1. Field of the Invention
This invention relates to antagonists of interleukin-4 signaling. In particular, this invention relates to certain triphenyl compounds that antagonize interleukin-4 signaling, to methods of making them, to pharmaceutical compositions containing them, and to their uses.
2. Description of the Related Art
Interleukin-4 (IL-4) is a pleiotropic cytokine that is produced primarily by T helper type 2 lymphocytes (TH2 cells). The most clinically significant activity of this cytokine is the stimulation of immunoglobin class switching of the immune system""s B-cells to IgE production. See P. Chomarat et al., xe2x80x9cAn update on interleukin-4 and its receptorxe2x80x9d, Eur. Cytokine Netw., 8(4), 333-344 (1997); R. A. Pauwels et al., xe2x80x9cCytokines and their receptors as therapeutic targets in asthmaxe2x80x9d, Clin. Exp. Allergy, 28(Suppl. 3), 1-5 (1998), and references discussed therein.
Ample evidence exists that antagonism of IL-4 can alleviate allergic responses. These include the correlation of allergy and asthma symptoms with IL-4 levels in both allergen immunotherapy and asthma patients, the reduction of spontaneous IgE production in lymphocytes following treatment with IL-4 antibodies, and the inability to induce asthma-associated eosinophilia in IL-4 gene knockout mice. Additional evidence exists correlating elevated levels of IL4 with osteoporosis, osteoarthritis, rheumatoid arthritis, and autoimmune and other inflammation related disorders. Antagonism of IL-4 might further prove useful for therapeutically desirable immunosuppression.
The attractiveness of developing a drug that antagonizes IL4 activity has not escaped the pharmaceutical industry. Immunex and Wyeth-Ayerst are developing a nebulized form of a soluble IL4 receptor for the treatment of moderate asthma. The drug, Nuvance, is now in Phase II clinical trials. Glaxo SmithKline is developing an IL-4 antibody that is currently in clinical trials for the treatment of asthma.
Small molecule IL-1 antagonists have been sought. See R. Sarabu, xe2x80x9cDesign and synthesis of small molecule interleukin-1 receptor antagonists based on a benzene template, Drug Design Discovery, 15, 191-198 (1998).
It would be desirable to develop a small-molecule IL-4 antagonist.
In a first aspect, this invention provides compounds of formula I and formula II: 
where:
Axe2x80x94B is selected from the group consisting of xe2x80x94CHRXxe2x80x94CHRXxe2x80x94, xe2x80x94CRYxe2x95x90CRYxe2x80x94, xe2x80x94CHRYxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHRYxe2x80x94, NR1xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NR1, xe2x80x94S(O)0-2xe2x80x94CHRXxe2x80x94, xe2x80x94CHRXxe2x80x94S(O)0-2xe2x80x94, xe2x80x94SO2xe2x80x94NR1xe2x80x94, xe2x80x94NR1xe2x80x94SO2xe2x80x94,xe2x80x94C(xe2x95x90O)xe2x80x94CHRXxe2x80x94, xe2x80x94CHRXxe2x80x94C(xe2x95x90O)xe2x80x94, and cycloalkylene;
each RX is independently selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, aminoalkyl, guanidinoalkyl, alkoxy, amino, alkylamino, dialkylamino, cycloamino, alkylcarbonylamino, guanidino, carboxy, alkoxycarbonyl, and tetrazole;
each RY is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxy, and alkoxycarbonyl;
each R1 is independently selected from the group consisting of hydrogen and lower alkyl;
R2 is selected from the group consisting of hydrogen, halo, and hydroxy;
R3 is selected from the group consisting of optionally fluorinated methoxy and optionally fluorinated ethoxy;
R4 is selected from the group consisting of hydrogen, hydroxy, amino, alkylamino, dialkylamino, and cycloamino;
R5 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, alkoxy, amino, alkylcarbonylamino, alkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino, carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloaminocarbonyl, and alkoxycarbonyl;
R6 is selected from the group consisting of hydrogen, halo, and hydroxy;
R8, R9, R11, R12, R14, R15, R17 and R18 are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, methoxy, and ethoxy;
R16 is selected from the group consisting of hydrogen, hydroxy, halo, haloalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, carboxy, alkoxycarbonyl, xe2x80x94SO2NR12, and xe2x80x94NR1SO2R1;
R19 is selected from the group consisting of hydrogen, hydroxy, halo, haloalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, carboxy, alkoxycarbonyl, xe2x80x94SO2NR12, and xe2x80x94NR1SO2R1;
and compounds of formula VI 
where
X is selected from xe2x80x94CHRXxe2x80x94and xe2x80x94CH2xe2x80x94CHRXxe2x80x94;
Axe2x80x94B is selected from the group consisting of xe2x80x94CHRXxe2x80x94CHRXxe2x80x94, xe2x80x94CRYxe2x95x90CRYxe2x80x94, xe2x80x94CHRYxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHRYxe2x80x94, xe2x80x94NR1xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94NR1, xe2x80x94S(O)0-2xe2x80x94CHRXxe2x80x94, xe2x80x94CHRXxe2x80x94S(O)0-2xe2x80x94, xe2x80x94SO2xe2x80x94NR1xe2x80x94, xe2x80x94NR1xe2x80x94SO2xe2x80x94, xe2x80x94C(xe2x95x90O)xe2x80x94CHRXxe2x80x94, xe2x80x94CHRXxe2x80x94C(xe2x95x90O), and cycloalkylene;
each RX is independently selected from the group consisting of hydrogen, hydroxy, alkyl, haloalkyl, aminoalkyl, guanidinoalkyl, alkoxy, amino, alkylamino, dialkylamino, cycloamino, alkylcarbonylamino, guanidino, carboxy, alkoxycarbonyl, and tetrazole;
each RY is independently selected from the group consisting of hydrogen, alkyl, haloalkyl, carboxy, and alkoxycarbonyl;
each R1 is independently selected from the group consisting of hydrogen and lower alkyl;
R2 is selected from the group consisting of hydrogen, halo and hydroxy;
R5 is selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, alkoxy, amino, alkylcarbonylamino, alkylsulfonylamino, benzenesulfonylamino, toluenesulfonylamino, carboxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloaminocarbonyl, and alkoxycarbonyl;
R6 is selected from the group consisting of hydrogen, halo, and hydroxy;
R8, R9, R11, R12, R14, R15, R17, and R18 are independently selected from the group consisting of hydrogen, halo, alkyl, haloalkyl, methoxy, and ethoxy;
R16 is selected from the group consisting of hydrogen, hydroxy, halo, haloalkyl, alkoxy, aminocarbonyl, alkylaminocarbonyl, carboxy, alkoxycarbonyl, xe2x80x94SO2NR12, and xe2x80x94NR1SO2R1;
and the pharmaceutically acceptable salts of all these compounds.
In a third aspect, this invention provides pharmaceutical compositions comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of at least one compound of this invention. These compositions find particular use as anti-asthmatic and anti-allergenic agents; and in the treatment of osteoporosis, osteoarthritis, rheumatoid arthritis, and autoimmune and other inflammation related disorders, and for therapeutically desirable immunosuppression.
In a fourth aspect, this invention provides a method of treating an animal having a disease capable of treatment by administration of an IL-4 antagonist, comprising administration to that animal of a therapeutically effective amount of at least one compound of this invention, optionally in conjunction with at least one other conventional therapeutic agent for the disease being treated.
In a fifth aspect, this invention provides methods of preparing the compounds of this invention.
Definitions
xe2x80x9cAlkylxe2x80x9d means a linear monovalent hydrocarbyl group having 1 to 5 carbon atoms, or a branched or cyclic hydrocarbyl group having 3 to 5 carbon atoms. Exemplary alkyl groups include methyl, ethyl, isopropyl, cyclopropyl, tert-butyl, cyclopropylmethyl, and pentyl. xe2x80x9cAlkoxyxe2x80x9d means the group xe2x80x94O-alkyl, where xe2x80x9calkylxe2x80x9d is as defined immediately before.
xe2x80x9cCycloalkylenexe2x80x9d means a cyclic hydrocarbyl group having 5 to 7 ring carbon atoms, bonded to an aryl group or other linker atom at both of two adjacent ring carbon atoms; such as 1,2-cyclohexylene. xe2x80x9cCycloalkylene also includes those compounds where the bond between the ring carbon atoms that are bonded to the aryl groups or other linker atoms is a double bond. xe2x80x9cCycloalkylenexe2x80x9d specifically includes cyclic compounds as defined immediately before where 1 or 2 of the ring carbon atoms are replaced by O, S, NH, or N-alkyl; such as 2,3-piperidinylene and 3,4-tetrahydropyranylene.
xe2x80x9cCycloaminoxe2x80x9d means a cyclic amino group having 5 to 7 ring atoms of which at least one is nitrogen and the remainder may all be carbon (e.g. pyrrolidino, piperidino) or one carbon may be replaced by O, S, NH, or N-alkyl (e.g. morpholino, piperazino, and the like).
xe2x80x9cAnimalxe2x80x9d includes humans and non-human mammals, such as companion animals (cats, dogs, and the like) and farm animals (cattle, horses, sheep, goats, swine, and the like).
xe2x80x9cDiseasexe2x80x9d includes any unhealthy condition of an animal, including particularly asthma, allergies, osteoporosis, osteoarthritis, rheumatoid arthritis, and autoimmune and other inflammation related disorders.
xe2x80x9cGuanidinoxe2x80x9d means the group xe2x80x94NHxe2x80x94C(xe2x95x90NH)NH2.
xe2x80x9cHalogenxe2x80x9d means fluorine, chlorine, or bromine; and xe2x80x9chaloxe2x80x9d likewise means fluoro, chloro, or bromo. xe2x80x9cHaloalkylxe2x80x9d means alkyl (as that term is defined above) substituted with 1 to 5 halogen atoms, especially fluorine or chlorine atoms.
xe2x80x9cOptionally fluorinated methoxyxe2x80x9d and xe2x80x9coptionally fluorinated ethoxyxe2x80x9d mean a methoxy group substituted with 0-3 fluorine atoms and an ethoxy group substituted with 0-5 fluorine atoms respectively.
xe2x80x9cPharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients may be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous.
xe2x80x9cPharmaceutically acceptable saltsxe2x80x9d means salts that are pharmaceutically acceptable and have the desired pharmacological properties. Such salts include salts that may be formed where acidic protons present in the compounds are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, e.g. sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as the amine bases, e.g. ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like. Such salts also include acid addition salts formed with inorganic acids (e.g. hydrochloric and hydrobromic acids) and organic acids (e.g. acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid). When there are two acidic groups present, a pharmaceutically acceptable salt may be a mono-acid-mono-salt or a di-salt; and similarly where there are more than two acidic groups present, some or all of such groups can be salified.
A xe2x80x9cprotecting groupxe2x80x9d has the meaning conventionally associated with it in organic synthesis, i.e. a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and such that the group can readily be removed after the selective reaction is complete.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount that, when administered to an animal for treating a disease, is sufficient to effect treatment for that disease.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes preventing the disease from occurring in an animal that may be predisposed to the disease but does not yet experience or exhibit symptoms of the disease (prophylactic treatment), inhibiting the disease (slowing or arresting its development), providing relief from the symptoms or side-effects of the disease (including palliative treatment), and relieving the disease (causing regression of the disease).
The compounds of this invention may possess one or more chiral centers or olefinic bonds, and, if they do, can therefore be produced as individual stereoisomers or as mixtures of stereoisomers, depending on whether individual stereoisomers or mixtures of stereoisomers of the starting materials are used. Unless indicated otherwise, the description or naming of a compound or group of compounds is intended to include both the individual stereoisomers or mixtures (racemic or otherwise) of stereoisomers. Methods for the determination of stereochemistry and the separation of stereoisomers are well known to a person of ordinary skill in the art [see the discussion in Chapter 4 of J. March, xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, N.Y., 1992].
Implicit hydrogen atoms are omitted from the formulae for clarity, but should be understood to be present.
Presently Preferred Compounds
While the broadest definition of the invention is set out in the Summary of the Invention, certain compounds of this invention are presently preferred.
Presently preferred compounds of this invention are compounds of formula III 
where:
Axe2x80x94B is xe2x80x94CHRXxe2x80x94CHRXxe2x80x94, xe2x80x94CHRYxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHRYxe2x80x94, NR1xe2x80x94C(xe2x95x90O)xe2x80x94, C(xe2x95x90O)xe2x80x94NR1, xe2x80x94SO2xe2x80x94NR1xe2x80x94, xe2x80x94NR1xe2x80x94SO2xe2x80x94;
and RX, RY, R4, R5, R12, R16, and R18 are as in the Summary of the Invention;
and their pharmaceutically acceptable salts.
More preferred compounds of this invention are compounds of formula IV 
where:
Axe2x80x94B is xe2x80x94CHRXxe2x80x94CHRXxe2x80x94, xe2x80x94CHRYxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94CHRYxe2x80x94;
and RX, RY, R5, R12, R16, and R18 are as in the Summary of the Invention;
and their pharmaceutically acceptable salts.
More preferred compounds of this invention are compounds of formula V 
where:
Axe2x80x94B is xe2x80x94CHRXxe2x80x94CHRXxe2x80x94; 
and RX, R5, R12, and R18 are as in the Summary of the Invention;
and their pharmaceutically acceptable salts.
Preferred compounds of this invention also include those compounds, or groups of compounds discussed above, in which:
(1) at least one of R2, R4, and R6 is not hydrogen;
(2) at least one of R14, R15, R16, R17, and R18 in formulae I, III, IV, and VI, or at least one of R14, R15, R17, R18, and R19 in formula II, is not hydrogen;
or both of these preferences are met.
Pharmacology and Utility
The compounds of this invention are antagonists of IL-4 signaling. Their activity as IL-4 signaling antagonists in vitro can be measured by methods such as the STAT6 phosphorylation assay discussed in J. Hon et al., Science, 265, 1701-1706 (1994), F. W. Quelle et al., Mol. Cell Biol., 15, 3336-3343 (1995), and K. Takeda et al., Nature, 380, 627-630 (1996); and as discussed in Example 3. Their activity can be measured in vivo by activity in the cynomolgus monkey primate model described in C. D. Wegner et al., xe2x80x9cModels of Pulmonary Disease: Acute and Chronic Allergic Asthma in the Monkey and Acute and Chronic Viral Pulmonitis in the Mousexe2x80x9d in xe2x80x9cCurrent Protocols in Pharmacologyxe2x80x9d, John Wiley and Sons, 1998, 5.2.1-5.2.19.
The therapeutic ratio of a compound can be determined, for example, by comparing the dose that gives effective anti-asthmatic or anti-allergic activity in a suitable in vivo model such as the cynomolgus model described in Wegner et al., with the dose that gives significant weight loss (or other observable side-effects) in the test animal species.
Pharmaceutical compositions and administration
In general, compounds of this invention will be administered in therapeutically effective amounts by any of the usual modes known in the art, either singly or in combination with at least one other compound of this invention and/or at least one other conventional therapeutic agent for the disease being treated. A therapeutically effective amount may vary widely depending on the disease, its severity, the age and relative health of the animal being treated, the potency of the compound(s), and other factors. Therapeutically effective amounts of compounds of this invention may range from approximately 0.01-100 mg/Kg body weight. A person of ordinary skill in the art will be able without undue experimentation, having regard to that skill and this disclosure, to determine a therapeutically effective amount of a compound of this invention for a given disease.
In general, compounds of this invention will be administered as pharmaceutical compositions by one of the following routes: oral, topical, systemic (e.g. transdermal, intranasal, by inhalation, or by suppository), or parenteral (e.g. intramuscular, subcutaneous, or intravenous injection). Compositions may take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions; and comprise at least one compound of this invention in combination with at least one pharmaceutically acceptable excipient. Suitable excipients are well known to persons of ordinary skill in the art, and they, and the methods of formulating the compositions, may be found in such standard references as A. R. Alfonso, xe2x80x9cRemington""s Pharmaceutical Sciencesxe2x80x9d, 17th ed., Mack Publishing Company, Easton Pa., 1985. Suitable liquid carriers, especially for injectable solutions, include water, aqueous saline solution, aqueous dextrose solution, and glycols.
Typically, compounds of this invention will be administered orally, by inhalation (especially for asthma and in pulmonary inflammatory conditions), or topically (especially for psoriasis). The amount of a compound of this invention in the composition may vary widely depending on the type of composition, size of a unit dosage, kind of excipients, and other factors well known to those of ordinary skill in the art. In general, the final composition may comprise from 0.0001 percent by weight (%w) to 10%w of the compound of this invention, preferably 0.001%w to 1%w, with the remainder being the excipient or excipients.
An composition may optionally contain, in addition to a compound of this invention, at least one other compound of this invention, and/or at least one other agent for the disease state being treated.
Preparation of the Compounds of this Invention
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Company (Milwaukee, Wis.), Bachem (Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methods well known to a person of ordinary skill in the art following procedures described in such references as Fieser and Fieser""s xe2x80x9cReagents for Organic Synthesisxe2x80x9d, vols. 1-17, John Wiley and Sons, New York, N.Y., 1991; Rodd""s xe2x80x9cChemistry of Carbon Compoundsxe2x80x9d, vols. 1-5 and supplements, Elsevier Science Publishers, 1989; xe2x80x9cOrganic Reactionsxe2x80x9d, vols. 1-40, John Wiley and Sons, New York, N.Y., 1991; March""s xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th ed., John Wiley and Sons, New York, N.Y., 1992; and Larock""s xe2x80x9cComprehensive Organic Transformationsxe2x80x9d, VCH Publishers, 1989. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to a person of ordinary skill in the art having regard to this disclosure.
The starting materials, intermediates, and compounds of this invention may be isolated and purified using conventional techniques, including filtration, distillation, crystallization, chromatography, and the like. They may be characterized using conventional methods, including physical constants and spectral data.
Unless specified to the contrary, the reactions described herein take place at atmospheric pressure over a temperature range between about 0xc2x0 C. and 125xc2x0 C.
General synthetic methods are discussed below.
Typically, an appropriately substituted biphenyl or biphenyl ether is reacted with an appropriately substituted benzene to form the linker xe2x80x94Axe2x80x94Bxe2x80x94 between the biphenyl/biphenyl ether and the benzene.
Where xe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CRYxe2x95x90CRYxe2x80x94, the alkene linker is readily prepared by the either of two methods. In the first method, a suitably substituted aryl aldehyde or ketone is reacted with the sodium salt of a suitably substituted triphenylphosphonium halide (Wittig reaction), prepared from the corresponding halomethyl compound. Thus, for example, a suitably substituted benzyltriphosphonium halide (prepared from the corresponding benzyl bromide) dissolved in a solvent such as tetrahydrofuran is treated with a solution of n-butyllithium at 0xc2x0 C., stirred at room temperature, then the suitably substituted biphenylaldehyde is added. The reaction is quenched with methanol, extracted, dried, and the extracts concentrated to yield the olefin-linked compound. In the second method, a suitably substituted aryl halide and a suitably substituted arylboronic acid (the Suzuki coupling reaction) or aryl halide and aryl trialkyltin (the Stille coupling reaction) are reacted in the presence of a Pd catalyst.
Where xe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CHRXxe2x80x94CHRXxe2x80x94, the 2 carbon alkyl linker is readily prepared by reduction of the corresponding alkene linker (see above) by any number of common reagents including H2(g) over Pd/C. Substituted analogs of the 2 carbon alkyl linker may be prepared by a variety of means known to a person of ordinary skill in the art. For example, the ketone linkage (see below) may be alkylated at the site neighboring the ketone functional group by combination with an electrophile in the presence of base. The ketone functional group may be converted to an amino group by reductive amination. The ketone linkage may also be converted to a substituted alkene linkage by reaction with the sodium salt of an appropriately substituted triphenylphosphonium halide reagent or similar. The hydroxyl group of the linkage sited as the precursor to the ketone may alternatively be converted to an ether or ester moiety by methods very familiar to a person of ordinary skill in the art.
Where xe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CHRYxe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94CHRYxe2x80x94, the ether linker may be prepared by any of three methods. In the first method, a suitably substituted aryl alcohol may be combined in the presence of base with an appropriately substituted halomethyl arene. In the second method, an appropriately substituted aryl alcohol may be combined with an appropriately substituted hydroxymethyl arene in the presence of triphenylphosphine and diethyl azodicarboxylate (the Mitsunobu reaction). In the third method, an appropriately substituted aryl halide may be combined with an appropriately substituted hydroxymethyl arene in the presence of sodium tert-butoxide and a Pd-based catalyst (Buchwald coupling conditions).
Where xe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94NR1xe2x80x94C(xe2x95x90O)xe2x80x94 or xe2x80x94C(xe2x95x90O)xe2x80x94NR1xe2x80x94, the amide linker may be prepared by either of two methods. In the first method, a suitably substituted arylamine is combined with a suitably substituted arylcarboxylic acid in the presence of one of a variety of condensation reagents known to a person of ordinary skill in the art. In the second method, a suitably substituted arylamine is combined with a suitably substituted activated arylcarboxylic acid derivative, such as an arylcarboxylic acid halide.
Where xe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94S(O)0-2xe2x80x94CHRXxe2x80x94 or xe2x80x94CHRXxe2x80x94S(O)0-2xe2x80x94, the thioether linkage may prepared by the combination of a suitably substituted arenethiol with a suitably substituted halomethyl arene. The sulfoxide linkage is prepared by single oxidation of the thioether linkage by any of a variety of oxidation reagents known to a person of ordinary skill in the art. The sulfone linkage is prepared from either the thioether or the sulfoxide by treatment with any of a variety of oxidation reagents also known to a person of ordinary skill in the art.
Where xe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94SO2xe2x80x94NR1xe2x80x94 or xe2x80x94NR1xe2x80x94SO2xe2x80x94, the sulfonamide linkage may be prepared by reaction of a suitably substituted arylamine with a suitably substituted arenesulfonyl halide, which may in turn be first prepared from the appropriately substituted arenesulfonic acid by one of a variety of methods known to a person of ordinary skill in the art.
Where xe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94C(Oxe2x95x90)xe2x80x94CHRXxe2x80x94 or xe2x80x94CHRXxe2x80x94C(xe2x95x90O)xe2x80x94, the ketone linkage is prepared by oxidation of the corresponding hydroxyl substituted linkage by the use of MnO2 or any other of a variety of oxidizing reagents known to a person of ordinary skill in the art. The hydroxy substituted linkage can be prepared by reaction of a suitably substituted aryl aldehyde with a suitably substituted arylmagnesium halide, prepared in advance from the corresponding aryl halide (the Grignard reaction).
Where xe2x80x94Axe2x80x94Bxe2x80x94 is 1,2-cycloalkylene, the cycloalkylene linkage containing a double bond between the bonding ring carbons may be prepared by the reaction of a 1,2 dihalocycloalkene sequentially with the appropriately substituted arylboronic acids (Suzuki coupling reaction) or aryl trialkyltin reagents (Stille coupling reaction) in the presence of a Pd catalyst. The reduced cycloalkylene linkage may be prepared by reduction of the corresponding double-bonded linkage by reaction with H2 (g) over Pd/C. In large part the cycloalkylene linkages where there are hetero atom(s) in the ring may be prepared in the same manner. Additional methods commonly used by persons of ordinary skill in the art to prepare a variety of 1,2-diaryl substituted cyclic moieties, too numerous to describe in detail here, can be found in xe2x80x9cHeterocyclic Chemistry, 2nd, ed.xe2x80x9d T. L. Gilchrist, 1992, Longman Scientific and Technical, Essex; and xe2x80x9cHeterocyclic Chemistry, 3d ed.xe2x80x9d J. A. Joule, K. Mills, and G. F. Smith, 1995, Chapman and Hall, London.
Under some circumstances, it may be appropriate to form the biphenyl linkage after forming the xe2x80x94Axe2x80x94Bxe2x80x94 linkage, as is shown in Example 1.
When the compound contains a biphenyl ether, as in formula II, it may be prepared by any of four methods. In the first method, a suitably substituted hydroxy arene is combined with a suitably substituted aryl fluoride or nitroarene in the presence of base. In the second method, a suitably substituted hydroxy arene is reacted with an appropriately substituted arylboronic acid under Evans conditions, i.e. in the presence of an appropriate copper-based catalyst. In the third method, a suitably substituted hydroxy arene is reacted with a suitably substituted aryl halide under Buchwald coupling conditions, i.e. in the presence of an appropriate palladium-based catalyst. In the fourth method an aryl vinyl ether is reacted with an appropriately substituted pyrone to form a cycloadduct (the Diels-Alder reaction), which subsequently undergoes the elimination of carbon dioxide to afford the biphenyl ether.
When the linker is of the form xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94, similar techniques may be used. A representative few are as follows:
When xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CHRXxe2x80x94CH(OH)xe2x80x94CHRYxe2x80x94, the 2-hydroxypropyl linkage may be prepared by the reaction of a suitably substituted arylacetaldehyde with a suitably substituted arylmethylmagnesium halide, prepared from the corresponding arenylmethyl halide (the Grignard coupling reaction).
When xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CHRXxe2x80x94NR1C(xe2x95x90O)xe2x80x94, the amidomethyl linkage may be prepared by the reaction of a suitably substituted arenecarboxylic acid or activated arenecarboxylic acid derivative with an appropriately substituted aminomethylarene, under conditions described above for the A-B linked amide case. When xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CHRxe2x80x94C(xe2x95x90O)xe2x80x94NR1xe2x80x94, the amidomethyl linkage may be prepared by the reaction of a suitably substituted areneacetic acid or activated areneacetic acid derivative with an appropriately substituted aminoarene, under the same conditions. When xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CHRXxe2x80x94NR1xe2x80x94C(xe2x95x90O)xe2x80x94, the amidoethyl linkage may be prepared by the reaction of a suitably substituted arenecarboxylic acid or activated arenecarboxylic acid derivative with an appropriately substituted aminoethylarene, and when xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CHRXxe2x80x94C(xe2x95x90O)xe2x80x94NR1xe2x80x94, the amidoethyl linkage may be prepared by the reaction of a suitably substituted arenepropionic acid or activated arenepropionic acid derivative with an appropriately substituted aminoarene, under the same conditions.
When xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CHRYxe2x80x94Oxe2x80x94CHRYxe2x80x94, the Cxe2x80x94Oxe2x80x94C ether linkage may prepared by combination of the appropriately substituted hydroxymethyl arene with the appropriately substituted halomethyl-, methanesulfonyloxy-, or p-toluenesulfonyloxymethyl arene in the presence of base; and similarly when xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94 is xe2x80x94CH2xe2x80x94CHRYxe2x80x94Oxe2x80x94CHRYxe2x80x94.
It will be evident that the biphenyl linkage may be formed either before or after the formation of the xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94 linkage: Example 2 describes a synthesis in which the biphenyl linkage is formed after the formation of the xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94 linkage.
It will also be evident that the phenyl rings may be substituted with substituents inert to the reaction conditions (or substituents protected against the reaction conditions associated with formation of the compound skeleton, where the protecting group can be removed without adverse effect on the remainder of the compound) without affecting the reactions described.
When a substituent is, for example, a carboxylic acid, it will typically be protected throughout the synthesis as an alkyl, e.g. C1-4 alkyl ester, typically the methyl ester; with the ester being removed in the final deprotection step by reaction with an aqueous base, such as aqueous lithium hydroxide. When a substituent is or contains an amine or guanidino group, it will typically be protected with a typical amine-protecting group well known to a person of ordinary skill in the art, such as tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), 9-fluorenylmethoxycarbonyl (FMOC), and the like, if needed, with the protecting group being removed in the final deprotection step by such methods as are conventional for removal of these amine-protecting groups. Under some circumstances, a carboxylic acid may be protected as an ester that is differentially removable, i.e. removable under circumstances where other carboxyl groups remain protected. When a substituent is a hydroxy group, it will typically be protected with a typical hydroxy-protecting group such as a tertiary silyl group, e.g. tert-butyldimethylsilyl. The choice of suitable protecting groups for substituents during the syntheses will be within the skill of a person of ordinary skill in the art having regard to that skill and this disclosure.
It will be apparent to a person of ordinary skill in the art, having regard to that skill, this disclosure, and the references cited herein, that generally any one of several different methods may be employed for the synthesis of a selected compound of this invention. For convenience, the synthesis may well be chosen based on the availability or cost of the starting materials and reagents for the methods available for that compound, or considering the number of steps necessary for the method. For example, if an appropriately substituted biphenyl or biphenyl ether is readily available or synthesizable, it may well be convenient to form the biphenyl/biphenyl ether linkage before formation of the xe2x80x94Axe2x80x94Bxe2x80x94 or xe2x80x94Xxe2x80x94Axe2x80x94Bxe2x80x94 linkage; but otherwise it may be preferable to form the biphenyl or biphenyl ether linkages later. A person of ordinary skill in the art, having regard to that skill, this disclosure, and the references cited herein, will be able to prepare desired compounds of formula I without undue experimentation.