EP1086066A1 - Antagonistes des recepteurs muscariniques - Google Patents

Antagonistes des recepteurs muscariniques

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Publication number
EP1086066A1
EP1086066A1 EP99928444A EP99928444A EP1086066A1 EP 1086066 A1 EP1086066 A1 EP 1086066A1 EP 99928444 A EP99928444 A EP 99928444A EP 99928444 A EP99928444 A EP 99928444A EP 1086066 A1 EP1086066 A1 EP 1086066A1
Authority
EP
European Patent Office
Prior art keywords
ligand
linker
hydrogen
alkyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP99928444A
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German (de)
English (en)
Other versions
EP1086066A4 (fr
Inventor
Mathai Mammen
David Oare
John H. Griffin
James Aggen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Innoviva Inc
Original Assignee
Advanced Medicine Inc
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Publication date
Application filed by Advanced Medicine Inc filed Critical Advanced Medicine Inc
Publication of EP1086066A1 publication Critical patent/EP1086066A1/fr
Publication of EP1086066A4 publication Critical patent/EP1086066A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/12—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with only hydrogen atoms attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • a ligand is a binding partner for a specific receptor or family of receptors.
  • a ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool.
  • This invention is directed to novel multibinding compounds (agents) that are muscarinic receptor antagonists and are therefore useful in the treatment and prevention of diseases such as chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.
  • each ligand, L, that is a muscarinic receptor antagonist in the multibinding compound of Formula (I) is independently selected from the group consisting of: ( 1 ) a compound of formula (a) :
  • K is a bond or an alkylene group
  • K" is a bond, -C(O)-, -S(O) n4 - (where n 4 is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group;
  • this invention is directed to a method for identifying multimeric ligand compounds possessing multibinding properties for a muscarinic receptor which method comprises:
  • the preparation of the multimeric ligand compound library is achieved by either the sequential or concurrent combination of the two or more stoichiometric equivalents of the ligands identified in (a) with the linkers identified in (b). Sequential addition is preferred when a mixture of different ligands is employed to ensure heterodimeric or multimeric compounds are prepared. Concurrent addition of the ligands occurs when at least a portion of the multimer comounds prepared are homomultimeric compounds.
  • the assay protocols recited in (d) can be conducted on the multimeric ligand compound library produced in (c) above, or preferably, each member of the library is isolated by preparative liquid chromatography mass spectrometry (LCMS).
  • FIG. 1 illustrates examples of multibinding compounds comprising 2 ligands attached in different formats to a linker.
  • FIG. 2 illustrates examples of multibinding compounds comprising 3 ligands attached in different formats to a linker.
  • FIG. 3 illustrates examples of multibinding compounds comprising 4 ligands attached in different formats to a linker.
  • FIG. 4 illustrates examples of multibinding compounds comprising >4 ligands attached in different formats to a linker.
  • substituted alkynyl refers to an alkynyl group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxya
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy
  • Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
  • Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl).
  • Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
  • heterocycle or “heterocyclic” or refers to a monoradical saturated unsaturated group having a single ring or multiple condensed rings, from 1 to 40 carbon atoms and from 1 to 10 hetero atoms, preferably 1 to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring.
  • heteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
  • any of the above groups which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are stericaUy impractical and/or synthetically non- feasible.
  • the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.
  • pharmaceutically-acceptable salt refers to salts which retain the biological effectiveness and properties of the multibinding compounds of this invention and which are not biologically or otherwise undesirable. In many cases, the multibinding compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
  • amines where the two or three substituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
  • suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri( 50-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.
  • carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyl carboxamides, dialkyl carboxamides, and the
  • protecting group refers to any group which when bound to one or more hydroxyl, thiol, amino or carboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group.
  • removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylidine, phenacyl, t-butyl- diphenylsilyl and any other group that can be introduced chemically onto a hydroxyl functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product.
  • Preferred removable thiol blocking groups include disulfide groups, acyl groups, benzyl groups, and the like.
  • selectivity is a measure of the binding preferences of a ligand for different ligand binding sites (receptors).
  • the selectivity of a ligand with respect to its target ligand binding site relative to another ligand binding site is given by the ratio of the respective values of K d (i.e., the dissociation constants for each ligand-receptor complex) or, in cases where a biological effect is observed below the K d , the ratio of the respective EC 50 's (i.e., the concentrations that produce 50% of the maximum response for the ligand interacting with the two distinct ligand binding sites (receptors)).
  • the ligand binding sites of the receptor that participate in biological multivalent binding interactions are constrained to varying degrees by their intra- and inter-molecular associations (e.g., such macromolecular structures may be covalently joined to a single structure, noncovalently associated in a multimeric structure, embedded in a membrane or polymeric matrix, and so on) and therefore have less translational and rotational freedom than if the same structures were present as monomers in solution.
  • agonism and “antagonism” are well known in the art.
  • modulatory effect refers to the ability of the ligand to change the activity of an agonist or antagonist through binding to a ligand binding site.
  • aUosteric modulator denotes a compound that can regulate the activity of a muscarinic receptor.
  • the aUosteric modulator can regulate the activity of a muscarinic receptor in several ways i.e., by increasing the affinity of a muscarinic receptor for its antagonists (see., Nedoma, J. S. et al., Synaptic Transmitters and Receptors (S. Tucek, ed.) Academia, Prague/Wiley, Chichester, 1987, 108-112; and Tucek, S. et al., Mol. Pharmacol. 1990, 38:674-680; Dong,
  • gallamine inhibits the binding of [3H]-(-)-N- methylscopolamine and other specific ligands to muscarinic receptors (see., Fryer, A.D and El-Fakahany, E.D., 1998, Membrane Biochem., 8, 122; and Jacoby, E.E., et al. 1993, J. Clin. Invest., 91, 1314).
  • therapeutically effective amount refers to that amount of multibinding compound which is sufficient to effect treatment, as defined above, when administered to a mammal in need of such treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
  • esters e.g., acetate, formate, and benzoate derivatives
  • carbamates e.g., N,N-dimethylaminocarbonyl
  • Het is a heteroaryl ring, preferably pyrrolyl, pyridinyl, or imidazolyl which optionally attaches the ligand to a linker;
  • R 42 and R 43 are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyl, aralkyl, or heterocyclylalkyl or a covalent bond attaching the ligand to a linker;
  • R 44 is alkyl, alkenyl or alkynyl; and W b is -N(O)n 23 or -N + -R 45 where n 23 is 0 or 1 , and R 45 is alkyl, alkenyl, alkynyl, or aralkyl, or a covalent bond attaching the ligand to a linker; provided that one of the R 5 ,R 6 , R 7 , R 8 , and the heterocycloamino group attaches the ligand to a linker.
  • C is an aryl ring which optionally attaches the ligand to a linker
  • R 10 is hydrogen, aryl, heteroaryl, alkyl substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching the ligand to a linker; and when Q is a single bond then Q" is a group of formula (iv):
  • a bivalent multibinding compound of Formula (I) can be prepared by covalently attaching the ligands, L, to a linker, X, as shown in Scheme I below.
  • a bivalent multibinding compound of Formula (I) can be prepared, as shown above, by covalently attaching the ligand, L, that is a muscarinic receptor antagonist or a muscarinic receptor modulator to a linker, X, where FG 1 and FG 2 represent a functional group such as halo, amino, hydroxy, thio, aldehyde, ketone, carboxy, carboxy derivatives such as acid halide, ester, amido, and the like.
  • the ligands are covalently attached to the linker using conventional chemical techniques providing for covalent linkage of the ligand to the linker. Reaction chemistries resulting in such linkages are well known in the art and involve the use of complementary functional groups on the linker and ligand as shown in Table I below.
  • First Reactive Group Second Reactive Group Linkage carboxyl amine amide sulfonyl halide amine sulfonamide hydroxyl alkyl/aryl halide ether hydroxyl isocyanate urethane amine epoxide ⁇ -hydroxy amine amine alkyl/aryl halide alkylamine hydroxyl carboxyl ester
  • ligands include Darifenacin and the derivatives thereof.
  • n 6 , J, R 12 , R 13 , and R 14 are as defined above, can be prepared by the procedures described in U.S. Patent No. 3,505,337, EP 418 716, Drugs of the Future, 1997, 22(2) 135, EP 603229, PCT Application No. WO 93/06098, Naito, R et al, Chem. Pharm. Bull. 1998, 46(8), 1274, Ninomiya K et al, Tetrahedron, 1974, 30, 2251 and PCT Application No. WO 92/06958.
  • Such ligands include Tiotropium, Ipratropium, Revatropate, Atropine, YM-58790, and the derivatives thereof.
  • n 8 , R 15 , G, G', and G" are as defined above, can be prepared by the procedures described in EP 801 067.
  • Such ligands include YM-53705, and the derivatives thereof.
  • n 9 , n 10 , S, P and P" are as defined above, can be prepared by the procedures described in JP 258 250;
  • R 16 -R 2 ' are as defined above, can be prepared by the procedures described in EP 325 571 and Drugs of the Future, 1997, 22(7), 733.
  • ligands include Tolterodine and the derivatives thereof.
  • R 22 - 26 are as defined above, can be prepared by the procedures described in EP 251 126.
  • Such ligands include Oxybutvnin and the derivatives thereof.
  • hydrophobic/hydrophilic characteristics of the linker as well as the presence or absence of charged moieties can readily be controlled by the skilled artisan.
  • hydrophobic nature of a linker derived from hexamethylene diamine (H 2 N(CH 2 ) 6 NH 2 ) or related polyamines can be modified to be substantially more hydrophilic by replacing the alkylene group with a poly(oxyalkylene) group such as found in the commercially available "Jeffamines"
  • Different frameworks can be designed to provide preferred orientations of the ligands.
  • Nodes (1,2), (2,0), (4,4), (5,2), (4,0), (6,2), (7,4), (9,4), (10,2), (9,0), (7,0) all represent carbon atoms.
  • Node (10,0) represents a chlorine atom. All other nodes (or dots) are points in space (i.e., represent an absence of atoms).
  • Nodes (1,2) and (9,4) are attachment points. Hydrogen atoms are affixed to nodes (2,4), (4,4), (4,0), (2,0), (7,4), (10,2) and (7,0).
  • Nodes (5,2) and (6,2) are connected by a single bond.
  • core structures other than those shown here can be used for determining the optimal framework display orientation of the ligands.
  • the process may require the use of multiple copies of the same central core structure or combinations of different types of display cores.
  • the above-described process can be extended to trimers ( Figure 3) and compound of higher valency. ( Figure 4)
  • Assays of each of the individual compounds of a collection generated as described above will lead to a subset of compounds with the desired enhanced activities (e.g., potency, selectivity, etc.).
  • the analysis of this subset using a technique such as Ensemble Molecular Dynamics will provide a framework orientation that favors the properties desired.
  • a wide diversity of linkers is commercially available (see, e.g., Available Chemical Directory (ACD)). Many of the linkers that are suitable for use in this invention fall into this category. Other can be readily synthesized by methods well known in the art and/or are described below.
  • linkers include aliphatic moieties, aromatic moieties, steroidal moieties, peptides, and the like. Specific examples are peptides or polyamides, hydrocarbons, aromatic groups, ethers, lipids, cationic or anionic groups, or a combination thereof.
  • linker can be modified by the addition or insertion of ancillary groups into or onto the linker, for example, to change the solubility of the multibinding compound (in water, fats, lipids, biological fluids, etc.), hydrophobicity, hydrophihcity, linker flexibility, antigenicity, stability, and the like.
  • Preferred lipids are phosphglycerides and sphingolipids, representative examples of which include phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidyl-ethanolamine, dipalmitoylphosphatidylcholine, dioleoylphosphatidylcholine, distearoyl-phosphatidylcholine or dilinoleoylphosphatidylcholine could be used.
  • Rigid groups can include, for example, those groups whose conformational lability is restrained by the presence of rings and/or multiple bonds within the group, for example, aryl, heteroaryl, cycloalkyl, cycloalkenyl. and heterocyclic groups.
  • Other groups which can impart rigidity include polypeptide groups such as oligo- or polyproline chains.
  • rigidity is imparted by the presence of cyclic groups (e.g., aryl, heteroaryl, cycloalkyl, heterocyclic, etc.).
  • the linker comprises one or more six-membered rings.
  • the ring is an aryl group such as, for example, phenyl or naphthyl.
  • the compounds of this invention are preferably represented by the empirical Formula (L) p (X) q where L, X,p and q are as defined above. This is intended to include the several ways in which the ligands can be linked together in order to achieve the objective of multivalency, and a more detailed explanation is described below.
  • the simplest and most preferred multibinding compound is a bivalent compound which can be represented as L-X-L, where each L is independently a ligand which may be the same or different and each X is independently the linker. Examples of such bivalent compounds are provided in FIG. 1 where each shaded circle represents a ligand.
  • a trivalent compound could also be represented in a linear fashion, i.e., as a sequence of repeated units L-X-L-X-L, in which L is a ligand and is the same or different at each occurrence, as can X.
  • each member of the library can be encrypted or tagged with appropriate information allowing determination of the structure of relevant members at a later time.
  • each member of the library can be encrypted or tagged with appropriate information allowing determination of the structure of relevant members at a later time. See, for example, Dower, et al., International Patent Application Publication No. WO 93/06121; Brenner, et al., Proc. Natl. Acad. Sci., USA, 89:5181 (1992); Gallop, et al., U.S. Patent No. 5,846,839; each of which are incorporated herein by reference in its entirety.
  • Exemplary linkers include the following linkers identified as X-1 through X- 418 as set forth below:
  • L-2/X-31 1 - L-2 X-312- L-2 X-313- L-2/X-314- L-2 X-315- L-2/X-316- L-2/X-317- L-2/X-318- L-2/X-319- L-2/X-320- L-2 X-321 - L-2/X-322- L-2/X-323- L-2/X-324- L-2/X-325- L-2/X-326- L-2/X-327- L-2/X-328-
  • compositions which contain, as the active ingredient, one or more of the compounds described herein associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves 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.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth. gelatin, calcium silicate, microcrystaUine cellulose, polyvinylpyrrolidone. cellulose, sterile water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as corn oil, cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Step 2 1 -Benzyl-4-piperidyl N-(2-biphenylyl)carbamate (12.5 g, 32.3 mmol) was dissolved in anhydrous methanol (150 ml) and formic acid (25 ml, 660 mmol) and the solution was flushed with gaseous nitrogen for 15 min. 10% Palladium on carbon (3 g) was added and the reaction mixture was stirred under nitrogen atmosphere . After 18 h, the reaction mixture was filtered through Celite R and the filtrate was concentrated to give a yellow solid. The solid was partitioned between 0.1 N hydrochloric acid (300 ml) and diethyl ethr (300 ml).
  • N-(3-bromopropyl)phthalimide (10 g, 37.3 mmol) was dissolved in dry acetonitrile (100 ml) and a solution of dimethylamine in tetrahydrofuran (56 ml, 111 mmol, 2 M) was added. The flask was fitted with a reflux condense and the solution was heated at reflux. After 22 h, the reaction mixture was concentrated in vacuo to give a yellow oil which was partitioned between ethyl acetate and 1 M sodium carbonate solution saturated with sodium chloride. The organic phase was collected and washed with brine, dried over potassium carbonate, filtered and concentrated to give a yellow oil.
  • 6-(Dimethylamino)hexanol (8.80 g, 60.6 mmol) was dissolved in an anhydrous 2: 1 mixture of tetrahydrofuran and dimethylformamide (150 ml) and the solution was cooled in an ice bath.
  • Sodium hydride (60% in oil, 3.23 g, 80.8 mmol) was added in portions and after 5 min. the water bath was removed.
  • 2-methoxybenzyl chloride (6.28 g, 40.4 mmol) was added. After 4 h, the reaction mixture was quenched with 1 M sodium thiosulfate and tetrahydrofuran was removed in vacuo.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • the components are blended and compressed to form tablets, each weighing 240 mg.
  • Example 11 A dry powder inhaler formulation is prepared containing the following components: Ingredient Weight %
  • Example 12 Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh
  • Capsules each containing 40 mg of medicament are made as follows:
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • Example 15 Suspensions, each containing 50 mg of medicament per 5.0 mL dose are made as follows:
  • the active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystaUine cellulose and sodium carboxymethyl cellulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Example 16 A formulation may be prepared as follows:
  • the active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425.0 mg quantities.
  • a formulation may be prepared as follows:
  • a topical formulation may be prepared as follows:
  • the white soft paraffin is heated until molten.
  • the liquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture is then cooled until solid.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • the construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference in its entirety.
  • patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
  • Example 19 M 3 Muscarinic Receptor In Vitro Binding Assay The M 3 muscarininc receptor binding activity of compounds of the invention was tested as follows: SF9 cell membranes containing human M 3 muscarinic receptor was obtained from NEN (Boston, MA). In 96-well microtiter plates, eight serial five-fold dilutions were prepared with the compound to be assayed; the highest concentration was typically 4 ⁇ M (4x the final concentration). To 100 ⁇ l of compound dilution was added 150 ⁇ L M 3 receptor membrane preparation in PBS/l .OmM MgCl 2 /pH 7.4. 50 ⁇ l of 3.2 nM 3H-N-methylscopolamine radioligand was added.
  • Rat heart tissue was typically prepared as follows. 25 ⁇ l of ice cold buffer (20mM HEPES, lOOmM NaCl/lOmM MgCl, at pH 7.5 with "Complete" protease inhibitor cocktail purchased from Boehringer Mannheim was added into an oakridge tube. To the tube was then added 2g of rat heart (purchased from Harlan). The contents of the tube were then transferred to a wheaton glass cylinder and homogenized using a Polytron homogenizer (setting 22, 15 seconds x2), and then transferred back to the oakridge tube, and centrifuged for 10 minutes at 1500g.
  • ice cold buffer (20mM HEPES, lOOmM NaCl/lOmM MgCl, at pH 7.5 with "Complete" protease inhibitor cocktail purchased from Boehringer Mannheim was added into an oakridge tube.
  • To the tube was then added 2g of rat heart (purchased from Harlan). The contents of the tube were then transferred to a wheaton glass cylinder and homogenized using
  • the supernatant was removed and then centrifuged for 20 minutes at 45000g.
  • the supernatant was removed and the pellet resuspended in 5mL buffer and transferred to a wheaton glass cylinder.
  • This material was then homogenized using a Potter type glass teflon homogenizer with 7-8 passes.
  • the material is then transferred to an oakridge tube and the total volume brought up to 25mL. This volume is then centrifuged for 20 minutes at 45000g, and the pellet resuspended in 2mL buffer using 2 passes of a teflon homogenizer, and stored at -80 degrees C until used.
  • the total volume in each well was 200 ⁇ l.
  • the filter plate was pre-blocked using 0.3% PEI for at least 15 minutes, and then washed twice with 200 ⁇ l PBS.
  • the assay plate was incubated for 1 hour at room temperature with gentle shaking. The contents of the assay plate were then transferred to the filter plate, and washed three times using 200ul PBS. About 40 ⁇ l of scint was added to each well and then the plate was allowed to sit at room temperature for 18h, and then counted using a Packard Topcount NXT. Counting was typically performed for 1 minute per well using a standard protocol on the Packard counter. The data was fit to the four parameter fit described above in Example 19.
  • Rat Bladder M 3 In Vitro Binding Assay Bladder was comprised of both M 2 and M 3 muscarinic receptors. The ratio was typically 4:1 M 2 :M 3 . In order to measure binding of test compounds to one of M 2 or M 3 , the other was blocked with a reversible ligand that binds selectively to that receptor. The following example illustrates the procedure for M 3 bladder binding.
  • Membranes from rat bladder were prepared in a similar fashion to that used to isolate heart membrane above. Eight serial five-fold dilutions are prepared with the compound to be assayed in compound dilution buffer (20 mM HEPES/lOOmM NaCl/1 OmM MgCl 2 /4 ⁇ M Methoctramine); the highest concentration was typically 4 ⁇ M (4x the final concentration). The concentration of methoctramine was sufficient to block >99% of the M2 receptor in bladder, but less than 40% of the M 3 receptor in bladder.
  • rat heart membrane To 50 ⁇ l of compound dilution in a 96-well assay plate is added an appropriate amount of rat heart membrane (usually 25 ⁇ l of membrane prep in 75 ⁇ l of 20mM HEPES, lOOmM NaCl/lOmM MgCl 2 at pH 7.5). The amount of membrane added depended in general on the results of signal optimization, and ranged from 12.5-25. Last, 50 ⁇ l of 2.12 nM 3H-N- methylscopolamine radioligand in compound dilution buffer was added. The total volume in each well was 200 ⁇ l. The final concentration of Methoctramine is 2 ⁇ M.
  • the filter plate was pre-blocked using 0.3% PEI for at least 15 minutes, and then washed twice with 200 ⁇ l PBS.
  • the assay plate is incubated for 1 hour at room temperature with gentle shaking.
  • the contents of the assay plate are then transferred to the filter plate, and washed three times using 200 ⁇ l PBS.
  • About 40 ⁇ l of scint is added to each well and then the plate is allowed to sit at room temperature for 18h, and then counted using a Packard Topcount NXT. Counting was typically performed for 1 minute per well using a standard protocol on the Packard counter, and the data was fit to the four parameter equation described in Example 19.
  • Example 22 Ex Vivo Rat Bladder Contraction Assay The ability of the test compound to inhibit cholinergically stimulated bladder contraction was tested as follows:
  • Rat Salivation Assay Male Sprague-Dawley rats weighing 250 - 300 g were anesthetized with pentobarbital (60mg/kg i.p.). Rats were placed on a heated blanket under a 20 degree incline. A swab was placed in the rat's mouth. Muscarinic antagonist or vehicle was administered i.v. via the tail vein. 5 min. later, oxotremorine
  • Example 24 In Vivo Bladder Assay Male Sprague-Dawley rats weighing 250 - 300 g were anesthetized with urethane (1.3 g/kg, i.p.), inactin (25 mg/kg, i.p.), and xylazine (4 mg, i.p.).
  • the jugular (or femoral) vein was Isolate and Hgated and a small incision was made in the vein distal to the ligation.
  • a catheter micro-Renathane tubing (0.014 mm ID x 0.033 mm OD) was filled with saline was nserted into the vein and secured into place with suture thread.
  • the trachea was isolated and place da small hole between two of the rings.
  • Tubing (1.57 mm ID x 2.08 mm OD) was inserted into the trachea and tied into place with suture thread. The incision was closed leaving the tubing exposed.
  • the tracheotomy was to prevent the animal from asphyxiating on his own saliva following oxotremorine administration.
  • the stomach was shaved and then cleaned with ethanol.
  • a midline sagital incision was made in the skin and muscle layers of the lower stomach.
  • the bladder was exposed and the saline filled cannula (22-gauge needle attached to a pressure transducer with PE 90 tubing) was inserted into the apex of the bladder to the most distal part of the bladder.
  • the bladder was placed back into the peritoneal cavity.
  • the bladder was emptied manually by disconnecting the cannula and allowing the contents to flow out until the bladder was approximately 1 cm in diameter.
  • the incision was closed with suture thread, first the muscle layer, then the skin in order to keep the bladder moist and warm.
  • the exposed portion of the cannula to the skin surface was sutured to hold it in place.
  • oxotremorine 0.3 mg/kg, SC, baseweight
  • SC baseweight
  • a test compound or a reference standard was injected with a dose equivalent to 0.005 - 0.01 mg/kg, IV, baseweight of atropine that produces a 30-70% decrease in intraluminal pressure.
  • a high dose of atropine 0.1 mg/kg was injected, IV to establish the true 100% inhibition point.
  • oxotremorine response zero inhibition
  • measure the mean pressure beginning 1 minute and ending 2 minutes after antagonist administration If the pressure has not leveled off after 1 minute, wait until it is stable and then take a 1 -minute sample of the mean.
  • measure the mean pressure beginning 1 minutes and ending 2 minutes after the high dose atropine challenge The percent inhibition by the antagonist can be determined by the ratio of the decrease from the zero to 100% values.
  • the formula is: oxotremorine mean - treatment mean * 100 oxotremorine mean - atropine mean.

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Abstract

L'invention concerne des composés à liaisons multiples, lesquels composés sont des antagonistes des récepteurs muscariniques. Les composés à liaisons multiples de l'invention renferment entre 2 et 10 ligands fixés de manière covalente à une ou plusieurs séquences de liaison. Chaque ligand est, indépendamment des autres, un antagoniste des récepteurs muscariniques ou un modulateur allostérique, à condition qu'un des ligands au moins soit un antagoniste des récepteurs muscariniques. Les composés à liaisons multiples de l'invention sont utiles dans le traitement et la prévention de maladies telles que la broncho-pneumopathie chronique obstructive, la bronchite chronique, la colopathie fonctionnelle, l'incontinence urinaire, etc..
EP99928444A 1998-06-08 1999-06-07 Antagonistes des recepteurs muscariniques Withdrawn EP1086066A4 (fr)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US8846698P 1998-06-08 1998-06-08
US88466P 1998-06-08
US9293898P 1998-07-15 1998-07-15
US92938P 1998-07-15
US12028799P 1999-02-16 1999-02-16
US120287P 1999-02-16
PCT/US1999/012733 WO1999064043A1 (fr) 1998-06-08 1999-06-07 Antagonistes des recepteurs muscariniques

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PE20040950A1 (es) 2003-02-14 2005-01-01 Theravance Inc DERIVADOS DE BIFENILO COMO AGONISTAS DE LOS RECEPTORES ADRENERGICOS ß2 Y COMO ANTAGONISTAS DE LOS RECEPTORES MUSCARINICOS
EP1615881A2 (fr) 2003-04-01 2006-01-18 Theravance, Inc. Diarylmethyle et composes apparentes ayant les activites agoniste du recepteur beta2 adrenergique et antagoniste de recepteur de muscarinic
EP1626970B1 (fr) 2003-05-28 2009-07-08 Theravance, Inc. Composes d'azabicycloalcane utilises en tant qu'antagonistes des recepteurs muscariniques
TW200510298A (en) 2003-06-13 2005-03-16 Theravance Inc Substituted pyrrolidine and related compounds
US7368463B2 (en) 2003-07-11 2008-05-06 Theravance, Inc. Substituted 4-amino-1-benzylpiperidine compounds
US7345060B2 (en) 2003-11-21 2008-03-18 Theravance, Inc. Compounds having β2 adrenergic receptor agonist and muscarinic receptor antagonist activity
TW200538095A (en) 2004-03-11 2005-12-01 Theravance Inc Biphenyl compounds useful as muscarinic receptor antagonists
WO2005087739A1 (fr) 2004-03-11 2005-09-22 Theravance, Inc. Composes biphenyle convenant en tant qu'antagonistes du recepteur muscarinique
WO2005087734A1 (fr) 2004-03-11 2005-09-22 Theravance, Inc. Composes biphenyle convenant comme antagonistes du recepteur muscarinique
EP1723112A1 (fr) 2004-03-11 2006-11-22 Theravance, Inc. Composes biphenyliques antagonistes du recepteur muscarinique
WO2005087735A1 (fr) 2004-03-11 2005-09-22 Theravance, Inc. Utilisation de composes biphenyles comme antagonistes des recepteurs muscariniques
TWI341836B (en) 2004-03-11 2011-05-11 Theravance Inc Biphenyl compounds useful as muscarinic receptor antagonists
WO2005087733A1 (fr) 2004-03-11 2005-09-22 Theravance, Inc. Composes biphenyle utiles comme antagonistes du recepteur muscarinique
JP2007528410A (ja) 2004-03-11 2007-10-11 セラヴァンス， インコーポレーテッド ムスカリンレセプターアンタゴニストとしての有用なビフェニル化合物
EP1856112A1 (fr) 2005-03-10 2007-11-21 Theravance, Inc. Composes de biphenyle utilises comme antagonistes des recepteurs muscariniques
US7659403B2 (en) 2005-03-10 2010-02-09 Theravance, Inc. Biphenyl compounds useful as muscarinic receptor antagonists
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WO1999064043A1 (fr) 1999-12-16
SG80041A1 (en) 2001-04-17
EP1086066A4 (fr) 2001-08-08
AU4550899A (en) 1999-12-30
AR018629A1 (es) 2001-11-28
AU763638B2 (en) 2003-07-31
NZ505329A (en) 2003-05-30

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