WO1999063999A1 - H1-histamine receptor antagonists - Google Patents
H1-histamine receptor antagonists Download PDFInfo
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- WO1999063999A1 WO1999063999A1 PCT/US1999/012626 US9912626W WO9963999A1 WO 1999063999 A1 WO1999063999 A1 WO 1999063999A1 US 9912626 W US9912626 W US 9912626W WO 9963999 A1 WO9963999 A1 WO 9963999A1
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- 0 CS(c1ccc(C*)cc1)(O)=O Chemical compound CS(c1ccc(C*)cc1)(O)=O 0.000 description 4
- XLUMOZQZGPJGTL-ROUUACIJSA-N OC(CC[C@@H](C(N[C@@H](Cc(cc1)ccc1O)C(O)=O)=O)NC(OCc1ccccc1)=O)=O Chemical compound OC(CC[C@@H](C(N[C@@H](Cc(cc1)ccc1O)C(O)=O)=O)NC(OCc1ccccc1)=O)=O XLUMOZQZGPJGTL-ROUUACIJSA-N 0.000 description 1
- VSSGEWPIFHKREK-UHFFFAOYSA-N OCCN1CCC(CCCC2CCN(CCO)CC2)CC1 Chemical compound OCCN1CCC(CCCC2CCN(CCO)CC2)CC1 VSSGEWPIFHKREK-UHFFFAOYSA-N 0.000 description 1
- VARKIGWTYBUWNT-UHFFFAOYSA-N OCCN1CCN(CCO)CC1 Chemical compound OCCN1CCN(CCO)CC1 VARKIGWTYBUWNT-UHFFFAOYSA-N 0.000 description 1
- FPQJEXTVQZHURJ-UHFFFAOYSA-N OCCNC(C(NCCO)=O)=O Chemical compound OCCNC(C(NCCO)=O)=O FPQJEXTVQZHURJ-UHFFFAOYSA-N 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N OCCNCCO Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- UIMJANTUJQGSEX-UHFFFAOYSA-N OCc(cccc1)c1-c1ccccc1CO Chemical compound OCc(cccc1)c1-c1ccccc1CO UIMJANTUJQGSEX-UHFFFAOYSA-N 0.000 description 1
- BWVAOONFBYYRHY-UHFFFAOYSA-N OCc1ccc(CO)cc1 Chemical compound OCc1ccc(CO)cc1 BWVAOONFBYYRHY-UHFFFAOYSA-N 0.000 description 1
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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- C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
- C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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- C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
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- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
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- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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Definitions
- Type I hypersensitivity reactions occur when antigens (allergens) stimulate the production of IgE antibodies by B lymphocytes 1 .
- the IgE in turn binds to high affinity Fc receptors on the surface of tissue mast cells or blood basophils 1 .
- the binding of IgE to the Fc receptors stimulates a degranulation reaction by mast cells or blood basophils, in which chemical mediators, such as histamine are released 1 .
- HI histamine receptors and provide potent, efficacious and long term effects effects.
- n 0, 1. or 2;
- Q is carbon or nitrogen
- R 3 is hydrogen or hydroxy
- R 4 is a covalent bond linking (a) to a linker; (b) a compound of formula (b) :
- R 5 is selected from the group consisting of hydrogen, halo, alkyl, carboxy, and alkylcarbox ⁇ :
- R 7 is -(alkylene)-O-R 9 where R 9 is alkyl; and R 8 is a covalent bond linking the ligand to a linker; (d) a compound of formula (d):
- R" is a covalent bond linking the ligand to a linker; and (e) a compound of formula (e):
- R 13 is alkyl
- R 14 is a covalent bond linking the ligand to a linker; and pharmaceutically acceptable salts thereof.
- R, R ' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic provided that at least one of
- Formula (I) independently has the formula: -X a -Z-(Y a -Z) m -X a - wherein: m is an integer of from 0 to 20;
- Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; each Y a at each separate occurrence is selected from the group consisting of -O-, -C(O)-, -OC(O)-, -C(O)O-, -NR-, -S(O)n-, -C(O)NR ⁇ -
- this invention is directed to general synthetic methods for generating large libraries of diverse multimeric compounds which multimeric compounds are candidates for possessing multibinding properties for HI histamine receptor.
- the diverse multimeric compound libraries provided by this invention are synthesized by combining a linker or linkers with a ligand or ligands to provide for a library of multimeric compounds wherein the linker and ligand each have complementary functional groups permitting covalent linkage.
- the library of linkers is preferably selected to have diverse properties such as valency, linker length, linker geometry and rigidity, hydrophilicity or hydrophobicity, amphiphilicity, acidity, basicity and polarization.
- the library of ligands is preferably selected to have diverse attachment points on the same ligand, different functional groups at the same site of otherwise the same ligand, and the like.
- FIGs. 6-12 illustrates synthesis of multibinding compounds of Formula (I). DET AILED DESCRIPTION OF THE INVENTION
- This invention is directed to multibinding compounds which are HI histamine receptor antagonists, pharmaceutical compositions containing such compounds and methods for treating diseases mediated by HI histamine receptor in mammals.
- HI histamine receptor antagonists HI histamine receptor antagonists
- pharmaceutical compositions containing such compounds pharmaceutical compositions containing such compounds and methods for treating diseases mediated by HI histamine receptor in mammals.
- substituted alkyl refers to an alkyl 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, alkoxyamino,
- 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
- acyloxy refers to the groups alkyl-C(O)O-, substituted alkyl- C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclic-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
- substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, cycloalkyl. substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic provided that both R's are not hydrogen.
- substituents 1 to 5 substituents. and preferably 1 to 3 substituents, selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl.
- cycloalkenyl refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation.
- suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl. cyclopent-3-enyl, cyclooct-3-enyl and the like.
- substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy.
- cycloalkyl substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl.
- 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.
- heteroaryloxy refers to the,group heteroaryl-O-.
- heterocycle or “heterocyclyl” 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 and further wherein one, two, or three ofthe ring carbon atoms may optionally be replaced with a carbonyl group (i.e., a keto group).
- heterocyclic groups can have a single ring or multiple condensed rings.
- Preferred heterocyclics include morpholino, piperidinyl, and the like.
- thioalkoxy or "alkylthio” refers to the group -S-alkyl.
- substituted thioalkoxy refers to the group -S-substituted alkyl.
- thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
- thioheteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
- 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 like.
- Pharmaceutically acceptable acid addition salts may 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.
- Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxy-carbonyl (FMOC), allyloxycarbonyl (ALOC), and the like which can be removed by conventional conditions compatible with the nature ofthe product.
- t-BOC t-butyoxycarbonyl
- CBZ benzyloxycarbonyl
- FMOC fluorenylmethoxy-carbonyl
- ALOC allyloxycarbonyl
- Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild conditions compatible with the nature ofthe product.
- esters such as methyl, ethyl, propyl, t-butyl etc. which can be removed by mild conditions compatible with the nature ofthe product.
- the term "optional” or “optionally” means that the subsequently described event, circumstance or substituent may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
- ligand structure that are not essential for specific molecular recognition and binding activity may be varied substantially, replaced or substituted with unrelated structures (for example, with ancillary groups as defined below) and, in some cases, omitted entirely without affecting the binding interaction.
- the primary requirement for a ligand is that it has a ligand domain as defined above.
- ligand is not intended to be limited to compounds known to be useful in binding to HI histamine receptor (e.g., known drugs).
- ligand can equally apply to a molecule that is not normally associated with HI histamine receptor binding properties.
- ligands that exhibit marginal activity or lack useful activity as monomers can be highly active as multivalent compounds because ofthe benefits conferred by multivalency.
- multibinding compound or agent refers to a compound that is capable of multivalency, as defined below, and which has 2-10 ligands covalently bound to one or more linkers.
- each ligand and linker in the multibinding compound is independently selected such that the multibinding compound includes both symmetric compounds (i.e., where each ligand as well as each linker is identical) and asymmetric compounds ((i.e., where at least one ofthe ligands is different from the other ligand(s) and/or at least one linker is different from the other linker(s)).
- the multibinding compound can be either a chiral or achiral molecule.
- Multibinding compounds provide a biological and/or therapeutic effect greater than the aggregate of unlinked ligands equivalent thereto which are made available for binding. That is to say that the biological and/or therapeutic effect ofthe ligands attached to the multibinding compound is greater than that achieved by the same amount of unlinked ligands made available for binding to the ligand binding sites (receptors).
- the phrase "increased biological or therapeutic effect” includes, for example: increased affinity, increased selectivity for target, increased specificity for target, increased potency, increased efficacy, decreased toxicity, improved duration of activity or action, increased ability to kill cells such as fungal pathogens, cancer cells, etc., decreased side effects, increased therapeutic index, improved bioavailibity, improved pharmacokinetics, improved activity spectrum, and the like.
- ligand binding site denotes the site on the Hl-histamine receptor that recognizes a ligand domain and provides a binding partner for the ligand.
- the ligand binding site may be defined by monomeric or multimeric structures. This interaction may be capable of producing a unique biological effect, for example, agonism, antagonism, and modulatory effects, or it may maintain an ongoing biological event, and the like.
- antagonism is well known in the art.
- modulatory effect refers to the ability ofthe ligand to change the activity of an agonist or antagonist through binding to a ligand binding site.
- pathologic condition which is modulated by treatment with a ligand covers all disease states (i.e., pathologic conditions) which are generally acknowledged in the art to be usefully treated with a ligand for the HI -histamine receptor in general, and those disease states which have been found to be usefully treated by a specific multibinding compound of our invention.
- disease states include, by way of example only, the treatment of a mammal afflicted with asthma, chronic bronchitis, and the like.
- linker identified where appropriate by the symbol 'X' refers to a group or groups that covalently attaches from 2 to 10 ligands (as identified above) in a manner that provides for a compound capable of multivalency.
- the linker is a ligand-orienting entity that permits attachment of at least two copies of a ligand (which may be the same or different) thereto.
- the term includes all stereoisomeric forms ofthe linker. In some cases, the linker may itself be biologically active.
- linker does not, however, extend to cover solid inert supports such as beads, glass particles, fibers, and the like. But it is understood that the multibinding compounds of this invention can be attached to a solid support if desired.
- linker or linkers For example, such attachment to solid supports can be made for use in separation and purification processes and similar applications.
- the extent to which multivalent binding is realized depends upon the efficiency with which the linker or linkers that joins the ligands presents these ligands to the array of available ligand binding sites. Beyond presenting these ligands for multivalent interactions with ligand binding sites, the linker or linkers spatially constrains these interactions to occur within dimensions defined by the linker or linkers.
- the structural features ofthe linker valency, geometry, orientation, size, flexibility, chemical composition, etc. are features of multibinding agents that play an important role in determining their activities.
- the linkers used in this invention are selected to allow multivalent binding of ligands to the ligand binding sites of a HI histamine receptor, whether such sites are located interiorly, both interiorly and on the periphery ofthe receptor structure, or at any intermediate position thereof.
- n O, 1. or 2;
- R 1 and R are independently selected from the group consisting of hydrogen, chloro, fluoro, methyl, carboxy, and -CH 2 COOH;
- R 6 is covalent bond linking (b) to a linker; (c) a compound of formula (c):
- A is nitrogen or oxygen;
- R 10 is hydrogen, chloro, or fluoro; and
- R 1 ' is a covalent bond linking the ligand to a linker; and (e) a compound of formula (e):
- R 14 is a covalent bond linking the ligand to a linker; and pharmaceutically acceptable salts thereof.
- reaction temperatures i.e.. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.
- Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
- Figure 1 illustrates a useful strategy for determining an optimal framework display orientation for ligand domains.
- Various other strategies are known to those skilled in the art of molecular design and can be used for preparing compounds of this invention.
- display vectors around similar central core structures such as a phenyl structure (Panel A) and a cyclohexane structure (Panel B) can be varied, as can the spacing ofthe ligand domain from the core structure (i.e., the length ofthe attaching moiety).
- core structures other than those shown here can be used for determining the optimal framework display orientation ofthe 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 2) and compound of higher valency. ( Figures 3 & 4)
- Hydrophobicity could be conferred by the inclusion of groups that include, but are not limited to, long chain saturated and unsaturated aliphatic hydrocarbon groups of up to 20 carbon atoms and such groups substituted by one or more aryl, heteroaryl, cycloalkyl, and/or heterocyclic group(s).
- the similarly charged ancillary groups will force the presenter linker into a configuration affording the maximum distance between each ofthe like charges.
- the energetic cost of bringing the like-charged groups closer to each other will tend to hold the linker in a configuration that maintains the separation between the like-charged ancillary groups.
- Further ancillary groups bearing opposite charges will tend to be attracted to their oppositely charged counterparts and potentially may enter into both inter- and intramolecular ionic bonds. This non-covalent mechanism will tend to hold the linker into a conformation which allows bonding between the oppositely charged groups.
- 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.
- linker moiety can be optionally substituted at any atom therein by one or more alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl. alkenyl, substituted alkenyl, cycloalkenyl. substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl and heterocyclic group.
- factors such as the proper juxtaposition ofthe individual ligands of a multibinding compound with respect to the relevant array of binding sites on a target or targets is important in optimizing the interaction ofthe multibinding compound with its target(s) and to maximize the biological advantage through multivalenc ⁇ '.
- One approach is to identify a library of candidate multibinding compounds with properties spanning the multibinding parameters that are relevant for a particular target. These parameters include: (1) the identity of ligand(s), (2) the orientation of ligands, (3) the valency ofthe construct, (4) linker length, (5) linker geometry. (6) linker physical properties, and (7) linker chemical functional groups.
- ligands which display an unfavorable property from among the previous list may obtain a more favorable property through the process of multibinding compound formation; i.e., ligands should not necessarily be excluded on such a basis.
- a ligand that is not sufficiently potent at a particular target so as to be efficacious in a human patient may become highly potent and efficacious when presented in multibinding form.
- a ligand that is potent and efficacious but not of utility because of a non- mechanism-related toxic side effect may have increased therapeutic index (increased potency relative to toxicity) as a multibinding compound.
- Compounds that exhibit short in vivo half-lives may have extended half-lives as multibinding compounds.
- Physical properties of ligands that limit their usefulness e.g. poor bioavailability due to low solubility, hydrophobicity, hydrophilicity
- each ligand at which to attach the ligand to the linker.
- the selected points on the ligand/linker for attachment are functionalized to contain complementary reactive functional groups. This permits probing the effects of presenting the ligands to their receptor(s) in multiple relative orientations, an important multibinding design parameter.
- the only requirement for choosing attachment points is that attaching to at least one of these points does not abrogate activity ofthe ligand.
- Such points for attachment can be identified by structural information when available. For example, inspection of a co-crystal structure of a protease inhibitor bound to its target allows one to identify one or more sites where linker attachment will not preclude the enzyme: inhibitor interaction.
- a 5HT 4 receptor antagonist and a bladder-selective muscarinic M 3 antagonist may be joined to a linker through attachment points which do not abrogate the binding affinity ofthe monomeric ligands for their respective receptor sites.
- the dimeric compound may achieve enhanced affinity for both receptors due to favorable interactions between the 5HT 4 ligand and elements ofthe M 3 receptor proximal to the formal M 3 antagonist binding site and between the M 3 ligand and elements ofthe 5HT 4 receptor proximal to the formal 5HT 4 antagonist binding site.
- the dimeric compound may be more potent and selective antagonist of overactive bladder and a superior therapy for urinary urge incontinence.
- Linker geometry and rigidity The combination of ligand attachment site, linker length, linker geometry, and linker rigidity determine the possible ways in which the ligands of candidate multibinding compounds may be displayed in three dimensions and thereby presented to their binding sites. Linker geometry and rigidity are nominally determined by chemical composition and bonding pattern, which may be controlled and are systematically varied as another spanning function in a multibinding array.
- linker geometry is varied by attaching two ligands to the ortho, meta, and para positions of a benzene ring, or in cis- or trcms-arrangements at the 1,1- vs. 1,2- vs. 1,3- vs. 1,4- positions around a cyclohexane core or in cis- or transarrangements at a point of ethylene unsaturation.
- Linker rigidity is varied by controlling the number and relative energies of different conformational states possible for the linker.
- linkers are nominally determined by the chemical constitution and bonding patterns ofthe linker, and linker physical properties impact the overall physical properties ofthe candidate multibinding compounds in which they are included.
- a range of linker compositions is typically selected to provide a range of physical properties (hydrophobicity, hydrophilicity, amphiphilicity, polarization, acidity, and basicity) in the candidate multibinding compounds.
- the particular choice of linker physical properties is made within the context ofthe physical properties ofthe ligands they join and preferably the goal is to generate molecules with favorable PK/ADME properties.
- linkers can be selected to avoid those that are too hydrophilic or too hydrophobic to be readily absorbed and/or distributed in vivo.
- Linker chemical functional groups Linker chemical functional groups are selected to be compatible with the chemistry chosen to connect linkers to the ligands and to impart the range of physical properties sufficient to span initial examination of this parameter.
- In vitro efficacy such as for receptor agonists and antagonists, ion channel blockers, and antimicrobial activity, can also be determined.
- Pharmacological data including oral absorption, everted gut penetration, other pharmacokinetic parameters and efficacy data can be determined in appropriate models. In this way, key structure-activity relationships are obtained for multibinding design parameters which are then used to direct future work.
- suitable divalent linkers include, by way of example only, those derived from dicarboxylic acids, disulfonylhalides, dialdehydes, diketones, dihalides, diisocyanates,diamines, diols, mixtures of carboxylic acids, sulfonylhalides, aldehydes, ketones, halides, isocyanates, amines and diols.
- carboxylic acid, sulfonylhalide, aldehyde, ketone, halide, isocyanate, amine and diol functional group is reacted with a complementary functionality on the ligand to form a covalent linkage.
- complementary functionality is well known in the art as illustrated in the following table: COMPLEMENTARY BINDING CHEMISTRIES
- First Reactive Group Second Reactive Group Linkage hydroxyl isocyanate urethane amine epoxide ⁇ -hydroxyamine hydroxyamine sulfonyl halide sulfonamide carboxyl acid amine amide hydroxyl alkyl/aryl halide ether aldehyde amine NaCNBH 3 amine ketone amine/NaCNBH 3 amine amine isocyanate urea
- Combinations of ligands (L) and linkers (X) per this invention include, by way example onh . homo- and hetero-dimers wherein the first ligand is selected from L-l through L-5 above and the second ligand and linker is selected from the following:
- the multibinding compounds of this invention are HI histamine receptor antagonists. Accordingly, the multibinding compounds and pharmaceutical compositions of this invention are useful in the treatment and prevention of diseases mediated by HI histamine receptor such as allergic rhinitis, urticaria, asthma, anaphylaxis, and the like.
- Binding to guinea pig ileum is also assessed in vitro using the method of Kamei et al. Arzneiffenforschung 1991 41(9): 932 and Cheng, H. C. Arzneistoffforschung 1982 32 (9a): 1160.
- the inhibitory effect of compounds on histamine-induced trachea contraction is evaluated in vitro using tissues isolated from guinea pigs and rats as described in Yakuo, I, et al. Folia Pharmacol Jpn.1994 103(3): 135.
- the selectivity of compounds for histamine receptors is determined by competitive radioligand binding to guinea pig membranes in vitro as described in Wiech, N.
- the compounds of this invention are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
- compositions which contain, as the active ingredient, one or more ofthe 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.
- compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight ofthe active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
- excipients include lactose, dextrose, sucrose, sorbitol. mannitol. starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline 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 ofthe invention can be formulated so as to provide quick, sustained or delayed release ofthe active ingredient after administration to the patient by employing procedures known in the art.
- compositions are preferably formulated in a unit dosage form, each dosage containing from about 0.001 to about 1 g, more usually about 1 to about 30 mg, ofthe active ingredient.
- unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to -82- produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
- the compound of Formula (I) above is employed at no more than about 20 weight percent ofthe pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
- the active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount ofthe compound actually administered will be determined by a physician, in the light ofthe relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered and its relative activity, the age, weight, and response ofthe individual patient, the severity ofthe patient's symptoms, and the like.
- the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound ofthe present invention.
- a solid preformulation composition containing a homogeneous mixture of a compound ofthe 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 ofthe type described above containing from, for example, 0.1 to about 500 mg ofthe active ingredient ofthe present invention.
- the tablets or pills ofthe present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids -83- and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
- liquid forms in which the novel compositions ofthe 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.
- 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 compositions may contain suitable pharmaceutically acceptable excipients as described supra.
- the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
- Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
- reaction solution is quenched in water, aqueous sodium bicarbonate is added and the aqueous mixture is extracted with methylene chloride.
- organic layer is washed with aqueous Na 2 CO 3 and with H 2 O, dried (Na 2 SO 4 ), filtered and concentrated -89- under reduced pressure to give the crude product.
- a solution of l-(4-chlorobenzhydryl)piperazine 1 (2 mmols) in methanol (10 mL) is acidified with acetic acid to pH 6.6 (pH meter) under a nitrogen atmosphere.
- a solution of aldehyde 10 (2 mmols) in methanol (5 mL) is added followed by sodium cyanoborohydride (3.5 mmol).
- the progress ofthe reaction is followed by thin layer chromatography. After reaction occurs, the reaction solution is quenched in water and the pH ofthe aqueous mixture is adjusted to greater than 10 with aqueous NaOH.
- Step 3 A solution of 14 (2 mmols) in methanol (10 mL) is acidified with acetic acid to pH 6.6 (pH meter) under a nitrogen atmosphere.
- reaction solution is quenched in water and the p ⁇ ofthe aqueous mixture is adjusted to greater than 10 with aqueous NaO ⁇ .
- the reaction mixture is extracted with ether, the organic extracts are washed with half-saturated saline, dried (Na 2 S0 4 ). filtered and concentrated under reduced pressure to give the crude product.
- the aqueous layer is extracted with additional CH 2 C1 2 , the combined -96- organic extracts are washed with half-saturated brine, dried (Na 2 SO 4 ), filtered and concentrated under reduced pressure giving the crude product.
- the desired compound 1 ,4-bis-(4-chlorobenzhydryl)piperazine 22 is obtained by purification of the crude product with the use of HPLC. Ethereal HC1 is added to a solution of 22 (1 mmol) in dry ether (10 mL).
- the precipitate is collected by filtration and is recrystallized from acetone-hexane, giving 22 as the dihydrochloride salt.
- the desired compound l-[(4-fluorophenyl)methyl]-N- ⁇ 4-[N-(4-chlorobenzhydryl)]piperidinyl ⁇ - lH-benzimidazoL-4-amine 24. is obtained by purification ofthe crude product with the use of ⁇ PLC.
- the desired compound l-(2-ethoxyethyl)-2-[hexahydro-4-(4-chlorobenzhydryl)-lH-l,4- diazepin-l-yl]-lH-benzimidazole 25 is obtained by purification ofthe crude product with the use of ⁇ PLC.
- the desired compound l,4-di-[l- (2-ethoxyethyl)-lH-benzimidazo-2-yl]hexahydro-lH-l,4-diazepine 27, is obtained by purification ofthe crude product with the use of ⁇ PLC.
- 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. -100-
- a dry powder inhaler formulation is prepared containing the following components:
- the active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
- Example 4 Tablets each containing 30 mg of active ingredient, are 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 150 mg quantities.
- 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 7 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 ofthe microcrystalline cellulose and sodium carboxymethyl cellulose in water.
- the sodium benzoate, flavor, and color are diluted with some ofthe water and added with stirring. Sufficient water is then added to produce the required volume.
- 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 m quantities.
- a formulation may be prepared as follows:
- Example 10 A topical formulation may be prepared as follows:
- Liquid Paraffin 20 g White Soft Paraffin to 100 g -103-
- transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds ofthe 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. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
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Abstract
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Claims
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008112257A1 (en) * | 2007-03-12 | 2008-09-18 | Nektar Therapeutics | Oligomer-antihistamine conjugates |
Families Citing this family (188)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6025154A (en) | 1995-06-06 | 2000-02-15 | Human Genome Sciences, Inc. | Polynucleotides encoding human G-protein chemokine receptor HDGNR10 |
US6713651B1 (en) * | 1999-06-07 | 2004-03-30 | Theravance, Inc. | β2-adrenergic receptor agonists |
US6541669B1 (en) | 1998-06-08 | 2003-04-01 | Theravance, Inc. | β2-adrenergic receptor agonists |
US6998233B2 (en) | 1998-06-26 | 2006-02-14 | Sunesis Pharmaceuticals, Inc. | Methods for ligand discovery |
US6919178B2 (en) | 2000-11-21 | 2005-07-19 | Sunesis Pharmaceuticals, Inc. | Extended tethering approach for rapid identification of ligands |
KR100623095B1 (en) * | 1998-10-22 | 2006-09-11 | 지옥표 | Thymol derivatives having anti-tumor activity, and anti-cancer agent comprising the same |
US20090216118A1 (en) * | 2007-07-26 | 2009-08-27 | Senorx, Inc. | Polysaccharide markers |
US6683115B2 (en) | 1999-06-02 | 2004-01-27 | Theravance, Inc. | β2-adrenergic receptor agonists |
US6593497B1 (en) | 1999-06-02 | 2003-07-15 | Theravance, Inc. | β2-adrenergic receptor agonists |
US6417212B1 (en) | 1999-08-27 | 2002-07-09 | Eli Lilly & Company | Modulators of peroxisome proliferator activated receptors |
FR2801305B1 (en) * | 1999-11-24 | 2002-12-06 | Galderma Res & Dev | VITAMIN D ANALOGS |
UA73965C2 (en) * | 1999-12-08 | 2005-10-17 | Theravance Inc | b2 ADRENERGIC RECEPTOR ANTAGONISTS |
OA11558A (en) * | 1999-12-08 | 2004-06-03 | Advanced Medicine Inc | Beta 2-adrenergic receptor agonists. |
DE10021106A1 (en) * | 2000-05-02 | 2001-11-08 | Univ Stuttgart | Polymeric membranes |
CZ20024180A3 (en) * | 2000-06-22 | 2003-04-16 | Novartis Ag | Solid oral pharmaceutical compositions containing valsartan |
US6451814B1 (en) * | 2000-07-17 | 2002-09-17 | Wyeth | Heterocyclic β-3 adrenergic receptor agonists |
AU1305302A (en) * | 2000-10-05 | 2002-04-15 | Immunex Corp | Nectin polypeptides, polynucleotides, methods of making and use thereof |
SE0004782D0 (en) * | 2000-12-22 | 2000-12-22 | Schmidt Ann Christin Koch | blocking agents |
US6451813B1 (en) | 2001-01-26 | 2002-09-17 | R. T. Alamo Ventures I, Llc | Treatment of gastroparesis in certain patient groups |
DE10111843A1 (en) * | 2001-03-13 | 2002-09-19 | Boehringer Ingelheim Pharma | Compounds for the treatment of inflammatory diseases |
WO2002083127A1 (en) * | 2001-04-09 | 2002-10-24 | Tokai University Educational System | Protein modification-inhibitory compositions |
US20030083339A1 (en) * | 2001-04-26 | 2003-05-01 | Masaaki Tamura | Compositions and methods for treating colorectal polyps and cancer |
AU783516B2 (en) * | 2001-04-30 | 2005-11-03 | Warner-Lambert Company | Methods, kits and compositions for using pyrrole derivatives |
ATE288745T1 (en) * | 2001-09-14 | 2005-02-15 | Sanol Arznei Schwarz Gmbh | TRANSDERMAL ADMINISTRATION SYSTEM FOR THE TREATMENT OF URINARY TRACT DISEASES |
UA78529C2 (en) | 2001-10-10 | 2007-04-10 | Wyeth Corp | Derivatives of [[2-(amino-3,4-dioxo-1-cyclobutene-1-yl)amino]alkyl] acid for treating pain |
US7220877B2 (en) | 2001-10-17 | 2007-05-22 | Novo Nordisk A/S | Compounds, their preparation and use |
TWI249515B (en) * | 2001-11-13 | 2006-02-21 | Theravance Inc | Aryl aniline beta2 adrenergic receptor agonists |
US20030229058A1 (en) * | 2001-11-13 | 2003-12-11 | Moran Edmund J. | Aryl aniline beta2 adrenergic receptor agonists |
WO2003042160A1 (en) * | 2001-11-13 | 2003-05-22 | Theravance, Inc. | Aryl aniline beta-2 adrenergic receptor agonists |
JP2005522460A (en) * | 2002-02-28 | 2005-07-28 | マリンクロッド・インコーポレイテッド | Method and system for separation and purification of at least one narcotic alkaloid using reverse phase preparative chromatography |
US8623822B2 (en) | 2002-03-01 | 2014-01-07 | Bracco Suisse Sa | KDR and VEGF/KDR binding peptides and their use in diagnosis and therapy |
CA2513044A1 (en) | 2002-03-01 | 2004-08-05 | Dyax Corp. | Kdr and vegf/kdr binding peptides and their use in diagnosis and therapy |
US7261876B2 (en) | 2002-03-01 | 2007-08-28 | Bracco International Bv | Multivalent constructs for therapeutic and diagnostic applications |
US7794693B2 (en) | 2002-03-01 | 2010-09-14 | Bracco International B.V. | Targeting vector-phospholipid conjugates |
AUPS127202A0 (en) * | 2002-03-20 | 2002-04-18 | Walter And Eliza Hall Institute Of Medical Research, The | Therapeutic ion channel blocking agents and methods of use thereof |
GB0211230D0 (en) | 2002-05-16 | 2002-06-26 | Medinnova Sf | Treatment of heart failure |
US6747043B2 (en) | 2002-05-28 | 2004-06-08 | Theravance, Inc. | Alkoxy aryl β2 adrenergic receptor agonists |
TW200409746A (en) * | 2002-07-26 | 2004-06-16 | Theravance Inc | Crystalline β2 adrenergic receptor agonist |
US7091196B2 (en) * | 2002-09-26 | 2006-08-15 | Rib-X Pharmaceuticals, Inc. | Bifunctional heterocyclic compounds and methods of making and using same |
DE10251170A1 (en) * | 2002-10-31 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | New beta agonists, processes for their production and their use as medicines |
US7816385B2 (en) | 2002-12-20 | 2010-10-19 | High Point Pharmaceuticals, Llc | Dimeric dicarboxylic acid derivatives, their preparation and use |
ES2351392T3 (en) * | 2003-02-14 | 2011-02-03 | Theravance Inc | BIFENILO DERIVATIVES THAT HAVE AGENIST ACTIVITY OF BETA2-ADRENERGIC RECEIVERS AND ANTAGONIST ACTIVITY OF MUSCARINIC RECEPTORS. |
PE20040950A1 (en) * | 2003-02-14 | 2005-01-01 | Theravance Inc | BIPHENYL DERIVATIVES AS AGONISTS OF ß2-ADRENERGIC RECEPTORS AND AS ANTAGONISTS OF MUSCARINAL RECEPTORS |
TWI324150B (en) * | 2003-02-28 | 2010-05-01 | Novartis Ag | Process for preparing 5-[(r)-2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-(1h)-quinolin-2-one salt |
BRPI0408117A (en) * | 2003-03-05 | 2006-03-01 | Rib X Pharmaceuticals Inc | bifunctional heterocyclic compounds and methods of production and use thereof |
US7317102B2 (en) | 2003-04-01 | 2008-01-08 | Theravance, Inc. | Diarylmethyl and related compounds |
US7253153B2 (en) | 2003-04-09 | 2007-08-07 | Wyeth | Derivatives of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)alkyl] phosphonic acid and methods of use thereof |
JP4467910B2 (en) * | 2003-05-16 | 2010-05-26 | 東芝モバイルディスプレイ株式会社 | Active matrix display device |
TW200510277A (en) * | 2003-05-27 | 2005-03-16 | Theravance Inc | Crystalline form of β2-adrenergic receptor agonist |
WO2004106333A1 (en) * | 2003-05-28 | 2004-12-09 | Theravance, Inc. | Azabicycloalkane compounds as muscarinic receptor antagonists |
TW200526547A (en) * | 2003-09-22 | 2005-08-16 | Theravance Inc | Amino-substituted ethylamino β2 adrenergic receptor agonists |
TW200514775A (en) | 2003-10-22 | 2005-05-01 | Wyeth Corp | Methods for the preparation of {2-[(8,9)-dioxo-2,6-diaza-bicyclo[5.2.0]-non-1(7)-en-2-yl]ethyl} phosphonic acid and esters thereof |
US20070149463A1 (en) * | 2003-10-30 | 2007-06-28 | Oyelere Adegboyega K | Bifunctional macrolide heterocyclic compounds and methods of making and using the same |
EP1699808A1 (en) * | 2003-11-18 | 2006-09-13 | Rib-X Pharmaceuticals, Inc. | Bifunctional macrolide heterocyclic compounds and methods of making and using the same |
TW200531692A (en) * | 2004-01-12 | 2005-10-01 | Theravance Inc | Aryl aniline derivatives as β2 adrenergic receptor agonists |
GB0401334D0 (en) | 2004-01-21 | 2004-02-25 | Novartis Ag | Organic compounds |
DE602005001929T2 (en) | 2004-01-22 | 2007-12-06 | Pfizer Inc. | SULFONAMIDE DERIVATIVES FOR THE TREATMENT OF DISEASES |
ES2293530T3 (en) | 2004-01-22 | 2008-03-16 | Pfizer, Inc. | DERIVATIVES OF SULFONAMIDS FOR THE TREATMENT OF DISEASES. |
US7320990B2 (en) | 2004-02-13 | 2008-01-22 | Theravance, Inc. | Crystalline form of a biphenyl compound |
JP5383037B2 (en) * | 2004-02-27 | 2014-01-08 | リブ−エックス ファーマシューティカルズ,インコーポレイテッド | Macrocyclic compounds and methods of making and using them |
GB0411056D0 (en) | 2004-05-18 | 2004-06-23 | Novartis Ag | Organic compounds |
EP1751086A2 (en) * | 2004-06-03 | 2007-02-14 | Theravance, Inc. | DIAMINE ß2 ADRENERGIC RECEPTOR AGONISTS |
JP2008501797A (en) * | 2004-06-08 | 2008-01-24 | マリンクロッド・インコーポレイテッド | Extraction of alkaloids from opium |
EP1758891A2 (en) | 2004-06-15 | 2007-03-07 | Pfizer Japan Inc. | Benzimidazolone carboxylic acid derivatives |
US7737163B2 (en) | 2004-06-15 | 2010-06-15 | Pfizer Inc. | Benzimidazolone carboxylic acid derivatives |
US7781478B2 (en) | 2004-07-14 | 2010-08-24 | Ptc Therapeutics, Inc. | Methods for treating hepatitis C |
JP2008507532A (en) * | 2004-07-21 | 2008-03-13 | セラヴァンス, インコーポレーテッド | Diaryl ether β2 adrenergic receptor agonist |
EP1778626A1 (en) * | 2004-08-16 | 2007-05-02 | Theravance, Inc. | Compounds having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity |
TWI374883B (en) | 2004-08-16 | 2012-10-21 | Theravance Inc | Crystalline form of a biphenyl compound |
WO2006023460A2 (en) * | 2004-08-16 | 2006-03-02 | Theravance, Inc. | COMPOUNDS HAVING β2 ADRENERGIC RECEPTOR AGONIST AND MUSCARINIC RECEPTOR ANTAGONIST ACTIVITY |
JP2008512470A (en) * | 2004-09-10 | 2008-04-24 | セラヴァンス, インコーポレーテッド | Amidine-substituted arylaniline compounds |
GT200500281A (en) | 2004-10-22 | 2006-04-24 | Novartis Ag | ORGANIC COMPOUNDS. |
GB0424284D0 (en) | 2004-11-02 | 2004-12-01 | Novartis Ag | Organic compounds |
GB0426164D0 (en) | 2004-11-29 | 2004-12-29 | Novartis Ag | Organic compounds |
JP4130220B1 (en) | 2005-02-22 | 2008-08-06 | ファイザー株式会社 | Oxindole derivatives as 5HT4 receptor agonists |
EP2484382A1 (en) | 2005-03-30 | 2012-08-08 | Schering Corporation | Medicament comprising a phosphodiesterase IV inhibitor in an inhalable form |
GB0507577D0 (en) | 2005-04-14 | 2005-05-18 | Novartis Ag | Organic compounds |
EP1877093A2 (en) * | 2005-04-15 | 2008-01-16 | Board of Trustees of Michigan State University | Ascorbate binding peptides |
ES2265276B1 (en) | 2005-05-20 | 2008-02-01 | Laboratorios Almirall S.A. | DERIVATIVES OF 4- (2-AMINO-1-HYDROXYETHYL) Phenol as agonists of the BETA2 ADRENERGIC RECEIVER. |
US8429052B2 (en) * | 2005-07-19 | 2013-04-23 | Lincoln National Life Insurance Company | Method and system for providing employer-sponsored retirement plan |
NZ566068A (en) | 2005-08-08 | 2011-03-31 | Argenta Discovery Ltd | Bicyclo[2.2.1]hept-7-ylamine derivatives and their uses |
GB0516313D0 (en) | 2005-08-08 | 2005-09-14 | Argenta Discovery Ltd | Azole derivatives and their uses |
TW200738658A (en) | 2005-08-09 | 2007-10-16 | Astrazeneca Ab | Novel compounds |
US7855196B2 (en) | 2005-08-22 | 2010-12-21 | Pierre Mainville | Composition comprising a benzodiazepine agonist and a benzodiazepine antagonist |
KR20080049113A (en) | 2005-10-21 | 2008-06-03 | 노파르티스 아게 | Human antibodies against il-13 and therapeutic uses |
EP1954285A2 (en) * | 2005-10-25 | 2008-08-13 | Alvine Pharmaceuticals, Inc. | Transglutaminase inhibitors and methods of use thereof |
US20070112017A1 (en) * | 2005-10-31 | 2007-05-17 | Braincells, Inc. | Gaba receptor mediated modulation of neurogenesis |
GB0601951D0 (en) | 2006-01-31 | 2006-03-15 | Novartis Ag | Organic compounds |
GB0602778D0 (en) * | 2006-02-10 | 2006-03-22 | Glaxo Group Ltd | Novel compound |
KR100643519B1 (en) * | 2006-02-13 | 2006-11-13 | 주식회사 시드컴 | Remote control device for camera cellular phone and control method |
TW200745163A (en) * | 2006-02-17 | 2007-12-16 | Syntonix Pharmaceuticals Inc | Peptides that block the binding of IgG to FcRn |
JP2009528365A (en) * | 2006-02-28 | 2009-08-06 | アムゲン インコーポレイティッド | Cinnoline and quinazoline derivatives as phosphodiesterase 10 inhibitors |
TW200745084A (en) * | 2006-03-08 | 2007-12-16 | Astrazeneca Ab | Novel compounds |
TW200745067A (en) | 2006-03-14 | 2007-12-16 | Astrazeneca Ab | Novel compounds |
SI2013211T1 (en) | 2006-04-21 | 2012-07-31 | Novartis Ag | Purine derivatives for use as adenosin a2a receptor agonists |
TW200811105A (en) | 2006-04-25 | 2008-03-01 | Theravance Inc | Dialkylphenyl compounds having beta2 adrenergic receptor agonist and muscarinic receptor antagonist activity |
WO2007127809A2 (en) * | 2006-04-27 | 2007-11-08 | Kuldeep Razden | P8 modulation to control hypertension |
WO2008100288A2 (en) * | 2006-09-15 | 2008-08-21 | The Burnham Institute | High affinity ephb receptor binding compounds and methods of use thereof |
ES2302447B1 (en) * | 2006-10-20 | 2009-06-12 | Laboratorios Almirall S.A. | DERIVATIVES OF 4- (2-AMINO-1-HYDROXYETHYL) Phenol as agonists of the BETA2 ADRENERGIC RECEIVER. |
TW200833670A (en) | 2006-12-20 | 2008-08-16 | Astrazeneca Ab | Novel compounds 569 |
DK2104535T3 (en) | 2007-01-10 | 2011-04-04 | Irm Llc | Compounds and Compositions as Channel Activating Protease Inhibitors |
BRPI0807972A2 (en) | 2007-01-24 | 2014-06-10 | Glaxo Group Ltd | PHARMACEUTICAL COMPOSITIONS UNDERSTANDING 3,5-DIAMINO-6- (2,3-DICHLOPHENYL) -L, 2,4-TRIAZINE OR R (-) - 2,4-DIAMINO-5- (2,3-DICHLOROPHENYL) -6- FLUOROMETILPIRIM IDINA AND ONE NK1 |
GB0702458D0 (en) | 2007-02-08 | 2007-03-21 | Astrazeneca Ab | Salts 668 |
EA200901082A1 (en) | 2007-02-09 | 2010-02-26 | Айрм Ллк | COMPOUNDS AND COMPOSITIONS AS PROTEASE INHIBITORS ACTIVATING CHANNELS |
ES2306595B1 (en) | 2007-02-09 | 2009-09-11 | Laboratorios Almirall S.A. | NAPADISYLATE SALT OF 5- (2 - ((6- (2,2-DIFLUORO-2-PHENYLETOXI) HEXIL) AMINO) -1-HYDROXYETHYL) -8-HYDROXYCHINOLIN-2 (1H) -ONE AS ADRENERGIC RECEIVER AGONIST BETA2 . |
US11241420B2 (en) | 2007-04-11 | 2022-02-08 | Omeros Corporation | Compositions and methods for prophylaxis and treatment of addictions |
AU2008240158B2 (en) | 2007-04-11 | 2014-07-10 | Omeros Corporation | Compositions and methods for prophylaxis and treatment of addictions |
US20160331729A9 (en) | 2007-04-11 | 2016-11-17 | Omeros Corporation | Compositions and methods for prophylaxis and treatment of addictions |
JP5244904B2 (en) | 2007-05-07 | 2013-07-24 | ノバルティス アーゲー | Organic compounds |
US8906844B2 (en) * | 2007-08-09 | 2014-12-09 | Biogen Idec Hemophilia Inc. | Immunomodulatory peptides |
US8119629B2 (en) | 2007-10-03 | 2012-02-21 | Bristol-Meyers Squibb Company | Carboxamide GABAA α2 modulators |
ES2320961B1 (en) * | 2007-11-28 | 2010-03-17 | Laboratorios Almirall, S.A. | DERIVATIVES OF 4- (2-AMINO-1-HYDROXYETHYL) PHENOL AS BETA2 ADRENERGIC RECEIVER AGONISTS. |
AR069637A1 (en) | 2007-12-10 | 2010-02-10 | Novartis Ag | PIRAZINE DERIVATIVES |
US8217064B2 (en) | 2007-12-20 | 2012-07-10 | Envivo Pharmaceuticals, Inc. | Tetrasubstituted benzenes |
JP5584138B2 (en) | 2008-01-11 | 2014-09-03 | ノバルティス アーゲー | Pyrimidines as kinase inhibitors |
EP2096105A1 (en) * | 2008-02-28 | 2009-09-02 | Laboratorios Almirall, S.A. | Derivatives of 4-(2-amino-1-hydroxyethyl)phenol as agonists of the b2 adrenergic receptor |
WO2009140039A2 (en) * | 2008-04-23 | 2009-11-19 | The Arizona Board Of Regents Acting For And On Behalf Of Arizona State University | Synthetic antibodies |
JP2011522860A (en) | 2008-06-10 | 2011-08-04 | ノバルティス アーゲー | Pyrazine derivatives as epithelial sodium channel blockers |
CN102124003A (en) | 2008-06-18 | 2011-07-13 | 阿斯利康(瑞典)有限公司 | Benzoxazinone derivatives acting as beta2-adrenoreceptor agonist for the treatment of respiratory disorders |
US20100048488A1 (en) * | 2008-08-01 | 2010-02-25 | Syntonix Pharmaceuticals, Inc. | Immunomodulatory peptides |
US8236786B2 (en) | 2008-08-07 | 2012-08-07 | Pulmagen Therapeutics (Inflammation) Limited | Respiratory disease treatment |
EP2346526A2 (en) | 2008-09-22 | 2011-07-27 | Massachusetts Institute of Technology | Compositions of and methods of using ligand dimers |
EP4212541A1 (en) | 2008-12-16 | 2023-07-19 | Genzyme Corporation | Oligosaccharide-protein conjugates and their intermediates |
UY32297A (en) | 2008-12-22 | 2010-05-31 | Almirall Sa | MESILATE SALT OF 5- (2 - {[6- (2,2-DIFLUORO-2-PHENYLITOXI) HEXIL] AMINO} -1-HYDROXYETHYL) -8-HYDROXYCHINOLIN-2 (1H) -ONA AS A RECEIVER AGONIST B (BETA ) 2 ACRENERGIC |
CA2748340C (en) | 2008-12-29 | 2017-01-24 | Trevena, Inc. | .beta.-arrestin effectors and compositions and methods of use thereof |
SI2379507T1 (en) | 2008-12-30 | 2014-02-28 | Pulmagen Therapeutics (Inflammation) Limited | Sulfonamide compounds for the treatment of respiratory disorders |
EP2228368A1 (en) | 2009-03-12 | 2010-09-15 | Almirall, S.A. | Process for manufacturing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy) hexyl]amino}-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one |
ES2635358T3 (en) | 2009-04-23 | 2017-10-03 | Theravance Respiratory Company, Llc | Diamine compounds that have muscarinic receptor antagonist activity and beta2 adrenergic receptor agonist |
WO2010150014A1 (en) | 2009-06-24 | 2010-12-29 | Pulmagen Therapeutics (Inflammation) Limited | 5r- 5 -deuterated glitazones for respiratory disease treatment |
EP2813227A1 (en) | 2009-10-22 | 2014-12-17 | Vertex Pharmaceuticals Incorporated | Compositions for treatment of cystic fibrosis and other chronic diseases |
GB0918924D0 (en) | 2009-10-28 | 2009-12-16 | Vantia Ltd | Azaindole derivatives |
GB0918923D0 (en) | 2009-10-28 | 2009-12-16 | Vantia Ltd | Aminothiazole derivatives |
GB0918922D0 (en) | 2009-10-28 | 2009-12-16 | Vantia Ltd | Aminopyridine derivatives |
WO2011098746A1 (en) | 2010-02-09 | 2011-08-18 | Pulmagen Therapeutics (Inflammation) Limited | Crystalline acid addition salts of ( 5r) -enanti0mer of pioglitazone |
GB201002224D0 (en) | 2010-02-10 | 2010-03-31 | Argenta Therapeutics Ltd | Respiratory disease treatment |
GB201002243D0 (en) | 2010-02-10 | 2010-03-31 | Argenta Therapeutics Ltd | Respiratory disease treatment |
US8247436B2 (en) | 2010-03-19 | 2012-08-21 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF |
EP2555788B1 (en) | 2010-03-24 | 2017-10-11 | Massachusetts Institute of Technology | NEUREGULIN DIMER FOR AN ErbB/HER RECEPTOR FOR USE IN REDUCING CARDIOTOXICITY. |
WO2012032546A2 (en) * | 2010-09-08 | 2012-03-15 | Cadila Healthcare Limited | Process for the preparation of salmeterol and its intermediates |
WO2012034095A1 (en) | 2010-09-09 | 2012-03-15 | Irm Llc | Compounds and compositions as trk inhibitors |
UY33597A (en) | 2010-09-09 | 2012-04-30 | Irm Llc | COMPOUNDS AND COMPOSITIONS AS INHIBITORS OF THE TRK |
US8372845B2 (en) | 2010-09-17 | 2013-02-12 | Novartis Ag | Pyrazine derivatives as enac blockers |
US9173887B2 (en) | 2010-12-22 | 2015-11-03 | Abbvie Inc. | Hepatitis C inhibitors and uses thereof |
WO2012116217A1 (en) | 2011-02-25 | 2012-08-30 | Irm Llc | Compounds and compositions as trk inhibitors |
UY34305A (en) | 2011-09-01 | 2013-04-30 | Novartis Ag | DERIVATIVES OF BICYCLIC HETEROCICLES FOR THE TREATMENT OF PULMONARY ARTERIAL HYPERTENSION |
CN103946221B (en) | 2011-09-16 | 2016-08-03 | 诺华股份有限公司 | For treating the heterocyclic compound of cystic fibrosis |
WO2013038381A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine/pyrazine amide derivatives |
US9056867B2 (en) | 2011-09-16 | 2015-06-16 | Novartis Ag | N-substituted heterocyclyl carboxamides |
WO2013038378A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
WO2013038373A1 (en) | 2011-09-16 | 2013-03-21 | Novartis Ag | Pyridine amide derivatives |
EP2578570A1 (en) | 2011-10-07 | 2013-04-10 | Almirall, S.A. | Novel process for preparing 5-(2-{[6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1(r)-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one via novel intermediates of synthesis. |
MX2014009233A (en) | 2012-01-31 | 2015-05-15 | Trevena Inc | Ã-arrestin effectors and compositions and methods of use thereof. |
US8809340B2 (en) | 2012-03-19 | 2014-08-19 | Novartis Ag | Crystalline form |
EP2641900A1 (en) | 2012-03-20 | 2013-09-25 | Almirall, S.A. | Novel polymorphic Crystal forms of 5-(2-{[6-(2,2-difluoro-2-phenylethoxy) hexyl]amino}-1-(R)-hydroxyethyl)-8-hydroxyquinolin-2(1h)-one, heminapadisylate as agonist of the ß2 adrenergic receptor. |
ES2656292T3 (en) | 2012-05-01 | 2018-02-26 | Translatum Medicus Inc. | Methods of treatment and diagnosis of eye diseases that cause blindness |
EP2888277A4 (en) | 2012-08-21 | 2016-05-18 | Ortho Clinical Diagnostics Inc | Antibodies to paliperidone and use thereof |
PL2888284T3 (en) | 2012-08-21 | 2023-02-27 | Janssen Pharmaceutica Nv | Antibodies to risperidone haptens and use thereof |
PT2887952T (en) | 2012-08-21 | 2019-08-30 | Janssen Pharmaceutica Nv | Antibodies to olanzapine haptens and use thereof |
CN106928369B (en) | 2012-08-21 | 2021-04-02 | 奥索临床诊断有限公司 | Antibodies to quetiapine and uses thereof |
EP2888590B1 (en) | 2012-08-21 | 2020-07-08 | Janssen Pharmaceutica NV | Antibodies to olanzapine and use thereof |
ES2664952T3 (en) | 2012-08-21 | 2018-04-24 | Janssen Pharmaceutica Nv | Antibodies for quetiapine haptens and their use |
CN104736566A (en) | 2012-08-21 | 2015-06-24 | 奥索临床诊断有限公司 | Antibodies to paliperidone haptens and use thereof |
PL3462173T3 (en) | 2012-08-21 | 2021-08-16 | Janssen Pharmaceutica Nv | Antibodies to risperidone and use thereof |
JP6270845B2 (en) | 2012-08-21 | 2018-01-31 | ヤンセン ファーマシューティカ エヌ.ベー. | Antibodies against aripiprazole and uses thereof |
CN104736567B (en) | 2012-08-21 | 2019-09-03 | 詹森药业有限公司 | The antibody and application thereof of Aripiprazole haptens |
EP2724723A1 (en) * | 2012-10-25 | 2014-04-30 | Universitätsklinikum Hamburg-Eppendorf | Tegaserod for use in the treatment of nerve injuries |
US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
EP3027199B1 (en) | 2013-08-01 | 2019-06-26 | Dignify Therapeutics, LLC | Compositions and methods for inducing urinary voiding and defecation |
EP3046920B1 (en) | 2013-09-20 | 2021-08-04 | BioMarin Pharmaceutical Inc. | Glucosylceramide synthase inhibitors for the treatment of diseases |
RU2693484C1 (en) | 2013-11-22 | 2019-07-03 | СиЭль БАЙОСАЕНСИЗ ЭлЭлСи | Gastrin antagonists for treating and preventing osteoporosis |
US9518086B2 (en) | 2014-02-07 | 2016-12-13 | Trevena, Inc. | Crystalline and amorphous forms of a β-arrestin effector |
PT3134396T (en) | 2014-04-24 | 2019-12-16 | Novartis Ag | Amino pyridine derivatives as phosphatidylinositol 3-kinase inhibitors |
US10004732B2 (en) | 2014-04-24 | 2018-06-26 | Novartis Ag | Amino pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
AU2014391610B2 (en) | 2014-04-24 | 2018-01-25 | Novartis Ag | Pyrazine derivatives as phosphatidylinositol 3-kinase inhibitors |
AU2015264367A1 (en) | 2014-05-19 | 2016-12-15 | Trevena, Inc. | Synthesis of Beta-Arrestin Effectors |
CN106336406B (en) * | 2015-07-10 | 2020-01-03 | 四川海思科制药有限公司 | Having beta2Octahydropentalene derivatives with receptor agonistic and M receptor antagonistic activity and their medical use |
EP3390455A1 (en) | 2015-12-17 | 2018-10-24 | Janssen Pharmaceutica NV | Antibodies to quetiapine and use thereof |
EP3390449A1 (en) | 2015-12-17 | 2018-10-24 | Janssen Pharmaceutica N.V. | Antibodies to risperidone and use thereof |
US11174250B2 (en) | 2016-03-01 | 2021-11-16 | Propellon Therapeutics Inc. | Substituted carboxamides as inhibitors of WDR5 protein-protein binding |
EP3423451B1 (en) | 2016-03-01 | 2022-08-17 | Propellon Therapeutics Inc. | Inhibitors of wdr5 protein-protein binding |
CN108508117A (en) * | 2017-02-24 | 2018-09-07 | 扬子江药业集团江苏紫龙药业有限公司 | The related substance control method of Rupatadine fumarate piece |
WO2019238962A1 (en) | 2018-06-14 | 2019-12-19 | University College Cork - National University Of Ireland, Cork | Peptide for disease treatment |
BR112021024668A2 (en) | 2019-06-10 | 2022-05-31 | Novartis Ag | Pyridine and pyrazine derivative for the treatment of CF, COPD and bronchiectasis |
CN110169969B (en) * | 2019-06-28 | 2022-05-27 | 南京医科大学 | Application of MK571 in preparation of medicine for preventing and treating heart diseases |
PE20220346A1 (en) | 2019-08-28 | 2022-03-14 | Novartis Ag | 1,3-HETEROARYL SUBSTITUTED DERIVATIVES AND THEIR USE IN THE TREATMENT OF DISEASES |
US20210110890A1 (en) * | 2019-10-11 | 2021-04-15 | Arium BioLabs LLC | Systems and methods of designing chemical libraries for allosteric modulator discovery |
TW202140550A (en) | 2020-01-29 | 2021-11-01 | 瑞士商諾華公司 | Methods of treating an inflammatory or obstructive airway disease using anti-tslp antibody |
CN112125924B (en) * | 2020-09-15 | 2021-09-24 | 吉林大学 | Spiral oligomer, bionic ion channel, preparation method and application |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4587046A (en) * | 1982-05-18 | 1986-05-06 | The Regents Of The University Of California | Drug-carrier conjugates |
US4695575A (en) * | 1984-11-13 | 1987-09-22 | Janssen Pharmaceutica, N.V. | 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines |
US5212187A (en) * | 1991-07-22 | 1993-05-18 | Zyma Sa | Pyridyl alkylamine compounds which are useful against histamine h1 and h2 receptors |
US5656739A (en) * | 1993-12-17 | 1997-08-12 | Cubicciotti; Roger S. | Nucleotide-directed assembly of bimolecular and multimolecular drugs and devices |
WO1997035195A1 (en) * | 1996-03-19 | 1997-09-25 | The Salk Institute For Biological Studies | In vitro methods for identifying modulators of members of the steroid/thyroid superfamily of receptors |
US5683998A (en) * | 1991-04-23 | 1997-11-04 | Toray Industries, Inc. | Tricyclic triazolo derivatives, processes for producing the same and the uses of the same |
Family Cites Families (83)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE1158082B (en) | 1960-12-17 | 1963-11-28 | Gruenenthal Chemie | Process for the preparation of alkylenediamine derivatives and their salts |
DE1250450B (en) | 1962-03-31 | 1967-09-21 | Deutsche Gold- und Silber-Scheideanstalt vormals Roessler, Frankfurt/M | Process for the production of amino alcohols and their acid addition salts and quaternary ammonium compounds |
NL130078C (en) | 1963-06-11 | |||
DE1215729B (en) | 1963-06-14 | 1966-05-05 | Lentia Gmbh | Process for the production of new bis-alkanolamine derivatives and their salts |
DE1802945C3 (en) | 1968-10-14 | 1974-03-07 | Lentia Gmbh, Chem. U. Pharm. Erzeugnisse - Industriebedarf, 8000 Muenchen | L-O-N ^ bis-square bracket on 2- (3 ', 4'-dihydroxyphenyl) -2-hydroxyäthyl square bracket on -hexamethylenediamine, its acid addition salts and process for the preparation of these compounds |
AT294046B (en) | 1969-07-08 | 1971-11-10 | Chemie Linz Ag | Process for the preparation of N, N'-bis [2- (3 ', 4'-dihydroxyphenyl) -2-hydroxyethyl] -hexamethylenediamine, its optically active forms and the salts thereof |
DE1935757B1 (en) | 1969-07-14 | 1970-11-12 | Lentia Gmbh | Process for the preparation of the N, N'-bis- [2- (3 ', 4'-dihydroxyphenyl) -2-hydroxyaethyl] -hexamethylene diamine, its optically active forms and their salts |
DE1936419C3 (en) | 1969-07-17 | 1975-07-10 | Lentia Gmbh, Chem. U. Pharm. Erzeugnisse - Industriebedarf, 8000 Muenchen | Process for the preparation of bis-alkanolamine derivatives and their salts |
AT310146B (en) | 1971-04-26 | 1973-09-25 | Boehringer Sohn Ingelheim | Process for the production of new N, N'-bis- (β-hydroxyarylethyl) -diaminoalkanes and their acid addition salts |
ZA723611B (en) | 1971-06-01 | 1973-03-28 | Smith Kline French Lab | N,n'-bis(2-(3-substituted-4-hydroxyphenyl)-ethyl or-2-hydroxyethyl)-polymethylene-diamines |
CH545764A (en) | 1971-07-27 | 1974-02-15 | ||
BE786713A (en) | 1971-07-27 | 1973-01-25 | Sandoz Sa | NEW AMINO-ALCOHOLS, THEIR PREPARATION AND THEIR APPLICATION AS MEDICINAL PRODUCTS |
BE794414A (en) | 1972-01-25 | 1973-07-23 | Sandoz Sa | NEW AMINO-ALCOHOLS, THEIR PREPARATION AND THEIR APPLICATION AS A MEDICINAL PRODUCT |
DE2366625C2 (en) | 1972-02-05 | 1988-06-09 | Yamanouchi Pharmaceutical Co., Ltd., Tokio/Tokyo, Jp | |
AT322534B (en) | 1972-03-16 | 1975-05-26 | Thomae Gmbh Dr K | PROCESS FOR THE PREPARATION OF NEW OPTICALLY ACTIVE 1- (4'-AMINO-3'-HALOGENPHENYL) -2-AMINO ETHANOLS AND THEIR ACID ADDITION SALTS |
DE2303304A1 (en) | 1973-01-24 | 1973-08-02 | Sandoz Ag | Bis (hydroxy phenyl ethanolamine or propanolamine) cpds - - bronchodilators |
DE2312234A1 (en) | 1973-03-12 | 1974-09-19 | Boehringer Sohn Ingelheim | Hexamethylene-diamine derivs from 1,6-hexane-diamine - esp. N,N'-bis (2-(3,4-dihydroxyphenyl)-2-hydroxyethyl)- deriv |
US4228237A (en) * | 1978-09-21 | 1980-10-14 | Calbiochem-Behring Corp. | Methods for the detection and determination of ligands |
US4312870A (en) * | 1979-06-21 | 1982-01-26 | Ciba-Geigy Corporation | Pyrazoloquinolines |
US4304721A (en) | 1979-09-06 | 1981-12-08 | Hoffmann-La Roche Inc. | Adrenergic blocking agents |
US4888356A (en) * | 1983-08-08 | 1989-12-19 | G. D. Searle And Company | Use of substituted dihydrobenzopyrans for allergy and inflammation |
US4665203A (en) * | 1983-08-08 | 1987-05-12 | G. D. Searle & Co. | Substituted dihydrobenzopyrans useful as leukotriene D4 inhibitors |
CA1337429C (en) | 1983-12-05 | 1995-10-24 | Guy Rosalia Eugene Van Lommen | Derivatives of 2,2'-iminobisethanol |
FR2562539B1 (en) * | 1984-04-06 | 1987-04-17 | Chauvin Blache Lab | NOVEL VINYL-4 BENZOIC ACID DERIVATIVES, PREPARATION METHOD THEREOF AND THERAPEUTIC APPLICATIONS THEREOF AND AS LIGANDS |
US4910152A (en) * | 1985-01-31 | 1990-03-20 | Meyers Vera K | Method for binding opioid receptors |
GB8507942D0 (en) | 1985-03-27 | 1985-05-01 | Beecham Group Plc | Compounds |
DK9987A (en) | 1986-01-11 | 1987-07-12 | Beecham Group Plc | ETHANOLAMINE DERIVATIVES |
US5428163A (en) * | 1986-12-31 | 1995-06-27 | Mills; Randell L. | Prodrugs for selective drug delivery |
NL8800823A (en) * | 1987-04-10 | 1988-11-01 | Sandoz Ag | METHOD FOR USING DOPAMINE RECEPTOR AGONISTS AND PHARMACEUTICAL PREPARATIONS CONTAINING THESE AGONISTS |
GB8928208D0 (en) * | 1989-12-13 | 1990-02-14 | Glaxo Group Ltd | Medicaments |
EP0510132B1 (en) | 1990-09-28 | 1997-05-14 | Neorx Corporation | Polymeric carriers for release of covalently linked agents |
US5744602A (en) * | 1990-10-31 | 1998-04-28 | Neurogen Corporation | Certain imidazoquinoxalines; a new class of GABA brain receptor ligands |
US5416191A (en) * | 1991-04-01 | 1995-05-16 | Cortech, Inc. | Bradykinin antagonists |
US5552398A (en) * | 1991-09-12 | 1996-09-03 | Smithkline Beecham P.L.C. | Azabicyclic compounds as 5-HT4 receptor antagonists |
WO1993006121A1 (en) | 1991-09-18 | 1993-04-01 | Affymax Technologies N.V. | Method of synthesizing diverse collections of oligomers |
DE69334206D1 (en) * | 1992-05-26 | 2008-04-03 | Purdue Research Foundation | SUBSTITUTED HEXAHYDROBENZO (A) PHENANTHRIDINE |
US5434174A (en) * | 1992-07-17 | 1995-07-18 | Eli Lilly And Company | Isoxazole derivatives for the treatment of irritable bowel syndrome |
US5783701A (en) * | 1992-09-08 | 1998-07-21 | Vertex Pharmaceuticals, Incorporated | Sulfonamide inhibitors of aspartyl protease |
JPH08502283A (en) * | 1992-10-16 | 1996-03-12 | スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー | 5-HT 4) Fused ring system N-alkylpiperidinyl-4-methylcarboxylic acid ester / amide for receptor antagonist |
PT675886E (en) * | 1992-12-10 | 2000-12-29 | Pfizer | NON-AROMATIC HETEROCYCLES WITH AMINYMETHYLENE SUBSTITUENTS AND THEIR USE AS ANTAGONISTS OF THE SUBSTANCE P |
GB9305718D0 (en) * | 1993-03-19 | 1993-05-05 | Glaxo Group Ltd | Medicaments |
US5334598A (en) * | 1993-03-19 | 1994-08-02 | Merck & Co., Inc. | Six-membered ring fused imidazoles substituted with phenoxyphenylacetic acid derivatives |
FR2712591B1 (en) * | 1993-11-19 | 1996-02-09 | Pf Medicament | New arylpiperazines derived from indole, their preparation and their therapeutic use. |
US5538965A (en) * | 1993-12-23 | 1996-07-23 | Allelix Biopharmaceuticals Inc. | Dopamine receptor ligands |
FR2715565B1 (en) * | 1994-01-31 | 1996-03-15 | Oreal | Stabilized cosmetic or dermatological composition containing several precursors of the same active ingredient to maximize its release, its use. |
US5688997A (en) * | 1994-05-06 | 1997-11-18 | Pharmacopeia, Inc. | Process for preparing intermediates for a combinatorial dihydrobenzopyran library |
US5463564A (en) | 1994-09-16 | 1995-10-31 | 3-Dimensional Pharmaceuticals, Inc. | System and method of automatically generating chemical compounds with desired properties |
KR100517210B1 (en) * | 1994-12-12 | 2006-06-07 | 오메로스 코포레이션 | Infusion solution for pain, inflammation and spasm |
US5837815A (en) * | 1994-12-15 | 1998-11-17 | Sugen, Inc. | PYK2 related polypeptide products |
US5902726A (en) * | 1994-12-23 | 1999-05-11 | Glaxo Wellcome Inc. | Activators of the nuclear orphan receptor peroxisome proliferator-activated receptor gamma |
HU226208B1 (en) | 1994-12-28 | 2008-06-30 | Janssen Pharmaceutica Nv | Use of nebivolol for producing anti-atherogenic pharmaceuticals |
GB9505692D0 (en) * | 1995-03-21 | 1995-05-10 | Glaxo Group Ltd | Chemical compounds |
US5876727A (en) * | 1995-03-31 | 1999-03-02 | Immulogic Pharmaceutical Corporation | Hapten-carrier conjugates for use in drug-abuse therapy and methods for preparation of same |
US5719156A (en) * | 1995-05-02 | 1998-02-17 | Schering Corporation | Piperazino derivatives as neurokinin antagonists |
IL118279A (en) | 1995-06-07 | 2006-10-05 | Abbott Lab | 3 - pyridyloxy (or thio) alkyl heterocyclic compounds, pharmaceutical compositions containing them and their uses in the preparation of medicaments for controlling chemical synaptic transmission |
WO1997000244A1 (en) * | 1995-06-19 | 1997-01-03 | Eli Lilly And Company | Process for parallel synthesis of a non-peptide library |
GB9517559D0 (en) * | 1995-08-26 | 1995-10-25 | Smithkline Beecham Plc | Novel compounds |
AU7432496A (en) * | 1995-10-13 | 1998-05-11 | Regents Of The University Of Minnesota | Consolidated ligands with increased affinities and methods of use thereof |
US5891643A (en) | 1995-11-14 | 1999-04-06 | Abbott Laboratories | Use of nuclear magnetic resonance to design ligands to target biomolecules |
US5846839A (en) | 1995-12-22 | 1998-12-08 | Glaxo Group Limited | Methods for hard-tagging an encoded synthetic library |
US5847008A (en) * | 1996-02-02 | 1998-12-08 | Merck & Co., Inc. | Method of treating diabetes and related disease states |
US5859051A (en) * | 1996-02-02 | 1999-01-12 | Merck & Co., Inc. | Antidiabetic agents |
ES2241036T3 (en) * | 1996-02-02 | 2005-10-16 | MERCK & CO., INC. | PROCESS OF TREATMENT OF DIABETES AND ASSOCIATED PATHOLOGICAL STATES. |
AU1856997A (en) * | 1996-02-02 | 1997-08-22 | Merck & Co., Inc. | Method for raising hdl cholesterol levels |
US5792766A (en) * | 1996-03-13 | 1998-08-11 | Neurogen Corporation | Imidazo 1,5-c! quinazolines; a new class of GABA brain receptor ligands |
US5965532A (en) | 1996-06-28 | 1999-10-12 | Trustees Of Tufts College | Multivalent compounds for crosslinking receptors and uses thereof |
WO1998002187A1 (en) * | 1996-07-11 | 1998-01-22 | Farmarc Nederland B.V. | Pharmaceutical composition containing acid addition salt of basic drug |
US6500934B1 (en) | 1996-07-24 | 2002-12-31 | Michael Rush Lerner | Bivalent agonists for G-protein coupled receptors |
DE19633560A1 (en) * | 1996-08-21 | 1998-02-26 | Basf Ag | Chromanyl-ascorbic acid derivatives, their preparation and use |
US5877214A (en) * | 1996-09-12 | 1999-03-02 | Merck & Co., Inc. | Polyaryl-poly(ethylene glycol) supports for solution-phase combinatorial synthesis |
WO1998011436A1 (en) | 1996-09-13 | 1998-03-19 | Whitehead Institute For Biomedical Research | Non-specific affinity enhancement to identify combinatorial library members |
DE19642751A1 (en) * | 1996-10-16 | 1998-04-23 | Deutsches Krebsforsch | Saccharide library |
WO1998019162A1 (en) * | 1996-10-31 | 1998-05-07 | Novalon Pharmaceutical Corporation | Identification of drugs using complementary combinatorial libraries |
ES2178015T3 (en) | 1996-11-11 | 2002-12-16 | Sepracor Inc | OPTICALLY PURE FORMOTEROL ISOMER PREPARATION PROCEDURE. |
JPH10152460A (en) | 1996-11-21 | 1998-06-09 | Kissei Pharmaceut Co Ltd | 2-amino-1-(4-hydroxy-2-methylphenyl)propanol derivative |
US5958703A (en) * | 1996-12-03 | 1999-09-28 | Glaxo Group Limited | Use of modified tethers in screening compound libraries |
DK0950057T3 (en) * | 1996-12-10 | 2003-03-10 | Abbott Lab | 3-pyridylene enantiomers and their use as analgesics |
ZA9711376B (en) * | 1996-12-20 | 1998-07-21 | Lundbeck & Co As H | Indole or dihydroindole derivatives |
US5830918A (en) * | 1997-01-15 | 1998-11-03 | Terrapin Technologies, Inc. | Nonpeptide insulin receptor agonists |
US5814647A (en) * | 1997-03-04 | 1998-09-29 | Board Of Regents, The University Of Texas System | Use of troglitazone and related compounds for the treatment of the climacteric symptoms |
US5876946A (en) * | 1997-06-03 | 1999-03-02 | Pharmacopeia, Inc. | High-throughput assay |
CA2240325A1 (en) | 1998-03-27 | 1998-11-14 | Synsorb Biotech, Inc. | Methods for screening compound libraries |
US6541669B1 (en) | 1998-06-08 | 2003-04-01 | Theravance, Inc. | β2-adrenergic receptor agonists |
-
1999
- 1999-06-02 US US09/323,943 patent/US6541669B1/en not_active Expired - Lifetime
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4587046A (en) * | 1982-05-18 | 1986-05-06 | The Regents Of The University Of California | Drug-carrier conjugates |
US4695575A (en) * | 1984-11-13 | 1987-09-22 | Janssen Pharmaceutica, N.V. | 4-[(bicycle heterocyclyl)-methyl and -hetero]-piperidines |
US5683998A (en) * | 1991-04-23 | 1997-11-04 | Toray Industries, Inc. | Tricyclic triazolo derivatives, processes for producing the same and the uses of the same |
US5212187A (en) * | 1991-07-22 | 1993-05-18 | Zyma Sa | Pyridyl alkylamine compounds which are useful against histamine h1 and h2 receptors |
US5656739A (en) * | 1993-12-17 | 1997-08-12 | Cubicciotti; Roger S. | Nucleotide-directed assembly of bimolecular and multimolecular drugs and devices |
WO1997035195A1 (en) * | 1996-03-19 | 1997-09-25 | The Salk Institute For Biological Studies | In vitro methods for identifying modulators of members of the steroid/thyroid superfamily of receptors |
Non-Patent Citations (2)
Title |
---|
LIPINSKI C A: "JOURNAL OF MEDICINAL CHEMISTRY BIOISOSTERIC DESIGN OF CONFORMATIONALLY RESTRICTED PYRIDYLTRIAZOLE HISTAMINE HGAMMA-RECEPTOR ANTAGONISTS", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 26, no. 01, 1 January 1983 (1983-01-01), US, pages 01 - 06, XP002923763, ISSN: 0022-2623, DOI: 10.1021/jm00355a001 * |
S.B.SHUKER ET AL.: "Discovering High-Affinity Ligands for Proteins: SAR by NMR", SCIENCE, AMERICAN ASSOCIATION FOR THE ADVANCEMENT OF SCIENCE, US, no. 274, 1 January 1996 (1996-01-01), US, pages 1531 - 1534, XP002074440, ISSN: 0036-8075, DOI: 10.1126/science.274.5292.1531 * |
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WO2008112257A1 (en) * | 2007-03-12 | 2008-09-18 | Nektar Therapeutics | Oligomer-antihistamine conjugates |
AU2008226791B2 (en) * | 2007-03-12 | 2014-01-16 | Nektar Therapeutics | Oligomer-antihistamine conjugates |
KR101561707B1 (en) | 2007-03-12 | 2015-10-19 | 넥타르 테라퓨틱스 | Oligomer-antihistamine conjugates |
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