatographed to give the dimer product 19-8 (where Li
nk is (CH ₂ ) ₅ ).

D. In a similar manner, using different bromoalkylsulfonyl chlorides as described herein gives the corresponding products of formula 19-8.

Example 25 (FIG. 19) Preparation of Dimeric Heterobaromers 19-11, wherein Link is (CH ₂ ) ₃ A. Using the procedure of Example 24A except that 4-bromobutanesulfonyl chloride is used instead of 6-bromohexanesulfonyl chloride, compound 19-9 (where Link is (CH ₂ ) ₃ Is prepared).

B. N-methyl N- (4-aminophenylethyl) 2- [4- (methylsulfonylamino) phenoxy] -ethylamine (8A-1, the preparation of which is described in Example 4A
(Described in and 4B) (2 mmol) is dissolved in MeCN (25 mL) and to this solution is added 3-bromopropanesulfonyl chloride (2 mmol). After 6 hours, 10% methanolic methylamine (1 mL) is added. The progress of this reaction is followed by tlc. The reaction was complete, the mixture was added to water and extracted with CH ₂ Cl _2. The extract is dried and evaporated and the residue is chromatographed to give N-methyl N- [4- (3-methylaminopropylsulfonyl) -aminophenylethyl] -2- [4- (methylsulfonylamino) [Phenoxy] ethylamine (19-10) is obtained.

C. The product from A (1 mmol) and the product from B (1 mmol)
1) is dissolved in EtOH (20 mL). To this mixture is added diisopropylethylamine (20 mmol). The progress of the reaction is monitored by tlc. The reaction was complete, the mixture was added to water and extracted with CH ₂ Cl _2. The extract was dried and evaporated and the residue chromatographed to give the title compound 19-11 (herein, Link is, (CH ₂₎ a ₃₎ is obtained.

D. In a similar manner, using different bromoalkylsulfonyl chlorides as described herein in Step A above gives the corresponding products of Formulas 19-11.

Example 26 (FIG. 20) 3-Cyclopropylmethyl 7- [2- [4-methylsulfonylaminophenoxy] ethyl] -9,9-tetramethylene-3,7-diazabicyclo [3.3. 1]
Preparation of Nonane (20-3, where X is O) 3-cyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane, (20-1, where R is H, and its preparation is described in Example 14A. Described) (2 mmol) in MeCN (20 mL)
Dissolve in To this solution is added 2- [4-methylsulfonylaminophenoxy] bromide
Ethyl (20-2, where R is O) (2 mmol) and K ₂ CO ₃ (
0.5 g) is added. The progress of the reaction is monitored by tlc. When the reaction is completed, the mixture is added to dilute NaHCO ₃ and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed to give the title compound 20-3.

B. In a similar manner, in A above, using 2- [4-methylsulfonylaminophenyl] ethyl bromide (20-2, where R is a direct bond) provides the corresponding product Certain 3-cyclopropylmethyl 7- [2- [4-methylsulfonylaminophenyl] ethyl] -9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane (20-3, X is a direct bond).

Example 27 (FIG. 20) 3,8-di- [2- [4-methylsulfonylaminophenoxy] ethyl] -9,
9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane (20-5
, Where X is O) 3,8-dibenzyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane (20-4, wherein R ₁ and R ₂ are benzyl;
Its preparation is described in EP 461574) (5 mmol),
Dissolve in EtOH (25 mL). 10% Pd / C (50 mg) and ammonium formate (200 mg) are added. The progress of this reaction is followed by tlc. Upon completion of the reaction, the solution was filtered and the solvent was removed under reduced pressure to give 9
, 9-Tetramethylene-3,7-diazabicyclo [3.3.1] nonane (20-
4, where R ₁ and R ₂ are H).

B. The above compound (1 mmol) is dissolved in MeCN, and to this solution is added diisopropylethylamine (5 mmol) and 2- [4-methylsulfonylaminophenoxy] ethyl bromide (0.5 mmol). The progress of this reaction is tlc
Monitor with. When the reaction is complete, the mixture is added to water and Et.
Extract with OAc. The extract is dried and evaporated, and the residue is chromatographed to give the title compound 20-5, where X is O.

C. In a similar manner, in B above, the use of 2- [4-methylsulfonylaminophenyl] ethyl bromide affords the corresponding product, 3,8-di- [2-
[4-Methylsulfonylaminophenyl] ethyl] -9,9-tetramethylene-
3,7-diazabicyclo [3.3.1] nonane (20-5, wherein X is a direct bond) is obtained.

Example 28 (FIG. 20) 3-Cyclopropylmethyl-7- [4- [2- [4-methylsulfonylaminophenoxy] ethylmethylamino] butyl] -9,9-tetramethylene-3, 7-
Preparation of diazabicyclo [3.3.1] nonane, 20-5, where X is O 3-cyclopropylmethyl-9,9-tetramethylene-3,7-diazabicyclo [3.3.1] nonane (20-1, where R is H) (5 mmol
l) and 1,4-dibromobutane (5 mmol) are dissolved in EtOH (30 mL). The progress of the reaction is monitored by tlc. When this reaction is completed,
N-methyl 2- (4-methylsulfonylaminophenoxy) ethylamine (20
-6, where X is O) (5 mmol) is added. The progress of this reaction is followed by tlc. When the reaction is completed, the mixture is added to dilute NaHCO ₃ and extracted with EtOAc. The extract is dried and evaporated and the residue is chromatographed to give the title compound 20-5 (where X
Is O).

B. In a similar manner, in A above, using 2- [4-methylsulfonylaminophenyl] ethyl bromide affords the corresponding product, 3-cyclopropylmethyl-7- [4- [2- [ 4-methylsulfonylaminophenyl] -ethylmethylamino] butyl] -9,9-tetramethylene-3,7-diazabicyclo [3
. 3.1] Nonane (20-5, where X is a direct bond).

C. In a similar manner, using a different dibromo compound instead of 1,4-dibromobutane gives the corresponding product analogous to 20-7.

Example 29 (FIG. 20) 1,3,5-tri- [2- [4- (methylsulfonylamino) phenoxy] ethylmethylaminomethyl] benzene (20-9, where X is O) A. N-methyl 2-[(4-methylsulfonylamino) phenoxy] ethylamine (20-6, where X is O) (3 mmol) and 1,3,5-
Tri- (bromomethyl) benzene (20-8) (1 mmol) was added to MeCN (2
5 mL), which contains K ₂ CO ₃ (0.5 g). The progress of this reaction is followed by tlc. When the reaction is completed, the mixture is added to water,
Then extract with EtOAc. The extract is dried and evaporated and the residue is chromatographed to give the title compound 20-9, where X is O
Is obtained).

B. In a similar manner, the corresponding product is obtained by using N-methyl 2-[(4-methylsulfonylamino) phenyl] -ethylamine (20-6, where X is a direct bond). 1,3,5-tri- [2- [4- (methylsulfonylamino) phenyl] ethylmethylamino-methyl] benzene (20-9,
Where X is a direct bond).

Although the invention has been described with reference to specific embodiments thereof, various modifications can be made without departing from the true spirit and scope of the invention, and equivalents thereof may be substituted. The gain should be understood by those skilled in the art. In addition, many modifications can be made to adapt a particular situation, material, composition of matter, process, process step, to the objective spirit and scope of the present invention. All such modifications are intended to be within the scope of the appended claims.

All publications, patent applications, and patents cited in the present application are hereby incorporated by reference in their entirety, in each individual publication, patent application, or patent, specifically and individually. To the same extent as is indicated, it is incorporated herein by reference.

Table 1: Multiple activities of antiarrhythmic drugs

[0355]

[Table 6] Table 2: Potassium channel ligand activity

[0356]

[Table 7]

[0357]

[Table 8] Table 4: Potassium channel ligand

[0358]

[Table 9] Table 4: Potassium channel ligands (continued)

[0359]

[Table 10] Table 5: Major cardiac K ⁺ currents and some drugs that inhibit them

[0360]

[Table 11]

[Brief description of the drawings]

FIG. 1 is a very schematic diagram of the transmembrane tissues of various cell membrane transporters.

FIG. 2 illustrates a method of optimizing the linker geometry to present a ligand (steric circle) in a bivalent compound: Phenyl diacetylene core structure B. Cyclohexanedicarboxylic acid core structure.

FIG. 3A shows a representative linker “core” structure.

FIG. 3B shows a representative linker “core” structure.

FIG. 4 contains (A) two ligands, (B) three ligands, (C) four ligands and (D) more than four ligands attached to the linker in different formats. 2 illustrates an example of a multi-binding compound.

FIG. 5 illustrates the ligand amiodarone, which can be used in preparing multi-binding compounds. Possible modifiable positions are indicated by arrows.

FIG. 6 illustrates a large number of reactive functional groups and the bonds formed by reactions between them.

FIG. 7 illustrates a convenient method for preparing the multi-binding compounds of the present invention.
In each of these figures, the closed circles correspond to the linker, which in the examples is "L
Ink ".

FIG. 8 illustrates a convenient method for preparing the multibinding compounds of the present invention.
In each of these figures, the closed circles correspond to the linker, which in the examples is "L
Ink ".

FIG. 9 illustrates a convenient method for preparing the multibinding compounds of the present invention.
In each of these figures, the closed circles correspond to the linker, which in the examples is "L
Ink ".

FIG. 10 illustrates a convenient method for preparing the multibinding compounds of the present invention. In each of these figures, the filled circles correspond to the linker, which in the examples is "
Link ".

FIG. 11 illustrates a convenient method for preparing the multibinding compounds of the present invention. In each of these figures, the filled circles correspond to the linker, which in the examples is "
Link ".

FIG. 12 illustrates a convenient method for preparing the multibinding compounds of the present invention. In each of these figures, the filled circles correspond to the linker, which in the examples is "
Link ".

FIG. 13 illustrates a convenient method for preparing the multibinding compounds of the present invention. In each of these figures, the filled circles correspond to the linker, which in the examples is "
Link ".

FIG. 14A illustrates a convenient method for preparing the multi-binding compounds of the present invention. In each of these figures, the solid circles correspond to linkers, which in the examples are:
It is called “Link”.

FIG. 14B illustrates a convenient method for preparing the multi-binding compounds of the present invention. In each of these figures, the solid circles correspond to linkers, which in the examples are:
It is called “Link”.

FIG. 15 illustrates a convenient method for preparing the multi-binding compounds of the present invention. In each of these figures, the filled circles correspond to the linker, which in the examples is "
Link ".

FIG. 16 illustrates a convenient method for preparing the multibinding compounds of the present invention. In each of these figures, the filled circles correspond to the linker, which in the examples is "
Link ".

FIG. 17 illustrates a convenient method for preparing the multibinding compounds of the present invention. In each of these figures, the filled circles correspond to the linker, which in the examples is "
Link ".

FIG. 18 illustrates a convenient method for preparing the multi-binding compounds of the present invention. In each of these figures, the filled circles correspond to the linker, which in the examples is "
Link ".

FIG. 19A illustrates a convenient method for preparing the multi-binding compounds of the present invention. In each of these figures, the solid circles correspond to linkers, which in the examples are:
It is called “Link”.

FIG. 19B illustrates a convenient method for preparing the multi-binding compounds of the present invention. In each of these figures, the solid circles correspond to linkers, which in the examples are:
It is called “Link”.

FIG. 20 illustrates a convenient method for preparing the multibinding compounds of the present invention. In each of these figures, the filled circles correspond to the linker, which in the examples is "
Link ".

FIG. 21 illustrates a convenient method for preparing the multi-binding compounds of the present invention. In each of these figures, the filled circles correspond to the linker, which in the examples is "
Link ".

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/407 A61K 31/407 4C084 31/4178 31/4178 4C086 31/4545 31/4545 4C206 45/00 45 / 00 4H006 47/48 47/48 4H045 A61P 9/00 A61P 9/00 43/00 111 43/00 111 C07C 311/10 C07C 311/10 311/12 311/12 311/22 311/22 311/30 311 / 30 C07D 257/02 C07D 257/02 307/80 307/80 401/06 401/06 405/12 405/12 487/04 137 487/04 137 487/08 487/08 G01N 33/15 G01N 33/15 Z 33/50 33/50 Z 33/566 33/566 // C07K 5/09 C07K 5/09 5/11 5/11 7/06 7/06 7/08 7/08 (31) Priority claim number 60 / 113,864 (32) Priority date December 24, 1998 (December 24, 1998) (33) Priority claiming country United States (US (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN , CU, CZ, DE, DK, 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, MD, MG, MK, MN, MW, MX, NO, NZ, L, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Eastman, Dona United States California 94563, Olinda, Don Gabriel Way 37 (72) Inventor Griffin, John H. United States California 94027, Atherton, Walnut Ave. 56 F-term (reference) 2G045 AA40 BA13 BA20 DA80 FB03 4C037 PA08 4C050 AA01 AA03 AA07 AA08 BB04 BB07 CC04 CC07 EE02 FF01 GG01 HH01 4C063 AA01 BB09 CC75 DD41 CC04 ZA382 ZC022 4C086 AA01 AA02 BA06 BC17 BC38 BC50 BC58 CB03 GA02 GA07 GA08 MA01 MA04 NA05 ZA38 ZC02 4C206 AA01 AA02 JA11 MA01 MA04 NA05 ZA38 ZC02 4H006 AA03 AB20 AB23 AB27 4H045 AA10 AA15 BA13 BA13

Claims (8)

[Claims] 1. A multibinding compound represented by the formula I: (L) _p (X) _q I where each L is a ligand which in each case may be the same or different, wherein the ligand is quinidine Glibenclamide, procaine, tetraethylammonium, clofilium, merperone, pinacidil, WAY-123,3
98, cromakalim, propofur, thiopentone, lysotilide, almocalant, bretylium, N-acetylprocainamide, tacrine, UK66,914
RP58866, 4-aminopyridine, RP49356, affinidine, chromanol 293B, L-768,673 and analogs thereof, betanidine, disopyramide, decylamiodarone, NE-10064, altilide, dofetilide, E-4031, sematilide, ambasilide, azimilide, Selected from the group consisting of tedisamil, drondarone, ibutilide, sotalol, benzodiazepine analogs and amiodarone; X is a linker which in each case can be the same or different; p is an integer from 2 to 10; A multi-binding compound, which is an integer of -20. 2. The compound according to claim 1, wherein p is 2 and q is 1. 3. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of one or more polybinding compounds according to claim 1 or 2 or a pharmaceutically acceptable salt thereof. Composition. 4. K in biological tissue⁺How to regulate channel activity
A composition for use in a pharmaceutical composition, the composition comprising a composition according to claim 1 or 2.
Containing a binding compound or a pharmaceutically acceptable salt thereof, and ⁺ A method comprising contacting a tissue having a channel with the composition.
,Composition. 5. The pharmaceutical composition according to claim 3, for use in a method of treating a disease or condition in a mammal resulting from the activity of a K ⁺ channel. 6. A method for identifying a multimeric ligand compound possessing multiple binding to a potassium channel, the method comprising: (a) identifying a ligand or a mixture of ligands. Wherein each ligand contains at least one reactive functional group; (b) identifying a library of linkers, wherein each linker in the library is (C) containing at least two functional groups having complementary reactivity to at least one of the reactive functional groups; (c) at least 2 stoichiometric equivalents of the ligand or mixture of ligands identified in (a) And the library of linkers identified in (b) under conditions where the complementary functional groups react to form a covalent bond between the linker and at least two of the ligands. Preparing a multimeric ligand compound library by combining them; and (d) assaying the multimeric ligand compound produced by the library prepared in (c) above to obtain a multimeric ligand possessing multiple binding properties Identify the compound. 7. A method for identifying a multimeric ligand compound possessing multiple binding to a potassium channel, the method comprising: (a) identifying a library of ligands. Wherein each ligand contains at least one reactive functional group; (b) identifying a linker or mixture of linkers, wherein each linker is a reactive functional group of the ligand. Contains at least two functional groups having complementary reactivity to at least one of the groups; (c) at least two stoichiometric equivalents of the library of ligands identified in (a) and identified in (b) Combining said linker or mixture of linkers under conditions wherein said complementary functional groups react to form a covalent bond between said linker and at least two of said ligands. Preparing a multimeric ligand compound library; and (d) assaying the multimeric ligand compound produced by the library prepared in (c) above, to obtain a multimeric ligand compound having multi-binding properties. To identify. 8. An iterative method for identifying multimeric ligand compounds that possess multibinding properties for potassium channels, comprising: (a) a first collection or iteration of multimeric compounds. Is prepared,
The first collection or repeat is prepared by contacting at least two stoichiometric equivalents of a ligand or a mixture of ligands targeting a receptor with a linker or a mixture of linkers, wherein the ligand or mixture of ligands comprises: The linker or linker mixture containing at least one reactive functional group, wherein the linker or linker mixture contains at least two functional groups having complementary reactivity to at least one of the reactive functional groups of the ligand, wherein The contacting is performed under conditions in which the complementary functional group reacts to form a covalent bond between the linker and at least two of the ligands; (b) the first of the multimeric compound Assaying collections or repeats, if any of the multimeric compounds possesses multibinding properties, which (C) repeating the processes (a) and (b) until at least one multimeric compound is found to have multibinding properties; (d) which Assessing whether the molecular constraints confer multi-binding properties or consistently on the multimeric compound found in the first iteration listed in (a)-(c) (E) creating a second collection or repeat of the multimeric compound,
The second collection or repeat creates specific molecular constraints that confer multi-binding properties to the multimeric compound found in the first repeat; (f) Which molecular constraints are listed in the (e). Assessing whether the multimeric compound found in the second collection or iteration provides enhanced multi-binding properties or consistently; and (g) optionally, the step ( Repeating e) and (f) to further create the molecular constraint.